JP2000191641A - Aminoguanidinehydrazone derivative, its production, and pharmaceutical preparation containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject novel compound, showing an Na-H exchange inhibiting function and useful as a remedy for ischemic diseases. SOLUTION: This compound is sown by formula I [A ring is a (substituted) 5-6 membered aromatic heterocyclic ring; B ring is a (substituted) 5-6 membered aromatic homocyclic or heterocyclic ring; R1 is H, OH or a lower akyl; and (n) is 0 or 1], e.g. (S)-(-)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4- methyl-5,6,7,8-tetrahydroquinoline. The compound shown by formula I is obtained by reacting mol of the compound shown by formula II with preferably 1 to 2 molls of an aminoguanidine compound shown by the formula H2N-N=C (NH2)(NHR1), in the presence of triethylamine, pyrrolidine, sodium acetate, boron trifluoride diethyl ether, hydrochloric acid, sulfuric acid, p-toluene solfonate or the like, as required, as the catalyst, preferably at a temp. of 0 to around 180 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to aminoguanidine hydrazone derivatives and agents useful as medicaments. The sodium-proton (Na-H) exchange inhibitor containing the aminoguanidine hydrazone derivative of the present invention can be used for myocardial infarction and associated dysfunction, arrhythmia, unstable angina, cardiac hypertrophy, PTCA (percutaneous transluminal coronary angioplasty) Surgery: percutaneous t
It has a prophylactic and therapeutic effect on reocclusion after ransluminal coronary angioplasty), hypertension and associated tissue damage.

[0002]

2. Description of the Related Art Na-H exchange inhibitors, which are considered to have an improving action and a cytoprotective action (especially for myocardium) against cell damage under ischemia, have been used in the field of therapeutic agents for ischemic diseases. Attention has been paid. Amiloride, an acylguanidine derivative and a potassium-sparing diuretic, is Na-H
It has an exchange inhibitory action, but its action is weak, and it has a strong sodium channel inhibitory action. As the Na-H exchange inhibitor, various acylguanidine derivatives are disclosed in JP-A-6-2.
28082, WO 96/04241, EP 70809
1 and EP 708088. on the other hand,
In EP456133, the formula

Embedded image Wherein A represents a bond or —CH ₂ —, and X represents a formula —C (=
Y) a group represented by -NR ₆ R ₇ , Y and Z represent NH,
R ₁ is hydrogen, lower alkyl, hydroxyl group, lower alkoxy or halogen, R ₂ is hydrogen or lower alkyl, R ₃ ,
R ₄ and R ₆ are hydrogen, R ₅ and R ₇ are each hydrogen,
Shows lower alkyl or hydroxyl group. Is disclosed as being useful as an anticancer agent or a therapeutic agent for protozoal infections. Also, Japanese Patent Publication No. 60-239454
Has the formula

Embedded image [Wherein, R represents hydrogen, halogen, etc., A represents a bond, CR ^{4
R 5, CR 6 R 7 -CR} 8 R 9, CR 10 R 11 -CR 12 R 13 -
The CR ¹⁴ R ¹⁵ or the like, X is ^{CR 1 R 2, O, S} (O) n (n =
0, 1, 2), NR ^{3 and the} like, and R ^{1 to} R ¹⁵ each represent hydrogen, an aromatic or heteroaromatic group which may be substituted, or the like. Is disclosed as having a digitalis-like action or a digitalis-antagonistic action.

[0003]

Amiloride is associated with a hypotensive action and a salt excretion action due to its strong sodium channel inhibitory action, and these actions are not desirable for the treatment of heart failure. The present invention relates to myocardial infarction and associated dysfunction, arrhythmia, unstable angina,
An object of the present invention is to provide a Na-H exchange inhibitor having a prophylactic and therapeutic effect on cardiac hypertrophy, reocclusion after PTCA, hypertension and accompanying tissue damage.

[0004]

Means for Solving the Problems The present inventors have proposed Na-H
As a result of various studies on exchange inhibitors, the formula (I)

Embedded image [In the formula, ring A is a 5- or 6-membered aromatic heterocyclic ring which may be substituted, and ring B is 5 or 6 which may be substituted.
R ¹ represents a hydrogen atom, a hydroxyl group or a lower alkyl group, and n represents 0 or 1. For the first time, and found that this compound (I) has an unexpectedly excellent Na-H exchange inhibitory action, Based on these, the present invention has been completed.

That is, the present invention provides (1) a compound (I), (2) a prodrug of the compound (I),

Embedded image [The symbols in the formula have the same meanings as described in the above (1). Or a salt thereof represented by the formula:

Embedded image [The symbols in the formula have the same meanings as described in the above (1). (5) The compound according to the above (1), wherein the aromatic heterocyclic ring is an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. (6) The compound according to (1), wherein the ring A is a pyridine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, an isoxazole ring or a pyrimidine ring, each of which may be substituted. ) B ring is pyridine ring optionally being substituted, respectively, a pyrrole ring, a furan ring, a thiophene ring or a benzene ring (1) compounds described, ^(8), wherein R ¹ is a hydrogen atom (1), wherein (9) The compound according to the above (1), wherein n is 1. (10) (S)-(−)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino- 4-meth 5,6,7,8-tetrahydroquinoline or a salt thereof; (11) (±) -7- (2,5- dichloro-thiophene -
3-yl) -5-guanidinoimino-4-methyl-5
6,7,8-tetrahydroquinoline or a salt thereof; (12) (S)-(-)-7- (2-chlorophenyl)
-5-guanidinoimino-4-methyl-5,6,7,8
(13) (±) -7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof; (14) (± ) -7- (2,5-Dichlorophenyl)-
5-guanidinoimino-4-methyl-5,6,7,8-
(15) (±) -7- (5-chloro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6, tetrahydrocinnoline or a salt thereof;
7,8-tetrahydroquinoline or a salt thereof; (16) (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6,6
7,8-tetrahydroquinoline or a salt thereof; (17) (±) -7- (2-chloro-5-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydroquinoline or a salt thereof; (18) (±) -7- (5-chloro-2-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydroquinoline or a salt thereof; (19) (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydrocinnoline or a salt thereof; (20) (±) -7- (5-chloro-2-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,6
7,21-tetrahydrocinnoline or a salt thereof; (21) a pharmaceutical composition comprising the compound of the above (1) or a salt thereof; (22) a pharmaceutical composition comprising the Na-H exchange inhibitor (23) The composition according to (21), which is an agent for preventing or treating ischemic heart disease, (24) The composition according to (23), wherein the ischemic heart disease is myocardial infarction, unstable angina pectoris or arrhythmia. (25) a composition according to the above (21), which is an agent for preventing or treating heart failure; and (26) a formula (II)

Embedded image [In the formula, ring A is a 5- or 6-membered aromatic heterocyclic ring which may be substituted, and ring B is 5 or 6 which may be substituted.
And n represents 0 or 1; Compound or a salt thereof of the formula _{(III) H 2 N-N} = C (NH 2) (NHR 1) [Formula represented by], R ¹ is a hydrogen atom, a hydroxyl group or a lower alkyl group. A compound represented by the formula (I):

Embedded image [The symbols in the formula are as defined above. And a method for producing the compound or a salt thereof.

In the above formula (I), the ring A represents a 5- or 6-membered aromatic heterocyclic ring which may be substituted. “A 5- or 6-membered aromatic heterocyclic ring which may be substituted” for A
Examples of the aromatic heterocyclic ring include, as atoms (ring atoms) constituting a ring system, 1 to 3 (preferably 1 to 2) hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like. At least one (preferably 1 to 3
, More preferably 1 to 2) aromatic heterocycles. Such "aromatic heterocycle" includes, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole,
1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4
-Thiadiazole, 1,3,4-thiadiazole, 1,2,
5- to 6-membered aromatic heterocycles such as 3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like. Among them, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 (preferably 1 to 2) heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom is preferable. Is a pyridine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, an isoxazole ring, a pyrimidine ring (preferably containing one or two nitrogen atoms such as a pyridine ring, a pyridazine ring, a pyrrole ring, and a pyrazole ring. A 5- or 6-membered nitrogen-containing aromatic heterocyclic ring or the like, and more preferably a nitrogen atom such as a pyridine ring, a pyrazole ring or a pyridazine ring, having 1 to 2 nitrogen atoms.
And a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring).

In the above formula (I), the ring B represents an optionally substituted 5- or 6-membered aromatic homo- or heterocyclic ring.
Examples of the "optionally substituted 5- or 6-membered aromatic homocyclic ring" for B include a benzene ring which may be substituted. As the aromatic heterocyclic ring of the “optionally substituted 5- to 6-membered aromatic heterocyclic ring” for B, for example, as an atom (ring atom) constituting a ring system,
Aromatic containing at least one (preferably one to three, more preferably one to two) of 1 to 3 (preferably 1 to 2) heteroatoms selected from oxygen, sulfur and nitrogen atoms, etc. And heterocycles. Such “aromatic heterocycle” includes, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole,
1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,
3-thiadiazole, 1,2,4-thiadiazole, 1,
3,4-thiadiazole, 1,2,3-triazole, 1,
5- or 6-membered aromatic heterocycles such as 2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc., among which heteroatoms selected from oxygen, sulfur and nitrogen are preferred. One atom
5 to 6, including 1 to 3 (preferably 1 to 2)
Membered aromatic heterocycles are preferred. Specific examples of preferred B ring include a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, and a pyridine ring (preferably a benzene ring, a furan ring,
Thiophene ring, etc.), and may contain one hetero atom selected from oxygen atom, sulfur atom and nitrogen atom.
And a 6-membered aromatic homo- or heterocyclic ring.

Rings A and B include, for example, (1) halogen atom, (2) hydroxyl group, (3) nitro group, (4) cyano group, (5) optionally substituted lower alkyl group, (6) An optionally substituted lower alkenyl group, (7) an optionally substituted lower alkynyl group, (8) an optionally substituted lower aralkyl group, (9) an optionally substituted lower alkoxy group, 1
0) an optionally substituted mercapto group, (11) an optionally substituted amino group, (12) an optionally esterified or amidated carboxyl group, (13) an optionally substituted sulfonyl group And (14) 1 to 4 (preferably 1 to 2) groups selected from the group consisting of an optionally substituted acyl group and (15) an optionally substituted phenyl group; May be
(16) Two adjacent substituents may be bonded to each other to form a divalent hydrocarbon group, and the nitrogen atom of the ring A or ring B may be oxidized. When the ring A or the ring B is a nitrogen-containing aromatic heterocyclic ring having a hydroxyl group as a substituent such as 2-oxypyridine, the ring A or the ring B is an oxo group such as α-pyridone. A nitrogen-containing aromatic heterocycle having a chemical structure equivalent to a nitrogen-containing aromatic heterocycle having a hydroxyl group as a substituent, wherein the ring A or the ring B has an oxo group. When it is a group heterocyclic ring, a substituent which the above-mentioned ring A or B may have may be present on a nitrogen atom of the ring A or B.

The halogen atom as (1) includes, for example, chlorine, bromine, fluorine, iodine and the like. As the optionally substituted lower alkyl group as (5),
For example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, s-butyl, pentyl, hexyl, etc.) and the like can be mentioned. Such a lower alkyl group includes a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, a nitro group, a cyano group, a lower (C _1-6 ) alkoxy group (eg, methoxy,
Ethoxy, propoxy, isopropoxy, butoxy, s
-Butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), halogeno lower (C _1-6 ) alkoxy groups (for example CF ₃
O, CHF ₂ O, etc.), and may be substituted at substitutable positions with 1 to 3 identical or different substituents selected from the group consisting of: Examples of the optionally substituted lower alkenyl group as (6) include vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- Pentenyl, 1-hexenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, 5
And C _2-6 alkenyl groups such as -hexenyl.
Such a lower alkenyl group includes a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, a nitro group, a cyano group, a lower (C _1-6 ) alkoxy group (eg, methoxy,
Ethoxy, propoxy, isopropoxy, butoxy, s
-Butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), halogeno lower (C _1-6 ) alkoxy groups (for example CF ₃
O, CHF ₂ O, etc.), and may be substituted at substitutable positions with 1 to 3 identical or different substituents selected from the group consisting of: Examples of the optionally substituted lower alkynyl group as (7) include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and a C _2-6 alkynyl group of 5-hexynyl and the like. Such a lower alkynyl group includes a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, a nitro group, a cyano group, a lower group.
(C _1-6 ) alkoxy groups (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy,
t-butoxy, pentyloxy, isopentyloxy,
Neopentyloxy, hexyloxy, etc.), halogeno lower (C _1-6 ) alkoxy groups (for example, CF ₃ O, CHF ₂ O
And the like, and may be substituted at substitutable positions with 1 to 3 identical or different substituents selected from
Examples of the optionally substituted lower aralkyl group as (8) include a C _7-10 aralkyl group such as benzyl and phenethyl (preferably a phenyl-C _1-6 alkyl group and the like). Such lower aralkyl groups include, for example, halogen atoms (eg, chlorine, bromine, fluorine, iodine, etc.), hydroxyl groups, nitro groups, cyano groups, and lower (C _1-6 ) alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), halogeno lower (C _1-6 ) alkyl group (for example, CF ₃ , CF ₂ CF ₃ , CH ₂ F, CHF)
₂ ), lower (C _1-6 ) alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-
Butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.),
A halogeno lower (C _1-6 ) alkoxy group (for example, CF ₃ O, C
HF ₂ O) or the like, and may be substituted at substitutable positions with one to three identical or different substituents selected from the group consisting of: As the optionally substituted lower alkoxy group as (9), a C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy , Neopentyloxy, hexyloxy, etc.). Such lower alkoxy groups include halogen atoms (eg, chlorine, bromine, fluorine, iodine, etc.),
Hydroxyl group, nitro group, cyano group, lower (C _1-6 ) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyl Oxy), halogeno lower (C _1-6 ) alkoxy groups (for example, CF ₃ O, CHF ₂ O, etc.) and 1 to 3 identical or different substituents substituted at substitutable positions. You may. As the optionally substituted mercapto group as (10), an optionally substituted C _1-6 alkylthio group (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, s-butylthio, t-butylthio, pentylthio) ,
Isopentylthio, neopentylthio, hexylthio, etc.). Such a C _1-6 alkylthio group is
Halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), hydroxyl group, nitro group, cyano group, lower (C _1-6 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t- Butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), halogeno lower (C _1-6 )
1 to 3 identical or different substituents selected from an alkoxy group (eg, CF ₃ O, CHF ₂ O, etc.),
It may be substituted at a substitutable position.

Optionally substituted amino as (11)
Examples of the group include lower (C_1-6) Alkyl (eg meth
, Ethyl, propyl, isopropyl, butyl, isobu
Tyl, s-butyl, t-butyl, pentyl, hexyl
Etc.), low grade (C_1-6) Alkoxy (eg methoxy, eth
Xy, propoxy, isopropoxy, butoxy, isobut
Toxic, s-butoxy, t-butoxy, pentyloxy
, Hexyloxy, etc.), halogeno lower (C_1-6) Archi
(For example, CF_Three, CF_ThreeCF_Two, CH_TwoF, CHF
_TwoEtc.), low grade (C_3-6) Cycloalkyl (eg, cyclopro
Pill, cyclobutyl, cyclopentyl, cyclohexyl
Etc.), hydroxyl, carbamoyl, phenyl, phenyl-low
Grade (C_1-6) Alkyl (eg, benzyl, phenethyl, 3
-Phenylpropyl, 4-phenylbutyl, etc.), lower
(C_1-6) Alkanoyl (eg, formyl, acetyl,
Lopionyl, butyryl, isobutyryl, valeryl, piva
Royl), C _3-6Cycloalkyl-carbonyl (eg,
For example, cyclopropyl carbonyl, cyclobutyl carbonyl
, Cyclopentylcarbonyl, cyclohexylcarbo
Nil, etc.), benzoyl, phenyl-C_2-6Alkanoyl
(Eg phenylacetyl, phenylpropionyl
Etc.), low grade (C_1-6) Alkoxy-carbonyl (e.g.
Toxoxycarbonyl, ethoxycarbonyl, propoxyca
Rubonyl, isopropoxycarbonyl, butoxycarbo
Nil, isobutoxycarbonyl, t-butoxycarbonyl
, Pentyloxycarbonyl, hexyloxycarbo
Phenyl), phenoxycarbonyl, phenyl-C_1-6A
Alkoxy-carbonyl (e.g., benzyloxycarbonyl)
, Phenylethoxycarbonyl, etc.), lower (C_1-6A)
Rukylsulfinyl (eg methylsulfinyl, ethi
Rusulfinyl, propylsulfinyl, isopropyl
Sulfinyl, butylsulfinyl, isobutylsulfur
Inyl, s-butylsulfinyl, t-butylsulfinyl
Nil, pentylsulfinyl, hexylsulfinyl
Etc.), C_3-6Cycloalkylsulfinyl (eg, cycloalkylsulfinyl)
Ropropylsulfinyl, cyclobutylsulfinyl,
Cyclopentyl sulfinyl, cyclohexyl sulfy
Phenyl), phenylsulfinyl, lower (C_1-6) Archi
Rusulfonyl (eg, methylsulfonyl, ethylsulfo
Nil, propylsulfonyl, isopropylsulfonyl,
Butylsulfonyl, isobutylsulfonyl, t-butyl
Sulfonyl, s-butylsulfonyl, pentylsulfonyl
, Hexylsulfonyl, etc.), C_3-6Cycloalkyls
Ruphonyl (eg, cyclopropylsulfonyl, cyclobut
Tylsulfonyl, cyclopentylsulfonyl, cyclohexyl
Xylsulfonyl, etc.), lower (C_1-6) Alkoxysulfo
Nil (eg, methoxysulfonyl, ethoxysulfonyl
, Propoxysulfonyl, isopropoxysulfonyl
, Butoxysulfonyl, isobutoxysulfonyl, s
-Butoxysulfonyl, t-butoxysulfonyl, pen
Tyloxysulfonyl, hexyloxysulfonyl, etc.)
And one or two selected from phenylsulfonyl and the like
An amino group which may be substituted the same or different
No. Also, two such substituents are nitrogen atoms
May form a cyclic amino group together with
Examples of the cyclic amino group such as
Peridino, morpholino, thiomorpholino, etc. are used
You. Individual permutations specifically exemplified as described above
Optional amino groups include, for example, a halogen atom (eg, a salt
, Bromine, fluorine, iodine, etc.), hydroxyl, nitro,
Ano group, lower (C_1-6) Alkyl groups (eg methyl, ethyl
Propyl, isopropyl, butyl, isobutyl, s
-Butyl, t-butyl, pentyl, hexyl, etc.), halo
Geno Lower (C_1-6) Alkyl groups (eg CF_Three, CF_TwoC
F_Three, CH_TwoF, CHF_TwoEtc.), low grade (C_1-6) Alkoxy group
(Eg methoxy, ethoxy, propoxy, isopropo
Xy, butoxy, s-butoxy, t-butoxy, pliers
Ruoxy, isopentyloxy, neopentyloxy,
Hexyloxy), halogeno lower (C_1-6) Alkoxy
Group (eg CF_ThreeO, CHF_TwoO, etc.)
Substitutable with three identical or different substituents
It may be substituted at the position.

In the carboxyl group which may be esterified or amidated as (12), examples of the esterified carboxyl group include a lower (C _1-6 ) alkoxy-carbonyl group (for example, methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.), C _3-6 cycloalkoxy- Carbonyl (eg, cyclopropoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.), phenyl-C _1-6 alkoxy-carbonyl (eg, benzyloxycarbonyl, phenyloxycarbonyl, etc.), nitroxy C _1-6 alkoxy- Carbonyl (eg, 2-nitroxyethoxycarbonyl, 3-nitroxypropoxycarbonyl, etc.) and the like. Examples of the amidated carboxyl group include carbamoyl, N-mono-lower (C _1-6 ) alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,
-Butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, etc.), N, N
-Di-lower (C _1-6 ) alkylcarbamoyl (eg N, N
- dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), C _3-6 cycloalkyl - carbamoyl (e.g. cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexyl Carbamoyl, etc.), phenyl-C _1-6 alkyl-
Carbamoyl (eg, benzylcarbamoyl, phenethylcarbamoyl, etc.), nitroxy C _1-6 alkylamino-carbonyl (eg, 2-nitroxyethylcarbamoyl, 3-nitroxypropylcarbamoyl, etc.), cyclic aminocarbonyl (eg, morpholinocarbonyl, piperidinocarbonyl) , Pyrrolidinocarbonyl, thiomorpholinocarbonyl, etc.), anilinocarbonyl and the like. Individual “carboxyl groups that may be esterified or amidated” specifically exemplified as described above
Is, for example, a halogen atom (eg, chlorine, bromine, fluorine,
Iodine, etc.), hydroxyl, nitro, cyano, lower
(C _1-6 ) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,
t-butyl, pentyl, hexyl, etc.), halogeno lower
(C _1-6 ) alkyl groups (for example, CF ₃ , CF ₂ CF ₃ , CH ₂
F, CHF _{2 and the} like), lower (C _1-6 ) alkoxy groups (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy,
One to three identical or different substituents selected from isopentyloxy, neopentyloxy, hexyloxy, etc., halogeno lower (C _1-6 ) alkoxy groups (eg, CF ₃ O, CHF ₂ O, etc.) May be substituted at a substitutable position.

The optionally substituted sulfonyl group as (13) includes, for example, lower (C _1-6 ) alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s -Butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), C _3-6 cycloalkylsulfonyl (eg, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl-C _1-6 alkylsulfonyl (Eg, benzylsulfonyl, phenethylsulfonyl, etc.), lower (C _1-6 ) alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl) Nyl, butoxysulfonyl, isobutoxysulfonyl, s-butoxysulfonyl, t-butoxysulfonyl, pentyloxysulfonyl, hexyloxysulfonyl, etc.), C _3-6 cycloalkyloxysulfonyl (for example, cyclopropoxysulfonyl, cyclobutyloxysulfonyl, cyclopentyloxy) Sulfonyl, cyclohexyloxysulfonyl, etc.), phenyl-C _1-6 alkoxysulfonyl (eg, benzyloxysulfonyl, phenethyloxysulfonyl, etc.), sulfamoyl, lower (C _1-6 ) alkylaminosulfonyl (eg, methylaminosulfonyl, ethylaminosulfonyl, Propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylaminosulfonyl, s-butylaminosulfonyl, - butyl aminosulfonyl, pentyl aminosulfonyl, hexyl aminosulfonyl, etc.), C _3-6 cycloalkyl-aminosulfonyl (e.g., cyclopropyl aminosulfonyl, cyclobutyl aminosulfonyl, cyclopentyl aminosulfonyl, cyclohexylaminosulfonyl, etc.), phenyl -C _{1- 6-} alkylaminosulfonyl (eg, benzylaminosulfonyl, phenethylaminosulfonyl, etc.), cyclic aminosulfonyl (eg, morpholinosulfonyl, piperidinosulfonyl, pyrrolidinosulfonyl, thiomorpholinosulfonyl, etc.), nitroxy C _1-6 alkylamino-sulfonyl (eg, 2-nitroxyethylaminosulfonyl, 3-nitroxypropylaminosulfonyl, etc.), anilinosulfonyl and the like. Each of the “optionally substituted sulfonyl groups” specifically exemplified as described above includes, for example, a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group,
Nitro group, cyano group, lower (C _1-6 ) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), halogeno lower (C _1-6) ) Alkyl groups (eg, C
F ₃ , CF ₂ CF ₃ , CH ₂ F, CHF ₂ etc.), lower (C _1-6 )
Alkoxy groups (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), halogeno lower (C
_1-6 ) It may be substituted at a substitutable position with 1 to 3 identical or different substituents selected from an alkoxy group (for example, CF ₃ O, CHF ₂ O, etc.).

The lower acyl group as (14) includes, for example, a lower acyl group derived from carboxylic acid, sulfinic acid or sulfonic acid. Here, the lower acyl group derived from a carboxylic acid includes, for example, lower (C _1-6 )
Alkyl-carbonyl (alkanoyl) (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, etc.), C _3-6 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), Benzoyl and the like. As a lower acyl group derived from sulfinic acid,
For example, lower (C _1-6 ) alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl,
Hexylsulfinyl), C _3-6 cycloalkylsulfinyl (eg, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, etc.), phenylsulfinyl and the like. Examples of the lower acyl group derived from sulfonic acid include lower (C _1-6 ) alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-
-Butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), _C3-6 cycloalkylsulfonyl (eg, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenylsulfonyl and the like. Individual `` lower acyl groups '' specifically exemplified as described above,
For example, a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, a nitro group, a cyano group, a lower (C _1-6 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,
Pentyl, hexyl, etc.), halogeno lower (C _1-6 ) alkyl groups (for example, CF ₃ , CF ₂ CF ₃ , CH ₂ F, CHF
₂ ), lower (C _1-6 ) alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-
Butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.),
A halogeno lower (C _1-6 ) alkoxy group (for example, CF ₃ O, C
HF ₂ O) or the like, and may be substituted at substitutable positions with one to three identical or different substituents selected from the group consisting of:

The optionally substituted phenyl group as (15) includes, for example, a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, a nitro group, a cyano group, a lower group.
(C _1-6 ) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,
t-butyl, pentyl, hexyl, etc.), halogeno lower
(C _1-6 ) alkyl groups (for example, CF ₃ , CF ₂ CF ₃ , CH ₂
F, CHF _{2 and the} like), lower (C _1-6 ) alkoxy groups (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy,
One to three identical or different substituents selected from isopentyloxy, neopentyloxy, hexyloxy, etc., halogeno lower (C _1-6 ) alkoxy groups (eg, CF ₃ O, CHF ₂ O, etc.) May be substituted at a substitutable position. (16) Examples of the divalent hydrocarbon group as, for example, the formula -CH = CH-CH = CH-, -CH = CH-CH 2 -CH 2 -, -CH 2 -CH = CH 2 -CH 2 - _{, -CH = CH-CH 2,} - (CH 2) a - (a is 3 or 4) include groups represented by. Here, the divalent hydrocarbon group forms a 5- or 6-membered ring together with the two ring-constituting atoms of the ring A, and the 5- or 6-membered ring is, for example, a lower (C _1-6 ) alkyl. Groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), halogen atoms (eg, chlorine, bromine, fluorine, iodine, etc.), lower (C
_1-6 ) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-
Butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), lower halogeno
(C _1-6 ) alkyl groups (for example, CF ₃ , CF ₂ CF ₃ , CH ₂
F, CHF ₂ etc.), halogeno lower (C _1-6 ) alkoxy groups (for example, CF ₃ O, CF ₂ CF ₃ O, CH ₂ FO, CHF ₂
O), lower (C _1-6 ) alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxy Carbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.), 1 to 3 identical or different substituents selected from a cyano group, a nitro group, a hydroxyl group and the like, and may be substituted at substitutable positions.

As the substituent for the ring A, an optionally halogenated lower (C _1-6 ) alkyl group (preferably methyl), an optionally halogenated lower (C _1-6 ) alkoxy group ( Preferably methoxy) and the like;

Embedded image [In the formula, the ring A ′ is a 5- or 6-membered aromatic heterocyclic ring which may further have a substituent other than the substituent Ra (preferably pyridine, pyrazole, pyrrole, furan, more preferably pyridine, A pyrazole), Z is an oxygen atom, a sulfur atom or a nitrogen atom, and Ra is a substituent (preferably an optionally halogenated lower ring) of the ring A described above.
(C _1-6 ) alkyl group, optionally halogenated lower
(C _1-6 ) alkoxy group). ] Is preferable.

As the substituent for the ring B, a halogen atom (preferably chlorine) or an optionally halogenated lower (C
_1-6 ) An alkyl group (preferably methyl), a hydroxyl group, an optionally halogenated lower (C _1-6 ) alkoxy group (preferably methoxy) and the like are preferable.

Embedded image [In the formula, the ring B ′ represents a 5- or 6-membered aromatic homo- or heterocyclic ring (preferably benzene or thiophene) which may further have a substituent other than the substituent Rb, Y represents a carbon atom, An oxygen atom, a sulfur atom or a nitrogen atom, Rb is a hydrogen atom or a substituent of the above-mentioned ring B (preferably a halogen atom, an optionally halogenated lower (C _1-6 ) alkyl group, a hydroxyl group, a halogenated Low-grade (C _1-6 )
Alkoxy group). ] Is preferable. In the above formula (I), R ¹ is a hydrogen atom, a hydroxyl group or a lower alkyl group (for example, a lower (C _1-6 ) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl) , Pentyl, hexyl, etc.), preferably methyl). As R ¹ , a hydrogen atom, a hydroxyl group and a methyl group are preferable, and among them, a hydrogen atom and a hydroxyl group are preferable, and a hydrogen atom is particularly preferable.
In the above formula (I), n represents 0 or 1 (preferably 1). Among them, compound (I) includes (S)-(-)
-7- (2,5-dichlorothiophen-3-yl) -5
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-
Methyl-5,6,7,8-tetrahydroquinoline,
(S)-(-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (2-chlorophenyl)
-5-guanidinoimino-4-methyl-5,6,7,8
-Tetrahydroquinoline, (±) -7- (2-bromophenyl) -5-guanidinoimino-4-methyl-5,
6,7,8-tetrahydroquinoline, 7- (3,5-dichlorothiophen-2-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, 7- (2,5 -Dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, 6- (2,5-dichlorothiophen-3-yl) -4-guanidinoimino-3-methyl-4, 5,
6,7-tetrahydroindazole, (±) -7-
(2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline, (±) -7- (5-chloro-2-methylphenyl)
-5-guanidinoimino-4-methyl-5,6,7,8
-Tetrahydroquinoline, (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-
Methyl-5,6,7,8-tetrahydroquinoline,
(±) -7- (2-chloro-5-fluorophenyl)-
5-guanidinoimino-4-methyl-5,6,7,8-
Tetrahydroquinoline, (±) -7- (5-chloro-2
-Fluorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±)
-7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline, (±) -7- (5-chloro-2-fluorophenyl ) -5-Guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof is preferred, especially (S)-(-)-7-
(2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (2,5-dichlorothiophen-3-yl ) -5-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (S)-
(-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (2-chlorophenyl) -5-guanidinoimino-4 -Methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydrocinnoline, (±) -7- (5-
(Chloro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino- 4-methyl-5,6,
7,8-tetrahydroquinoline, (±) -7- (2-chloro-5-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline, (±) -7- (5-chloro-2-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydroquinoline, (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline, (±) -7 -(5-chloro-2-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-Tetrahydrocinnoline or a salt thereof is preferred. A prodrug of the compound represented by the above formula (I) is a compound that converts into a compound represented by the above formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, enzymatic oxidation, A compound that undergoes reduction, hydrolysis, or the like to change to the compound represented by the above formula (I), or a compound that undergoes hydrolysis, etc. by gastric acid or the like, to change to the compound represented by the above formula (I). As a prodrug of the compound represented by the formula (I), a compound in which the amino group of the compound represented by the formula (I) is acylated, alkylated, or phosphorylated (for example, a compound represented by the formula (I)) The amino group of the compound represented is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated ,
(Pivaloyloxymethylated, tert-butylated compounds, etc.) and compounds in which the hydroxyl group of the compound represented by the above formula (I) is acylated, alkylated, phosphorylated or borated (for example, the above formula ( Acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, dimethylaminomethylcarbonylated, etc., the hydroxyl group of the compound represented by I)),
Alternatively, a compound in which the carboxyl group of the compound represented by the above formula (I) is esterified or amidated (for example, the carboxyl group of the compound represented by the above formula (I) is ethyl esterified, phenyl esterified, Methyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl Esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These compounds can be produced from the compound represented by the above formula (I) by a method known per se. The prodrug of the compound represented by the formula (I) can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pages 163 to 198, Molecular Design. It may be changed to the compound represented by I).

The salts of compound (I) and its synthetic intermediates include, for example, hydrochloride, hydrobromide, sulfate, nitrate,
Inorganic acid salts such as phosphates, for example, acetates, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, and other organic acid salts, for example, aspartic acid, glutamic acid, pyro Salts with amino acids such as glutamic acid, arginine, lysine and ornithine, such as metal salts such as sodium salt, potassium salt, calcium salt and aluminum salt, such as triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt and the like And pharmaceutically acceptable salts thereof. Compound (I) may be either a hydrate or a non-hydrate. When compound (I) exists as a configuration isomer (configuration isomer), a diastereomer, a conformer, or the like, each can be isolated by a separation and purification means known per se, if desired. it can. Compound (I) has a geometrical isomerism based on a configuration of a fused heterocyclic ring containing ring A in a hydrazone structure portion, and may exist as E and Z isomers or a mixture thereof. Furthermore, when R ¹ represents a hydroxyl group or a lower alkyl group, it has geometrical isomerism based on the double bond of the guanidino group, and may exist as E and Z isomers or a mixture thereof. The compounds of the present invention include the individual isomers shown below and mixtures thereof.

Embedded image Further, the compound (I) has optical isomerism based on the asymmetric carbon present in the portion substituted by the ring B and the like, and each asymmetric carbon exists in an R-form, an S-form or a mixture thereof. obtain. These can be separated into individual R-forms and S-forms by ordinary optical splitting means.
Also, any of the racemates is included in the present invention. For example, the compounds of the present invention include the following individual optically active substances and mixtures thereof.

Embedded image

In the present specification, a starting compound of compound (I) or a synthetic intermediate or a salt thereof is referred to as “or a salt thereof”.
Is sometimes abbreviated as a starting compound of compound (I) or a synthetic intermediate. Compound (I) is equivalent to compound (Ia) and compound (Ib) in chemical structure.

Embedded image Compound (I) can be prepared, for example, by the method described in Japanese Patent Application Laid-Open No. Hei 7-309837, Japanese Patent Application No. 9-224945 (Japanese Patent Application Laid-Open No. Hei 10-114475), Japanese Patent Application No. 9-224946 (Japanese Patent Application Laid-Open No. Hei 10-114744), or a method analogous thereto. In addition to the formula

Embedded image [The symbols in the formula are as defined above. And a salt thereof, and a compound represented by the formula (III) H ₂ NN = C (NH ₂ ) (NHR ¹ ) wherein the symbols are as defined above. And a salt thereof. Compound (III) is compound (I)
I) Usually, about 1 to about 2 moles are used per 1 mole. In this reaction, if necessary, about 1/10 to about 10-fold molar amount of triethylamine, pyrrolidine, sodium acetate, boron trifluoride / diethyl ether, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or the like is added as a catalyst. By
The reaction can also proceed smoothly. For example, the condensation reaction is carried out in an inert solvent such as methanol, ethanol,
Propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), The reaction can be performed in acetic acid, pyridine, water or the like, or a mixed solvent thereof. The reaction is carried out in a temperature range from about 0 ° C to about 180 ° C.

Compounds (II) and (III) used as starting materials can be produced by a known method or a method analogous thereto. can do. Reaction Formula I

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Embedded image In each of the formulas in the above reaction formula I, R ² to R ¹⁹ and R ²² to R ²⁴ represent the substituents on the ring A, and M ¹ to M ⁶ represent a leaving group.

Hereinafter, each step will be described in detail. (Step 1) After reacting the compound (XIII) with the compound (XIV), the hydroxyl group is oxidized and cyclized, whereby the ketone compound (IV) can be produced. Further, if necessary, the compound (IV) can be produced by reacting the cyclized product with the compound (XV) in the presence of a base to introduce a substituent R ⁴ into the ketone compound. This condensation reaction is performed with an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol, hexane,
The reaction is performed in a temperature range of about 0 ° C. to about 130 ° C. in toluene, benzene, dichloromethane, acetic acid or the like, or a mixed solvent thereof. The reaction time is about 1 hour to about 10
0 hours. Compound (XIV) is generally used at about 1 to about 2 mol per 1 mol of compound (XIII). In addition, the reaction can proceed smoothly by adding molecular sieves or the like. Subsequent oxidation, ring closure, and dehydration reactions may be carried out by a method known per se, for example, when an equivalent to about 2 moles of an aromatic halide is used as an oxidizing agent, the reaction is carried out in an amount of about 0.1 to about 2.0.
In the presence of 1 to about 20 mole percent transition metal catalyst and 1 equivalent to about 2 moles of base, an inert solvent such as tetrahydrofuran, dimethoxyethane, dimethylformamide, N-methylpyrrolidone, hexane, toluene, benzene, dichloromethane The reaction is performed in a temperature range of about 50 ° C. to about 200 ° C. in chloroform, chloroform, or a mixed solvent thereof. Reaction times are from about 1 hour to about 50 hours. As the aromatic halide used as the oxidizing agent, bromobenzene, bromomesitylene, ortho-bromotoluene and the like can be mentioned. Examples of the transition metal catalyst include nickel, palladium, platinum, platinum, ruthenium, and the like. The use of a palladium catalyst such as tetrakis (triphenylphosphine) palladium allows the reaction to proceed smoothly. As the base, potassium carbonate, sodium hydride and the like can be used. The reaction is preferably carried out using an inert gas (eg, nitrogen,
(Argon) atmosphere. The reaction with compound (XV) is carried out in an inert solvent such as tetrahydrofuran, dimethoxyethane, dimethylformamide, N-methylpyrrolidonehexane, toluene, benzene, dichloromethane, chloroform, or the like, or a mixed solvent thereof at about 0 ° C.
It is carried out in a temperature range from about 150 ° C. to about 150 ° C. Reaction times are from about 1 hour to about 50 hours. As the base, triethylamine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t
-Butoxide and the like can be used. Compound (XV) is usually used in about 1 to about 2 mol per 1 mol of compound (XIII).

(Step 2) Compound (XIII) is reacted with an aminating agent to give an enamine derivative.
I) (wherein R ²⁰ is —CH ₂ COCH ₃ , —C≡CH, —C
H ₂ CH (OMe) _{2 and the} like are shown. ) To produce the ketone compound (V). Further, if necessary, compound (XIII) is converted to compound (X
The ketone compound (V) can also be produced by reacting with V) without isolating the enamine derivative. The amination is carried out in the presence of an aminating agent such as ammonium acetate in an inert solvent such as methanol, ethanol, benzene,
Toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, etc.
Alternatively, in these mixed solvents, about 0 ° C. to about 15 ° C.
It is performed in a temperature range of 0 ° C. Reaction times are from about 1 hour to about 100 hours. The aminating agent is generally used in an amount of about 1 to about 10 mol per 1 mol of compound (XIII). The condensation and cyclization reactions are carried out in an inert solvent such as methanol, ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide and the like, or these. In a temperature range of about 0 ° C. to about 150 ° C. Reaction times are from about 1 hour to about 50 hours. Compound (XVI) is generally used at about 1 to about 5 mol per 1 mol of compound (XIII). Even when the enamine derivative is not isolated, the reaction is carried out in the same manner in the presence of an aminating agent such as ammonium acetate.

(Step 3) Compound (XIII) and compound (XV
After the reaction of II), the compound can be cyclized and oxidized to produce the ketone compound (V). This condensation reaction is performed with an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol, hexane,
The reaction is carried out in a temperature range of about 0 ° C. to about 130 ° C. in toluene, benzene, dichloromethane, or a mixed solvent thereof. Reaction times are from about 1 hour to about 100 hours. Compound (XVII) is generally used at about 1 to about 2 mol per 1 mol of compound (XIII). The subsequent ring closure and oxidation reaction may be carried out in the absence of a solvent or in an inert solvent such as diphenyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, xylene, toluene, or a mixed solvent thereof in the air (or under an oxygen atmosphere). It is carried out in a temperature range from room temperature to about 300 ° C. Reaction times are from about 1 hour to about 10 hours.

(Step 4) The ketone compound (VI) can be produced by reacting the compound (XIII) with an aminating agent, then reacting with the compound (XVIII), and then cyclizing the compound. The amination is performed in the same manner as in Step 2. Subsequent condensation reaction is an inert solvent such as methanol, ethanol, benzene, toluene, chloroform,
Dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate,
Dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof at about 0 ° C. to about 100 ° C.
The temperature range is as follows. The reaction time is from about 1 hour to about 5
0 hours. Compound (XVIII) is generally used in about 1 to about 2 mol per 1 mol of compound (XIII). Subsequent ring closure reaction is without solvent, or an inert solvent such as tetrahydrofuran, diphenyl ether, dimethoxyethane,
The reaction is performed in a temperature range of about 50 ° C. to about 300 ° C. in methanol, ethanol, dichloromethane, chloroform, hexane, benzene, toluene, or a mixed solvent thereof. Reaction times are from about 10 minutes to about 5 hours.

(Step 5) By halogenating the compound (VI) produced in the step 4, the ketone compound (VII)
(Wherein, X represents a halogen atom). The halogenation reaction is carried out by a method known per se, for example, when phosphorus oxychloride is used as a halogenating agent, a halogenating agent is used in an amount of about 1 to about 20 times, and no solvent is used.
Alternatively, the reaction is carried out in an inert solvent such as tetrahydrofuran, dimethoxyethane, hexane, toluene, benzene, dichloromethane, chloroform and the like, or a mixed solvent thereof at a temperature of about 0 ° C to about 150 ° C. Reaction times are from about 30 minutes to about 10 hours. Further, by adding dimethylformamide or the like, the reaction can proceed smoothly.

(Step 6) The ketone compound (VIII) can be produced by reacting the compound (VII) produced in the step 5 with the compound (XIX). The reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether,
Dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, etc.
Alternatively, in these mixed solvents, about 0 ° C. to about 15 ° C.
It is performed in a temperature range of 0 ° C. Reaction times are from about 30 minutes to about 50 hours. Compound (XIX) is Compound (XIII)
Usually, about 1 to about 2 moles are used per 1 mole, but they can be used as a solvent. Optionally, as a base,
Lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used.

(Step 7) Compound (XIII) and compound (X
After reacting X), the compound (XXI) (wherein AB represents an optionally substituted hydrazine, hydroxylamine or the like) is reacted and cyclized to give a ketone compound (IX) or ( IX ').
The condensation reaction is carried out by a means known per se, a condensing agent, for example,
In the presence of DCC, WSC, etc., in an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, hexane, toluene, benzene, dichloromethane, chloroform, ethyl acetate, etc., or a mixed solvent thereof. The reaction is carried out in a temperature range of about 0 ° C. to about 150 ° C. as a base. Reaction times are from about 1 hour to about 50 hours. Compound (X
X) is usually about 1 to about 3 per mole of compound (XIII).
Use moles. The subsequent ring closure reaction is carried out in an inert solvent such as tetrahydrofuran, diphenyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, or the like, or a mixed solvent thereof. C. to a temperature of about 150.degree. Reaction times are from about 1 hour to about 50 hours. Compound (XXI) is generally used at about 1 to about 2 mol per 1 mol of compound (XIII).

(Step 8) Compound (XIII) and compound (XX)
After the reaction of II), the compound (XXIII) is reacted and cyclized, whereby the ketone compound (X) can be produced. The condensation reaction is performed in the same manner as in the condensation reaction in Step 7. The subsequent cyclization reaction is performed in an inert solvent such as tetrahydrofuran, diphenyl ether, dimethoxyethane, methanol, ethanol, hexane, benzene, toluene, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, or the like, or a mixed solvent thereof. It is carried out in a temperature range from 0 ° C to about 150 ° C. Reaction times are from about 1 hour to about 100 hours. In this reaction, the product of the first condensation reaction is reacted with an amine to give an enamine derivative, and then the compound (XX
Reaction with III) allows the reaction to proceed smoothly.

(Step 9) Compound (XIII) and compound (XX)
After the reaction of IV), the compound is cyclized to produce a ketone compound (XI). This condensation reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof in the presence of a base. , In a temperature range from about 0 ° C to about 100 ° C. Reaction times are from about 30 minutes to about 20 hours. As the base,
Lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used. Compound (XXIV) is compound (XI
II) About 1 to 2 mol is usually used per 1 mol. The subsequent cyclization reaction is carried out without solvent or in an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, dimethylformamide, dimethylsulfoxide, xylene, toluene, dichloromethane, chloroform, or a mixed solvent thereof. It is carried out in a temperature range from room temperature to about 300 ° C.
Reaction times are from about 1 hour to about 50 hours.

(Step 10) The compound (XIII) is halogenated and then reacted with Na ₂ S or the like, and the product is reacted with the compound (XXV) to be cyclized, whereby the ketone compound (XI
I) can be manufactured. The halogenation reaction is carried out by a means known per se, for example, when phosphorus trichloride is used as the halogenating agent, about 1/3 to about 5 times the molar amount of the halogenating agent is used, and no solvent or an inert solvent such as In tetrahydrofuran, dimethoxyethane, hexane, toluene, benzene, dichloromethane, chloroform, or the like, or a mixed solvent thereof at about 0 ° C. to about 150 ° C.
It is performed in a temperature range of ° C. Reaction times are from about 30 minutes to about 10 hours. The reaction with Na ₂ S or the like is carried out in an inert solvent such as water, tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, etc., or a mixed solvent thereof at about 0 ° C. About 100 ° C
The temperature range is as follows. Reaction times are from about 30 minutes to about 10 hours. The condensation reaction is performed with an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane,
The reaction is carried out in methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof in the presence of a base at a temperature of about 0 ° C to about 100 ° C. The reaction time is about 30 minutes to about 20 minutes.
Time. As the base, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used.
Compound (XXV) is usually used in about 1 to about 2 mol per 1 mol of compound (XIII). The subsequent cyclization reaction was carried out without solvent,
Alternatively, an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, dimethylformamide, dimethylsulfoxide, xylene, toluene, dichloromethane, chloroform, etc., or a mixed solvent thereof at room temperature to about 3 wt.
It is performed in a temperature range of 00 ° C. Reaction times are from about 1 hour to about 100 hours. (Step 11) Compound (XIII) is converted to compound (XXVII) wherein R ²¹ represents phenyl which may be substituted, such as phenyl, 4-methylphenyl, and 4-methoxyphenyl. And then reacting with a compound (XXVIII) in the presence of a base to produce a ketone compound (XXVI). The reaction with compound (XXVII) is carried out with an inert solvent such as methanol, ethanol,
Toluene, benzene, dichloromethane, chloroform,
The reaction is carried out in 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide or the like, or a mixed solvent thereof at a temperature of about 0 ° C. to about 150 ° C. Reaction times are from about 1 hour to about 100 hours. The aminating agent is a compound (XII
I) Usually, about 1 to about 10 mol is used per 1 mol.
The reaction with the compound (XXVIII) and the cyclization reaction are performed in an inert solvent such as methanol, ethanol, toluene, benzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, and dimethylsulfoxide. Or in a mixed solvent thereof at about 0 ° C
It is carried out in a temperature range from about 150 ° C. to about 150 ° C. Reaction times are from about 1 hour to about 50 hours. As the base, potassium carbonate, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used. Compound (XVI) is generally used at about 1 to about 5 mol per 1 mol of compound (XIII).

The ketone compounds obtained in these steps 1 to 11 can be used for the next reaction without isolation and purification. However, in all of the above production methods, when the compound has a carbonyl group, an amino group, a hydroxyl group, and a carboxyl group, a general protecting group may be introduced into the compound in advance by a method known per se. ,
After the reaction, the desired product can be obtained by removing the protecting group, if necessary. Here, as the protecting group for the carbonyl group, for example, a cyclic or non-cyclic acetal or ketal which may have a substituent, a cyclic or non-cyclic dithioacetal or a dithioketal which may have a substituent are used. Can be Here, as the protecting group for the amino group, for example, lower (C _1-6 ) alkyl-carbonyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, etc.), benzoyl and the like are used. Examples of the hydroxyl-protecting group include methoxydimethylmethyl, trimethylsilyl, t-butyldimethylsilyl, trimethylsilylethoxymethyl (SEM), methoxymethyl, benzyloxymethyl, tetrahydropyranyl (THP) and the like. As the protecting group for the carboxyl group, for example, lower (C
_1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), C _7-12 aralkyl (eg, benzyl, phenethyl, 4-phenylpropyl, 4-
Phenylbutyl, 1-naphthylmethyl, etc.). Further, the carboxyl group may be converted to a 2-oxazoline ring for protection. As a method for introducing and removing a protecting group, a method known per se or a method analogous thereto (for example, a method described in Protective Groups in Organic Chemistry (JFW McOmie et al., Plenum Press)) is used. For example, a method of treating with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

Of the above compound (I), its starting compound or synthetic intermediate, a basic compound can be converted into a salt using an acid according to a conventional method. Suitable acids for this reaction are preferably those which give pharmacologically acceptable salts. For example, hydrochloric acid, hydrobromic acid, phosphoric acid,
Examples include inorganic acids such as sulfuric acid, nitric acid, and sulfamic acid, and organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, glutamic acid, and pyroglutamic acid. When the obtained compound is a salt, it may be converted to a free base according to a conventional method.

Further, among the compound (I) or its starting compound or synthetic intermediate, a compound having an acidic group such as, for example, -COOH can be converted into a salt according to a conventional method. Preferred examples of such salts include salts with alkali metals, alkaline earth metals, ammonium, substituted ammonium and the like, and more specifically, for example, sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium , Tri-C _1-6
Salts with alkylammonium (for example, trimethylammonium, triethylammonium and the like), triethanolammonium and the like can be mentioned. In each of the above reactions, unless otherwise specified, the raw materials are usually used in an equimolar amount, and the reaction time is usually about 1 to 24 hours. The compound (I) or its starting compound thus obtained can be subjected to ordinary separation and purification means from the reaction mixture, such as extraction, concentration, neutralization, filtration, crystallization, recrystallization, column (or thin-layer) chromatography and the like. Can be isolated.

Na-H of the present invention containing compound (I)
The exchange inhibitor may be an animal, particularly a mammal (eg, a human, monkey, pig, dog, cat, rabbit, guinea pig, rat,
Mouse, etc.), exhibit an excellent Na-H exchange inhibitory action and a cell dysfunction-improving action / cytoprotective action (especially for myocardium) based thereon, and arechemic diseases (for example, myocardial infarction and accompanying dysfunction, Ischemic heart disease such as unstable angina), restenosis after PTCA, arrhythmia, heart failure, cardiac hypertrophy, hypertension and associated tissue damage, ischemic brain disease (eg, associated with cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage) Prophylactic / therapeutic agents such as myocardial infarction and associated dysfunction, ischemic heart disease such as unstable angina, restenosis after PTCA, arrhythmia, heart failure, cardiac hypertrophy, etc. And more preferably as a prophylactic / therapeutic agent for ischemic heart disease such as myocardial infarction and a prophylactic / therapeutic agent for heart failure and the like. Here, the concept of prevention of heart failure includes treatment of prognosis of myocardial infarction, and the concept of treatment of heart failure also includes suppression of progression or worsening of heart failure.

The compound (I) used as an active ingredient in the present invention has low toxicity, has good absorption even by oral administration,
Since it is also excellent in stability, when it is used as the above-mentioned medicine, it is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent, and an appropriate amount, powder, granules,
It can be safely orally or parenterally administered as a pharmaceutical composition such as tablets, capsules (including soft capsules and microcapsules), liquids, injections, and suppositories.

The Na-H exchange inhibitor and the pharmaceutical composition of the present invention can be formulated according to a usual method. The content of the compound (I) contained in the pharmaceutical composition of the present invention is as follows:
It is about 0.01 to about 20% (W / W).

In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono- or di- or triglycerides.

Suppositories for rectal administration include the drug and suitable nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at intestinal temperature and melt in the rectum. It can be manufactured by mixing with a substance that releases a drug.

Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills and capsules. In such dosage forms, the active ingredient compound may comprise at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans, pectin. , Tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms also
As usual, further additives can be included, such as inert diluents, lubricants such as magnesium stearate,
Parabens, preservatives such as sorbic acid, ascorbic acid,
Examples include antioxidants such as α-tocopherol and cysteine, disintegrants, binders, thickeners, buffering agents, sweeteners, flavoring agents, and perfumes. Tablets and pills can also be prepared with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs,
Suspensions, solutions and the like, which may contain an inert diluent commonly used in the art, such as water.

The dose varies depending on the administration subject, administration route and symptoms. When administered orally to a patient with myocardial infarction (adult weighing about 60 kg), the dose is usually about 0.1% as compound (I) as a single dose. 005 to 10 mg / kg, preferably 0.01 to 5 mg / kg, more preferably about 0.02 to 1 mg / kg (about 0.3 to 600 mg / person, preferably 0.6 to 300 mg / person, more preferably Is 1.2 to 60 mg / person), and it is desirable to administer these doses about 1 to about 3 times a day depending on the symptoms. In the case of an acute onset of the disease, for example immediately after the onset of myocardial infarction, higher doses and especially frequent administrations, for example 1
Four doses per day may be required. Particularly in the case of myocardial infarction patients during intensive care, for example, intravenous administration may require about 100 mg / person per day. The compound (I) of the present invention is particularly useful for preventing or treating ischemic disease, particularly ischemic heart disease, particularly myocardial infarction, heart failure, and arrhythmia, by combining with a compound having endothelin antagonistic activity or a salt thereof. It exerts a remarkable effect and can compensate for various drawbacks observed when the drug is administered alone, for example, a pharmaceutical effect, safety,
In terms of stability, dosage, dosage form, method of use, etc., it is possible to exhibit exceptionally remarkable effects which were not observed when each single drug was administered. Specific examples of the compound having an endothelin antagonistic activity or a salt thereof include, for example, EP-A-552489, EP-A-52831.
2, EP-A-499266, WO91 / 13089,
EP-A-436189, EP-A-457195, E
PA-510526, WO92 / 12991, JP-A-4-288099, JP-A-4-24497, JP-A-4
-261198, EP-A-496452, EP-A-
526708, EP-A-526624, EP-A-5
10526, EP-A-460679, WO92 / 20
706, EP-A-626174, EP-A-6554
63, EP-A-714909, JP-A-7-17316
Examples thereof include the compounds described in 1, etc. Among them, the following compounds are preferably used. Cy
clo [-D-Asp-Asp (R1) -Asp-D-
Thg (2) -Leu-D-Trp-] [In the amino acid sequence, Asp (R1) represents an aspartic acid β-4-phenylpiperazineamide residue, and Thg (2) represents a 2-thienylglycine residue. ] (Hereinafter sometimes referred to as compound A);

Embedded image (Bosentan);

Embedded image (SB-217242);

Embedded image (SB-209670);

Embedded image (TBC-11251); Cyclo [-Asp-Pro-Val-Leu-Tr
p-] (BQ-123);

Embedded image (TBC-11251); among others, Cyclo [-D-Asp-Asp (R1)
-Asp-D-Thg (2) -Leu-D-Trp-]
[In the amino acid sequence, Asp (R1) is aspartic acid β
-4-Phenylpiperazineamide residue was converted to Thg (2)
Represents a 2-thienylglycine residue. Or a salt thereof, and particularly, Cyclo [-D-Asp-Asp
(R1) -Asp-D-Thg (2) -Leu-DT
rp-] [In the amino acid sequence, Asp (R1) represents an aspartic acid β-4-phenylpiperazineamide residue at Th
g (2) represents a 2-thienylglycine residue. ] 2N
a salt is preferably used. Further, when a compound having an endothelin antagonistic activity or a salt thereof is used in combination with a compound (I) having an Na-H exchange inhibitory activity,
These drugs may be separately or simultaneously mixed and formulated with pharmacologically acceptable carriers, excipients, binders, diluents and the like, and administered orally or parenterally as a pharmaceutical composition. Can be. If the drugs are formulated separately,
When formulated separately, they can be mixed and administered with a diluent or the like at the time of use.However, individual formulations formulated separately can be administered to the same subject simultaneously or separately with a time lag. You may. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, an ampoule containing a powdered individual drug and two or more drugs mixed at the time of use and dissolved) Kit products for administration of the same formulation to the same subject simultaneously or separately at different times, such as injectable kits containing diluents for Tablets in the same or separate bags,
If necessary, a column for describing the time for administering the drug was provided.
Tablet kits for administering more than one kind of tablets at the same time or separately at different times are also included in the present invention. When the compound having endothelin antagonistic activity or a salt thereof and the compound (I) having Na-H exchange inhibitory activity are used in combination, the dose is determined based on the minimum recommended clinical dose of each drug. It can be appropriately selected depending on the subject, age and weight of the subject to be administered, symptoms, administration time, administration method, dosage form, drug combination, and the like.
The dosage for a particular patient will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, drug combination, and the extent of the condition the patient is treating at the time. , Taking into account these and other factors. Typically, the individual daily dose for the combination of a compound having an endothelin antagonistic activity or a salt thereof and the compound (I) having an Na-H exchange inhibitory activity is determined by the fact that they are administered alone. Is in the range of about 1/50 or more of the minimum recommended clinical dose and not more than the maximum recommended level (preferably not more than the minimum recommended clinical dose, more preferably not more than 最 the minimum recommended clinical dose). To illustrate these combinations, for example, an adult (body weight of about 60
kg) of a patient with myocardial infarction (adult with a body weight of about 60 kg) is usually administered in a single dose of about 0.002 to 5 mg / kg, preferably 0.000, as a Na-H exchange inhibitor.
The dose is about 5 to 2 mg / kg, more preferably about 0.02 to 1 mg / kg.
It is desirable to administer about 1 to about 3 times a day. In the case of an acute onset of the disease, for example, immediately after the onset of myocardial infarction, higher doses and especially frequent dosing may be necessary, for example, four times a day. In particular, for example, in the case of myocardial infarction patients during intensive care, about 50 mg per day is administered for intravenous administration.
/ People may be required. On the other hand, the endothelin antagonist is, for example, about 10 to 300 mg / human / day (preferably about 20 to 200 mg / human / day, more preferably
Doses ranging from about 50-100 mg / human / day (preferably doses by intravenous administration) can be effectively combined with Na-H exchange inhibitors. Of course, these dose ranges can be adjusted on a unit basis necessary to divide up the daily dose; however, as noted above, the dose can be sex,
It is determined in consideration of diet, administration time, administration method, excretion rate, drug combination, and other factors.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Reference Examples showing the production of starting materials and Examples showing the production of compound (I), but the present invention is not limited thereto. Not something. In addition, room temperature in this specification indicates 0 to 25 ° C., and each symbol has the following meaning. mp: melting point s: singlet d: doublet t: triplet dd: double doublet ddd: double double doublet
ublet) q: quartet m: multiplet br: broad CDCl ₃ : heavy chloroform CD ₃ OD: heavy methanol DMSO: dimethyl sulfoxide DCC: dicyclohexylcarbodiimide WSC: water-soluble carbodiimide

[0041]

EXAMPLES Reference Example 1 A mixture of 5-phenylcyclohexane-1,3-dione (15.0 g), 2-aminoethanol (6.3 g), molecular sieve 4A (100 g), and tetrahydrofuran (200 ml) Was heated to reflux for 12 hours. After cooling, insolubles were filtered off, and the solvent was distilled off under reduced pressure to obtain an oil. Dissolve this in dimethylformamide (5 ml),
2-bromomesitylene (0.20 g), tetrakistriphenylphosphine palladium (30 mg), potassium carbonate (0.28 g)
And stirred at 150 ° C. for 2 hours. Concentrate under reduced pressure,
The residue was dissolved in ethyl acetate, aqueous sodium hydrogen carbonate,
The extract was washed sequentially with water and a saturated saline solution, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and 6-phenyl-4,5,6,7-tetrahydroindole-4-one (0.
11 g) were obtained. mp. 187-189 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.72 (1H, s), 2.76 (1H, dd, J = 1
6, 20 Hz), 3.02 (1H, dd, J = 16, 26 Hz), 3.06 (1H,
dd, J = 16, 20 Hz), 3.43-3.61 (1H, m), 6.56 (1
H, t, J = 3 Hz), 6.72 (1H, t, J = 3 Hz), 7.10-7.
48 (5H, m) 9.31 (1H, br).

Reference Example 2 5-phenylcyclohexane-1,3-dione (5.0 g), 3-aminopropan-2-ol (2.6 g), molecular sieve 4
A mixture of A (30 g) and tetrahydrofuran (70 ml) was heated to reflux for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (130 ml), and 2-bromomesitylene (5.3 g), tetrakistriphenylphosphinepalladium (0.77 g), potassium carbonate (7.
3 g) and stirred at 150 ° C. for 4 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to form colorless crystals.
3-methyl-6-phenyl-4,5,6,7-tetrahydroindole
4-One (2.3 g) was obtained. mp. 169 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 2.32 (3H, s), 2.70 (1H, s), 2.74
(1H, dd, J = 16, 21 Hz), 2.98 (1H, dd, J = 13, 16
Hz), 3.02 (1H, s), 3.42-3.62 (1H, m), 6.45 (1H,
s), 7.15-7.42 (5H, m) 8.14 (1H, br).

Reference Example 3 5-phenylcyclohexane-1,3-dione (4.0 g), 4-aminobutan-2-ol (2.5 g), molecular sieves 4A
(24 g) and a mixture of tetrahydrofuran (60 ml) were heated under reflux for 13 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (100 ml), 2-bromomesitylene (4.2 g), tetrakistriphenylphosphinepalladium (0.6 g), potassium carbonate (5.9 g)
g) was added and stirred at 150 ° C. for 5 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindo- as colorless crystals.
Le-4-one (2.6 g) was obtained. ^{. mp 177 - 179 ℃ 1 H} -NMR (CDCl 3) δ: 1.22 (3H, t, J = 7 Hz), 2.64 - 2.
86 (4H, m), 2.89-3.09 (2H, m), 3.42-3.63 (1H,
m), 6.48 (1H, s), 7.22-7.42 (5H, m) 8.25 (1H, b
r).

Reference Example 4 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminopropanol (2.1 g), molecular sieves 4A (24 g)
g) and tetrahydrofuran (60 ml) were heated under reflux for 14 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Dissolve the residue in dimethylformamide (100 ml),
2-bromomesitylene (4.2 g), tetrakistriphenylphosphine palladium (0.6 g), potassium carbonate (5.9 g)
And stirred at 150 ° C. for 3.5 hours. Concentrate under reduced pressure,
The residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 2-methyl-6-phenyl-4,5,6,7 as colorless crystals. -Tetrahydroindole-4-one (3.2 g) was obtained. mp.203-205 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.63-2.84 (2H,
m), 2.85-3.14 (2H, m), 3.41-3.59 (1H, m), 6.21
(1H, s), 7.21-7.41 (5H, m) 8.85 (1H, br).

Reference Example 5 A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminocyclohexanol (3.2 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was prepared. Mix 12
Heated to reflux for an hour. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (100 ml), 2-bromomesitylene (4.2 g), tetrakistriphenylphosphinepalladium (0.6 g), potassium carbonate
(5.9 g) was added and stirred at 150 ° C. for 4 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 2-phenyl-1,2,3,4,5,6 as colorless crystals. , 7,8-Octahydrocarbazol-4-one
(3.4 g) was obtained. mp. 257-259 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.90 (4H, m), 2.26-2.82
(6H, m), 2.84-3.06 (2H, m), 3.40-3.60 (1H, m),
7.16-7.48 (5H, m), 8.07 (1H, br).

Reference Example 6 5-phenylcyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (0.97 g), molecular sieves 4A (12 g), tetrahydrofuran (30 g) ml) of the mixture to 12
Heated to reflux for an hour. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (40 ml), 2-bromomesitylene (2.0 g), tetrakistriphenylphosphinepalladium (0.29 g), potassium carbonate
(2.7 g) and stirred at 150 ° C. for 5 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 3-methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydroindole-4-one (1.1 as colorless crystals).
g) was obtained. mp.190-191 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 2.34 (3H, s), 2.53
-3.08 (4H, m), 3.67 -3.85 (1H, m), 6.46 (1H, s),
7.05-7.34 (4H, m), 8.30 (1H, br).

Reference Example 7 60% sodium hydride (0.14 g, washed three times with hexane)
6-phenyl-4, suspension in dimethylformamide (10 ml)
5,6,7-Terahydroindole-4-one (0.6 g) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of methyl iodide (0.44 g) in dimethylformamide (1 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to form 1-methyl-6-phenyl-4,5,6 as colorless crystals. , 7-Tetrahydroindole-4-
On (0.57 g) was obtained. mp. 166-167 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.71 (1H, s), 2.75 (1H, dd, J = 1
6, 21 Hz), 2.87 (1H, dd, J = 11, 16 Hz), 3.05 (1H,
dd, J = 5, 16 Hz), 3.43-3.66 (1H, m), 3.56 (3H,
s), 6.46-6.67 (2H, m), 7.22-7.44 (5H, m).

Reference Example 8 60% sodium hydride (0.085 g, washed three times with hexane)
3-methyl-6-phenyl-4,5,6,7-terahydroindole-4-one (0.4 g) in a suspension of dimethylformamide (10 ml)
Was added and stirred at room temperature for 30 minutes. A solution of methyl iodide (0.28 g) in dimethylformamide (1 ml) was added at 0 ° C, and the solution was added at room temperature.
Stirred for hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give 1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one compound as colorless crystals.
(0.37 g) was obtained. mp.155-156 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.57-3.08 (4H,
m), 3.36-3.62 (1H, m), 3.48 (3H, s), 6.32 (1H,
s), 7.20-7.45 (5H, m).

Reference Example 9 60% sodium hydride (0.18 g, washed three times with hexane)
6-phenyl-4, suspension in dimethylformamide (10 ml)
5,6,7-Terahydroindole-4-one (0.8 g) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of 1-bromopropane (0.51 g) in dimethylformamide (3 ml) was added, and the mixture was stirred at the same temperature for 1 hour.
The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
The extract was washed with water and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 6-phenyl-1-propyl
-4,5,6,7-Tetrahydroindole-4-one (0.92 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7 Hz), 1.63-1.
85 (2H, m), 2.6-2.77 (2H, m), 2.87 (1H, dd, J = 1
1, 16 Hz), 3.04 (1H, dd, J = 5, 16 Hz), 3.42-3.6
1 (1H, m), 3.77 (1H, t, J = 7 Hz), 6.59 (1H, d, J
= 3 Hz), 6.76 (1H, d, J = 3 Hz), 7.22-7.44 (5H,
m).

Reference Example 10 60% sodium hydride (0.18 g, washed three times with hexane)
6-phenyl-4, suspension in dimethylformamide (10 ml)
5,6,7-Terahydroindole-4-one (0.8 g) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of benzyl bromide (0.71 g) in dimethylformamide (3 ml) was added, and the mixture was stirred at the same temperature for 2.5 hours.
The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
The extract was washed with water and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and then recrystallized from ethyl acetate-isopropyl ether to form 1-benzyl-6-phenyl-4,5,6, as colorless crystals. 7-tetrahydroindole-4
-On (0.86 g) was obtained. mp.122-123 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.61-3.06 (4H, m), 3.41-3.61
(1H, m), 5.05 (2H, s), 6.66 (1H, dd, J = 3, 6 Hz),
7.03 (1H, dd, J = 3, 7 Hz), 7.20-7.40 (8H, m).

Reference Example 11 A suspension of 60% sodium hydride (washed three times with 0.17 g hexane) in dimethylformamide (10 ml) was treated with 6-phenyl-4,5,
6,7-Terahydroindole-4-one (0.8 g) was added at room temperature.
Stir for 30 minutes. A solution of benzoyl chloride (0.59 g) in dimethylformamide (3 ml) was added, and the mixture was stirred at the same temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 1-benzoyl- as colorless crystals.
6-phenyl-4,5,6,7-tetrahydroindole-4-one
(0.78 g) was obtained. mp. 140-142 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.72-2.99 (2H, m), 3.22-3.43
(1H, m), 3.45-3.80 (2H, m), 6.64 (1H, d, J = 4 H
z), 6.91 (1H, d, J = 4 Hz), 7.22 (5H, m), 7.45-
7.60 (3H, m) 7.63-7.83 (2H, m).

Reference Example 12 60% sodium hydride (0.18 g, washed three times with hexane)
6-phenyl-4, suspension in dimethylformamide (10 ml)
5,6,7-Terahydroindole-4-one (0.8 g) was added, and the mixture was stirred at room temperature for 30 minutes. Methanesulfonyl chloride (0.48 g)
Of dimethylformamide (3 ml) was added, and the mixture was stirred at the same temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and then recrystallized from ethyl acetate-hexane to give 1-methanesulfonyl-6-phenyl-4,5,6,7- as colorless crystals. Tetrahydroindole-4-one (0.51 g) was obtained. mp.172-173 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.65-2.92 (2H, m), 3.03-3.32
(1H, m), 3.21 (3H, s), 3.44-3.66 (2H, m), 6.71 (1
H, d, J = 3 Hz), 7.14 (1H, d, J = 3 Hz), 7.21-7.
43 (5H, m).

Reference Example 13 60% sodium hydride (0.085 g, washed three times with hexane)
3-methyl-6-phenyl-4,5,6,7-terahydroindole-4-one (0.4 g) in a suspension of dimethylformamide (10 ml)
Was added and stirred at room temperature for 30 minutes. Methanesulfonyl chloride
(0.22 g) in dimethylformamide (2 ml) was added, and the mixture was stirred at the same temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 1-methanesulfonyl-3-methyl-6-phenyl-4, as colorless crystals.
5,6,7-Tetrahydroindole-4-one (0.50 g) was obtained. mp.80-83 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, s), 2.62-2.88 (2H,
m), 2.95-3.28 (1H, m), 3.17 (3H, s), 3.41-3.63
(2H, m), 6.87 (1H, s), 7.15-7.43 (5H, m).

Reference Example 14 60% sodium hydride (0.13 g, washed three times with hexane)
3-ethyl-6-phenyl-4,5,6,7-terahydroindole-4-one (0.64 g) in dimethylformamide (10 ml) suspension
Was added and stirred at room temperature for 30 minutes. Methanesulfonyl chloride
(0.34 g) in dimethylformamide (1 ml) was added, and the mixture was stirred at the same temperature for 24 hours and at 40 ° C. for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from diisopropyl ether-hexane to give 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one as colorless crystals. (0.26 g)
I got mp. 153-154 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J
= 7 Hz), 2.57-3.28 (5H,
m), 3.16 (3H, s), 3.38 −
3.57 (2H, m), 6.87 (1H,
s), 7.17-7.43 (5H, m).

Reference Example 15 A suspension of 60% sodium hydride (0.12 g, washed three times with hexane) in dimethylformamide (10 ml) was added with 3-methyl-
-6- (2-methylphenyl) -4,5,6,7-terahydroindole
-4-one (0.60 g) was added, and the mixture was stirred at room temperature for 30 minutes. Methanesulfonyl chloride (0.43 g) in dimethylformamide (3
ml) solution and stirred at the same temperature for 12 hours, methanesulfonyl chloride (0.74 g) was added, and the mixture was further stirred for 3 hours. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane) to obtain crystals. The crystals were recrystallized from ethyl acetate-hexane to give 1-colorless crystals.
Methanesulfonyl-3-methyl-6- (2-methylphenyl) -4,
5,6,7-Tetrahydroindole-4-one (0.35 g) was obtained. ^{. mp 163 - 165 ℃ 1 H} -NMR (CDCl 3) δ: 2.31 (3H, s), 2.37 (3H, s), 2.57
-2.89 (5H, m), 3.04 (1H, dd, J = 11, 17 Hz), 3.43
(1H, dd, J = 4, 17 Hz), 3.63-3.87 (2H, m), 6.89
(1H, s), 7.15-7.34 (4H, m).

Reference Example 16 5- (2-fluorophenyl) -1,3-cyclohexanedione (2.
0 g), 3-aminopropan-2-ol (0.95 g), molecular sieves 4A (12 g), tetrahydrofuran (30 ml)
Was heated at reflux for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (40 ml), 2-bromomesitylene (1.9 g), tetrakistriphenylphosphine palladium (0.28 g),
Potassium carbonate (2.7 g) was added, and the mixture was stirred at 150 ° C for 5 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The residue was recrystallized from ethyl acetate-hexane to give 6- (2-fluorophenyl) -3.
-Methyl-4,5,6,7-tetrahydroindole-4-one (0.96
g) was obtained. mp. 198-200 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.63 (1H, dd, J =
4, 16 Hz), 2.80 (1H, dd, J = 12, 16 Hz), 2.83-3.
16 (2H, m), 3.68-3.86 (1H, m), 6.42 (1H, s), 6.9
7-7.34 (4H, m), 9.71 (1H, br).

Reference Example 17 60% sodium hydride (0.16 g, washed three times with hexane)
To a suspension of dimethylformamide (10 ml) in 3-methyl-6- (2
-Fluorophenyl) -4,5,6,7-tetrahydroindole-
4-One (0.80 g) was added and the mixture was stirred at room temperature for 30 minutes. Methanesulfonyl chloride (0.41 g) in dimethylformamide (3 m
l) The solution was added and stirred at the same temperature for 14 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 1-colorless crystals.
Methanesulfonyl-3-methyl-6- (2-fluorophenyl)-
4,5,6,7-Tetrahydroindole-4-one (0.47 g) was obtained. mp.130-134 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.00 (3H, s), 2.71 (1H, dd, J =
4, 16 Hz), 2.87 (1H, dd, J = 13, 16 Hz), 2.83-3.
26 (1H, m), 3.46 (1H, dd, J = 4, 18 Hz), 3.68- 3.9
4 (1H, m), 6.88 (1H, s), 7.02-7.35 (4H, m).

Reference Example 18 5- (2-chlorophenyl) cyclohexane-1,3-dione
(2.0 g), 3-aminopropan-2-ol (0.88 g), molecular sieves 4A (12 g), tetrahydrofuran (30 m
The mixture of l) was heated at reflux for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (40 ml), 2-bromomesitylene (1.8 g), tetrakistriphenylphosphine palladium (0.26 g),
Potassium carbonate (2.5 g) was added, and the mixture was stirred at 150 ° C for 5 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The residue was recrystallized from ethyl acetate-hexane to give 6- (2-chlorophenyl) -3.
-Methyl-4,5,6,7-tetrahydroindole-4-one (1.3
g) was obtained. mp. 201-209 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 2.54-2.86 (1H,
m), 2.90 (1H, dd, J = 11, 16 Hz), 3.1 (1H, dd, J =
5, 16 Hz), 3.94-4.15 (1H, m), 6.46 (1H, s), 7.14
-7.43 (4H, m), 8.27 (1H, br).

Reference Example 19 60% sodium hydride (0.18 g, washed three times with hexane)
6- (2-chlorophenyl) -3-methyl-4,5,6,7-tetrahydroindole-4-to a suspension of dimethylformamide (10 ml)
ON (1.0 g) was added and the mixture was stirred at room temperature for 30 minutes. , Methanesulfonyl chloride (0.53 g) in dimethylformamide (3 ml)
The solution was added and stirred at the same temperature for 9 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 6- (2-
(Chlorophenyl) -1-methanesulfonyl-3-methyl-4,5,6,
7-Tetrahydroindole-4-one (0.3 g) was obtained. mp. 167-168 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.3 (3H, s), 2.64-2.79 (1H, m),
2.82 (1H, dd, J = 11,16 Hz), 3.03 (1H, dd, J = 1
1, 18 Hz), 3.19 (3H, s), 3.49 (1H, dd, J = 4, 18 H
z), 3.93-4.11 (1H, m), 6.88 (1H, s), 7.12-7.46
(4H, m).

Reference Example 20 5-thienylcyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (1.0 gl), molecular sieves 4A (12 g), tetrahydrofuran (30 g) ml) of the mixture to 12
Heated to reflux for an hour. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (40 ml), and 2-bromomesitylene (2.1 g), tetrakistriphenylphosphinepalladium (0.30 g), potassium carbonate
(2.8 g) and stirred at 150 ° C. for 7 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give 3-methyl-6- (2-thienyl) -4,5,6,7-tetrahydroindole-4-one (0.72 g). Was. mp. 195-196 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.72 (1H, dd, J = 1
1, 16 Hz), 2.88 (1H, dd, J = 5, 16 Hz), 3.00 (1H,
dd, J = 11, 16 Hz), 3.20 (1H, dd, J = 5, 16 Hz), 3.
70-3.93 (1H, m), 6.46 (1H, s), 6.86-7.02 (2H,
m), 7.18 (1H, dd, J = 1 Hz), 8.18 (1H, br).

Reference Example 21 60% sodium hydride (0.11 g, washed three times with hexane)
To a suspension of dimethylformamide (10 ml) in 3-methyl-6- (2
-Thienyl) -4,5,6,7-tetrahydroindole-4-one
(0.60 g) was added and the mixture was stirred at room temperature for 30 minutes. A solution of methanesulfonyl chloride (0.36 g) in dimethylformamide (2 ml) was added, and the mixture was stirred at the same temperature for 14 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
The extract was washed with water and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to form 1-methanesulfonyl-3-methyl-6- (2 -Thienyl) -4,5,6,7-tetrahydroindole-4-one (0.28 g) was obtained. mp. 135-136 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 2.70-3.30 (3H,
m), 3.19 (3H, s), 3.61 (1H, dd, J = 5, 17 Hz), 3.7
6-3.93 (1H, m), 6.87 (1H, s), 6.84-6.98 (2H,
m), 7.19 (1H, dd, J = 1, 5 Hz).

Reference Example 22 60% sodium hydride (0.16 g, washed three times with hexane)
6-phenyl-4, suspension in dimethylformamide (10 ml)
5,6,7-Terahydroindole-4-one (0.8 g) was added, and the mixture was stirred at room temperature for 30 minutes. p-Toluenesulfonyl chloride (0.76
g) was added and stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hex
ne), and as colorless crystals 1- (4-methylphenyl) sulfonyl-6-phenyl-4,5,6,7-tetrahydroindole-4
-On (1.2 g) was obtained. mp. 118-120 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.68 (1H, s), 2.86
-3.07 (1H, m), 3.36 -3.56 (2H, m), 6.66 (1H, d, J
= 3 Hz), 7.16-7.46 (8H, m), 7.73 (1H, d, J = 9 H
z).

Reference Example 23 5- (2-methylphenyl) cyclohexane-1,3-dione (1.0
g), acetic acid (0.27 g), dimethylaminopyridine (0.60 g)
To a solution of the above in dimethylformamide (45 ml) was added dicyclohexylcarbodiimide (1.0 g), and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with an aqueous potassium hydrogen sulfate solution, and the insoluble matter was filtered. 1N aqueous sodium hydroxide was added, the aqueous layer was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to obtain 2- (1-hydroxyethylidene) -5- (2-methylphenyl) cyclohexane-1,3-dione (0.69 g) as colorless crystals. Was. mp 78-81 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 2.55-2.99 (4H,
m), 2.66 (3H, s), 3.46 -3.67 (1H, m), 3.71-3.77
(1H, m), 7.10-7.32 (4H, m).

Reference Example 24 2- (1-hydroxyethylidene) -5- (2-methylphenyl) cyclohexane-1,3-dione (0.45 g), hydrazine hydrate
A solution of (0.1 g) in ethanol (10 ml) was heated to reflux for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 3-methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydroindazol-4-one as colorless crystals.
(0.40 g) was obtained. mp. 205-207 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 2.59 (3H, s), 2.5-
2.83 (2H, m), 2.96 (1H, dd, J = 11, 16 Hz), 3.1
(1H, dd, J = 5, 16 Hz), 3.61-3.80 (1H, m), 7.17-
7.34 (5H, m).

Reference Example 25 5- (2-chlorophenyl) cyclohexane-1,3-dione (1.5
g), acetic acid (0.73 g), dimethylaminopyridine (0.12 g)
To a solution of the above in dimethylformamide (65 ml) was added dicyclohexylcarbodiimide (1.5 g), and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give 2- (1
-Hydroxyethylidene) -5- (2-chlorophenyl) cyclohexane-1,3-dione (1.4 g) was obtained. mp. 100-101 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.66 (3H, s), 2.53-3.04 (4H,
m), 3.76-3.95 (1H, m), 7.17-7.45 (5H, m).

Reference Example 26 2- (1-hydroxyethylidene) -5- (2-chlorophenyl) cyclohexane-1,3-dione (0.31 g), hydrazine hydrate
(0.065 g) in ethanol (10 ml) was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 6- (2-chlorophenyl) as colorless crystals.
-3-methyl-4,5,6,7-tetrahydroindazol-4-one
(0.26 g) was obtained. mp. 168-170 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.59 (3H, s), 2.6-2.8 (2H, m),
2.94 (1H, dd, J = 11,16 Hz), 3.22 (1H, dd, J = 4,
16 Hz), 3.90-4.06 (1H, m), 7.07-7.43 (4H, m).

Reference Example 27 5- (2-methoxyphenyl) -1,3-cyclohexanedione (2.
0 g), acetic acid (0.99 g), dimethylaminopyridine (1.7 g)
To a solution of the above in dimethylformamide (100 ml) was added dicyclohexylcarbodiimide (2.5 g), and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue.
The extract was washed successively with an aqueous solution of potassium hydrogen sulfate and water. 1N aqueous sodium hydroxide was added, the aqueous layer was neutralized with 1 hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
Dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from diisopropyl ether-hexane to give 2-acetyl-5- (2-methoxyphenyl) cyclohexane-1,3-dione (2.0 g) as colorless crystals. mp 65-66 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.53-3.06 (4H, m), 2.65 (3H,
s), 3.61-3.80 (1H, m), 3.84 (3H, m), 6.84-7.03
(2H, m), 7.06-7.18 (2H, m), 7.20-7.40 (2H, m).

Reference Example 28 2-acetyl-5- (2-methoxyphenyl) cyclohexane-1,
A solution of 3-dione (0.10 g) and hydrazine hydrate (0.21 g) in ethanol (20 ml) was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 6- (2-methoxyphenyl) -3-methyl-4,5,6, as colorless crystals.
7-Tetrahydroindazol-4-one (0.77 g) was obtained. mp.183-185 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.57 (3H, s), 2.69 (1H, dd, J =
5, 17 Hz), 2.82 (1H, dd, J = 11, 13 Hz), 3.01 (1H,
dd, J = 11, 16 Hz), 3.14 (1H, dd, J = 5, 16Hz),
3.74-3.94 (1H, m), 3.82 (3H, s), 6.86-7.0 (2H,
m), 7.17-7.31 (2H, m).

Reference Example 29 6- (2-methoxyphenyl) -3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.28 g), lithium iodide (0.4%)
A mixture of 4 g) and collidine (0.79 g) was heated under reflux for 5 hours. Collidine was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from acetone-hexane to give 6- (2-hydroxyphenyl) -3-methyl- as colorless crystals. 4,5,6,7-
Tetrahydroindazol-4-one (0.05 g) was obtained. mp. 252-255 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 2.69 (1H, dd, J =
4, 17 Hz), 2.89 (1H, dd, J = 12, 17 Hz), 3.02-3.
07 (4H, m), 3.33-3.56 (2H, br), 3.70-3.88 (1H,
m), 6.77-6.88 (2H, m), 7.05-7.19 (2H, m).

Reference Example 30 5- (2-chlorophenyl) cyclohexane-1,3-dione (1.0
g), propionic acid (0.60 g), dimethylaminopyridine
To a solution of (0.82 g) in dimethylformamide (30 ml) was added dicyclohexylcarbodiimide (1.2 g), and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed sequentially with 1N hydrochloric acid and water. 1N aqueous sodium hydroxide was added, and the aqueous layer was washed with diethyl ether and washed with 1N
Neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was recrystallized from diisopropyl ether-hexane to give 5- (2-chlorophenyl) -2 as colorless crystals.
-Propionylcyclohexane-1,3-dione (0.67 g) was obtained. mp 63-64 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7 Hz), 1.50 (1H,
br), 2.57 (1H, dd, J = 12, 16 Hz), 2.67 (1H, dd, J
= 2, 5 Hz), 2.68-2.96 (2H, m), 3.02 (2H, q, J =
7 Hz), 3.66 (1H, m), 6.97-7.48 (4H, m).

Reference Example 31 5- (2-chlorophenyl) -2-propionylcyclohexane-
A solution of 1,3-dione (0.6 g) and hydrazine hydrate (0.12 g) in ethanol (20 ml) was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane.
6- (2-chlorophenyl) -3-ethyl-4,5,6, as colorless crystals
7-Tetrahydroindazol-4-one (0.47 g) was obtained. mp. 180-181 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7 Hz), 2.74 (1H,
s), 2.78 (1H, s), 2.94 (1H, dd, J = 11, 16 Hz),
3.01 (2H, q, J = 7 Hz), 3.22 (1H, dd, J = 5,16 H
z), 3.86-4.06 (1H, m), 7.16-7.37 (3H, m), 7.41
(1H, dd, J = 2, 7Hz).

Reference Example 32 60% sodium hydride (0.22 g, washed three times with hexane)
To the mixture was added ethanol (30 ml). 5-phenylcyclohexane-1,3-dione (1.0 g) followed by chloroacetone (0.49
g) was added at 0 ° C., and the mixture was stirred at room temperature for 20 minutes and refluxed for 13 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g) as colorless crystals. Was. mp.104-106 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.60-2.86 (2H,
m), 2.92-3.23 (2H, m), 3.42-3.64 (1H, m), 7.11
(1H, s), 7.16-7.48 (5H, m).

Reference Example 33 5- (3-bromophenyl) cyclohexane-1,3-
DMF of dione (mp 182-183 ° C .; 1.34 g)
(20 ml) solution in sodium methoxide (0.30
g) was added, and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere.
Chloroacetone (0.45 ml) was added, and the mixture was stirred at 90 ° C. for 2 hours. Then, potassium carbonate (0.69 g) was added, and the mixture was stirred at 150 ° C. overnight (13 hours). After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, purified by elution with ethyl acetate / hexane, and purified by 6- (3-bromophenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g). ) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, d, J = 1.4H)
z), 2.72 (2H, d, J = 8.4 Hz), 2.9
8 (1H, dd, J = 11.0 & 17.0 Hz);
13 (1H, dd, J = 5.4 & 17.0 Hz);
49 (1H, m), 7.12 (1H, s), 7.20-
7.44 (4H, m).

Reference Example 34 60% sodium hydride (0.44 g, washed three times with hexane)
Was suspended in dimethylformamide (10 ml) and then 5-
(4-methylphenyl) cyclohexane-1,3-dione (2.0
g) and chloroacetone (0.92 g) were added at room temperature for 1 hour
Stir at 13 ° C for 13 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from hexane to give 3-methyl-6- (4-methylphenyl) -4,5 as colorless crystals. , 6,7-Tetrahydrobenzofuran-4-one (0.51 g) was obtained. mp.113-114 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 2.35 (3H, s), 2.60
-2.76 (2H, m), 2.99 (1H, dd, J = 11, 17 Hz), 3.13
(1H, dd, J = 6, 17 Hz), 3.40-3.60 (1H, m), 7.04
-7.30 (4H, m), 7.11 (1H, s).

Reference Example 35 5- (4-fluorophenyl) cyclohexane-1,3
-Dione (mp 175-176 ° C; 1.03 g) in a solution of ethanol (10 ml) in sodium ethoxide (0.
37 g), and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere. Chloroacetone (0.45ml) DMF (10m
1) After adding the solution, the mixture was stirred at 100 ° C. overnight (13 hours). After air-cooling the reaction solution, it was concentrated under reduced pressure.
Ethyl acetate was added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, purified by elution with ethyl acetate / hexane, and purified by 6- (4-fluorophenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.12 g). ) Got. mp 81-82 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, d, J = 1.2H)
z), 2.71 (2H, d, J = 8.6 Hz), 2.9
7 (1H, dd, J = 10.6 & 16.8 Hz);
13 (1H, dd, J = 5.4 & 17.0 Hz);
52 (1H, m), 7.04 (2H, t, J = 8.6H)
z), 7.12 (1H, s), 7.26 (2H, dd,
J = 5.2 & 8.6 Hz).

Reference Example 36 60% sodium hydride (0.44 g, washed three times with hexane)
Was suspended in dimethylformamide (10 ml), 5- (4-bromophenyl) cyclohexane-1,3-dione (2.6 g) was added, and chloroacetone (0.92 g) was added.
Stir at 13 ° C for 13 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from hexane to be 3-methyl-6- (4-bromophenyl) -4,5 as colorless crystals. , 6,7-Tetrahydrobenzofuran-4-one (0.35 g) was obtained. mp. 102-103 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.66-2.77 (2H,
m), 2.97 (1H, dd, J = 11, 17 Hz), 3.18 (1H, dd, J
= 12, 17 Hz), 3.40-3.62 (1H, m), 7.08-7.24 (2H,
m), 7.12 (1H, s), 7.43-7.55 (2H, m).

Reference Example 37 5- (4-methoxyphenyl) cyclohexane-1,3-dione (0.
A mixture of 95 g), dimethyl-1,2-propadien-1-ylsulfonium bromide (1.5 g), sodium ethoxide (0.31 g), and ethanol (10 ml) was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in toluene (20 ml), p-toluenesulfonic acid (0.85 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed successively with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (E
tOAc / hexane) to give 6- (4-methoxyphenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran as colorless crystals.
4-one (0.14 g) was obtained. mp. 82-83 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, d, J = 1 Hz), 2.60-2.
80 (2H, m), 2.93 (1H, dd, J = 11, 17 Hz), 3.09 (1H,
dd, J = 5, 17 Hz), 3.36-3.55 (1H, m), 3.79 (3
H, s), 6.83-6.94 (2H, m), 7.10 (1H, d, J = 1 H
z), 7.13-7.24 (2H, m).

Reference Example 38 60% sodium hydride (0.21 g, washed three times with hexane)
To the mixture was added ethanol (30 ml). 5- (2-methylphenyl)
Add cyclohexane-1,3-dione (1.0 g) and then chloroacetone (0.45 g) at 0 ° C, stir at room temperature for 20 minutes,
The mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 3-methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydrobenzofuran-4-one ( 0.18 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.36 (3H, s), 2.54
-2.83 (2H, m), 2.88 -3.15 (2H, m), 3.66-3.86 (1
H, m), 7.12 (1H, s), 7.16-7.33 (5H, m).

Reference Example 39 5- (2,5-dimethylphenyl) cyclohexane-
1,3-dione (mp194-195 ° C; 1.08g)
To a DMF (20 ml) solution was added 60% sodium hydride (0.22 g), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. After adding chloroacetone (0.45 ml), the mixture was stirred at 150 ° C. overnight (16 hours). After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, purified by elution with ethyl acetate / hexane, and purified by 6- (2,5-dimethylphenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0 .36 g). ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, d, J = 1.4H)
z), 2.30 (3H, s), 2.32 (3H, s),
2.60 (1H, dd, J = 4.4 & 16.4 Hz),
2.75 (1H, dd, J = 12.2 & 16.4H
z), 2.99 (1H, d, J = 2.0 Hz), 3.0
3 (1H, s), 3.73 (1H, m), 6.99 (2
H, d, J-7.6 Hz), 7.09 (1H, d, J =
7.6 Hz), 7.10 (1H, s), 7.11 (1
H, s).

Reference Example 40 5- (2-trifluoromethylphenyl) cyclohexane-1,3-dione (mp 198-199 ° C .; 1.28
g) in DMF (20 ml) was added with 60% sodium hydride (0.22 g), and the solution was added at room temperature under argon atmosphere at room temperature for 15 minutes.
For a minute. After adding chloroacetone (0.45 ml), the mixture was stirred at 150 ° C. overnight (14 hours). After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with ethyl acetate / hexane, and purified with 3-methyl-6.
-(2-trifluoromethylphenyl) -4,5,6
7-tetrahydrobenzofuran-4-one (0.28
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, d, J = 1.2H)
z), 2.65 (1H, dd, J = 4.8 & 16.6H
z), 2.80 (1H, dd, J = 12.2 & 16.4)
Hz), 2.96-3.18 (2H, m), 3.98
(1H, m), 7.13 (1H, s), 7.40 (1
H, m), 7.59 (2H, d, J = 3.6 Hz),
7.69 (1H, d, J = 8.0 Hz).

Reference Example 41 5- (2-fluorophenyl) cyclohexane-1,3
-DM of dione (mp 180-181 ° C; 1.03g).
F (20 ml) solution in 60% sodium hydride (0.2
2 g), and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere. After adding chloroacetone (0.45 ml), 15
Stirred at 0 ° C. overnight (14 hours). The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
-(2-Fluorophenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.2
2 g) were obtained. mp 71-72 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, d, J = 1.0H)
z), 2.69 (1H, dd, J = 4.4 & 16.2H
z), 2.85 (1H, dd, J = 11.8 & 16.2)
Hz), 2.98-3.22 (2H, m), 3.82
(1H, m), 7.03-7.17 (2H, m), 7.
12 (1H, s), 7.22-7.31 (2H, m).

Reference Example 42 60% sodium hydride (0.39 g, washed three times with hexane)
Was suspended in dimethylformamide (10 ml), and 5- (2,4-difluorophenyl) cyclohexane-1,3-dione (2.0
g) and then chloroacetone (0.83 g) were added, and the mixture was stirred at room temperature for 1 hour and at 150 ° C. for 12 hours. The solvent is distilled off under reduced pressure,
The residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexan
e), the obtained crystals were recrystallized from hexane, and as colorless crystals 6- (2,4-difluorophenyl) -3-methyl-4,5,
6,7-Tetrahydrobenzofuran-4-one (0.13 g) was obtained. mp.101-102 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, d, J = 1 Hz), 2.67 (1H,
dd, J = 5, 16 Hz), 2.81 (1H, dd, J = 11, 16 Hz),
2.92-3.23 (2H, m), 3.66-3.88 (1H, m), 6.76-
6.92 (2H, m), 7.11 (1H, d, J = 1 Hz), 7.14-7.30
(2H, m).

Reference Example 43 5- (2-chlorophenyl) cyclohexane-1,3-
DMF of dione (mp157-158 ° C; 1.11 g)
(20 ml) solution containing 60% sodium hydride (0.22
g) was added, and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere.
After adding chloroacetone (0.45 ml),
For 15 hours. The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate.
The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
(2-chlorophenyl) -3-methyl-4,5,6,7
-Tetrahydrobenzofuran-4-one (0.35 g)
I got ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.73
(1H, s), 2.77 (1H, d, J = 5.2H
z), 2.97 (1H, dd, J = 10.6 & 17.0)
Hz), 3.20 (1H, dd, J = 5.2 & 16.8)
Hz), 4.05 (1H, m), 7.12 (1H,
s), 7.20-7.34 (3H, m), 7.41 (1
H, dd, J = 1.2 & 7.0 Hz).

Reference Example 44 5- (2,3-dichlorophenyl) cyclohexane-
1,3-dione (mp 205-206 ° C; 1.29 g)
Sodium ethoxide (0.37 g) was added to a solution of the above in ethanol (10 ml), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. Chloroacetone (0.45ml) DMF
(10 ml) After the solution was added, the mixture was stirred at 100 ° C. overnight (13 hours). The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, purified by elution with ethyl acetate / hexane, and purified by 6- (2,3-dichlorophenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0. 18 g) were obtained. mp 116-117 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, d, J = 1.4H)
z), 2.72 (1H, s), 2.76 (1H, d, J
= 2.4 Hz), 2.95 (1H, dd, J = 10.6)
& 16.8 Hz), 3.21 (1H, dd, J = 5.0)
& 17.0Hz), 4.10 (1H, m), 7.13
(1H, s), 7.22-7.28 (2H, m), 7.
39-7.43 (1H, m).

Reference Example 45 5- (2,6-dichlorophenyl) cyclohexane-
1,3-dione (mp 203-204 ° C; 1.29 g)
To a DMF (20 ml) solution was added 60% sodium hydride (0.22 g), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. After adding chloroacetone (0.45 ml), the mixture was stirred at 150 ° C. overnight (15 hours). The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, purified by elution with ethyl acetate / hexane, and purified with 6- (2,6-dichlorophenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0. 42 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.47
(1H, dd, J = 4.4 & 16.8 Hz), 2.89
(1H, dd, J = 5.8 & 17.2 Hz), 3.61
(1H, dd, J = 14.0 & 16.8 Hz), 3.8
7 (1H, dd, J = 12.4 & 17.2 Hz);
54 (1H, m), 7.13 (1H, s), 7.15
(1H, dt, J = 1.0 & 8.0 Hz), 7.28-
7.39 (2H, m).

Reference Example 46 5- (2-bromophenyl) cyclohexane-1,3-
DMF of dione (mp174-175 ° C; 1.07g)
(15 ml) solution in 60% sodium hydride (0.18
g) was added, and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere.
After adding chloroacetone (0.36 ml),
For overnight (13 hours). The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate.
The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
(2-bromophenyl) -3-methyl-4,5,6,7
-Tetrahydrobenzofuran-4-one (0.28 g)
I got ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.72
(1H, s), 2.76 (1H, d, J = 2.4H
z), 2.94 (1H, dd, J = 10.8 & 17.2)
Hz), 3.20 (1H, dd, J = 5.2 & 17.0)
Hz), 4.02 (1H, m), 7.09-7.17.
(1H, m), 7.13 (1H, s), 7.29-7.
35 (2H, m), 7.59 (1H, d, J = 8.4H
z).

Reference Example 47 5- (2-methoxyphenyl) cyclohexane-1,3
-DM of dione (mp 144-145 ° C; 1.09 g).
F (15 ml) solution in 60% sodium hydride (0.2
2 g), and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere. After adding chloroacetone (0.45 ml), 15
Stirred at 0 ° C. overnight (14 hours). The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
-(2-methoxyphenyl) -3-methyl-4,5,
6,7-tetrahydrobenzofuran-4-one (0.2
0 g). mp 79-80 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, d, J = 1.2H)
z), 2.66 (1H, dd, J = 4.2 & 16.4H
z), 2.84 (1H, dd, J = 12.0 & 16.4)
Hz), 3.05 (1H, d, J = 3.4 Hz), 3.
09 (1H, s), 3.83 (3H, s), 3.88
(1H, m), 6.90 (1H, d, J = 8.2H
z), 6.95 (1H, dt, J = 1.2 & 7.6H)
z), 7.10 (1H, d, J = 1.4 Hz), 7.1
8-7.29 (2H, m).

Reference Example 48 5- (2-furyl) cyclohexane-1,3-dione (mp 155-156 ° C .; 0.89 g) in DMF (18
ml) solution, 60% sodium hydride (0.22 g) was added, and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. After adding chloroacetone (0.45 ml), the mixture was stirred at 150 ° C. overnight (15 hours). The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate),
Concentrated under reduced pressure. The residue was subjected to silica gel chromatography,
Purification by elution with ethyl acetate / hexane gave 6- (2-furyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.23 g). mp 60-61 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, d, J = 1.4H)
z), 2.70 (1H, dd, J = 10.2 & 16.4)
Hz), 2.84 (1H, dd, J = 5.0 & 16.8)
Hz), 3.05 (1H, dd, J = 9.6 & 17.2).
Hz), 3.24 (1H, dd, J = 5.4 & 17.2)
Hz), 3.63 (1H, m), 6.09 (1H, d,
J = 3.2 Hz), 6.31 (1H, dd, J = 1.8)
& 3.4 Hz), 7.11 (1H, s), 7.35 (1
H, d, J = 1.8 Hz).

Reference Example 49 60% sodium hydride (0.44 g, washed three times with hexane)
Was suspended in dimethylformamide (10 ml), 5- (2-thienyl) cyclohexane-1,3-dione (1.9 g) and then chloroacetone (0.92 g) were added, and the mixture was added at room temperature for 1 hour and at 150 ° C. for 13 hours. Stirred. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from hexane to give 3-methyl-6- (2-thienyl) -4,5, as colorless crystals. 6,7-tetrahydrobenzofuran
-4-One (0.34 g) was obtained. mp. 81-82 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 2.75 (1H, dd, J = 1
1, 17 Hz), 2.90 (1H, dd, J = 4, 17 Hz), 3.05 (1H,
dd, J = 10, 17 Hz), 3.30 (1H, dd, J = 5, 17Hz), 3.
76-3.93 (1H, m), 6.87-7.03 (2H, m), 7.12 (1H, m
s), 7.21 (1H, dd, J = 1, 5 Hz)

Reference Example 50 5- (5-methyl-2-thienyl) cyclohexane-
1,3-dione (mp178-179 ° C; 1.04g)
Sodium ethoxide (0.37 g) was added to a solution of the above in ethanol (15 ml), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. After adding chloroacetone (0.45 ml), the mixture was stirred at 100 ° C. for 1 hour. The reaction solution was air-cooled, concentrated under reduced pressure, and mesitylene (15 ml) was added to the residue.
Stirred at 0 ° C. for 4 hours. The reaction solution was air-cooled, concentrated under reduced pressure, and the residue was extracted with ice water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate),
Concentrated under reduced pressure. The residue was subjected to silica gel chromatography,
Purification was performed by elution with ethyl acetate / hexane, and 6- (5-methyl-2-thienyl) -3-methyl-4,5,6,7-
Tetrahydrobenzofuran-4-one (0.18 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.45
(3H, s), 2.69 (1H, dd, J = 11.0 &
16.4 Hz), 2.85 (1 H, dd, J = 4.4 &
16.4 Hz), 3.00 (1H, dd, J = 10.4)
& 17.2 Hz), 3.24 (1H, dd, J = 5.0)
& 17.0Hz), 3.73 (1H, m), 6.59
(1H, d, J = 3.2 Hz), 6.67 (1H, d,
J = 3.4 Hz), 7.11 (1H, s).

Reference Example 51 5-phenylcyclohexane-1,3-dione (0.9
4g) in a solution of DMF (20 ml) in potassium carbonate (0.4 g).
76 g) and bromomethyltrifluoromethyl ketone (1.05 g) were added, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. Then, potassium carbonate (0.69 g) was added,
Stirred at 150 ° C. overnight (13 hours). After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane.
Trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g) was obtained. mp 107-108 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.80 (1 H, d, J = 2.4 H)
z), 2.85 (1H, s), 3.09 (1H, dd,
J = 10.8 & 17.2 Hz), 3.23 (1H, d
d, J = 5.4 & 17.2 Hz), 3.59 (1H,
m), 7.26-7.44 (5H, m), 7.72 (1
H, d, J = 1.4 Hz).

Reference Example 52 5- (4-Fluorophenyl) cyclohexane-1,3
To a solution of -dione (1.03 g) in ethanol (20 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. Bromomethyltrifluoromethylketone (1.05 g) was added, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure, and DMF (20 ml) and potassium carbonate (0.6
9 g), and the mixture was added at 150 ° C. under an argon atmosphere overnight (15 g).
H). After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, purified by elution with ethyl acetate / hexane, and purified with 6- (4-fluorophenyl) -3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0 .27 g). mp 105-106 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.76 (1 H, d, J = 2.2 H)
z), 2.80 (1H, s), 3.04 (1H, dd,
J = 11.0 & 17.2 Hz), 3.21 (1H, d
d, J = 5.6 & 17.2 Hz), 3.57 (1H,
m), 7.05 (2H, t, J = 8.8 Hz), 7.2
5 (2H, dd, J = 5.8 & 8.8 Hz), 7.73
(1H, s).

Reference Example 53 5- (2-methylphenyl) cyclohexane-1,3-dione (2.0
g), 1-bromo-3,3,3-trifluoroacetone (1.9 g),
A mixture of potassium carbonate (2.7 g) and dimethylformamide (30 ml) was stirred at room temperature for 2 hours and at 150 ° C. for 12 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / hexane) .The obtained crystals were recrystallized from isopropyl ether-hexane to give 3-trifluoromethyl-6- (2-methyl Phenyl) -4,5,6,7-tetrahydrobenzofuran-4-one (0.26 g) was obtained. mp. 105-107 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.66-2.90 (2H,
m), 2.97-3.19 (2H, m), 3.73-3.92 (1H, m), 7.18
-7.33 (4H, m), 7.74 (1H, d, J = 2 Hz).

Reference Example 54 5- (2-bromophenyl) cyclohexane-1,3-
Sodium methoxide (0.30 g) was added to a solution of dione (1.34 g) in DMF (20 ml), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. Bromomethyltrifluoromethylketone (1.05 g) was added, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. Then potassium carbonate (0.69
g) was added and the mixture was stirred at 150 ° C. overnight (15 hours) under an argon atmosphere. After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with ethyl acetate / hexane, and purified by 6- (2-bromophenyl) -3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0. .29 g). ¹ H-NMR (CDCl ₃ ) δ: 2.82 (2H, d, J = 8.4H)
z), 3.02 (1H, dd, J = 10.8 & 17.4)
Hz), 3.30 (1H, dd, J = 5.0 & 17.2)
Hz), 4.07 (1H, m), 7.12-7.21
(1H, m), 7.26-7.40 (2H, m), 7.
62 (1H, d, J = 8.2 Hz), 7.74 (1H,
d, J = 1.4 Hz).

Reference Example 55 Sodium ethoxide (0.37 g) was added to a solution of 5- (2-furyl) cyclohexane-1,3-dione (0.89 g) in ethanol (15 ml), and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere. Stirred. Bromomethyltrifluoromethylketone (1.05 g) was added, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure, DMF (20 ml) and potassium carbonate (0.69 g) were added to the residue, and the mixture was stirred at 150 ° C overnight (15 hours) under an argon atmosphere. After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
6- (2-furyl) -3-trifluoromethyl-4,
5,6,7-Tetrahydrobenzofuran-4-one (0.23 g) was obtained. mp 94-95 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.79 (1 H, dd, J = 10.
4 & 16.6 Hz), 2.93 (1H, dd, J = 4.
6 & 17.2 Hz), 3.14 (1H, dd, J = 9.
0 & 17.2 Hz), 3.33 (1H, dd, J = 5.
0 & 17.6Hz), 3.70 (1H, m), 6.12
(1H, d, J = 3.2 Hz), 6.32 (1H, d
d, J = 1.8 & 3.2 Hz), 7.36 (1H, d,
J = 1.8 Hz), 7.72 (1H, d, J = 1.4H)
z).

Reference Example 56 5-phenylcyclohexane-1,3-dione (0.9
To a solution of 4 g) in ethanol (15 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred at room temperature under an argon atmosphere for 15 minutes. Ethyl bromopyruvate (0.83m
l) was added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere.
The reaction solution was concentrated under reduced pressure, and the residue was xylene (15 ml).
Was added and stirred at 150 ° C. for 4 hours under an argon atmosphere.
After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction.
The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane.
Ethoxycarbonyl-6-phenyl-4,5,6,7-
Tetrahydrobenzofuran-4-one (1.04 g) was obtained. mp 103-104 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.2H)
z), 2.81 (1H, d, J = 1.6 Hz), 2.8
5 (1H, s), 3.08 (1H, dd, J = 10.8)
& 17.0Hz), 3.23 (1H, dd, J = 5.2)
& 17.2 Hz), 3.57 (1H, m), 4.36
(2H, q, J = 7.2 Hz), 7.27-7.41
(5H, m), 7.93 (1H, s).

Reference Example 57 5- (2-chlorophenyl) cyclohexane-1,3-
Sodium ethoxide (0.75 g) was added to a solution of dione (2.23 g) in ethanol (30 ml), and the mixture was stirred at room temperature for 15 minutes under an argon atmosphere. Ethyl bromopyruvate (1.66 ml) was added, and the mixture was added at room temperature under an argon atmosphere.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and DMF was added to the residue.
(30 ml) and potassium carbonate (1.38 g), and the mixture was stirred at 150 ° C. overnight (14 hours) under an argon atmosphere.
After the reaction solution was air-cooled, ice water and ethyl acetate were added for extraction.
The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
(2-chlorophenyl) -3-ethoxycarbonyl-
4,5,6,7-Tetrahydrobenzofuran-4-one (0.14 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2H)
z), 2.82 (1H, s), 2.86 (1H, d, J
= 1.4 Hz), 3.03 (1H, dd, J = 10.6)
& 17.2 Hz), 3.29 (1H, dd, J = 5.2)
& 17.2 Hz), 4.07 (1H, m), 4.36
(2H, q, J = 7.2 Hz), 7.20-7.33
(3H, m), 7.42 (1H, dd, J = 2.2 &
6.4 Hz), 7.94 (1 H, s).

REFERENCE EXAMPLE 58 2-butyn-1-ol (75.4 g) in tetrahydrofuran (800 m
l) To the solution was added methanesulfonyl chloride (129.4 g),
Then, triethylamine (130.6 g) was added dropwise. The mixture was stirred at room temperature for 19 hours, and the solvent was distilled off under reduced pressure. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was treated with dimethylformamide (2
000 ml), potassium phthalimide (166.6 g) was added, and the mixture was stirred at 60 ° C for 19 hours. The solvent is distilled off under reduced pressure,
Water was added. The precipitated crystals are washed with water and ethyl acetate,
Dried. Ethanol (1500 ml) and hydrazine-hydrate (57.7 g) were added to the obtained crystals, and the mixture was heated under reflux for 2.5 hours. After cooling, concentrated hydrochloric acid (140 ml) was added to make it acidic, and the insoluble matter was filtered off. The insolubles were washed with water, and the washing was combined with the filtrate and concentrated. Ethanol was added to the residue, insolubles were removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-ethanol to give 1-amino-2-butyne hydrochloride (75.0 g) as colorless crystals. mp 205 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H, t, J = 3 Hz), 3.63 (2H,
q, J = 3 Hz), 8.46 (3H, br).

Reference Example 59 5- (2-methylphenyl) cyclohexane-1,3-dione (1.5
g), 1-amino-2-butyne hydrochloride (0.86 g), molecular
Triethylamine (0.74 g) was added to a mixture of Sieves 4A (2 g) and tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 hour and then heated to reflux for 17 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was stirred at 220 ° C. for 4 hours. Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 4-methyl-7- (2-methylphenyl)-as colorless crystals. 5,6,7,8-Tetrahydroquinolin-5-one (0.52 g) was obtained. mp.104-106 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s), 2.70 (3H, s), 2.75
-3.03 (2H, m), 3.17 -3.48 (2H, m), 3.54-3.77 (1
H, m), 7.08 (1H, d, J = 5 Hz), 7.10-7.34 (4H, m)
8.47 (1H, d, J = 5 Hz).

Reference Example 60 5- (2,5-dimethylphenyl) cyclohexane-1,3-dione
(1.73 g) and ammonium acetate (1.93 g) in ethanol (20
under reflux for 14 hours. The reaction solution was concentrated under reduced pressure, water (20 ml) was added to the residue, and the crystals were collected by filtration. The crystals are washed with water, then with toluene, dried and dried with 1-amino-5
-(2,5-dimethylphenyl) cyclohexen-3-one (1.72
g) was obtained as pale yellow crystals. mp. 169-170 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.11 (1H, d), 2.24 (3H, s), 2.2
5 (3H, s), 2.39 (2H, m), 2.51 (1H, m), 3.29 (1H,
m), 5.01 (1H, s), 6.80 (2H, broad), 6.92 (1H, d),
7.04 (1H, d), 7.14 (1H, s).

Reference Example 61 1-amino-5- (2,5-dimethylphenyl) cyclohexene-3-
(1.7 g) was dissolved in a mixed solvent of ethanol (35 ml) and toluene (90 ml), and 3-oxobutyraldehyde dimethyl acetal (2.66 g) and granular potassium hydroxide (440 mg) were added. (Bath temperature). 30 minutes, 1 hour, 1 hour
After 30 minutes, granular potassium hydroxide (90 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and ethyl acetate (40 m
l) and water (20 ml) were added, shaken and separated. The ethyl acetate layer was washed with brine, and ethyl acetate was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc / he
xane), and purified by elution with ethyl acetate / hexane.7- (2,5-dimethylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.37 g) Was obtained as colorless crystals. mp. 95-96 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 2.35 (3H, s), 2.72
(3H, s), 2.91 (2H, m), 3.35 (2H, m), 3.66 (1H, m),
7.09 (4H, m), 8.50 (1H, d).

Reference Example 62 5- (2-Fluorophenyl) cyclohexane-1,3-dione (0.
98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) were added to triethylamine (0.48 g), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was heated under reflux for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was heated to 220 ° C for 6 hours. After cooling, ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane),
7- (2-fluorophenyl) -4-methyl-5,6,7, as an oil
8-Tetrahydroquinolin-5-one (0.35 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.83-3.08 (2H,
m), 3.29-3.46 (2H, m), 3.71-3.77 (1H, m), 7.02
-7.36 (5H, m), 8.49 (1H, d, J = 4 Hz).

Reference Example 63 5- (2,4-difluorophenyl) cyclohexane-1,3-dione (2.0 g), 1-amino-2-butyne hydrochloride (0.94 g), molecular sieves 4A (4 g), tetrahydrofuran (40 ml)
Triethylamine (0.90 g) was added to the mixture of
Stir for an hour and then heat to reflux for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Residue 5 hours 220
Stir at ℃. Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from isopropyl ether-hexane to give 7- (2,4-difluorophenyl)-as colorless crystals. Four-
Methyl-5,6,7,8-tetrahydroquinolin-5-one (0.47g)
I got mp. 106-107 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.78-3.04 (2H,
m), 3.46-3.52 (1H, m), 3.63-3.83 (1H, m), 6.75
-6.93 (2H, m), 7.10 (1H, d, J = 5 Hz), 7.12- 7.32
(1H, m), 8.49 (1H, d, J = 5 Hz).

Reference Example 64 5- (2-chlorophenyl) -1,3-cyclohexanedione (1.1
g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g), and tetrahydrofuran (20 ml) were added to triethylamine (0.48 g), and stirred at room temperature for 1 hour. Then, the mixture was heated under reflux for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was stirred for 4 hours at 220 ° C. Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 7- (2-chlorophenyl) -4-methyl-5 as colorless crystals. , 6,7,8-Tetrahydroquinolin-5-one (0.20 g) was obtained. mp. 97-98 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s), 2.84 (1H, dd, J = 1
3, 16 Hz), 3.02 (1H, ddd, J = 2, 4, 16 Hz), 3.30
(1H, dd, J = 12, 17 Hz), 3.48 (1H, ddd, J = 2, 4,
17 Hz), 3.88-4.07 (1H, m), 7.11 (1H, d, J = 5 H
z), 7.16-7.34 (4H, m), 8.50 (1H, d, J = 5 Hz).

Reference Example 65 1-Amino-5- (2-chlorophenyl) cyclohexen-3-one
(2.7 g) in ethanol (50 ml) and toluene (150 ml) was dissolved in acetylacetaldehyde dimethyl acetal (4.0 ml).
g) and 85% potassium hydroxide (0.67 g) were added, and the mixture was heated under reflux. 85% potassium hydroxide (0.14 g) is added 3 times at 30 minute intervals,
Thereafter, the mixture was further refluxed for 1 hour. The solvent is distilled off under reduced pressure,
Ethyl acetate was added to the residue, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc-hexane).
7- (2-chlorophenyl) -4-methyl-5,6,
7,8-Tetrahydroquinolin-5-one (2.5 g) was obtained. The melting point and NMR data were identical to those of the compound obtained in Reference Example 64.

Reference Example 66 5- (2,3-dichlorophenyl) cyclohexane-1,3-dione
(1.8 g) and ammonium acetate (1.7 g) in ethanol (20 m
Heated to reflux in l) for 14 hours. The reaction was concentrated under reduced pressure,
Water (20 ml) was added to the residue, and the crystals were collected by filtration. The crystals were washed with water, then with toluene, dried and dried to give 1-amino-5-
(2,3-Dichlorophenyl) cyclohexen-3-one (1.6 g)
Was obtained as pale yellow crystals. 209-210 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (1H, dd),
2.61 (3H, m), 3.67 (1H,
m), 5.03 (1H, s), 6.90 (2
H, broad), 7.37 (1H, t),
7.48 (1H, dd), 7.55 (1H, dd)
dd).

Reference Example 67 1-amino-5- (2,3-dichlorophenyl) cyclohexene-
3-one (1.5 g) in ethanol (30 ml) and toluene (90 ml)
And 3-oxobutyraldehyde dimethyl acetal (2 g) and granular potassium hydroxide (330 mg) were added thereto, followed by stirring at 115 ° C. (bath temperature). 30 minutes, 1 hour, 1 hour
After 30 minutes, granular potassium hydroxide (70 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. After cooling the reaction solution, it was concentrated under reduced pressure, and the residue was ethyl acetate (50 ml),
Water (20 ml) was added, shaken and separated. The ethyl acetate layer was washed with brine, and ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexan
e) and purified by elution with ethyl acetate / hexane,
(2,3-Dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.05 g) was obtained as colorless crystals. mp.123-124 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.72 (3H, s), 2.81 (1H, dd), 3.03
(1H, dd), 3.29 (1H, dd), 3.49 (1H, ddd), 4.03 (1
H, m), 7.13 (1H, d), 7.24 (2H, m), 7.43 (1H, m), 8.
51 (1H, d).

Reference Example 68 5- (2,6-dichlorophenyl) cyclohexane-1,3-dione
(1.8 g) and ammonium acetate (1.7 g) in ethanol (20 m
Heated to reflux in l) for 60 hours. The reaction was concentrated under reduced pressure,
Ethyl acetate (80 ml) and water (20 ml) were added to the residue, shaken and separated. The ethyl acetate layer was washed with water (3 times with 10 ml) and concentrated under reduced pressure. Ethyl acetate (8 ml) was added to the residue, and the precipitated crystals were collected by filtration and dried to give 1-amino-5- (2,6-dichlorophenyl) cyclohexen-3-one (1.43 g) as pale yellow crystals. Obtained. mp. 216-217 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.00 (1H, dd),
2.24 (1H, dd), 3.05 (1H, dd)
dd), 3.28 (1H, dd), 4.14
(1H, m), 5.04 (1H, s),
6.87 (2H, broad), 7.32 (1
H, t), 7.47 (2H, m).

Reference Example 69 1-amino-5- (2,6-dichlorophenyl) cyclohexene-
3-one (1.25 g) in ethanol (23 ml) and toluene (70 ml)
And 3-oxobutyraldehyde dimethyl acetal (1.84 g) and granular potassium hydroxide (303 mg) were added thereto, followed by stirring at 115 ° C. (bath temperature). After 30 minutes, 1 hour, and 1 hour and 30 minutes, granular potassium hydroxide (62 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. After cooling the reaction mixture, it was concentrated under reduced pressure.
l) and water (15 ml) were added, shaken and separated. The upper layer was washed with brine, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / hexane), and eluted with ethyl acetate / hexane. The eluate was concentrated under reduced pressure, the residue was dissolved in a mixed solvent of ether (4 ml) and ethanol (2 ml), concentrated hydrochloric acid (0.25 ml) was added, and the precipitated crystals were collected by filtration and mixed with the same mixed solvent. After washing and drying, 7- (2,6-dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (0.75 g) was obtained as colorless crystals. mp. 184-185 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.60 (1H, ddd), 2.79 (3H, s),
3.35 (1H, ddd), 3.74 (1H, dd), 4.19 (1H, dd), 4.53
(1H, m), 7.38 (1H, t), 7.54 (2H, d), 7.75 (1H,
d), 8.77 (1H, d).

Reference Example 70 5- (2-bromophenyl) cyclohexanedi-1,3-one (1.5
g), 1-amino-2-butyne hydrochloride (0.59 g) and tetrahydrofuran (30 ml) were added with triethylamine (0.57 g), and the mixture was stirred at room temperature for 1 hour and heated under reflux for 13 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Diphenyl ether was added to the residue, and the mixture was heated at 250 ° C. for 12 hours. After cooling, diethyl ether was added, and the mixture was extracted with 1N hydrochloric acid. The aqueous layer was washed with diethyl ether, neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give crystals of 7- (2-bromophenyl) -4-methyl-
5,6,7,8-Tetrahydroquinolin-5-one (0.52 g) was obtained. mp. 106-107 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s), 2.82 (1H, dd, J = 1
3, 16 Hz), 3.03 (1H, ddd, J = 2, 4, 10 Hz), 3.28
(1H, dd, J = 12, 17 Hz), 3.49 (1H, dq, J = 2,4, 11
Hz), 3.86-4.06 (1H, m), 7.08-7.47 (4H, m), 7.
57-7.66 (1H, m), 8.50 (1H, d, J = 5 Hz).

Reference Example 71 5- (2-methoxyphenyl) -1,3-cyclohexanedione (1.
0 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular
Triethylamine (0.48 g) was added to a mixture of Sieves 4A (2 g) and tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 hour, and then heated and refluxed for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was heated to 220 ° C for 4 hours. After cooling, ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane),
7- (2-methoxyphenyl) -4-methyl-5,6,7, as an oil
8-Tetrahydroquinolin-5-one (0.4 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.75-3.05 (2H,
m), 3.23-3.48 (2H, m), 3.71-3.93 (1H, m), 3.83
(3H, s), 6.86 (2H, m), 7.07 (1H, d, J = 5 Hz), 7.1
8-7.32 (2H, m) 8.47 (1H, d, J = 5 Hz).

Reference Example 72 A solution of boron tribromide (0.96 g) in dichloromethane (30 ml) was added.
7- (2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.33 g) in dichloromethane at 78 ° C
(1 ml) solution was added dropwise. Gradually return to room temperature and leave at room temperature for 1.5
Stir for hours. Carefully, ice and aqueous sodium hydrogen carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtO
Ac / hexane) to give 7- (2-hydroxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one as colorless crystals
(0.23 g) was obtained. mp. 198-199 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.75 (3H, s), 2.86-3.27 (3H,
m), 3.65-3.96 (2H, m), 6.73-6.96 (2H, m), 7.01
-7.30 (5H, m) 7.18 (1H, d, J = 5 Hz), 8.51 (1H,
d, J = 5 Hz).

Reference Example 73 5- (2-furyl) cyclohexane-1,3-dione (1.78 g) and ammonium acetate (2.3 g) were heated under reflux in ethanol (35 ml) for 15 hours. The reaction solution was concentrated under reduced pressure, and water (30
ml) was added, and the crystals were collected by filtration. The crystals were washed with water, then with ethyl acetate and dried to give 1-amino-5- (2-furyl) cyclohexen-3-one (1.35 g) as pale yellow crystals. mp.144-145 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.31 (3H, m), 2.62 (1H, dd), 3.
29 (1H, m), 4.96 (1H, s), 6.12 (1H, d), 6.37 (1H,
m), 6.84 (2H, broad), 7.54 (1H, d).

Reference Example 74 1-amino-5- (2-furyl) cyclohexen-3-one (1.25 g)
Was dissolved in a mixed solvent of ethanol (30 ml) and toluene (90 ml), and 3-oxobutyraldehyde dimethyl acetal was dissolved.
(2.36 g) and granular potassium hydroxide (390 mg) were added at 115 ° C.
(Bath temperature). 30 minutes later, 1 hour later, 1 hour 30 minutes later,
Add granular potassium hydroxide (80 mg) to the reaction solution,
Thereafter, the mixture was stirred at the same temperature for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure. Ethyl acetate (50 ml) and water (15 ml) were added to the residue, shaken, and separated. The upper layer was washed with saturated saline,
Ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc / hexane), purified by elution with ethyl acetate / hexane, and purified with 7- (2-furyl) -4-methyl-5,6,7,8-tetrahydroquinoline-5. -One (1.0 g) was obtained as colorless crystals. mp. 70-71 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, s), 2.92 (1H, dd), 3.08
(1H, dd), 3.40 (1H, dd), 3.59 (2H, m), 6.08 (1H,
d), 6.31 (1H, dd), 7.08 (1H, d), 7.36 (1H, d), 8.4
9 (1H, d).

Reference Example 75 5- (2-thienyl) cyclohexane-1,3-dione (1.5 g), 1-
Triethylamine (0.78 g) was added to a mixture of amino-2-butyne hydrochloride (0.82 g), molecular sieves 4A (3 g), and tetrahydrofuran (30 ml), and the mixture was stirred at room temperature for 1 hour, and then heated under reflux for 12 hours. did. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. Diphenyl ether in the residue
(80 ml) and stirred at 250 ° C. for 6 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtO
Ac / hexane) and colorless crystals of 4-methyl-7- (2-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (0.67
g) was obtained. mp. 105-107 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.69 (3H, s), 2.90 (1H, dd, J = 1
1, 16 Hz), 3.14 (1H, ddd, J = 2, 4, 11 Hz), 3.37
(1H, dd, J = 11, 16 Hz), 3.61 (1H, ddd, J = 2, 4, 1
1 Hz), 3.69-3.88 (1H, m), 6.86-7.04 (2H, m),
7.09 (1H, d, J = 5 Hz), 7.21 (1H, dd, J = 1, 5 Hz),
8.49 (1H, d, J = 5 Hz).

Reference Example 76 5- (5-Methyl-2-thienyl) cyclohexane-1,3-dione
(4.16 g) and ammonium acetate (4.6 g) in ethanol (50 m
Heated to reflux in l) for 15 hours. The reaction was concentrated under reduced pressure,
Water (60 ml) was added to the residue, and the crystals were collected by filtration. The crystals were washed with water, then with toluene, dried and dried to give 1-amino-5-
(5-Methyl-2-thienyl) cyclohexen-3-one (3.37 g)
Was obtained as pale yellow crystals. mp. 172-173 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (6H, m), 2.61 (1H, dd), 3.
42 (1H, m), 4.98 (1H, s), 6.62 (1H, dd), 6.68 (1H,
d), 6.83 (2H, broad).

Reference Example 77 1-amino-5- (5-methyl-2-thienyl) cyclohexene-3-
(1.66 g) was dissolved in a mixed solvent of ethanol (30 ml) and toluene (90 ml), and 3-oxobutyraldehyde dimethyl acetal (2.6 g) and granular potassium hydroxide (430 mg) were added. (Bath temperature). 30 minutes, 1 hour, 1 hour
After 30 minutes, granular potassium hydroxide (80 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. After cooling the reaction mixture, the solvent was distilled off under reduced pressure.
ml) and water (10 ml) were added, shaken and separated. The upper layer was washed with brine and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc / hexane), eluted with ethyl acetate / hexane and purified to give 4-methyl-7- (5-
(Methyl-2-thienyl) -5,6,7,8-tetrahydroquinoline-5-
One (1.78 g) was obtained as a pale orange oil. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 2.68 (3H, s), 2.86
(1H, dd), 3.10 (1H, ddd), 3.33 (1H, dd), 3.53 (1H,
dd), 3.70 (1H, m), 6.60 (1H, dd), 6.67 (1H, d), 7.
08 (1H, d), 8.48 (1H, d).

Reference Example 78 5- (5-Chloro-2-thienyl) cyclohexane-1,3-dione
(2.2 g), 1-amino-2-butyne hydrochloride (1.0 g) and tetrahydrofuran (40 ml) in a mixture of triethylamine (0.96 g).
g) was added, and the mixture was stirred at room temperature for 1 hour, and then heated and refluxed for 12 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was heated to 250 ° C for 3.5 hours. After cooling, the mixture was subjected to silica gel column chromatography (EtOAc-hexane) to give 7- (5-chloro-2-thienyl) -4-methyl-5,6,7,8 as an oil.
-Tetrahydroquinolin-5-one (0.79 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, s), 2.84 (1H, dd, J = 1
1, 17 Hz), 3.08 (1H, dq, J = 2, 4, 10 Hz), 3.31 (1
H, dd, J = 11, 17 Hz), 3.47-3.77 (3H, m), 6.63-
6.8 (2H, m), 7.11 (1H, d, J = 5 Hz), 8.49 (1H, d,
J = 5 Hz).

Reference Example 79 5- (3-methyl-2-thienyl) -1,3-cyclohexanedione
(3.0 g), ammonium acetate (3.3 g) in ethanol (60 m
l) The solution was heated to reflux for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added. The precipitated crystals were collected by filtration and washed with water. Dried to give 1-amino-5- (3-methyl-2
-Thienyl) cyclohexen-3-one (2.7 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.39 (1H, dd, J = 1
2, 17 Hz), 2.46-2.75 (4H, m), 3.52-3.76 (1H,
m), 5.31 (1H, s), 5.71 (1H, br), 6.81 (1H, d, J = 5
Hz), 7.08 (1H, d, J = 5 Hz).

Reference Example 80 1-amino-5- (3-methyl-2-thienyl) cyclohexene-3-
Acetylacetaldehyde dimethyl acetal (4.3 g) in ethanol (50 ml), toluene (150 ml) solution
g) and 85% potassium hydroxide (0.71 g) were added, and the mixture was heated under reflux. 85% potassium hydroxide (0.15 g) is added 3 times at 30 minute intervals,
Thereafter, the mixture was further refluxed for 1 hour. The solvent is distilled off under reduced pressure,
Ethyl acetate was added to the residue, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc-hexane).
4-methyl-7- (3-methyl-2-thienyl)-
5,6,7,8-Tetrahydroquinolin-5-one (2.3 g) was obtained. mp. 104-105 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 2.71 (3H, s), 2.83
(1H, dd, J = 12, 16 Hz), 3.03 (1H, dq, J = 2, 4, 1
7 Hz), 3.31 (1H, dd, J = 12, 17 Hz), 3.49 (1H, dq,
J = 2, 14, 17 Hz), 3.68-3.89 (1H, m), 6.84 (1H,
d, J = 5 Hz), 7.07-7.16 (2H, m), 8.50 (1H, d, J
= 5 Hz).

Reference Example 81 5- (3-chloro-2-thienyl) -1,3-cyclohexanedione
(0.6 g), ammonium acetate (0.61 g) in ethanol (20 m
l) The solution was heated to reflux for 13 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the organic layer was washed with water saturated saline. It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (6 ml) and toluene (18 ml), acetylacetaldehyde dimethyl acetal (0.86 g) and powdered 85% potassium hydroxide (0.14 g) were added, and the mixture was heated under reflux. Powdered 85% potassium hydroxide (0.029 g) at 30 minute intervals
It was added once and then refluxed for another hour. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline in that order, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc
7- (3-chloro-2-thienyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one
(0.3 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.82 (1H, dd, J = 1
2, 17 Hz), 3.08 (1H, ddd, J = 2, 4, 16 Hz), 3.32
(1H, dd, J = 11, 17 Hz), 3.54 (1H, ddd, J = 2, 4,
17 Hz), 3.86-4.06 (1H, m), 6.93 (1H, d, J = 5 H
z), 7.12 (1H, d, J = 5 Hz), 7.2 (1H, d, J = 5 Hz),
8.50 (1H, d, J = 5 Hz).

Reference Example 82 5- (2-pyridyl) cyclohexane-1,3-dione (2.0 g), 1-
Amino-2-butyne hydrochloride (0.1.1 g), molecular sieves 4A (2 g), tetrahydrofuran (30 ml), ethanol
(10 ml) was added to triethylamine (2.1 g),
Stir at room temperature for 1 hour and then heat to reflux for 4 hours. After cooling, insolubles were filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / MeOH).
The resulting solid was stirred at 220 ° C. for 10 hours. . Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography.
(EtOAc / hexane) to give 4-methyl-7- (2-
Pyridyl) -5,6,7,8-tetrahydroquinolin-5-one (0.2
8 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.69 (3H, s), 2.98 (1H, ddd, J =
1, 4, 16 Hz), 3.15 (1H, dd, J = 11, 16 Hz), 3.37-
3.76 (3H, m), 7.08 (1H, d, J = 5 Hz), 7.18 (1H, dd
d, J = 1, 5, 8 Hz), 7.24 (1H, d, J = 8 Hz), 7.66
(1H, dt, J = 2.8 Hz), 8.47 (1H, d, J = 5 Hz), 8.58
(1H, ddd, J = 1, 2, 5 Hz).

Reference Example 83 5- (4-pyridyl) cyclohexane-1,3-dione (0.90 g), 1
Triethylamine (0.48 g) was added to a mixture of -amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 hour, and then stirred for 15 hours. Heated to reflux. After cooling, the insoluble matter is filtered off,
The solvent was distilled off under reduced pressure. The residue was heated to 220 ° C for 3.5 hours. After cooling, ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / MeOH) to give 4-methyl-7- (4-pyridyl) -5,6,7,8-tetrahydroquinolin-5-one as an oil ( 0.1 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.69 (3H, s), 2.87 (1H, dd, J = 1
2, 16 Hz), 2.92-3.08 (1H, m), 3.25-3.62 (3H,
m), 7.12 (1H, d, J = 5 Hz), 7.22- 7.35 (1H, m), 8.
50 (1H, d, J = 5 Hz), 8.57-8.65 (1H, m).

Reference Example 84 5- (4-Fluorophenyl) cyclohexane-1,3-dione (0.
Triethylamine (0.48 g) was added to a mixture of 98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g), and tetrahydrofuran (20 ml), and the mixture was heated under reflux for 14 hours. After cooling, the insolubles were filtered off, and the solvent was distilled off under reduced pressure.
The residue was heated to 220 ° C for 6 hours. After cooling, ethyl acetate,
An aqueous sodium hydrogen carbonate solution was added, and the organic layer was washed with water and saturated saline in this order, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtO
Ac / hexane) and 7- (4-fluorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one as an oil
(0.35 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.8
0-3.08 (2H, m), 3.29-3.55 (2H, m), 3.71-3.88
(1H, m), 7.02-7.36 (5H, m), 8.50 (1H, d, J = 5 H
z).

Reference Example 85 A solution of 5-phenylcyclohexane-1,3-dione (5.0 g) and ammonium acetate (6.1 g) in ethanol (100 ml) was heated under reflux for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added. The precipitated crystals were collected by filtration and washed with water. Drying gave 1-amino-5-phenylcyclohexen-3-one (5.2 g) as pale yellow crystals. mp.190-191 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.40-2.86 (4H, m), 3.26-3.45
(1H, m), 4.95 (2H, br), 5.35 (1H, d, J = 1 Hz), 7.
16-7.43 (2H, m).

Reference Example 86 5-methoxymethylene-2,2-dimethyl- [1,3] dioxane-4,
1-Amino-5-phenylcyclohexen-3-one (2.0 g) was added to a solution of 6-dione (1.8 g) in acetonitrile (15 ml), and the mixture was stirred at room temperature for 24 hours. The crystals were collected by filtration and washed with acetonitrile to give 2,2-dimethyl-5-[(3-oxo-5-phenyl-1-cyclohexenylamino) methylene]-[1,3] dioxane-4,6 as crystals. -Dione (1.2 g) was obtained. mp 201 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.74 (6H, s), 2.59-2.97 (4H,
m), 3.36-3.58 (1H, m), 5.99 (1H, s), 7.22- 7.50
(5H, m), 8.39 (1H, d, J = 14 Hz), 11.03 (1H, d, J
= 12 Hz).

Reference Example 87 2,2-Dimethyl-5-[(3-oxo-5-phenyl-1-cyclohexenylamino) methylene]-[1,3] dioxane-4,6-dione
(1.0 g) of diphenyl ether (15 ml)
Stir at 280 ° C for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with petroleum ether. The crystals were recrystallized from ethanol to obtain 7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.51 g) as crystals. mp 207-209 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.84-3.17 (2H, m), 3.34 (1H, d
d, J = 11, 13 Hz), 3.32- 3.64 (2H, m), 6.80 (1H,
d, J = 6 Hz), 7.24- 7.48 (5H, m), 8.42 (1H, d, J =
6 Hz).

Reference Example 88 Under ice cooling, 7-phenyl-1,4,5,6,
7,8-Hexahydroquinoline-4,5-dione (0.35 g) was added and 1
Heated at 00 ° C. for 2 hours. After cooling, phosphorus oxychloride was distilled off under reduced pressure. Add 1N aqueous sodium hydroxide to the residue,
Extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain 4-chloro-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g) as colorless crystals. mp. 71-72 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.92 (1H, dd, J = 12, 16 Hz), 3.0
6 (1H, ddd, J = 3, 4,17 Hz), 3.36 (1H, dd, J = 12,
17 Hz), 3.40-3.61 (1H, m), 7.21-7.45 (5H, m),
7.37 (1H, d, J = 5 Hz), 8.51 (1H, d, J = 5 Hz).

Reference Example 89 4-Chloro-7-phenyl-5,6,7,8-tetrahydroquinoline-5
To a solution of -one (0.23 g) in methanol (20 ml) was added sodium methoxide (0.096 g), and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off, and ethyl acetate was added to the residue.
The extract was washed successively with a saturated saline solution and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to give 4-methoxy-7-phenyl-5,6,7,8-
Tetrahydroquinolin-5-one (0.21 g) was obtained. mp.130-131 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.86 (1H, dd, J = 13, 16 Hz), 2.9
9 (1H, ddd, J = 2, 5, 18 Hz), 3.28 (1H, dd, J = 12,
16 Hz), 3.34-3.57 (2H, m), 3.99 (3H, s), 6.83 (1
H, d, J = 6 Hz), 7.20-7.43 (5H, m), 8.52 (1H, d,
J = 6 Hz).

Reference Example 90 5- (2-chlorophenyl) cyclohexane-1,3-dione (2.5
g) and a solution of ammonium acetate (2.6 g) in ethanol (50 ml) was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 1-amino acid as pale yellow crystals.
-5- (2-chlorophenyl) cyclohexen-3-one (2.2 g)
I got mp. 199 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 2.44-2.72 (4H, m), 3.77-3.97
(1H, m), 4.68 (2H, br), 5.35 (1H, s), 7.15-7.43
(4H, m).

Reference Example 91 5-methoxymethylene-2,2-dimethyl- [1,3] dioxane-4,
1-Amino-5- (2-chlorophenyl) cyclohexen-3-one (2.2 g) was added to a solution of 6-dione (1.7 g) in acetonitrile (15 ml).
g) was added and the mixture was stirred at room temperature for 13 hours. The precipitated crystals were collected by filtration and washed with acetonitrile to give 2,2-dimethyl-5-[(3-oxo-5- (2-chlorophenyl) -1-cyclohexenylamino) methylene]-[1 [3] dioxane-4,6-dione (1.7 g) was obtained. mp. 112 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.75 (6H, s), 2.62-2.84 (3H,
m), 2.95 (1H, dd, J = 5,17 Hz), 3.89-4.09 (1H,
m), 6.0 (1H, d, J = 2 Hz), 7.14- 7.52 (4H, m), 8.38
(1H, d, J = 14 Hz), 11.03 (1H, d, J = 14 Hz).

Reference Example 92 2,2-dimethyl-5-[(3-oxo-5- (2-chlorophenyl) -1-
Cyclohexenylamino) methylene]-[1,3] dioxane-
A mixture of 4,6-dione (1.6 g) and diphenyl ether (20 ml) was stirred at 260 ° C. for 30 minutes. The solvent is distilled off under reduced pressure,
The obtained crystals were washed with petroleum ether. The crystals were recrystallized from ethanol to give 7- (2-chlorophenyl) -1,4,5,6,7,8-
Hexahydroquinoline-4,5-dione (1.1 g) was obtained. mp. 243 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.59-2.77 (1H, m), 2.92-3.6
(3H, m), 3.77-4.0 (1H, m), 6.53 (1H, bs), 7.23
-7.58 (4H, m), 8.03 (1H, bs).

Reference Example 93 Phosphorus oxychloride (5.4 g) was added to 7- (2-chlorophenyl) -1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.
60 g) and heated at 100 ° C. for 2 hours. After cooling, phosphorus oxychloride was distilled off under reduced pressure. 1N aqueous sodium hydroxide was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give 4-chloro-7- (2-chlorophenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.55 g) as colorless crystals. mp.130-131 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.89 (1H, dd, J = 12, 16 Hz), 3.0
8 (1H, dq, J = 2, 4, 17 Hz), 3.32 (1H, dd, J = 12,
17 Hz), 3.53 (1H, dq, J = 2, 4, 17 Hz), 3.92-4.
08 (1H, m), 7.16-7.58 (5H, m), 8.52 (1H, d, J =
5 Hz).

Reference Example 94 To a solution of 4-chloro-7- (2-chlorophenyl-5,6,7,8-tetrahydroquinolin-5-one (0.2 g) in methanol (20 ml) was added sodium methoxide (0.074 g). After cooling, the solvent was distilled off, ethyl acetate was added to the residue, and the organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 7- (2-chlorophenyl) -4-methoxy-5,6,7,8-tetrahydroquinolin-5-one (0.1 g) as colorless crystals. mp. 116-117 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.81 (1H, dd, J = 12, 16 Hz), 3.0
(1H, dq, J = 2, 4, 17Hz), 3.25 (1H, dd, J = 12, 1
7 Hz), 3.45 (1H, dq, J = 2, 4, 17 Hz), 3.80- 4.16
(1H, m), 4.00 (3H, s), 6.85 (1H, d, J = 6 Hz), 7.1
6-7.45 (5H, m), 8.53 (1H, d, J = 6 Hz).

Reference Example 95 A mixture of 5-phenylcyclohexane-1,3-dione (1.2 g) and ammonium acetate (0.49 g) in ethanol (30 ml) was added to a mixture of 3-phenylcyclohexane-1,3-dione (1.2 g) and ethanol (30 ml).
Butyn-2-one (0.44 g) was added, and the mixture was stirred at room temperature for 1.5 hours and heated under reflux for 18 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 2-methyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.88 g) as colorless crystals.
I got mp. 79-81 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.61 (3H, s), 2.85 (1H, dd, J = 1
2, 17 Hz), 3.00 (1H, ddd, J = 1, 4, 17 Hz), 3.23-
3.63 (3H, m), 7.18 (1H, d, J = 8 Hz), 7.22- 7.43
(5H, m) 8.21 (1H, d, J = 8 Hz).

Reference Example 96 Acetyl acetone (1.1 g) was added to a mixture of 5-phenylcyclohexane-1,3-dione (2.0 g) and ammonium acetate (0.90 g) in ethanol (30 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was stirred and heated under reflux for 21 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and insolubles were removed by filtration. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography (EtOAc / hexane).
The resulting crystals were recrystallized from diisopropyl ether-hexane to give 2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.6 g) as colorless crystals. )
I got mp. 97-99 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 2.64 (3H, s), 2.70
-3.01 (2H, m), 3.17- 3.53 (3H, m), 6.92 (1H, s),
7.15-7.42 (5H, m).

Reference Example 97 5- (2-methylphenyl) cyclohexane-1,3-dione (1.0
g) and ammonium acetate (0.42 g) in ethanol (20 ml) were stirred at room temperature for 15 minutes to give 3-butyn-2-one (0.54 g).
g) was added and the mixture was heated under reflux for 16 hours. The solvent is distilled off under reduced pressure,
The residue was dissolved in ethyl acetate, aqueous sodium hydrogen carbonate,
The extract was washed sequentially with water and a saturated saline solution, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexane) to give 2,4-
Dimethyl-7- (2-methylphenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.50 g) was obtained. mp. 106-107 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s), 2.53 (3H, s), 2.66
(3H, s), 2.73-3.00 (2H, m), 3.15-3.37 (2H, m),
3.54-3.77 (1H, m), 6.95 (1H, s), 7.00 -7.33 (4
H, m).

Reference Example 98 5- (2-fluorophenyl) cyclohexane-1,3-dione (1.
0 g), ammonium acetate (0.97 g) 1-pentanol (30
The mixture was heated to reflux for 30 minutes, and 3-butyn-2-one (0.
After adding 97 g), the mixture was heated under reflux for 14.5 hours. 3-butyn-2-one (0.49 g) was added, and the mixture was further heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (E
The resultant was subjected to tOAc / hexane) to give 7- (2-fluorophenyl) -2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 2.66 (3H, s), 2.77
-3.04 (2H, m), 3.24- 3.44 (2H, m), 3.51-3.94
(1H, m), 6.96 (1H, s), 7.00-7.33 (4H, m).

Reference Example 99 5- (2-chlorophenyl) cyclohexane-1,3-dione (1.1
g), ammonium acetate (1.1 g) and 1-pentanol (30 ml)
Was heated to reflux for 30 minutes. 3-butyn-2-one (0.9
7 g) and heated to reflux, and after 14.5 hours, 3-butyn-2-one
(0.49 g) was added, and the mixture was further heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtO
Ac / hexane) and 7- (2-chlorophenyl)-
2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one
(0.2 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 2.67 (3H, s), 2.8
(1H, dd, J = 12, 16 Hz), 2.9-3.07 (1H, m), 3.27
(1H, dd, J = 11, 17 Hz), 3.35-3.52 (1H, m), 3.76
-4.08 (1H, m), 6.97 (1H, s), 7.17-7.54 (4H,
m).

Reference Example 100 5- (2-methylphenyl) cyclohexane-1,3-dione (1.0
g), ammonium acetate (0.8 g) 1-pentanole (30 m
l) A mixture of 3-butyn-2-one (1.1 g) was heated to reflux for 7 hours. The solvent was distilled off under reduced pressure, and the residue was added with ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / hexan).
e) 2,4-dimethyl-7- (2-pyridyl) -5,
6,7,8-Tetrahydroquinolin-5-one (0.08 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H, s), 2.66 (3H, s), 2.89
-3.33 (1H, m), 3.12 (1H, dd, J = 11, 16 Hz), 3.31
-3.53 (2H, m), 3.56-3.72 (1H, m), 6.94 (1H, s),
7.13-7.30 (2H, m), 7.60-7.72 (1H, m), 8.58 (1
(H, d, J = 5 Hz).

Reference Example 101 5- (2-methylphenyl) cyclohexane-1,3-dione (1.3
g) and ammonium acetate (0.49 g) in ethanol (30 ml) were stirred at room temperature for 30 minutes to give 3-butyn-2-one (0.44 g).
g) was added. The reaction solution was stirred at room temperature for 1.5 hours and heated under reflux for 27 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc
/ Hexane) to give 2-methyl-7- (2-methylphenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.88
g) was obtained. mp.76-77 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.62 (3H, s), 2.65
-3.0 (2H, m), 3.16 -3.43 (2H, m), 3.56-3.82 (1
(H, m), 7.03-7.33 (5H, m) 8.23 (1H, d, J = 8 Hz).

Reference Example 102 2-acetyl-5- (2-chlorophenyl) cyclohexane-1,3-dione (0.48 g), pyrrolidine (0.16 ml), anhydrous sodium sulfate (1.02 g)
Benzene (15 ml) was added to the mixture under argon atmosphere.
The mixture was heated and stirred at ℃ for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure. The residue is formamidine acetate (0.19 g),
Potassium carbonate (0.25g), methanol (10ml)
Was added and stirred at 90 ° C. for 2 hours under an argon atmosphere. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was extracted by adding water and ethyl acetate. The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and the residue was purified by silica gel chromatography, eluting with ethyl acetate / hexane.
7- (2-chlorophenyl) -4-methyl-5,6,
7,8-tetrahydroquinazolin-5-one (41 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.81-3.11 (2H, m),
2.90 (3H, s), 3.19-3.50 (2H,
m), 4.00 (1H, m), 7.21-7.33 (3
H, m), 7.44 (1H, dd, J = 1.4 & 7.0)
Hz), 9.06 (1H, s).

Reference Example 103 2-acetyl-5- (2-chlorophenyl) cyclohexane-1,3-dione (0.79 g), pyrrolidine (0.27 ml), anhydrous sodium sulfate (1.70 g)
Toluene (20 ml) was added under an argon atmosphere.
The mixture was heated and stirred at 0 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure. On the other hand, acetamidine hydrochloride (0.28 g)
To the mixture were added sodium ethoxide (0.21 g) and ethanol (10 ml), and the mixture was stirred at room temperature for 2 hours. This reaction solution was added to the above-mentioned enamine residue, and 90 ° C. under an argon atmosphere.
For 5 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was extracted by adding water and ethyl acetate. The upper layer was washed with saturated saline and dried (anhydrous magnesium sulfate).
4-Dimethyl-5,6,7,8-tetrahydroquinazolin-5-one (0.30 g) was obtained. mp 108-109 ° C (isopropyl ether). ¹ H-NMR (CDCl ₃ ) δ: 2.73 (3H, s), 2.78-
3.08 (2H, m), 2.92 (3H, s), 3.1
4-3.44 (2H, m), 3.97 (1H, m),
7.2-7.4 (3H, m), 7.24 (1H, d, J
= 7.2 Hz).

Reference Example 104 4-Methylpyridine-2,3-dicarboxylic anhydride (743 mg) was dissolved in tetrahydrofuran (10 ml), and 1.1 M of 2-methylphenylmagnesium bromide was stirred in an ice bath.
A tetrahydrofuran solution (4.1 ml) was added dropwise. After the dropwise addition, the mixture was stirred in an ice bath for 30 minutes, and 2N hydrochloric acid (3 m
l) was added and the mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture was adjusted to 3 by adding 2 N hydrochloric acid, and then ethyl acetate (200 mL) was added.
l) and water (100 ml) were added, shaken and separated. The upper layer was washed with water (3 times with 20 ml) and concentrated under reduced pressure. Benzene residue
(10 ml), thionyl chloride (2 ml) was added, the mixture was stirred at 90 ° C. (bath temperature) for 1 hour and 30 minutes, and the reaction solution was concentrated under reduced pressure. 60% oily sodium hydride (640 mg) was washed with hexane to remove oil, and tetrahydrofuran
(15 ml), and dimethyl malonate (2.11 g) was added quickly while stirring in an ice bath. After the generation of hydrogen gas ceased, the bath was removed, and a solution obtained by dissolving the concentrated residue in tetrahydrofuran (12 ml) was added with vigorous stirring. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. To the residue were added 2 M sodium carbonate (20 ml) and water (12 ml), and the mixture was heated under reflux for 20 minutes. After cooling the reaction solution, ethyl acetate (100 ml) was added, and the mixture was shaken and separated. Wash the upper layer with water (2
0 ml twice), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with ethyl acetate / hexane, and purified with 6-methoxycarbonyl-4-methyl-7- (2-methylphenyl). ) 5-Oxo-cyclopenta-1,3-diene [2,1-b] pyridine (0.07 g) was obtained as a yellow candy. ¹ H-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 2.62 (3H, s), 3.73
(3H, s), 7.05 (1H, d), 7.36 (4H, m), 8.40 (1H, d).

Reference Example 105 6-Methoxycarbonyl-4-methyl-7- (2-methylphenyl) -5-oxo-cyclopenta-1,3-diene [2,1-b] pyridine (110 mg) was dissolved in methanol ( 10 ml) and tetrahydrofuran
(10 ml) in a mixed solvent, 5% Pd-C (35 mg) was added, and the mixture was stirred under a hydrogen atmosphere at normal temperature and normal pressure. After completion of the reaction, the catalyst was removed by filtration and concentrated under reduced pressure. The residue was treated with acetic acid (2 m
l), add concentrated sulfuric acid (0.2 ml) and water (0.2 ml), and add 13
The mixture was stirred at 0 ° C. (bath temperature) for 30 minutes. Water (30 ml) was added to the reaction solution, and the mixture was concentrated to about 5 ml. Ethyl acetate (30
ml) and washed with aqueous sodium bicarbonate. The ethyl acetate layer was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, and purified by elution with ethyl acetate / hexane.
Methyl-7- (2-methylphenyl) -5-oxo-cyclopenta [2,1-b] pyridine (48 mg) was obtained as a yellow candy. ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 2.66 (1H, dd), 2.71
(3H, s), 3.29 (1H, dd), 4.86 (1H, dd), 6.68 (1H,
dd), 7.10 (4H, m), 8.61 (1H, d).

Reference Example 106 A solution of S-methylisothiosemicarbazide p-toluenesulfonate (831 mg) in 40% methylamine in methanol (1 m
l) and left at room temperature for 10 days. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate to give 1-amino-3-methylguanidine p-toluenesulfonate (650 mg) as colorless crystals. mp 110-111 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 2.73 (3H, m), 4.6
6 (2H, broad), 7.13 (2H, d), 7.28 (2H, broad), 7.5
0 (2H, d), 8.59 (1H, broad).

Reference Example 107 5- (3-thienyl) cyclohexane-1,3-dione (10.5 g) and ammonium acetate (13.1 g) were added to ethanol (200 ml) for 16 hours.
Heated to reflux for an hour. The reaction solution is concentrated under reduced pressure, and water is added to the residue.
(50 ml), and the crystals were collected by filtration, washed with water and toluene, and dried to give 1-amino-5- (3-thienyl) cyclohexen-3-one (10 g) as pale yellow crystals. Was. mp 142-143 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (2H, d), 2.52 (2H, d), 3.3
0 (1H, m), 4.99 (1H, s), 6.80 (2H, broad), 7.12 (1
H, dd), 7.25 (1H, m), 7.47 (1H, dd).

Reference Example 108 1-Amino-5- (3-thienyl) cyclohexen-3-one (10 g)
With ethanol (200 ml) and toluene (600 m
l) and mixed with 3-oxobutyraldehyde dimethyl acetal (17.4 g) and granular potassium hydroxide (2.87 g).
g) was added and the mixture was stirred at 115 ° C. (bath temperature). After 30 minutes, 1 hour, and 1 hour and 30 minutes, granular potassium hydroxide (590
mg) was added to the reaction solution, and then stirred at the same temperature for 1 hour.
After cooling the reaction solution, the solvent was distilled off under reduced pressure. Ethyl acetate (250 ml) and water (70 ml) were added to the residue, and the mixture was shaken and separated. The ethyl acetate layer was washed with water (3 times with 40 ml) and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc / he
xane), and purified by elution with ethyl acetate / hexane. Obtained as crystals. mp. 92-93 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.69 (3H, s), 2.85 (1H, dd), 3.09
(1H, ddd), 3.28 (1H, dd), 3.61 (2H, m), 7.08 (3H,
m), 7.38 (1H, m), 8.49 (1H, d).

Reference Example 10 9 4-Methyl-7- (3-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (1.22 g) was dissolved in ethyl acetate (50 ml), and pyridine (474 mg) and sulfuryl chloride (1.49 g) was added with stirring in an ice bath. After stirring for 30 minutes under the same conditions, excess sodium bicarbonate aqueous solution was added,
The mixture was stirred at room temperature for 10 minutes and separated. The ethyl acetate layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
(EtOAc / hexane), elution and purification with ethyl acetate / hexane, and 7- (2,5-dichlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinoline- 5-One (720 mg) was obtained as colorless crystals. mp.130-131 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.67 (3H, s), 2.75 (1H, dd), 2.93
(1H, ddd), 3.22 (1H, dd), 3.39 (1H, ddd), 3.66 (1
H, m), 6.72 (1H, s), 7.11 (1H, d), 8.50 (1H, d) .Also, 7- (2-chlorothiophen-3-yl) -4-methyl-5,6,
7,8-Tetrahydroquinolin-5-one (310 mg) was obtained as a pale yellow candy. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.77 (1H, dd), 2.97
(1H, ddd), 3.29 (1H, dd), 3.32 (1H, ddd), 3.72 (1
H, m), 6.89 (1H, d), 7.12 (2H, m), 8.50 (1H, d).

Reference Example 110 A mixture of 5-phenylcyclohexane-1,3-dione (1.0 g) and ammonium acetate (0.45 g) in ethanol (30 ml) was stirred at room temperature for 1 hour, and heated under reflux for 6 hours. After cooling, ethyl propiolate (0.55 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and heated under reflux for 14.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from ethanol to obtain 7-phenyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.19 g) as colorless crystals. . mp. 254 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.68-3.60 (5H, m), 6.28 (1H,
d, J = 9 Hz), 7.22-7.6 (5H, m), 7.82 (1H, dd, J
= 2, 9 Hz), 12.21 (1H, s).

Reference Example 111 3-ethoxycarbonyl-6-phenyl-4,5,6
7-tetrahydrobenzofuran-4-one (0.71
g) was dissolved in THF (10 ml), 1N sodium hydroxide (5.0 ml) was added, and the mixture was stirred at room temperature overnight (12 hours). The reaction solution was concentrated under reduced pressure, and the residue was acidified with potassium hydrogen sulfate, and extracted with ethyl acetate.
The upper layer was washed with saturated saline, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was washed with isopropyl ether to give 3-carboxy-6-phenyl-4,5,
6,7-tetrahydrobenzofuran-4-one (0.5
9 g) were obtained. mp 202-203 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.95 (1 H, d, J = 1.4 H)
z), 2.99 (1H, s), 3.17 (1H, dd,
J = 10.6 & 17.6Hz), 3.32 (1H, d
d, J = 5.4 & 17.6 Hz), 3.68 (1H,
m), 7.27-7.45 (6H, m), 8.14 (1
H, s).

Reference Example 112 3-carboxy-4-oxo-6-phenyl-4,5,
WSC was added to a suspension of 6,7-tetrahydrobenzofuran (1.28 g) in dichloromethane (25 ml) under ice-cooling.
(1.15 g) and N-hydroxybenztriazole (0.92 g) were added, followed by stirring at room temperature for 30 minutes. Then, concentrated aqueous ammonia (4.1 g) was added, and the mixture was added at room temperature overnight (1 g).
(2 hours). Water was added to the reaction solution for extraction. Wash the lower layer with saturated saline and dry (anhydrous magnesium sulfate)
And concentrated under reduced pressure. The residue was washed with ethyl acetate and isopropyl ether to give 3-carbamoyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-.
ON (0.36 g) was obtained. mp 252-253 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.89 (2H, d, J = 8.6H)
z), 3.12 (1H, dd, J = 10.6 & 17.2)
Hz), 3.27 (1H, dd, J = 5.4 & 17.2)
Hz), 3.61 (1H, m), 5.64 (1H, br)
oad), 7.27-7.43 (5H, m), 8.09.
(1H, s), 9.49 (1H, broad).

Reference Example 113 2-Chlorobenzaldehyde (70.3 g) was added to acetone (294).
ml) and an aqueous solution of sodium hydroxide (22.0 g) (1.4 l ml), and the mixture was stirred at room temperature for 5 hours. Excess acetone was distilled off under reduced pressure, and ethyl acetate (1.4 l) was added to the residue for extraction. The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and evaporated under reduced pressure to give crude 2-chlorobenzalacetone (94.6 g) as a yellow oil. This oil was used for the next reaction without further purification. 20% sodium ethoxide ethanol solution (1
To 70.1 g), diethyl malonate (80.1 g) was added at room temperature (a precipitate was immediately formed), and then a solution of crude 2-chlorobenzalacetone (94.6 g) in ethanol (40 ml) was added. The reaction mixture was heated and stirred at 90 ° C. for 2 hours, air-cooled, and ice-cooled (1 hour). The precipitate was collected by filtration, washed sequentially with ethyl acetate and isopropyl ether to give crude 6- (2-chlorophenyl) -2-
Hydroxy-4-oxo-2-cyclohexene-1-carboxylic acid ethyl ester monosodium salt (151.0 g) was obtained as a pale yellow powder. Add 2 M sodium hydroxide (350 m
l) was added, and the mixture was heated and stirred at 100 ° C. for 2 hours. 2.5 after air cooling
M sulfuric acid (350 ml) was added in 15 minutes, and the mixture was heated and stirred at 100 ° C. for 2 hours. After air cooling, ethyl acetate (1.4 l) was added for extraction.
The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and the ethyl acetate was distilled off under reduced pressure. The precipitated crystals were washed sequentially with ethyl acetate-isopropyl ether (1: 4) and isopropyl ether to give 5- (2-chlorophenyl) cyclohexane-1,3-dione (82.1 g) as colorless crystals. mp 157-158 ° C.

Reference Example 114 3-Methyl-2-thiophenecarboxaldehyde (25 g) was dissolved in acetone (125 ml), sodium hydroxide (8.7 g), and water (600 g).
ml), and the mixture was stirred at room temperature for 13 hours. Excess acetone was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried, and then ethyl acetate was distilled off under reduced pressure to obtain an oil. To a sodium ethoxide ethanol solution prepared from 60% sodium hydride (8 g, washed three times with hexane) and ethanol (200 ml) was added diethyl malonate (32.0 g) at room temperature, and then the oil obtained above was added. added. The reaction mixture was heated under reflux for 2 hours, air-cooled and then ice-cooled. The precipitate was collected by filtration and washed with cold ethanol. To this was added 2M sodium hydroxide (125 ml), and the mixture was heated and stirred at 100 ° C for 2.5 hours. After air cooling, 5N sulfuric acid was added, and the mixture was heated and stirred at 100 ° C. for 1 hour. After air cooling, the precipitate was collected by filtration, washed with water, then with toluene, dried and dried with 5- (3-
Methyl-2-thienyl) cyclohexane-1,3-dione (20.9
g) was obtained as colorless crystals. mp.166-168 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.43-2.69 (4H,
m), 3.53-3.76 (1H, m), 4.4-6.4 (1H, br), 5.55
(1H, s), 6.81 (1H, d, J = 5 Hz), 7.09 (1H, d, J = 5
Hz).

Reference Example 115 3-Chloro-2-thiophenecarboxaldehyde (4.2 g) was dissolved in acetone (25 ml), sodium hydroxide (1.3 g), and water (120 ml).
The mixture was added to l) and stirred at room temperature for 13 hours. Excess acetone was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried,
Ethyl acetate was distilled off under reduced pressure to obtain an oil. To a solution of sodium ethoxide (1.8 g) in ethanol (30 ml) at room temperature was added diethyl malonate (4.1 g), followed by the oil obtained above. The reaction mixture was heated under reflux for 6 hours, air-cooled and then ice-cooled. The precipitate was collected by filtration and washed with cold ethanol. To this was added 2 M sodium hydroxide (16 ml), and the mixture was heated with stirring at 100 ° C. for 2.5 hours. After air cooling, add 2.5 M sulfuric acid (16 ml), add 100
The mixture was heated and stirred at 30 ° C for 30 minutes. After air cooling, the precipitate is collected by filtration,
Washed with water followed by toluene and dried. The crystals were recrystallized from ethyl acetate to give 5- (3-chloro-2-thienyl) cyclohexane-1,3-dione (1.4 g) as colorless crystals. mp.145-146 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.47-3.07 (4H, m), 3.70-3.99
(1H, m), 5.11 (1H, br), 5.65 (1H, s), 6.90 (1H, d,
J = 5 Hz), 7.18 (1H, d, J = 5 Hz).

Example 1 (Production of Compound 1) 6-phenyl-4,5,6,7-tetrahydroindole-4-one
(0.11 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid
(0.026 ml), a mixture of water (0.026 ml) and ethanol (10 ml) was heated to reflux for 20 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, 1N aqueous sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, 4N hydrochloric acid was added, and the solvent was distilled off. The residue was recrystallized from ethanol to give 4-guanidinoimino-6-
Phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 1) (70 mg) was obtained as colorless crystals. .... mp 192 - 194 ℃ Elemental analysis C ₁₅ Calcd as _{H 17 N 5 · 2HCl C,} 52.95; H, 5.63; N, 20.58 Found C, 52.83; H, 5.57; N, 20.42 1 H-NMR ( DMSO-d ₆ ) δ: 2.68-3.16 (4H, m), 3.24-
3.48 (1H, m), 6.84 (1H, s), 6.95 (1H, s), 7.21-7.
50 (5H, m), 7.74 (4H, br), 10.15 (1H, br), 11.77
(1H, br).

Example 2 (Production of compound 2) 3-Methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.41
g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml), ethanol (50 m
The mixture of l) was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, added with aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 1N hydrochloric acid (2 ml) was added to the residue, and the solvent was distilled off. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-phenyl-.
4,5,6,7-tetrahydroindole hydrochloride (compound 2)
(0.1 g) was obtained as colorless crystals. . mp 176 ° C. (decomposition) Elemental analysis _{C 16 H 19 N 5 · 2HCl} · 0.2H Calcd As _{2 O C, 53.70;. H} , 6.03;. N, 19.57 Found C, 53.59; H, 6.05; N, 19.45 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.11 (3H, s), 2.63 - 3.16 (4
H, m), 3.20-3.44 (1H, m), 6.4-8.1 (4H, br), (1
H, s), 6.72 (1H, s), 7.20-7.50 (5H, m), 10.1 (1
H, br), 11.48 (1H, s).

Example 3 (Production of compound 3) 3-Ethyl-6-phenyl-4,5,6,7-tetrahydroindole
-4-one (0.5 g), aminoguanidine hydrochloride (0.25 g),
A mixture of concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (30 ml) was heated under reflux for 7 hours. 1N Hydrochloric acid (0.1 ml) was added, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with water and recrystallized from ethanol to give 3-ethyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (compound 3) (0.22 g) was obtained as colorless crystals. mp.158-160 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t, J = 7 Hz), 2.48
-2.76 (2H, m), 2.82 -3.10 (2H, m), 3.14-3.35 (1
H, m), 6.46 (1H, s), 6.6-8.4 (4H, br), 7.20-7.5
0 (5H, m), 10.7 (1H, s), 10.8 (1H, s).

Example 4 (Production of compound 4) 2-Methyl-6-phenyl-4,5,6,7-tetrahydroindole
A mixture of -4-one (0.8 g), aminoguanidine hydrochloride (0.41 g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml), and ethanol (50 ml) was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, the residue was suspended in ethyl acetate, washed with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, 1N hydrochloric acid was added, and the solvent was distilled off. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-2-methyl-6-phenyl-4,5,6,7.
-Tetrahydroindole hydrochloride (compound 4) (0.92 g)
Was obtained as colorless crystals. . mp 215 ° C. (decomposition) Calcd As Elemental analysis _{C 16 H 19 N 5 · 2HCl} C, 54.24;. H, 5.97;. N, 19.77 Found C, 53.89; H, 5.99;. N, 19.49 1 H-NMR (DMSO-d ₆ ) δ: 2.23 (3H, s), 2.80-3.21 (4
H, m), 3.35-3.54 (1H, m), 6.44 (1H, s), 7.23-7.
52 (5H, m), 8.02 (4H, br), 10.8 (1H, br), 12.29 (1
H, br).

Example 5 (Production of Compound 5) 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (0.8 g), aminoguanidine hydrochloride (0.35 g) g),
A mixture of concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (50 ml) was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / MeOH). The residue was dissolved in ethanol, 1N hydrochloric acid (4 ml) was added, the solvent was distilled off, and the residue was recrystallized from ethanol to give 4-guanidinoimino-2-
Phenyl-1,2,3,4,5,6,7,8-octahydrocarbazole hydrochloride (compound 5) (0.53 g) was obtained as an amorphous. ¹ H-NMR (DMSO-d ₆ ) δ: 1.56-1.83
(4H, m), 2.40-2.70 (5H, m), 2.75-3.38 (4H, m),
6.4-8.4 (5H, br), 7.20-7.52 (5H, m), 10.72 (1
H, s).

Example 6 (Production of compound 6) 3-Methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydroindol-4-one (0.70 g), aminoguanidine hydrochloride
(0.34 g), concentrated hydrochloric acid (0.44 ml), water (0.44 ml), ethanol
(50 ml) was heated at reflux for 12 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / MeOH / Et ₃ N). The obtained oil was dissolved in ethanol, 1N hydrochloric acid was added, and the solvent was distilled off. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydroindole hydrochloride (compound 6) ( 0.04 g) was obtained as colorless crystals. . mp 187 ° C. (decomposition) Elemental analysis _{C 17 H 21 N 5 · 2HCl} · 0.5H Calcd As _{2 O C, 54.14;. H} , 6.56;. N, 17.54 Found C, 54.36; H, 6.53; N, 17.59 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.22 (3H, s), 2.34 (3H, s),
2.4-2.65 (1H, m), 2.7-3.02 (3H, m), 3.34-3.5
3 (1H, m), 6.48 (1H, s), 6.85-7.8 (4H, br), 7.1
-7.48 (4H, m), 10.36 (1H, s), 10.77 (1H, s).

Example 7 (Production of compound 7) 1-methyl-6-phenyl-4,5,6,7-tetrahydroindole
-4-one (0.50 g), aminoguanidine hydrochloride (0.26 g),
A mixture of concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (50 ml) was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, 1N aqueous sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, 1N hydrochloric acid was added, and the solvent was distilled off. The residue was recrystallized from ethanol to give 4-guanidinoimino-1-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (compound 7) (0.37 g) as colorless crystals. Was. . mp 205 ° C. (decomposition) Calcd As Elemental analysis _{C 16 H 19 N 5 · 2HCl} C, 54.24;. H, 5.97;. N, 19.77 Found C, 53.97; H, 5.91;. N, 19.55 1 H-NMR (DMSO-d ₆ ) δ: 2.78-3.24 (4H, m), 3.30-
3.50 (1H, m), 6.62 (3H, s), 6.88 (1H, d, J = 3 Hz),
7.16 (1H, d, J = 3 Hz), 7.22-7.57 (5H, m), 7.97
(4H, br), 10.5 (1H, br).

Example 8 (Production of Compound 8) 1,3-Dimethyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one (0.31 g), aminoguanidine hydrochloride (0.15 g)
g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml), ethanol (50
ml) of the mixture was heated to reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, 1N hydrochloric acid was added, and the solvent was distilled off. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1,3-dimethyl-6-phenyl-4,5,
6,7-tetrahydroindole hydrochloride (compound 8) (0.1
g) was obtained as colorless crystals. mp. 230 ° C (decomposition) Elemental analysis value C ₁₇ H ₂₁ N ₅ · HCl · 0.5 H ₂ O Calcd. C, 59.90; H, 6.80; N, 20.55. Found C, 60.14; H, 6.63; N, 20.49 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.19 (3H, s), 2.35 - 3.56 (5
H, m), 3.45 (3H, s), 6.49 (1H, s), 6.8-8.4 (4H,
br), 7.22-7.48 (5H, m), 10.68 (1H, br).

Example 9 (Preparation of Compound 9) 6-phenyl-1-propyl-4,5,6,7-tetrahydroindo-
Le-4-one (0.80 g), aminoguanidine hydrochloride (0.46 g)
g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml), ethanol (50 m
The mixture of l) was heated at reflux for 30 minutes. The solvent is distilled off under reduced pressure,
The residue was dissolved in water, washed with diethyl ether, added with 1N aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, 4N hydrochloric acid in ethyl acetate (2 ml) was added, and the solvent was distilled off. The residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-1-propyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 9) (1.0 g) in E / Z form In the form of colorless crystals. . mp 155 ° C. (decomposition) Calcd As Elemental analysis _{C 18 H 23 N 5 · 2HCl} C, 56.54;. H, 6.59;. N, 18.32 Found C, 56.23; H, 6.59;. N, 18.22 1 H-NMR (DMSO-d ₆ ) δ: 0.86 (3H, t, J = 7 Hz), 1.58
-1.83 (2H, m), 2.73- 3.53 (5H, m), 3.72-4.08
(2H, m), 6.89 (1H, d, J = 3 Hz), 7.07 (1H, d, J =
3 Hz), 7.21-7.60 (5H, m), 7.8-8.2 (4H, br), 1
0.2-11.0 (1H, br) .and d: 0.83 (3H, t, J = 7
Hz), 1.58-1.83 (2H, m), 2.73-3.53 (5H, m), 3.7
2-4.08 (2H, m), 6.56 (1H, d, J = 3 Hz), 6.75 (1
H, d, J = 3Hz), 7.21-7.60 (5H, m), 7.2-7.75 (4
H, br), 10.76 (1H, br).

Example 10 (Preparation of Compound 10) 1-benzyl-6-phenyl-4,5,6,7-tetrahydroindo-
Ru-4-one (0.8 g), aminoguanidine hydrochloride (0.32 g),
A mixture of concentrated hydrochloric acid (0.13 ml), water (0.13 ml) and ethanol (50 ml) was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was washed with water. The residue was dissolved in ethanol, 4N hydrochloric acid-ethyl acetate solution (1 ml) was added, and the mixture was concentrated. The residue was recrystallized from ethanol to give 1-benzyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (compound 10) (0.67 g) as colorless crystals. . mp. 142 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.45-2.79 (2H, m), 2.90-
3.10 (2H, m), 3.13-3.37 (1H, m), 5.13 (2H, s),
6.63 (1H, d, J = 3 Hz), 6.83-8.12 (4H, br), 6.87
(1H, d, J = 3 Hz), 7.06-7.42 (10H, m), 10.82
(1H, br).

Example 11 (Production of Compound 11) 1-benzoyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one (0.68 g), aminoguanidine hydrochloride (0.26 g)
g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml), ethanol (50 m
The mixture of l) was heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was washed with water. The crystal was recrystallized from ethanol to give 1-benzoyl-4-guanidinoimino-6-phenyl-4,5,
6,7-tetrahydroindole hydrochloride (compound 11) (0.8
3 g) was obtained as colorless crystals. mp. 168 ° C (decomposition) Elemental analysis value C ₂₂ H ₂₁ N ₅ O · HCl · H ₂ O Calcd. C, 62.04; H, 5.68; N, 16.44. Found C, 61.89; H, 5.98; N, 16.45 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.67 (1H, dd, J = 13, 16 Hz),
3.01-3.53 (4H, m), 6.91 (1H, d, J = 3 Hz), 6.96
(1H, d, J = 3 Hz), 7.22-7.78 (10H, m) 7.0- 8.2
(4H, br). 10.92 (1H, s).

Example 12 (Production of compound 12) 1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one (0.40 g), aminoguanidine hydrochloride
(0.17 g), a mixture of concentrated hydrochloric acid (0.069 ml), water (0.069 ml), and ethanol (40 ml) were heated under reflux for 20 minutes. The solvent was distilled off under reduced pressure, the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole. Hydrochloride (Compound 1
2) (0.41 g) was obtained as colorless crystals. . mp 270 ° C. (decomposition) Calcd As Elemental analysis _{C 16 H 19 N 5 O 2} S · HCl C, 50.32;. H, 5.28;. N, 18.34 Found C, 50.05; H, 5.22;. N, 18.19 1 H-NMR (DMSO-d ₆ ) δ: 2.48-2.69 (1H, m), 2.95-
3.66 (4H, m), 3.50 (3H, s), 6.95 (1H, d, J = 4 Hz),
7.18 (1H, d, J = 3 Hz), 7.24-7.51 (5H, m), 7.13
-8.0 (4H, br), 10.8 (1H, br).

Example 13 (Production of compound 13) 1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one (0.41 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.068 ml), water (0.068 m
l) and a mixture of ethanol (30 ml) was heated under reflux for 20 minutes.
The reaction solution was left in a refrigerator for 12 hours, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and recrystallized from water to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (compound 1
3) (0.25 g) was obtained as colorless crystals. mp. 260 ° C (decomposition) Elemental analysis value C ₁₇ H ₂₁ N ₅ O ₂ S ・ HCl ・ 0.5H ₂ O Calcd. C, 50.42; H, 5.73; N, 17.30. Found C, 50.56; H, 5.45; N, 17.33. ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 2.48-2.71 (1
H, m), 2.95-3.66 (4H, m), 3.45 (3H, s), 6.9-8.3
(4H, br), 6.96 (1H, s), 7.20-7.53 (5H, m), 10.8
4 (1H, br).

Example 14 (Production of Compound 14) 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole-4-one (0.25 g), aminoguanidine hydrochloride (0.091 g), concentrated hydrochloric acid (0.039 ml), water (0.039 m
l) and ethanol (30 ml) were heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate and then with water, and washed with 3-ethyl-4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride. (Compound 14) (0.92 g) was obtained as colorless crystals. mp. 260 ° C (decomposition) Elemental analysis value C ₁₈ H ₂₃ N ₅ O ₂ S.HCl Calcd. C, 52.74; H, 5.90; N, 17.08. Found C, 52.37; H, 5.89; N, 16.93. ¹ H-NMR (DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7 Hz), 2.40
-2.83 (1H, m), 2.73 (2H, d, J = 7 Hz), 2.96-3.5
9 (4H, m), 3.46 (3H, s), 6.8-8.0 (4H, br), 6.92
(1H, s), 7.22-7.53 (5H, m), 10.8 (1H, br).

Example 15 (Production of Compound 15) 1-methanesulfonyl-3-methyl-6- (2-methylphenyl)-
4,5,6,7-tetrahydroindole-4-one (0.20 g), aminoguanidine hydrochloride (0.073 g), concentrated hydrochloric acid (0.032 ml), water
(0.032 ml) and a mixture of ethanol (20 ml) were heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was subjected to silica gel column chromatography (EtOAc / MeOH), and the obtained crystals were concentrated by adding 1N hydrochloric acid. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1-.
Methanesulfonyl-3-methyl-6- (2-methylphenyl) -4,
5,6,7-tetrahydroindole hydrochloride (compound 15)
(0.16 g) was obtained as colorless crystals. mp. 228-230 ° C Elemental analysis: C ₁₈ H ₂₃ N ₅ O ₂ S ・ HCl ・ 0.6H ₂ O Calcd. C, 51.38; H, 6.04; N, 16.65. Found C, 51.54; H, 6.03; N , 16.40. ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 2.36 (3H, s),
2.89-3.58 (5H, m), 3.45 (3H, s), 6.8-8.1 (4H,
br), 7.15-7.28 (3H, m), 7.48 (1H, d, J = 7H), 1
0.76 (1H, s).

Example 16 (Production of compound 16) 1-methanesulfonyl-3-methyl-6- (2-fluorophenyl)
-4,5,6,7-tetrahydroindole-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.047 ml), water
(0.047 ml) and a mixture of ethanol (30 ml) were heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 6- (2-fluorophenyl) -4-guanidinoimino-
1-methanesulfonyl-3-methyl-4,5,6,7-tetrahydroindole hydrochloride (compound 16) (0.2 g) was obtained as colorless crystals. mp. 286 ° C (decomposition) Elemental analysis value C ₁₇ H ₂₀ FN ₅ O ₂ S.HCl.0.5H ₂ O Calcd. C, 48.28; H, 5.24; N, 16.56. Found C, 48.26; H, 5.07; N, 16.82. ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 2.44-2.74 (1
H, m), 2.98-3.64 (3H, m), 3.46 (3H, s), 6.8-8.0
(4H, br), 6.99 (1H, s), 7.17-7.63 (4H, m), 10.8
1 (1H, s).

Example 17 (Production of compound 17) 6- (2-chlorophenyl) -1-methanesulfonyl-3-methyl-
4,5,6,7-tetrahydroindole-4-one (0.25 g), aminoguanidine hydrochloride (0.086 g), concentrated hydrochloric acid (0.11 ml), water
(0.11 ml) and a mixture of ethanol (30 ml) were heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from water-ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-1-methanesulfonyl-3-methyl-4,5,6,7- Tetrahydroindole hydrochloride (compound 17) (0.22 g) was obtained as colorless crystals. mp. 258 ° C (decomposition) Elemental analysis: C ₁₇ H ₂₀ ClN ₅ O ₂ S.HCl. 0.5 H ₂ O Calcd. C, 46.47; H, 5.05; N, 15.94. Found C, 46.39; H, 4.92; ^{. N, 15.98 1 H-NMR} (DMSO-d 6) δ: 2.26 (3H, d, J = 1 Hz), 2.53
-2.74 (1H, m), 2.96 -3.56 (3H, m), 3.45 (3H, s),
3.58-3.81 (1H, m), 6.99 (1H, d, J = 1 Hz), 7.1-
7.85 (4H, br), 7.27-7.66 (4H, m), 10.92 (1H,
s).

Example 18 (Production of compound 18) 1-methanesulfonyl-3-methyl-6- (2-thienyl) -4,5,6,7
-Tetrahydroindole-4-one (0.20 g), aminoguanidine hydrochloride (0.075 g), concentrated hydrochloric acid (0.032 ml), water (0.032 m
l) and a mixture of ethanol (30 ml) was heated under reflux for 1 hour.
The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol.
4-guanidinoimino-1-methanesulfonyl-3-methyl-6-
(2-Thienyl) -4,5,6,7-tetrahydroindole hydrochloride (compound 18) (0.26 g) was obtained as colorless crystals. . mp 297 ° C. (decomposition) Elemental analysis C ₁₅ Calcd as _{H 19 N 5 O 2 S 2} · HCl C, 44.82;. H, 5.02;. N, 17.42 Found C, 44.76; H, 4.97; N, 17.43. ¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (3H, d, J = 1 Hz), 2.67
(1H, dd, J = 11, 16 Hz), 2.96-3.52 (3H, m), 3.33
(3H, s), 3.58-3.76 (1H, m), 6.7-7.8 (4H, br),
6.95-7.03 (2H, m), 7.09 (1H, d, J = 3 Hz), 7.40
(1H, dd, J = 1,5 Hz), 10.99 (1H, s).

Example 19 (Preparation of Compound 19) 1- (4-methylphenyl) sulfonyl-6-phenyl-4,5,6,7-
Tetrahydroindole-4-one (1.0 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml),
A mixture of ethanol (50 ml) was heated at reflux for 20 minutes. The solvent was distilled off under reduced pressure, the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1- (4-methylphenyl) sulfonyl-6-phenyl-4,5,6,7 -Tetrahydroindole hydrochloride (compound 19) (1.1 g) was obtained as colorless crystals. .... mp 252 - 256 Calcd As ℃ Elemental analysis _{C 22 H 23 N 5 O 2} S · HCl C, 57.70; H, 5.28; N, 15.29 Found C, 57.33; H, 5.26; N, 15.23 1 H -NMR (DMSO-d ₆ ) δ: 2.41 (3H, s), 2.48-2.74 (1
H, m), 2.85-3.06 (2H, m), 3.16-3.40 (2H, m), 6.
97 (1H, d, J = 4 Hz), 7.21-7.52 (8H, m), 7.81 (1
H, d, J = 8 Hz), 6.8-8.1 (4H, br), 10.84 (1H, d,
J = 9 Hz).

Example 20 (Production of compound 20) 3-Methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.072 g) g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml), ethanol
(30 ml) of the mixture was heated with stirring at 50 ° C. for 3 hours at 80 ° C. for 1.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with diethyl ether. An aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and 1N hydrochloric acid (1.5 ml) was added. The crystals obtained by evaporating the solvent under reduced pressure were recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydroindazole hydrochloride. (Compound 20) (0.18 g) was obtained as colorless crystals. . mp 211 ° C. (decomposition) Elemental analysis _{C 16 H 20 N 6 · 2HCl} · 0.3H Calcd As _{2 O C, 51.29;. H} , 6.08;. N, 22.43 Found C, 51.64; H, 6.07; N, 22.33 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.33 (3H, s), 2.47 (3H, s),
2.4-2.66 (4H, m), 2.77-3.04 (2H, m), 3.36-3.
48 (1H, m), 6.9-7.9 (4H, br), 7.14-7.25 (3H,
m), 7.38-7.47 (1H, m), 10.71 (1H, s).

Example 21 (Production of compound 21) 3-Methyl-6- (2-chlorophenyl) -4,5,6,7-tetrahydroindazol-4-one (0.22 g), aminoguanidine hydrochloride (0.098 g) ), Concentrated hydrochloric acid (0.084 ml), water (0.084 ml), and ethanol (40 ml) were heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with diethyl ether. The mixture was concentrated under reduced pressure, and the obtained crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6- (2-chlorophenyl) -3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (compound 21) (0.26 g) was obtained as colorless crystals. . mp 220 ° C. (decomposition) Elemental analysis _{C 15 H 17 ClN 6 · 2HCl} · 0.5H Calcd As _{2 O C, 45.19;. H} , 5.06;. N, 21.08 Found C, 45.41; H, 4.76; N, 21.08 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.48 (3H, s), 2.68 (1H, dd, J
= 12, 17 Hz), 2.94 (2H, d, J = 8 Hz), 3.05 (1H, d
d, J = 2, 16 Hz), 3.53-3.72 (1H, m), 6.9 -7.9 (4
H, br), 7.24-7.53 (3H, m), 7.56-7.63 (1H, m),
10.86 (1H, s).

Example 22 (Production of compound 22) 6- (2-chlorophenyl) -3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.05 g), aminoguanidine hydrochloride (0.47 g) ), Concentrated hydrochloric acid (0.44 ml), water (0.44 ml), and ethanol (70 ml) were heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 4-guanidinoimino-6- (2-chlorophenyl) -3-methyl-4,5,
6,7-Tetrahydroindazole (0.6 g) was obtained as amorphous. 4-guanidinoimino-6- (2-chlorophenyl) -3-methyl-4,5,6,7-tetrahydroindazole (0.3
g) in ethanol (10 ml) in methanesulfonic acid (0.18
g) was added and concentrated. The obtained crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6- (2-chlorophenyl)-
3-methyl-4,5,6,7-tetrahydroindazole methanesulfonate (compound 22) (0.28 g) was obtained. mp. 235 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (6H, s), 2.47 (3H, s),
2.64 (1H, dd, J = 12, 16 Hz), 2.84-3.07 (3H, m),
3.53-3.72 (1H, m), 6.9-7.9 (4H, br), 7.24-
7.53 (3H, m), 7.58-7.67 (1H, m), 10.39 (1H, s).

Example 23 (Production of compound 23) 4-guanidinoimino-6- (2-chlorophenyl) -3-methyl-
Benzenesulfonic acid (0.18 g) was added to a solution of 4,5,6,7-tetrahydroindazole (0.3 g) in ethanol (10 ml) and concentrated. The obtained crystals were recrystallized from water-ethanol to give 4
-Guanidinoimino-6- (2-chlorophenyl) -3-methyl-4,
5,6,7-Tetrahydroindazole benzene sulfonate (Compound 23) (0.39 g) was obtained. .... mp 160 - 162 ℃ Calcd As Elemental analysis _{C 15 H 17 ClN 6 · 2PhSO} 3 H C, 51.22; H, 4.62; N, 13.27 Found C, 51.11; H, 4.67; N, 13.27 1 H- NMR (DMSO-d ₆ ) δ: 2.45 (3H, s), 2.63 (1H, dd, J
= 13, 16 Hz), 2.82 -3.07 (3H, m), 3.51-3.74 (1
H, m), 6.9-7.9 (4H, br), 7.24-7.69 (14H, m), 1
0.30 (1H, s).

Example 24 (Production of compound 24) 4-guanidinoimino-6- (2-chlorophenyl) -3-methyl-
Sulfuric acid (0.053 ml) was added to a solution of 4,5,6,7-tetrahydroindazole (0.3 g) in ethanol (10 ml) and concentrated. The obtained crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6- (2-chlorophenyl) -3-methyl-4,5,6,7-tetrahydroindazole sulfate (compound 24) (0.29 g). I got mp. 196 ° C (decomposition) Elemental analysis value C ₁₅ H ₁₇ ClN ₆ · H ₂ SO ₄ · EtOH Calcd. C, 44.30; H, 5.47; N, 18.23. Found C, 44.16; H, 5.35; N, 18.05 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.46 (3H, s), 2.64 (1H, dd, J
= 12, 16 Hz), 2.82 -3.09 (3H, m), 3.4-3.8 (1H,
m), 6.9-8.0 (4H, br), 7.34-7.53 (3H, m), 7.60
-7.66 (1H, m), 10.31 (1H, s).

Example 25 (Production of Compound 25) 6- (2-methoxyphenyl) -3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.2 g), aminoguanidine hydrochloride (0.095 g), concentrated hydrochloric acid (0.12 ml), water (0.12 ml), and ethanol (30 ml) were heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate.
After concentration under reduced pressure, the resulting crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6- (2-methoxyphenyl) -3-.
Methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 25) (0.3 g) was obtained as colorless crystals. mp. 202 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.46 (3H, s), 2.6 (1H, dd, J
= 8, 20 Hz), 2.76-3.04 (3H, m), 3.43-3.63 (1H,
m), 3.81 (3H, s), 6.8-8.1 (4H, br), 6.89 -7.07
(2H, m), 7.22-7.40 (1H, m), 10.77 (1H, s).

Example 26 (Production of compound 26) 6- (2-hydroxyphenyl) -3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.04 g), aminoguanidine hydrochloride (0.02 g) g), concentrated hydrochloric acid (0.041 ml), water (0.041 ml),
A mixture of ethanol (10 ml) was heated at reflux for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The crystals obtained by evaporating the solvent under reduced pressure were recrystallized from ethanol to give 4-guanidinoimino-6- (2-hydroxyphenyl) -3-methyl-4,5,6,7-tetrahydroindazole hydrochloride. (Compound 26) (0.06 g) was obtained as colorless crystals. mp. 168 ° C (decomposition) Elemental analysis value C ₁₅ H ₁₈ N ₆ O 2HCl 2H ₂ O Calcd. C, 44.23; H, 5.94; N, 20.63. Found C, 44.13; H, 5.85; N, 20.77 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.45 (3H, s), 2.4 - 2.72 (1H,
m), 2.74-3.03 (3H, m), 3.34-3.60 (1H, m), 6.7
-8.0 (4H, br), 6.72-6.93 (2H, m), 7.02 -7.16 (1
H, m), 7.21-7.30 (1H, m), 10.59 (1H, s).

Example 27 (Production of compound 27) 6- (2-chlorophenyl) -3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.44 g), aminoguanidine hydrochloride (0.19 g) ), Concentrated hydrochloric acid (0.24 ml), water (0.24 ml), and ethanol (40 ml) were heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol-water to give 6- (2-chlorophenyl) -3-ethyl-4-guanidinoimino.
-4,5,6,7-tetrahydroindazole hydrochloride (compound 2
7) (0.6 g) was obtained as colorless crystals. mp.196-200 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (3H, t, J = 7 Hz), 2.69
(1H, dd, J = 12, 16 Hz), 2.81-3.15 (3H, m), 2.95
(2H, q, J = 7 Hz), 3.51-3.71 (1H, m), 6.7- 8.2
(4H, br), 7.24-7.51 (3H, m), 7.6 (1H, dd, J = 2,
7 Hz), 10.89 (1H, s).

Example 28 (Production of compound 28 and compound 29) 2-acetyl-5- (2-chlorophenyl) cyclohexane-1,3-
A solution of dione (0.5 g), methylhydrazine sulfate (0.30 g) and triethylamine (0.21 g) in ethanol (20 ml) was added to 30
Heated to reflux for minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. Under reduced pressure,
The solvent was distilled off. Dissolve the residue in ethanol (20 ml),
Aminoguanidine hydrochloride (0.23 g), concentrated hydrochloric acid (0.48 ml),
Water (0.48 ml) was added, and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over sodium sulfate. The crystals obtained by evaporating the solvent under reduced pressure were recrystallized from ethyl acetate-methanol to give crystals (0.34 g).
I got The mother liquor was concentrated, ethyl acetate was added, the insolubles were removed by filtration, and the mixture was concentrated to obtain an amorphous substance (0.14 g). 1N Hydrochloric acid (1 ml) was added to the amorphous and concentrated under reduced pressure. The obtained crystals were recrystallized from water-ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-1,3-dimethyl-4,5,6,7
-Tetrahydroindazole hydrochloride (compound 28) (0.12
g) was obtained as colorless crystals. . mp 193 ° C. (decomposition) Elemental analysis _{C 16 H 19 N 6 · 2HCl} · 0.1H Calcd As _{2 O C, 47.39;. H} , 5.27;. N, 20.72 Found C, 47.18; H, 5.29; N, 20.54 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.39 (3H, s), 2.64 (1H, dd, J
= 12, 16 Hz), 2.84 -3.14 (3H, m), 3.56-3.77 (1
H, m), 3.69 (3H, s), 7.1-8.0 (4H, br), 7.27-7.
55 (3H, m), 7.62 (1H, dd, J = 2, 7 Hz), 11.02 (1H,
s). 1N Hydrochloric acid (2.5 ml) was added to the crystals obtained by recrystallization from ethyl acetate-methanol, and the mixture was concentrated under reduced pressure. The obtained crystals were recrystallized from water-ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-2,3-dimethyl-4,5,6,7-tetrahydroindazole hydrochloride (compound 29) (0.27 g) )
Was obtained as colorless crystals. ... mp 182 - 183 ℃ Elemental analysis _{C 16 H 19 N 6 · 2HCl} · 0.5H Calcd As _{2 O C, 46.56; H,} 5.37; N, 20.36 Found C, 46.59; H, 5.40; N, 20.37. ¹ H-NMR (DMSO-d ₆ ) δ: 2.54 (3H, s), 2.65 (1H, dd, J
= 12, 17 Hz), 2.8-2.95 (2H, m), 3.03 (1H, dd, J
= 3, 16 Hz), 3.4-3.8 (1H, m), 3.75 (3H, s), 7.0
-8.3 (4H, br), 7.26-7.56 (3H, m), 7.6 (1H, dd,
J = 1, 7 Hz), 10.76 (1H, s).

Example 29 (Compound 30a, Compound 30
b) 2-acetyl-5- (2-chlorophenyl) cyclohexane-1,3-
Dione (0.5 g), hydroxylamine hydrochloride (0.13 g),
A solution of triethylamine (0.19 g) in ethanol (15 ml) was added to 2
The mixture was heated under reflux for 4 hours, added with triethylamine (0.19 g), and further heated under reflux for 24 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline,
Dried over magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (EtOAc / hex).
ane) to give an oil (0.2 g). This oil was dissolved in ethanol (20 ml), and aminoguanidine hydrochloride (0.08
9g), concentrated hydrochloric acid (0.038 ml) and water (0.038 ml) were added, and the mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc-EtOAc / MeOH) to obtain an oil. To this oil was added 1N hydrochloric acid (1 ml) and concentrated. The obtained crystals were recrystallized from ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenz [d] isoxazole hydrochloride (compound 3
0a), 6- (2-chlorophenyl) -4-guanidinoimino-3-
An approximately 1: 2 mixture (0.25 g) of methyl-4,5,6,7-tetrahydrobenz [c] isoxazole hydrochloride (compound 30b) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3H, s), 2.37-2.83 (1
H, m), 2.96-3.23 (3H, m), 3.28-3.9 (1H, m), 7.2
-7.8 (4H, br), 7.27-7.63 (4H, m), 10.97 (1H,
s). and 2.72 (3H, s), 2.37-2.83 (1H, m), 2.96
-3.23 (3H, m), 3.28-3.9 (1H, m), 7.2-7.8 (4H,
br), 7.27-7.63 (4H, m), 10.97 (1H, s).

Example 30 (Production of Compound 31) 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.092
g), concentrated hydrochloric acid (0.04 ml), water (0.040 ml), ethanol (20 m
The mixture of l) was heated at reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 31) (0.10 g). ) Was obtained as colorless crystals. mp. 250 ° C (decomposition) Elemental analysis value C ₁₆ H ₁₈ N ₄ O · HCl Calcd. C, 60.28; H, 6.01; N, 17.57. Found C, 59.92; H, 5.95; N, 17.66. ¹ H- NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 2.36-2.72 (1
H, m), 2.89-3.12 (3H, m), 3.20-3.50 (1H, m), 6.
80-8.0 (4H, br), 7.25-7.48 (6H, m), 10.80 (1H,
s).

Example 31 (Production of compound 32) 6- (3-Bromophenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.1
4 g), aminoguanidine hydrochloride (51 mg), ethanol (10 ml) and 6N hydrochloric acid (0.04 ml) were added, and 9
The mixture was heated and stirred at 0 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol, ethyl acetate and isopropyl ether, dried and dried to give (E) -6- (3-
(Bromophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 32) (76 mg) was obtained. mp 285 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₄ OBr · HCl Calcd. C, 48.32; H, 4.56;
N, 14.09 Found C, 48.14; H, 4.44;
N, 13.91 ¹ H-NMR (DMSO-d ₆ ) δ: 2.20 (3H,
d, J = 1.2 Hz), 2.63 (1H, dd, J = 1)
2.4 & 16.2 Hz), 2.98-3.10 (3H,
m), 3.24-3.44 (1H, m), 7.0-7.
8 (4H, broad), 7.32 (1H, t, J =
7.6 Hz), 7.40 (1H, s), 7.45 (1
H, t, J = 1.8 Hz), 7.49 (1H, t, J =
1.8Hz), 7.67 (1H, s).

Example 32 (Production of compound 33) 3-Methyl-6- (4-methylphenyl) -4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.14 g) g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml), and ethanol (30 ml) were heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6- (4-methylphenyl) -4,5,6,7-
Tetrahydrobenzofuran hydrochloride (Compound 33) (0.30
g) was obtained as colorless crystals. mp. 260 ° C (decomposition) Elemental analysis value C ₁₇ H ₂₀ N ₄ O · HCl Calcd. C, 61.35; H, 6.36; N, 16.83. Found C, 60.97; H, 6.07; N, 16.76. ¹ H- NMR (DMSO-d ₆ ) δ: 2.19 (3H, s), 2.29 (3H, s),
2.52-2.64 (1H, m), 2.86-3.08 (3H, m), 3.18-
3.52 (2H, m), 6.7-7.9 (4H, br), 7.09-7.36 (4H,
m), 7.39 (1H, s), 10.86 (1H, s).

Example 33 (Production of compound 34) 6- (4-Fluorophenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.1
2 g) and aminoguanidine hydrochloride (59 mg) were added with ethanol (10 ml) and 6N hydrochloric acid (0.046 ml), and the mixture was heated with stirring at 90 ° C. for 1 hour. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol and isopropyl ether, dried and dried to give (E) -6- (4-fluorophenyl) -4-guanidinoimino-3-methyl-4. ,
5,6,7-Tetrahydrobenzofuran hydrochloride (Compound 34) (0.12 g) was obtained. mp 277 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₄ OF.HCl.0.2 H ₂ O. Calcd. C, 56.46; H, 5.45;
N, 16.46 Found C, 56.27; H, 5.38;
N, 16.64 ¹ H-NMR (DMSO-d ₆ ) δ: 2.19 (3H,
s), 2.70 (1H, dd, J = 12.2 & 16.6)
Hz), 2.96-3.09 (3H, m), 3.2-
3.5 (1H, m), 6.9-7.7 (4H, broa
d), 7.18 (2H, t, J = 5.8 & 8.6H)
z), 7.41 (1H, s), 7.48 (2H, dd,
J = 5.8 & 8.6 Hz).

Example 34 (Production of compound 35) 3-Methyl-6- (4-bromophenyl) -4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g) g), a mixture of concentrated hydrochloric acid (0.049 ml), water (0.049 ml), and ethanol (30 ml) was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6- (4-bromophenyl) -4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 35) (0.25 g)
Was obtained as colorless crystals. mp. 235 ° C (decomposition) Elemental analysis value C ₁₆ H ₁₇ N ₄ OBr · HCl Calcd. C, 48.32; H, 4.56; N, 14.09. Found C, 48.25; H, 4.71; N, 14.34. ¹ H- NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 2.5-2.77 (1H,
m), 2.86-3.13 (2H, m), 3.20-3.50 (1H, m), 7.0
-7.8 (4H, br), 7.37-7.63 (4H, m), 7.40 (1H, s),
10.86 (1H, s).

Example 35 (Production of Compound 36) 3-Methyl-6- (4-methoxyphenyl) -4,5,6,7-tetrahydrobenzofuran-4-one (0.10 g), aminoguanidine hydrochloride (0.045 g) g), a mixture of concentrated hydrochloric acid (0.02 ml), water (0.02 ml), and ethanol (30 ml) was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 4-guanidinoimino-6- (4-methoxyphenyl) -3-methyl-4,5,6,7.
-Tetrahydrobenzofuran hydrochloride (compound 36) (0.08
g) was obtained as colorless crystals. mp. 182 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 2.48-2.68 (1
H, m), 2.90-3.08 (3H, m), 3.20-3.50 (1H, m), 3.
75 (3H, s), 6.8-8.0 (4H, br), 6.86-6.97 (2H,
m), 7.28-7.42 (2H, m), 7.37 (1H, s), 10.78 (1H,
s).

Example 36 (Production of Compound 37) 3-methyl-6- (2-methylphenyl) -4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.087 g), a mixture of concentrated hydrochloric acid (0.037 ml), water (0.037 ml), and ethanol (20 ml) was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6- (2-methylphenyl) -4,5,6,7-
Tetrahydrobenzofuran hydrochloride (Compound 37) (0.17
g) was obtained as colorless crystals. mp. 266 ° C (decomposition) Elemental analysis value C ₁₇ H ₂₀ N ₄ O · HCl Calcd. C, 61.35; H, 6.36; N, 16.83. Found C, 61.02; H, 6.04; N, 16.81. ¹ H- NMR (CD ₃ OD) δ: 2.24 (3H, s), 2.38 (3H, s), 2.
59 (1H, dd, J = 41, 44Hz), 2.84-3.12 (1H, m), 3.
52-3.70 (1H, m), 7.08-7.60 (5H, m).

Example 37 (Preparation of compound 38) 6- (2,5-Dimethylphenyl) -3-methyl-4,
5,6,7-tetrahydrobenzofuran-4-one (0.36 g), aminoguanidine hydrochloride (157 m
g) with ethanol (28 ml) and 6N hydrochloric acid (0.12 m
l) was added and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was ethanol, ethyl acetate,
Wash sequentially with isopropyl ether, dry and (E)
-4-guanidinoimino-6- (2,5-dimethylphenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 38) (0.21 g) was obtained. mp 235-236 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H,
s), 2.27 (3H, s), 2.29 (3H, s),
2.5-2.64 (1H, m), 2.90-3.01
(3H, m), 3.3-3.6 (1H, m), 6.97
(1H, d, J = 7.6 Hz), 7.08 (1H, d,
J = 7.6 Hz), 7.10 (4H, broad),
7.26 (1H, s), 7.40 (1H, s).

Example 38 (Production of compound 39) 3-Methyl-6- (2-trifluoromethylphenyl)
-4,5,6,7-tetrahydrobenzofuran-4-one (0.28 g), aminoguanidine hydrochloride (105 m
g) in ethanol (20 ml) and 6N hydrochloric acid (0.082).
ml), and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was sequentially washed with ethanol, ethyl acetate, and isopropyl ether, and dried.
(E) -4-guanidinoimino-3-methyl-6- (2
-Trifluoromethylphenyl) -4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 39) (0.2
1 g). mp 275 ° C (decomposition). Elemental analysis value: C ₁₇ H ₁₇ N ₄ OF ₃ .HCl.0.3 H ₂ O: Calcd. C, 52.06; H, 4.78;
N, 14.29 Found C, 52.82; H, 4.63;
N, 14.39 ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H,
d, J = 1.2 Hz), 2.71-3.24 (4H,
m), 3.53 (1H, m), 7.36 (4H, bro
ad), 7.46 (1H, s), 7.53 (1H, t,
J = 8.2 Hz), 7.74 (1 H, d, J = 8.0 H)
z), 7.75 (1H, d, J = 8.0 Hz), 7.9
7 (1H, d, J = 7.8 Hz).

Example 39 (Production of compound 40) 6- (2-Fluorophenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.2
1 g), aminoguanidine hydrochloride (95 mg), ethanol (17 ml) and 6N hydrochloric acid (0.074 ml) were added, and the mixture was heated with stirring at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol, ethyl acetate and isopropyl ether, dried, and dried (E) -6- (2
-Fluorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 40) (0.19 g) was obtained. mp 288 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₄ OF.HCl.0.2 H ₂ O. Calcd. C, 56.46; H, 5.45;
N, 16.46 Found C, 56.46; H, 5.35;
N, 16.74 ¹ H-NMR (DMSO-d ₆ ) δ: 2.20 (3H,
s), 2.69 (1H, dd, J = 12.0 & 16.4).
Hz), 2.98-3.11 (3H, m), 3.58
(1H, m), 7.0-7.7 (4H, broad),
7.16-7.55 (4H, m), 7.41 (1H,
s).

Example 40 (Production of compound 41) 6- (2,4-difluorophenyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.13 g), aminoguanidine hydrochloride (0.058 g), concentrated hydrochloric acid (0.074 ml), water (0.074 ml),
A mixture of ethanol (30 ml) was heated at reflux for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from water-ethanol.
6- (2,4-Difluorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 41) (0.17 g) was obtained as colorless crystals. mp. 278 ° C (decomposition) Elemental analysis value C ₁₆ H ₁₆ F ₂ N ₄ O ・ HCl ・ 0.1H ₂ O Calcd. C, 53.89; H, 4.86; N, 15.71. Found C, 53.80; H, 4.90; ^{. N, 15.97 1 H-NMR} (DMSO-d 6) δ: 2.20 (3H, d, J = 1 Hz), 2.68
(1H, dd, J = 1, 5 Hz), 2.80-3.66 (4H, m), 6.9-
7.85 (4H, br), 7.05-7.62 (3H, m), 7.42 (1H, d, J
= 1 Hz), 10.92 (1H, s).

Example 41 (Production of compound 42) 6- (2-Chlorophenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.3
5 g) and aminoguanidine hydrochloride (148 mg) were added with ethanol (27 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was heated with stirring at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol, ethyl acetate and isopropyl ether, dried, and dried (E) -6- (2
-Chlorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 42) (0.38 g). mp 300 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₄ OCl.HCl. C, 54.40; H, 5.14;
N, 15.86 Found C, 54.19; H, 5.13;
N, 15.81 ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H,
s), 2.69 (1H, dd, J = 12.0 & 16.2).
Hz), 2.99-3.09 (3H, m), 3.71
(1H, m), 7.0-7.8 (4H, broad),
7.27-7.51 (3H, m), 7.42 (1H,
s), 7.61 (1H, dd, J = 2.0 & 7.4H)
z).

Example 42 (Preparation of compound 43) 6- (2,3-Dichlorophenyl) -3-methyl-4,
5,6,7-tetrahydrobenzofuran-4-one (0.15 g), aminoguanidine hydrochloride (56 mg)
And ethanol (10ml) and 6N hydrochloric acid (0.044m
l) was added and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was ethanol, ethyl acetate,
Wash sequentially with isopropyl ether, dry and (E)
-6- (2,3-Dichlorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 43) (0.16 g) was obtained. mp 286 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₆ N ₄ OCl ₂ .HCl C, 49.57; H, 4.42;
N, 14.45 Found C, 49.31; H, 4.55;
N, 14.14 ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H,
d, J = 1.0 Hz), 2.68 (1H, dd, J = 1)
2.2 & 16.2 Hz), 2.98-3.09 (3H,
m), 3.77 (1H, m), 7.39 (4H, bro
ad), 7.39-7.49 (1H, m), 7.44.
(1H, s), 7.61 (2H, d, J = 8.4H
z).

Example 43 (Preparation of compound 44) 6- (2,6-Dichlorophenyl) -3-methyl-4,
5,6,7-tetrahydrobenzofuran-4-one (0.42 g), aminoguanidine hydrochloride (157 m
g) with ethanol (30 ml) and 6N hydrochloric acid (0.12 m
l) was added and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was ethanol, ethyl acetate,
Wash sequentially with isopropyl ether, dry and (E)
-6- (2,6-Dichlorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 44) (0.33 g) was obtained. mp 280 ° C (decomposition). Elemental analysis C ₁₆ H ₁₇ N ₄ Calcd as OCl · HCl · H ₂ O. C, 47.37; H, 4.72;
N, 13.81 Found C, 47.73; H, 4.77;
N, 13.84 ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H,
s), 2.87 (1H, t, J = 5.4 Hz), 2.9
5 (1H, t, J = 5.2 Hz), 3.24 (1H, d
d, J = 13.4 & 16.8 Hz), 3.59 (1H,
dd, J = 11.8 & 16.6 Hz), 4.22 (1
H, m), 7.2-7.8 (4H, broad), 7.
38 (1H, t, J = 8.0 Hz), 7.46 (1H,
s), 7.55 (1H, t, J = 8.4 Hz).

Example 44 (Production of compound 45) 6- (2-Bromophenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.2
8 g) and aminoguanidine hydrochloride (102 mg), ethanol (20 ml) and 6N hydrochloric acid (0.080 ml) were added, and the mixture was heated with stirring at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropyl ether in that order, dried and dried to give (E) -6-
(2-bromophenyl) -4-guanidinoimino-3-
Methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 45) (0.31 g) was obtained. mp 296 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₄ OBr · HCl Calcd. C, 48.32; H, 4.56;
N, 14.09 Found C, 48.16; H, 4.48;
N, 13.90 ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H,
d, J = 1.2 Hz), 2.67 (1H, dd, J = 1)
1.8 & 15.8 Hz), 2.96-3.09 (3H,
m), 3.68 (1H, m), 7.1-7.8 (4H,
broad), 7.21-7.48 (4H, m), 7.
44 (1H, s), 7.65 (2H, dt, J = 1.2
& 8.2Hz).

Example 45 (Preparation of Compound 46) 6- (2-methoxyphenyl) -3-methyl-4,5
6,7-tetrahydrobenzofuran-4-one (0.1
9 g) and aminoguanidine hydrochloride (82 mg), ethanol (15 ml) and 6N hydrochloric acid (0.064 ml) were added, and the mixture was heated with stirring at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol, ethyl acetate and isopropyl ether, dried, and dried to give (E) -4-guanidinoimino-6- (2-methoxyphenyl) -3- Methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 46) (0.19 g) was obtained. mp 279 ° C (decomposition). Elemental analysis value: C ₁₇ H ₂₀ N ₄ O ₂ .HCl.0.3 H ₂ O Calcd. C, 57.64; H, 6.15;
N, 15.82 Found C, 57.45; H, 6.07;
N, 15.82 ¹ H-NMR (DMSO-d ₆ ) δ: 2.20 (3H,
d, J = 1.2 Hz), 2.66 (1H, dd, J = 1)
2.0 & 16.4 Hz), 2.83-3.10 (3H,
m), 3.62 (1H, m), 3.82 (3H, s),
6.96 (1H, t, J = 7.4 Hz), 7.03 (1
H, d, J = 7.4 Hz), 7.1-7.7 (4H, b
load), 7.23-7.37 (2H, m), 7.4.
0 (1H, d, J = 1.2 Hz).

Example 46 (Production of compound 47) 6- (2-Furyl) -3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g), aminoguanidine hydrochloride (113 mg) ) To ethanol (2
0 ml) and 6N hydrochloric acid (0.088 ml), and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol, ethyl acetate and isopropyl ether, dried, and dried (E) -6- (2-furyl) -4-guanidinoimino-3-methyl. −4,5
6,7-tetrahydrobenzofuran hydrochloride (compound 4
7) (0.22 g) was obtained. mp 300 ° C. or more Elemental analysis value C ₁₄ H ₁₆ N ₄ O ₂ .HCl C, 54.46; H, 5.55;
N, 18.15 Found C, 54.23; H, 5.51;
N, 18.19 ¹ H-NMR (DMSO-d ₆ ) δ: 2.18 (3H,
d, J = 1.0 Hz), 2.67 (1H, dd, J =
9.0 & 16.0Hz), 2.94 (1H, dd, J =
9.4 & 16.4 Hz), 3.08-3.19 (2H,
m), 3.50 (1H, m), 6.27 (1H, d, J
= 3.2 Hz), 6.41 (1H, dd, J = 1.8 &
3.2Hz), 7.37 (4H, broad), 7.4
0 (1H, s), 7.59 (1H, d, J = 1.2H
z).

Example 47 (Production of compound 48) 3-Methyl-6- (2-thienyl) -4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.1 g)
5g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml), ethanol (30
ml) of the mixture was heated at reflux for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6- (2-thienyl) -4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 48). ) (0.36 g) as colorless crystals. mp 285 ° C (decomposition) Elemental analysis value C ₁₄ H ₁₆ N ₄ OS · HCl Calcd. C, 51.77; H, 5.27; N, 17.25. Found C, 51.69; H, 5.31; N, 17.38. ¹ H- NMR (DMSO-d ₆ ) δ: 2.19 (3H, s), 2.71 (1H, dd, J
= 11, 17 Hz), 2.96 (1H, dd, J = 10, 17 Hz), 3.12
-3.3 (2H, m), 3.62-3.79 (1H, m), 6.8-7.9 (4
H, br), 6.99 (1H, dd, J = 4, 5 Hz), 7.08 (1H, d, J
= 3 Hz), 7.3-7.42 (2H, m), 11.05 (1H, s).

Example 48 (Preparation of compound 49) 6- (5-Methyl-2-thienyl) -3-methyl-4,
5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (81 mg)
To ethanol (15ml) and 6N hydrochloric acid (0.063m
l) was added and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was ethanol, ethyl acetate,
Wash sequentially with isopropyl ether, dry and (E)
-4-guanidinoimino-6- (5-methyl-2-thienyl) -5-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 49) (0.18 g) was obtained. mp 287 ° C (decomposition). Elemental analysis _{C 15 H 18 N 4 OS ·} HCl · 0.2H Calcd the ₂ O. C, 52.60; H, 5.71;
N, 16.45 Found C, 52.70; H, 5.61;
N, 16.56 ¹ H-NMR (DMSO-d ₆ ) δ: 2.18 (3H,
d, J = 1.4 Hz), 2.40 (3H, s), 2.6
1-2.97 (2H, m), 3.06-3.19 (2
H, m), 3.63 (1H, m), 6.65 (1H, d
d, J = 1.2 & 3.4 Hz), 6.82 (1H, d,
J = 3.2 Hz), 7.40 (1H, s), 7.41
(4H, broad).

Example 49 (Preparation of Compound 50) 6-phenyl-3-trifluoromethyl-4,5,6
7-tetrahydrobenzofuran-4-one (0.13
g), aminoguanidine hydrochloride (51 mg), ethanol (10 ml) and 6N hydrochloric acid (0.04 ml) were added, and
The mixture was heated and stirred at 4 ° C. for 4 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate, and isopropyl ether in that order, dried, and dried with (E) -4-guanidinoimino-6-phenyl-3-trifluoromethyl-
4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 50) (0.12 g) was obtained. mp 291 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.69 (1H,
dd, J = 12.2 & 16.4 Hz), 3.04-3.
17 (3H, m), 3.2-3.5 (1H, m), 7.
2-7.9 (4H, broad), 7.28-7.46
(5H, m), 8.45 (1H, s).

Example 50 (Production of compound 51) 6- (4-Fluorophenyl) -3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-
ON (0.25 g), aminoguanidine hydrochloride (93 m
g) in ethanol (20 ml) and 6N hydrochloric acid (0.072).
ml), and the mixture was heated and stirred at 90 ° C. for 4 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was sequentially washed with ethanol, ethyl acetate, and isopropyl ether, and dried.
(E) -6- (4-Fluorophenyl) -4-guanidinoimino-3-trifluoromethyl-4,5,6,7-
Tetrahydrobenzofuran hydrochloride (Compound 51) (0.
20 g) were obtained. mp 283 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.68 (1H,
dd, J = 12.4 & 16.0 Hz), 3.04-3.
15 (3H, m), 3.2-3.5 (1H, m), 7.
0-7.8 (4H, broad), 7.20 (2H,
t, J = 9.0 Hz), 7.49 (2H, dd, J =
5.4 & 8.8 Hz), 8.45 (1H, d, J = 1.
4 Hz).

Example 51 (Production of compound 52) 3-trifluoromethyl-6- (2-methylphenyl) -4,5,6,7-
Tetrahydrobenzofuran-4-one (0.15 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.025 ml), water (0.025 g)
ml) and ethanol (30 ml) were heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate to give 3-trifluoromethyl-4-guanidinoimino-6- (2-methylphenyl) -4,5,6,7-tetrahydro Benzofuran hydrochloride (compound 52) (0.08 g) was obtained as colorless crystals. mp. 247 ° C (decomposition) Elemental analysis C ₁₇ H ₁₇ F ₃ N ₄ O ・ HCl Calcd. C, 52.79; H, 4.69; N, 14.48. Found C, 52.79; H, 4.44; N, 14.46. ¹ H -NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.66 (1H, dd, J
= 13, 16 Hz), 2.96-3.72 (4H, m), 6.2-8.2 (4H,
br), 7.12-7.33 (3H, m), 7.46 (1H, d, J = 7Hz),
8.43 (1H, s), 11.21 (1H, s).

Example 52 (Production of compound 53) 6- (2-bromophenyl) -3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.29 g), aminoguanidine hydrochloride Salt (90m
g) in ethanol (16 ml) and 6N hydrochloric acid (0.070).
ml), and the mixture was heated and stirred at 90 ° C. for 4 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was sequentially washed with ethanol, ethyl acetate, and isopropyl ether, and dried.
(E) -6- (2-Bromophenyl) -4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 53) (0.1
3 g) was obtained. mp 289 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₄ N ₄ OBrF ₃ .HCl. C, 42.55; H, 3.35;
N, 12.40 Found C, 42.67; H, 3.35;
N, 12.26 ¹ H-NMR (DMSO-d ₆ ) δ: 2.76 (1H,
dd, J = 12.8 & 16.2 Hz), 3.05-3.
15 (3H, m), 3.73 (1H, m), 7.0-
8.0 (4H, broad), 7.26 (1H, t, J
= 7.0 Hz), 7.46 (1H, t, J = 7.2H)
z), 7.63 (1H, d, J = 7.2 Hz), 7.6
8 (1H, d, J = 8.0 Hz), 8.45 (1H,
s).

Example 53 (Production of compound 54) 6- (2-Furyl) -3-trifluoromethyl-4,
5,6,7-tetrahydrobenzofuran-4-one (0.22 g), aminoguanidine hydrochloride (90 mg)
Ethanol (16ml) and 6N hydrochloric acid (0.070m
l) was added and the mixture was heated and stirred at 90 ° C. for 4 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was ethanol, ethyl acetate,
Wash sequentially with isopropyl ether, dry and (E)
-6- (2-Furyl) -4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (compound 54) (0.12 g) was obtained. mp 282 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.75 (1H,
dd, J = 10.8 & 16.6 Hz), 3.04 (1
H, dd, J = 9.4 & 17.2 Hz), 3.20 −
3.31 (2H, m), 3.59 (1H, m), 6.2
8 (1H, d, J = 3.4 Hz), 6.40 (1H, d
d, J = 2.0 & 3.2 Hz), 7.10 (4H, br)
oad), 7.57 (1H, d, J = 1.8 Hz),
8.36 (1H, d, J = 1.4 Hz).

Example 54 (Production of compound 55) 3-Ethoxycarbonyl-6-phenyl-4,5,6
7-tetrahydrobenzofuran-4-one (0.28
g), aminoguanidine hydrochloride (111 mg), ethanol (20 ml) and 6N hydrochloric acid (0.086 ml) were added, and the mixture was heated with stirring at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was sequentially washed with ethanol, ethyl acetate, and isopropyl ether, dried, and dried to give (E) -3-ethoxycarbonyl-4-guanidinoimino-6-phenyl-4, 5,6,7-Tetrahydrobenzofuran hydrochloride (compound 55) (0.25 g) was obtained. mp 260 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (3H,
t, J = 7.0 Hz), 2.69 (1H, dd, J = 1)
2.8 & 16.4 Hz), 2.98-3.11 (3H,
m), 3.2-3.5 (1H, m), 4.25 (2H,
q, J = 7.0 Hz), 7.2-7.9 (4H, bro
ad), 7.28-7.46 (5H, m), 8.38.
(1H, s).

Example 55 (Production of compound 56) 6- (2-Chlorophenyl) -3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g), aminoguanidine hydrochloride ( 49m
g) in ethanol (9 ml) and 6N hydrochloric acid (0.038 m
l) was added and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was ethanol, ethyl acetate,
Wash sequentially with isopropyl ether, dry and (E)
-6- (2-Chlorophenyl) -3-ethoxycarbonyl-4-guanidinoimino-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 56) (90 mg) was obtained. mp 277 ° C (decomposition). Elemental analysis value: C ₁₈ H ₁₉ N ₄ O ₃ Cl.HCl C, 52.57; H, 4.90;
N, 13.62 Found C, 52.37; H, 4.90;
N, 13.69 ¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (3H,
t, J = 7.0 Hz), 2.71 (1H, dd, J = 1)
2.4 & 16.0 Hz), 2.99-3.13 (3H,
m), 3.75 (1H, m), 4.26 (2H, q, J
= 7.0 Hz), 7.1-8.2 (4H, m), 7.2
9-7.62 (4H, m), 8.39 (1H, s).

Example 56 (Production of compound 57) 4-Methyl-7- (2-methylphenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.10 g)
4g), concentrated hydrochloric acid (0.018 ml), water (0.018 ml), ethanol (30
ml) of the mixture was heated to reflux for 7 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 5-
Guanidinoimino-4-methyl-7- (2-methylphenyl) -5,
6,7,8-tetrahydroquinoline hydrochloride (compound 57) (0.4
g) was obtained as colorless crystals. . mp 218 ° C. (decomposition) Elemental analysis _{C 18 H 21 N 5 · 2HCl} · 0.5H Calcd As _{2 O C, 55.53;. H} , 6.21;. N, 17.99 Found C, 55.54; H, 6.19; N, 18.11 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.35 (3H, s), 2.64 - 2.96 (1
H, m), 2.91 (3H, s), 3.07-3.61 (4H, m), 6.9-8.
4 (4H, br), 7.03-7.30 (3H, m), 7.37-7.48 (1H,
m), 7.86 (1H, d, J = 6 Hz), 8.65 (1H, d, J = 6 H
z), 11.36 (1H, s).

Example 57 (Production of compound 58) 7- (2,5-dimethylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (100 mg), aminoguanidine hydrochloride (46 mg) and concentrated hydrochloric acid (0.1 ml) were heated under reflux in ethanol (2 ml) for 1 hour and 30 minutes. The reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol, dried and dried to give 7- (2,5-dimethylphenyl) -5-guanidinoimino-4-methyl-5,6,7, 8-Tetrahydroquinoline hydrochloride (Compound 58) (131 mg) was obtained as pale yellow crystals. mp. 260-262 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H, s),
2.30 (3H, s), 2.77 (1H,
m), 2.88 (3H, s), 3.13 (1
H, m), 3.40 (3H, m), 6.99
(1H, d), 7.10 (1H, d),
7.28 (1H, s), 7.85 (2H,
d), 7.90 (4H, broad), 8.6
4 (1H, d.)

Example 58 (Production of Compound 59) 7- (2-Fluorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g), aminoguanidine hydrochloride (0.16 g) g), a mixture of concentrated hydrochloric acid (0.21 ml), water (0.21 ml), and ethanol (40 ml) was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate.
An aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is dissolved in ethanol.
1N Hydrochloric acid (3 ml) was added, and the mixture was concentrated under reduced pressure. Residue in ethanol
Recrystallized from toluene to give 7- (2-fluorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 59) (0.33 g) as colorless crystals. . . mp 240 ° C. (decomposition) Elemental analysis _{C 17 H 18 FN 5 · 2HCl} · 0.2H Calcd As _{2 O C, 52.64;. H} , 5.30;. N, 18.06 Found C, 52.63; H, 5.17; N, 17.92 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.80 - 4.0 (5H, m), 2.83 (3H,
s), 7.19-7.44 (3H, m), 7.50-8.02 (4H, br), 7.5
1-7.63 (1H, m), 7.77 (1H, d, J = 6Hz), 8.60 (1H,
d, J = 6Hz), 11.28 (1H, s).

Example 59 (Production of compound 60) 7- (2,4-difluorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.43 g), aminoguanidine hydrochloride (0.18 g), a mixture of concentrated hydrochloric acid (0.39 ml), water (0.39 ml), and ethanol (50 ml) were heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and concentrated under reduced pressure. The residue was recrystallized from water-ethanol to give 7-
(2,4-difluorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 6
0) (0.45 g) was obtained as colorless crystals. . mp 286 ° C. (decomposition) Elemental analysis _{C 17 H 17 N 5 F 2} · 2HCl · 0.2H Calcd As _{2 O C, 50.31;. H} , 4.82;. N, 17.25 Found C, 50.20; H, 4.77; N ^{, 17.31 1 H-NMR (DMSO} -d 6) δ:. 2.70 - 3.03 (1H, m), 2.88 (3
H, s), 3.14-3.32 (1H, m), 3.32-3.64 (3H, m), 7.
08-7.34 (2H, m), 7.50-8.40 (4H, br), 7.83 (1H,
d, J = 6 Hz), 8.63 (1H, d, J = 6 Hz), 11.59 (1H,
s).

Example 60 (Production of compound 61) 7- (2-chlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.20 g), aminoguanidine hydrochloride (0.2%)
085 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml), ethanol (20
ml) of the mixture was heated to reflux for 6 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 7-
(2-chlorophenyl) -5-guanidinoimino-4-methyl-5,
6,7,8-tetrahydroquinoline hydrochloride (compound 61) (0.2
1 g) was obtained as colorless crystals. mp. 204 ℃ (decomposition) Elemental analysis value C ₁₇ H ₁₈ N ₅ Cl ・ 2HCl ・ 0.8H ₂ O Calcd. C, 49.18; H, 5.24; N, 16.87. Found C, 49.46; H, 5.10; N, 16.88. ¹ H-NMR (DMSO-d ₆ ) δ: 2.65-3.00 (1H, m), 2.88 (3
H, s), 3.15-3.78 (4H, m), 7.2-8.2 (4H, br), 7.2
8-7.53 (3H, m), 7.58-7.66 (1H, m), 7.83 (1H, d,
J = 6 Hz), 8.63 (1H, d, J = 6 Hz), 11.45 (1H, s).

Example 61 (Production of Compound 62) 7- (2,3-Dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (306 mg), aminoguanidine hydrochloride ( 122 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (4 ml).
Heated to reflux for an hour. The reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol, dried and dried to give 7- (2,3-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8. -Tetrahydroquinoline hydrochloride (Compound 62) (425 mg) was obtained as colorless crystals. . mp 270-272 ° C. Elemental analysis C ₁₇ H ₁₇ N ₅ Cl Calcd a _{2 · 2HCl C, 46.92;.} H, 4.40;. N, 16.09 Found C, 46.99; H, 4.42;. N, 15.90 1 H- NMR (DMSO-d ₆ ) δ: 2.88 (4H, m), 3.27 (1H, dd),
3.45 (2H, m), 3.74 (1H, m), 7.46 (1H, t), 7.63 (2
H, d), 7.82 (1H, d), 7.94 (4H, broad), 8.63 (1H,
d), 11.50 (1H, broad).

Example 62 (Production of compound 63) 7- (2,6-dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (171 mg), aminoguanidine hydrochloride ( 67 mg) and concentrated hydrochloric acid (0.1 ml) were heated under reflux in ethanol (3 ml) for 2 hours. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethanol to give 7- (2,6-dichlorophenyl).
-5-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 63) (195 mg) was obtained as colorless crystals. mp. 300 ° C or higher Elemental analysis value C ₁₇ H ₁₇ N ₅ Cl ₂ .2HCl .1 / 4H ₂ O Calcd. C, 56.44; H, 4.47; N, 15.93. Found C, 56.24; H, 4.35; N, 16.19. ¹ H-NMR (DMSO-d ₆ ) δ: 2.85 (3H, s), 3.07 (1H, dd),
3.28 (1H, d), 3.38 (1H, dd), 4.10 (2H, m), 7.41 (1
H, t), 7.57 (2H, d), 7.80 (1H, d), 7.89 (4H, broa
d), 8.62 (1H, d), 11.46 (1H, broad).

Example 63 (Production of compound 64) (±) -7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (1123.9 g)
Was suspended in methanol (1200 ml), and a methanol solution of 28% sodium methoxide (119.2 ml) was added dropwise. 3 at 50 ° C
Stir for 0 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the crystals were collected by filtration. The crystals were washed with water and dried to give (±) -7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline as colorless crystals (109.3
g) was obtained. (±) -7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline (10
9.3 g) of isopropyl alcohol (700 m
l) A solution of L-pyroglutamic acid (10 g) in isopropyl alcohol (700 ml) was added dropwise to the solution at 50 ° C over 1.5 hours. The mixture was stirred at 50 ° C for 1 hour and at room temperature for 2 days. The crystals were collected by filtration, washed with isopropyl alcohol, and (-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline L-pyroglutamate (55.5 g , 88% e
e) was obtained. Recrystallization from ethanol gave L-pyroglutamate (44.3 g, 97% ee). The obtained salt crystals were suspended in methanol (500 ml), and a methanol solution (10.9 mmol) of 28% sodium methoxide was added. The mixture was stirred at 50 ° C. for 30 minutes, and the solvent was distilled off under reduced pressure. The obtained crystals are washed with water and dried to give (-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline (38.9
g) was obtained. (This compound is identified by X-ray crystal structure analysis.
It was confirmed that the absolute configuration was S-configuration. This was dissolved in ethanol (400 ml), and methanesulfonic acid (14.3 g) was added. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give (-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline Methanesulfonic acid salt (Compound 64) (46.8 g,
99.2% ee). mp. 194-195 ° C Elemental analysis: C ₁₇ H ₁₈ N ₅ Cl.2MeSO ₃ H Calcd. C, 43.88; H, 5.04; N, 13.47; Cl, 6.82. Found C, 43.67; H, 4.90; N, ^{. 13.18; Cl, 6.76 1 H} -NMR (DMSO-d 6) δ: 2.40 (6H, s), 2.78 (1H, dd, J
= 12, 18 Hz), 2.89 (3H, s), 3.08-3.32 (2H, m),
3.44-3.80 (2H, m), 7.2-8.1 (4H, br), 7.31-7.
56 (3H, m), 7.58-7.66 (1H, m), 7.86 (1H, d, J =
6 Hz), 8.66 (1H, d, J = 6 Hz), 10.77 (1H, s).

Example 64 (Production of Compound 65) (a) -7- (2-Chlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) was added to CHIRALCEL OD ( Was eluted with isopropyl alcohol-hexane.) To give (-)-7- (2-chlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.33 g). Obtained. This was dissolved in ethanol (25 ml), and aminoguanidine hydrochloride (0.
16 g), concentrated hydrochloric acid (0.3 ml) and water (0.3 ml) were added, and the mixture was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. Add aqueous sodium bicarbonate,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were dissolved in ethanol.
(2.4 mmol) and concentrated. The resulting crystals are ethanol-
Recrystallized from ru-acetone, (+)-7- (2-chlorophenyl)
-5-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 65) (0.52 g) was obtained as colorless crystals. ... mp 194 - 196 ℃ Elemental analysis C ₁₇ H ₁₈ Calcd As _{ClN 5 · 2MeSO 3 H C,} 43.88; H, 5.04; N, 13.47; Cl, 6.82 Found C, 43.59; H, 4.59; N, 13.38 ^{;. Cl, 6.82 1 H-} NMR (DMSO-d 6) was consistent with compound 64.

Example 65 (Production of Compound 66) 7- (2-Bromophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.49 g), aminoguanidine hydrochloride (0.19 g)
9g), concentrated hydrochloric acid (0.39 ml), water (0.39 ml), ethanol (50 m
The mixture of l) was heated at reflux for 6.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-water to give 7- (2
-Bromophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydroquinoline hydrochloride (Compound 66) (0.47
g) was obtained as colorless crystals. . mp 233 ° C. (decomposition) Elemental analysis _{C 17 H 18 BrCl 2 N 5} · 2HCl · 0.5H Calcd As _{2 O C, 44.96;. H} , 4.66;. N, 15.42 Found C, 45.23; H, 4.67; N , 15.61. ¹ H-NMR (DMSO-d ₆ ) δ: 2.75-3.03
(1H, m), 2.88 (3H, s), 3.
16-3.60 (4H, m), 7.22-
7.35 (1H, m), 7.41-7.56
(1H, m), 7.69-7.75 (2
H, m), 7.4-8.6 (4H, br),
7.82 (1H, d, J = 6 Hz),
8.63 (1H, d, J = 6 Hz), 1
1.39 (1H, s).

Example 66 (Production of compound 67) 7- (2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.40 g), aminoguanidine hydrochloride (0.17 g) g), a mixture of concentrated hydrochloric acid (0.22 ml), water (0.22 ml), and ethanol (40 ml) was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 5-guanidinoimino-7- (2-methoxyphenyl) -4-.
Methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 67) (0.3 g) was obtained as colorless crystals. mp. 192 ° C (decomposition) Elemental analysis value C ₁₈ H ₂₁ N ₅ O ・ 2HCl ・ 0.2H ₂ O Calcd. C, 54.06; H, 5.90; N, 17.51. Found C, 54.15; H, 5.93; N, ^{. 17.71 1 H-NMR (DMSO} -d 6) δ: 2.70 - 3.90 (5H, m), 2.87 (3
H, s), 3.83 (3H, s), 6.93-7.06 (2H, m), 7.23-
7.40 (2H, m), 7.50-8.02 (4H, br), 7.78 (1H, d, J
= 6Hz), 8.61 (1H, d, J = 6Hz), 11.20 (1H, s).

Example 67 (Production of Compound 68) 7- (2-Hydroxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride (0.037 g) g), concentrated hydrochloric acid (0.048 ml), water (0.048 ml), and ethanol (10 ml) were heated under reflux for 4 hours. After cooling,
The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and concentrated under reduced pressure. The obtained crystals were washed with ethanol while hot to give 5-guanidinoimino-7- (2-hydroxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 68) (0.09 g) was obtained as colorless crystals. mp. 161 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.78-3.03
(1H, m), 2.90 (3H, s), 3.
08-3.97 (1H, m), 3.36-
3.62 (3H, m), 6.76-7.
32 (6H, m), 7.4-8.2 (4
H, br), 7.89 (1H, d, J =
6 Hz), 8.65 (1H, d, J = 6)
Hz), 9.8 (1H, br), 11.38
(1H, s).

Example 68 (Production of compound 69) 7- (2-furyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (227 mg), aminoguanidine hydrochloride (122 mg)
mg) and concentrated hydrochloric acid (0.1 ml) were heated under reflux in ethanol (3 ml) for 2 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration and washed with ethanol to give 7- (2-furyl) -5-guanidinoimino-.
4-Methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 69) (305 mg) was obtained as colorless crystals. . mp 300 ° C. or higher Elemental analysis C ₁₅ H ₁₇ N ₅ Calcd as O · 2HCl C, 50.57;. H, 5.38; N, 19.66 Found C, 50.62; H, 5.25;. N, 19.67 1 H-NMR (DMSO -d ₆ ) δ: 2.85 (3H, s), 2.98 (1H, dd),
3.30 (2H, m), 3.56 (2H, m), 6.42 (2H, d), 7.63 (1
H, d), 7.82 (1H, d), 7.98 (4H, broad), 8.64 (1H,
d), 11.79 (1H, s).

Example 69 (Production of compound 70) 4-Methyl-7- (2-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (0.52 g), aminoguanidine hydrochloride (0.25 g)
g), concentrated hydrochloric acid (0.53 ml), water (0.53 ml), ethanol (50 m
The mixture of l) was heated at reflux for 7 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, and concentrated under reduced pressure. The residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7- (2-thienyl) -5,6,7,8-tetrahydroquinoline hydrochloride (Compound 70) (0.57 g). Obtained as colorless crystals. mp. 225 ° C (decomposition) Elemental analysis value C ₁₅ H ₁₇ N ₅ S · 2HCl · H ₂ O Calcd. C, 46.16; H, 5.42; N, 17.94. Found C, 46.44; H, 5.51; N, 18.13 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.60 - 3.08 (1H, m), 2.86 (3
H, s), 3.28-3.80 (4H, m), 6.96-7.08 (1H, m), 7.
14 (1H, s), 7.43 (1H, d, J = 5 Hz), 7.6-8.2 (4H,
br), 7.81 (1H, d, J = 6 Hz), 8.63 (1H, d, J = 6 H
z), 11.69 (1H, s).

Example 70 (Production of compound 71) 4-Methyl-7- (5-methyl-2-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (257 mg), aminoguanidine hydrochloride Salt (117 mg), concentrated hydrochloric acid (0.2 ml) in ethanol (5 ml)
Heated to reflux for minutes. The reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol, and dried to give 5-guanidinoimino-4-methyl-7- (5-methyl-2-thienyl) -5,6,7. , 8-Tetrahydroquinoline hydrochloride (Compound 71) (273 mg) was obtained as pale yellow crystals. . mp 271-273 ° C. Elemental analysis C ₁₆ H ₁₉ N ₅ Calcd as S · 2HCl C, 49.74;. H, 5.48; N, 18.13 Found C, 49.66; H, 5.31;. N, 18.06 1 H-NMR ( DMSO-d ₆ ) δ: 2.41 (3H, s), 2.86 (3H, s),
2.94 (1H, dd), 3.31 (2H, m), 3.52 (2H, m), 6.66 (1
H, dd), 6.90 (1H, d), 7.82 (1H, d), 7.96 (4H, broa
d), 8.63 (1H, d), 11.73 (1H, s).

Example 71 (Production of compound 72) 7- (5-Chloro-2-thienyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.79 g), aminoguanidine hydrochloride A mixture of salt (0.33 g), concentrated hydrochloric acid (0.7 ml), water (0.7 ml) and ethanol (40 ml) was heated under reflux for 8.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ethanol and recrystallized from ethanol-water. The obtained crystals were further washed with ethanol, and 7- (5-chloro-2-thienyl) -4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 72) (0.26 g) was used as crystals. Obtained. mp. 215 ° C (decomposition) Elemental analysis value C ₁₅ H ₁₆ ClN ₅ S ・ 2HCl ・ 0.2H ₂ O Calcd. C, 43.90; H, 4.52; N, 17.07. Found C, 43.88; H, 4.44; N, 16.91. ¹ H-NMR (DMSO-d ₆ ) δ: 2.7-3,12 (1H, m), 2.86 (3H,
s), 3.22-3.75 (4H, m), 6.9-7.2 (2H, m), 7.6-
8.8 (4H, br), 7.81 (1H, d, J = 5 Hz), 8.63 (1H, d,
J = 5 Hz), 11.79 (1H, s).

Example 72 (Production of compound 73) 4-Methyl-6- (3-methyl-2-thienyl) -4,5,6,7-tetrahydroquinolin-5-one (0.8 g), aminoguanidine hydrochloride salt
(0.36 g), concentrated hydrochloric acid (0.78 ml), water (0.78 ml), ethanol
(50 ml) was heated at reflux for 5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from ethanol.
5-guanidinoimino-4-methyl-7- (3-methyl-2-thienyl) -5,6,7,8-tetrahydroquinoline hydrochloride (compound 7
3) (0.94 g) was obtained as colorless crystals. mp. 184-187 ° C Elemental analysis: C ₁₆ H ₁₉ ClN ₅ S ・ 2HCl ・ 1H ₂ O Calcd. C, 47.53; H, 5.73; N, 17.32. Found C, 47.58; H, 5.76; N, 17.32. ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 2.76 (1H, dd, J
= 12, 19 Hz), 2.88 (3H, s), 3.2-3.57 (3H, m),
3.62-3.83 (1H, m), 6.87 (1H, d, J = 5 Hz), 7.33
(1H, d, J = 5 Hz), 7.4-8.4 (4H, br), 7.84 (1H,
d, J = 6 Hz), 8.64 (1H, d, J = 6 Hz), 11.46 (1H,
s).

Example 73 (Production of compound 74) 7- (3-chloro-2-thienyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride salt
(0.14 g), concentrated hydrochloric acid (0.27 ml), water (0.27 ml), ethanol
(30 ml) was heated at reflux for 6 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, and 4N hydrochloric acid-ethyl acetate solution (0.
4 ml) and concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol-water to give 7- (3-chloro-2-thienyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 74) (0.23 g) was obtained as colorless crystals. mp. 203 ° C (decomposition) Elemental analysis value C ₁₅ H ₁₆ ClN ₅ S · 2HCl Calcd. C, 44.29; H, 4.46; N, 17.22. Found C, 44.27; H, 4.46; N, 17.01. ¹ H- NMR (DMSO-d ₆ ) δ: 2.7-2.97 (1H, m), 2.86 (3H,
s), 3.22-4.4 (4H, m), 7.08 (1H, d, J = 5 Hz), 7.
4-8.4 (4H, br), 7.63 (1H, d, J = 5 Hz), 7.8 (1H, br)
d, J = 5 Hz), 8.62 (1H, d, J = 6 Hz), 11.43 (1H,
s).

Example 74 (Production of compound 75) 4-methyl-7- (2-pyridyl) -5,6,7,8-tetrahydroquinolin-5-one (0.28 g), aminoguanidine hydrochloride (0.14 g)
g), concentrated hydrochloric acid (0.41 ml), water (0.41 ml), ethanol (30 m
The mixture of l) was heated at reflux for 6 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and concentrated under reduced pressure. The residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7- (2-pyridyl) -5,6,7,8-tetrahydroquinoline hydrochloride (Compound 75) (0.37 g). Obtained as colorless crystals. . mp 260 ° C. (decomposition) Elemental analysis _{for C 16 H 18 N 6 ·} 3HCl · 0.2H Calcd As _{2 O C, 47.18;. H} , 5.30;. N, 20.63 Found C, 47.16; H, 5.45; N, 20.86. ¹ H-NMR (DMSO-d ₆ ) δ: 2.82 (3H, s), 3.03-3.78 (5
H, m), 7.4-8.3 (4H, br), 7.53-7.63 (1H, m), 7.
78 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 6 Hz), 8.06
-8.17 (1H, m), 8.65 (1H, d, J = 6 Hz), 8.70 (1H,
d, J = 5 Hz), 11.57 (1H, s).

Example 75 (Production of compound 76) 4-methyl-7- (4-pyridyl) -5,6,7,8-tetrahydroquinolin-5-one (0.1 g), aminoguanidine hydrochloride (0.049 g) ),
A mixture of concentrated hydrochloric acid (0.15 ml), water (0.15 ml), and ethanol (10 ml) was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7- (4-pyridyl) -5,6,7,8-tetrahydroquinoline hydrochloride ( Compound 76) (0.13 g) was obtained as colorless crystals. . mp 267 ° C. (decomposition) Elemental analysis _{C 16 H 18 N 6 · 3HCl} · 0.5H Calcd As _{2 O C, 46.56;. H} , 5.37;. N, 20.36 Found C, 46.66; H, 5.41; N, 20.51 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.70 - 4.2 (5H, m), 2.85 (3H,
s), 7.60-8.4 (4H, br), 7.76 (1H, d, J = 6 Hz),
8.17 (2H, d, J = 5 Hz), 8.61 (1H, d, J = 6 Hz), 8.
97 (2H, d, J = 5 Hz), 11.82 (1H, s).

Example 76 (Production of compound 77) 7- (4-Fluorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.2 g), aminoguanidine hydrochloride
(0.091 g), concentrated hydrochloric acid (0.2 ml), water (0.2 ml), ethanol (3
(0 ml) was heated to reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate and then from ethanol-water to give 7- (4-fluorophenyl) -5.
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 77) (0.17 g) was obtained as colorless crystals. . mp 259 ° C. (decomposition) Elemental analysis _{C 17 H 18 FN 5 · 2HCl} · H 2 O as Calcd C, 50.75;. H, 5.51;. N, 17.41 Found C, 51.02; H, 5.58; N, 17.38. ¹ H-NMR (DMSO-d ₆ ) δ: 2.73-2.87 (1H, m), 2.86 (3
H, s), 3.00-4.1 (4H, m), 7.13-7.32 (2H, m), 7.4
3-7.60 (2H, m), 7.60-8.08 (4H, br), 7.78 (1H,
d, J = 6 Hz), 8.61 (1H, d, J = 6 Hz), 11.41 (1H,
s).

Example 77 (Production of compound 78) Aminoguanidine hydrochloride (0.023 g) in ethanol (10 ml)
Methanesulfonic acid (0.02 g) was added to the solution, and the mixture was heated under reflux for 30 minutes. To this solution was added 4-methoxy-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.05 g), and the mixture was stirred at room temperature for 2 hours and 20 minutes and at 50 ° C. for 25 minutes. Further, methanesulfonic acid (0.02 g) was added, and the mixture was stirred at 50 ° C. for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methoxy-7-phenyl-.
5,6,7,8-Tetrahydroquinoline methanesulfonate (compound 78) (0.09 g) was obtained as colorless crystals. . mp 203 ° C. (decomposition) Elemental analysis _{C 16 H 18 N 6 · 2MeSO} 3 Calcd the _{H · H 2 O C, 41.19} ;. H, 5.09;. N, 12.64 Found C, 41.17; H, 5.25; N, ^{. 12.75 1 H-NMR (DMSO} -d 6) δ: 2.38 (6H, s), 2.66 - 2.88 (1
H, m), 3.03-3.90 (4H, m), 4.19 (3H, s), 6.8-8.4
(4H, br), 7.22-7.48 (5H, m), 7.64 (1H, d, J = 7
Hz), 8.73 (1H, d, J = 7 Hz), 10.87 (1H, s).

Example 78 (Preparation of compound 79) Aminoguanidine hydrochloride (0.048 g) in methanol (20 m
l) To the solution was added methanesulfonic acid (0.042 g), and the mixture was heated under reflux for 1 hour. Add 7- (2-chlorophenyl) -4-methoxy-5,6,7,8-tetrahydroquinolin-5-one (0.12 g) and methanesulfonic acid (0.042 g) and add 9 hours at 50 ° C and 16 hours at 60 ° C Heated. The solvent was distilled off under reduced pressure, water was added, and the mixture was washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from water-ethanol to give 7- (2-chlorophenyl) -5-guanidinoimino-4-methoxy-5,6,7,8-tetrahydroquinolinemethanesulfone. The acid salt (compound 79) (0.19 g) was obtained as colorless crystals. mp. 158-159 ° C Elemental analysis: C ₁₇ H ₁₈ ClN ₅ O ・ 2MeSO ₃ H ・ H ₂ O Calcd. C, 41.19; H, 5.09; N, 12.64. ^{. 12.75 1 H-NMR (DMSO} -d 6) δ: 2.54 (6H, s), 2.72 - 2.84 (1
H, m), 3.06-3.57 (3H, m), 3.63-4.3 (1H, m), 4.2
1 (3H, s), 7.2-8.0 (4H, br), 7.36-7.63 (5H,
m), 8.61 (1H, d, J = 7 Hz).

Example 79 (Production of compound 80 and compound 81) 4-chloro-7- (2-chlorophenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.1 g), aminoguanidine hydrochloride (0.0
40 g), concentrated hydrochloric acid (0.034 ml), water (0.034 ml), ethanol
(20 ml) mixture was heated at room temperature for 30 minutes and at 50 ° C. for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. Aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (EtOAc / MeOH / EtOAc).
₃ N). 1N hydrochloric acid was added to each of the obtained two types of amorphous and concentrated, and 7- (2-chlorophenyl) -4-ethoxy-5-guanidinoimino-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 80) (0.05 g) as colorless crystals
7- (2-chlorophenyl) -5-guanidinoimino-1,4,5,6,7,
8-Hexahydroquinolin-4-one hydrochloride (Compound 81)
(0.04 g) was obtained as amorphous. 7- (2-chlorophenyl) -4-ethoxy-5-guanidinoimino
-5,6,7,8-tetrahydroquinoline hydrochloride (compound 8
0): mp. 214 ° C (decomposition) Elemental analysis value C ₁₆ H ₁₆ F ₂ N ₄ O · HCl · 0.1H ₂ O Calcd. C, 53.89; H, 4.86; N, 15.71. Found C, 53.80; H ^{, 4.90; N, 15.97 1 H} -NMR (DMSO-d 6) δ:. 1.47 (3H, t, J = 7 Hz), 2.81
(1H, dd, J = 12, 16 Hz), 3.06-3.88 (4H, m), 4.29
-4.66 (2H, m), 6.4-8.4 (4H, br), 7.28 -7.62 (4
H, m), 8.69 (1H, d, J = 7 Hz), 11.48 (1H, s) .7- (2-chlorophenyl) -5-guanidinoimino-1,4,5,6,7,
8-hexahydroquinolin-4-one hydrochloride (compound 8
1): ¹ H-NMR (DMSO-d ₆ ) δ: 2.87 (1H, dd,
J = 3, 16 Hz), 3.16 (1H,
dd, J = 13, 17 Hz), 3.25
-3.65 (2H, m), 3.86-4.
08 (1H, m), 7.14 (1H, d,
J = 7 Hz), 7.31-7.63 (5
H, m), 7.8-8.25 (4H, b
r), 8.45 (1H, d, J = 7H
z), 10.43 (1H, br), 11.21
(1H, s).

Example 80 (Production of compound 82) 2-Methyl-7-phenyl-5,6,7,8-tetrahydroquinoline
A mixture of -5-one (0.3 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.063 ml), water (0.063 ml), and ethanol (30 ml) was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, added with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer,
The extract was washed with water and saturated saline and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol, and 1N hydrochloric acid was added to distill off the solvent. The residue was recrystallized from ethanol to give 5-guanidinoimino-2-methyl-7-phenyl-5,6,
7,8-tetrahydroquinoline hydrochloride (Compound 82) (0.34
g) was obtained as colorless crystals. . mp 300 ° C. or higher as elemental analysis _{C 17 H 19 N 5 · 2HCl} Calcd C, 55.74;. H, 5.78;. N, 19.12 Found C, 55.41; H, 5.60;. N, 18.94 1 H-NMR (DMSO -d ₆ ) δ: 2.65-2.96 (1H, m), 2.78 (3
H, s), 3.15-3.61 (4H, m), 7.25-7.55 (5H, m), 7.
6-8.7 (4H, br), 7.78 (1H, d, J = 8Hz), 9.72 (1H,
d, J = 8Hz), 11.51 (1H, s).

Example 81 (Production of compound 83) 2,4-Dimethyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g)
g), concentrated hydrochloric acid (0.06 ml), water (0.06 ml), ethanol (30 m
The mixture of l) was heated at reflux for 4 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, added with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethanol.
The solvent was distilled off by adding 1N hydrochloric acid. The residue was recrystallized from ethanol to give 5-guanidinoimino-2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 8
3) (0.25 g) was obtained as colorless crystals. . mp 270 ° C. (decomposition) Calcd As Elemental analysis _{C 18 H 21 N 5 · 2HCl} C, 56.85;. H, 6.10;. N, 18.41 Found C, 56.49; H, 6.00;. N, 18.04 1 H-NMR (DMSO-d ₆ ) δ: 2.5-3.8 (5H, m), 2.72 (3H,
s), 2.82 (3H, s), 7.23-7.60 (6H, m), 7.6-8.2
(4H, br), 7.71 (1H, s), 11.33 (1H, s).

Example 82 (Production of compound 84) 2,4-dimethyl-7- (2-methylphenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.48 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml), and ethanol (50 ml) were heated and refluxed for 4 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with diethyl ether.
An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol, and 1N hydrochloric acid was added. The solvent was distilled off under reduced pressure, and 5-guanidinoimino-2,4-dimethyl-7- (2-methylphenyl) -5,6,7,8
-Tetrahydroquinoline hydrochloride (Compound 84) (0.58 g)
Was obtained as amorphous. ¹ H-NMR (DMSO-d ₆ ) δ: 2.34 (3H, s), 2.62-2.92 (1
H, m), 2.74 (3H, s), 2.85 (3H, s), 3.10-3.58 (4
H, m), 7.10-7.50 (4H, m), 7.63-8.40 (4H, br),
7.74 (1H, s), 11.33 (1H, s).

Example 83 (Production of compound 85) 7- (2-Fluorophenyl) -2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g), aminoguanidine hydrochloride (0.052 g), a mixture of concentrated hydrochloric acid (0.067 ml), water (0.067 ml), and ethanol (10 ml) was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 7- (2-fluorophenyl) -5-guanidinoimino-2,4-
Dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 85) (0.12 g) was obtained. . mp 232 ° C. (decomposition) Elemental analysis _{C 18 H 20 FN 5 · 2HCl} · 1.2H Calcd As _{2 O C, 51.48;. H} , 5.86;. N, 16.68 Found C, 51.37; H, 5.97; N, 16.68 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.70 (3H, s), 2.82 (3H, s),
2.60-2.96 (1H, m), 3.11-3.28 (1H, m), 3.34-
3.63 (3H, m), 7.17-7.43 (3H, m), 7.51-7.62 (3H,
m), 7.69 (1H, s), 7.83 (4H, br), 11.35 (1H, s).

Example 84 (Production of compound 86) 7- (2-chlorophenyl) -2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.20 g), aminoguanidine hydrochloride ( 0.081 g), a mixture of concentrated hydrochloric acid (0.1 ml), water (0.1 ml), and ethanol (20 ml) was heated under reflux for 13.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate.
The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol.
7- (2-chlorophenyl) -5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 8
6) (0.11 g) was obtained as colorless crystals. . mp 227 ° C. (decomposition) Elemental analysis _{C 18 H 21 ClN 5 · 2HCl} · 0.5H Calcd As _{2 O C, 51.02;. H} , 5.47;. N, 16.53 Found C, 50.96; H, 5.34; N, 16.64 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.73 (3H, s), 2.85 (3H, s),
2.6-3.0 (1H, m), 3.24 (1H, dd, J = 5, 19 Hz), 3.3
3-3.76 (3H, m), 7.30-7.56 (3H, m), 7.6 -8.3 (4
H, br), 7.64 (1H, dd, J = 2, 7 Hz), 7.74 (1H, s),
11.47 (1H, s).

Example 85 (Production of compound 87) 2,4-Dimethyl-7- (2-pyridyl) -5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride ( 0.03
7g), concentrated hydrochloric acid (0.079 ml), water (0.079 ml), ethanol (10
ml) of the mixture was heated to reflux for 7 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-2,4-dimethyl-7- (2-pyridyl) -5,6,7,8
-Tetrahydroquinoline hydrochloride (Compound 87) (0.1 g) was obtained as colorless crystals. mp. 201 ° C (decomposition) Elemental analysis value C ₁₇ H ₂₀ N ₆ 3HCl 3H ₂ O Calcd. C, 43.28; H, 6.20; N, 17.81. Found C, 43.36; H, 5.98; N, 18.04. ¹ H-NMR (DMSO-d ₆ ) δ: 2.73 (3H, s), 2.83 (3H, s),
3.12 (1H, dd, J = 10, 18 Hz), 3.24-3.80 (5H, m),
7.2-8.40 (4H, br), 7.57-7.66 (1H, m), 7.76 (1
H, s), 7.82 (1H, d, J = 8 Hz), 8.12-8.23 (1H,
m), 8.73 (1H, d, J = 4 Hz), 11.62 (1H, s).

Example 86 (Production of compound 88) 2-Methyl-7- (2-methylphenyl) -5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.2 g)
6 g), concentrated hydrochloric acid (0.12 ml), water (0.12 ml), ethanol (30
ml) of the mixture was heated at reflux for 2.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, washed with diethyl ether, added with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethanol.
1N Hydrochloric acid (2.5 ml) was added and the solvent was distilled off. The residue was washed with ethanol to give 5-guanidinoimino-2-methyl-7- (2-methylphenyl) -5,6,7,8-tetrahydroquinoline hydrochloride (Compound 88) (0.32 g) as colorless crystals. Was. . mp 206 ° C. (decomposition) Elemental analysis _{C 18 H 21 N 5 · 2HCl} · 0.3H Calcd As _{2 O C, 56.05;. H} , 6.17;. N, 18.16 Found C, 56.12; H, 6.36; N, 18.23 ^{. 1 H-NMR (DMSO-} d 6) δ: 2.36 (3H, s), 2.65 - 2.90 (1
H, m), 2.79 (3H, s), 3.10-3.65 (4H, m), 7.10-
7.32 (4H, m), 7.42 (1H, d, J = 7 Hz), 7.80 (1H, d,
J = 8 Hz), 7.6-8.7 (4H, br), 9.34 (1H, d, J = 8
Hz), 11.51 (1H, s).

Example 87 (Preparation of compound 89) 7- (2-Chlorophenyl) -4-methyl-5,6
7,8-tetrahydroquinazolin-5-one (40 m
g), aminoguanidine hydrochloride (16 mg), ethanol (3 ml) and 6N hydrochloric acid (0.025 ml) were added,
The mixture was heated and stirred at 3 ° C. for 3 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethanol, ethyl acetate and isopropyl ether, dried, and dried with (E) -7- (2-chlorophenyl) -5-guanidinoimino-4-methyl. −
5,6,7,8-Tetrahydroquinazoline hydrochloride (compound 89) (38 mg) was obtained. mp 284 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₆ Cl.2HCl.0.5 H ₂ O Calcd. C, 46.79; H, 4.91;
N, 20.46 Found C, 46.73; H, 4.62;
^{N, 20.55 1 H-NMR (} DMSO-d 6) δ: 2.7-3.0
(2H, m), 2.83 (3H, s), 3.1-3.4
(2H, m), 3.59 (1H, m), 7.32-7.
64 (4H, m), 7.76 (4H, broad),
8.89 (1H, s).

Example 88 (Preparation of Compound 90) 7- (2-Chlorophenyl) -2,4-dimethyl-5
6,7,8-tetrahydroquinazolin-5-one (0.
20 g) and aminoguanidine hydrochloride (77 mg), ethanol (14 ml) and 6N hydrochloric acid (0.12 ml) were added, and the mixture was heated with stirring at 90 ° C. for 3 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate, and isopropyl ether in that order, dried, and dried (E) -7- (2
-Chlorophenyl) -5-guanidinoimino-2,4-
Dimethyl-5,6,7,8-tetrahydroquinazoline hydrochloride (Compound 90) (0.14 g) was obtained. mp 242-244 ° C. Elemental analysis value: C ₁₇ H ₁₉ N ₆ Cl.2HCl.0.2 H ₂ O Calcd. C, 48.69; H, 5.14;
N, 20.04 Found C, 48.65; H, 5.09;
N, 19.84 ¹ H-NMR (DMSO-d ₆ ) δ: 2.65 (3H,
s), 2.7-3.0 (2H, m), 2.86 (3H,
s), 3.1-3.4 (2H, m), 3.59 (1H,
m), 7.30-7.52 (3H, m), 7.61 (1
H, dd, J = 1.4 & 7.4 Hz), 7.80 (4
H, broad).

Example 89 (Production of Compound 91) 4-methyl-7- (2-methylphenyl) -5-oxo-cyclopenta [2,1-b] pyridine (48 mg), aminoguanidine hydrochloride (25 mg)
mg) and concentrated hydrochloric acid (40 mg) were heated under reflux in ethanol (1 ml) for 2 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol, dried and dried with 5-guanidinoimino-4-methyl-7- (2-methylphenyl) cyclopenta [2,1-b] pyridine. The hydrochloride (compound 91) (48 mg) was obtained as yellow crystals. . mp 203-204 ° C. decomposition Elemental analysis _{C 17 H 19 N 5 · 2HCl} · 2H 2 O as Calcd C, 50.75;. H, 6.26; N, 17.41 Found C, 50.89; H, 6.36;. N, 17.45 1 H-NMR (DMSO-d ₆ ) δ: 2.40 (3H, s), 2.75 (3H, s),
2.80 (1H, dd), 3.62 (1H, dd), 4.99 (1H, dd), 6.66
(1H, dd), 7.19 (3H, m), 7.45 (1H, d), 7.74 (4H, br
oad), 8.51 (2H, d), 11.45 (1H, s).

Example 90 (Production of compound 92) 6- (2-chlorophenyl) -3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (78 mg), 1-amino-3-methyl Guanidine p-toluenesulfonate (86 mg), concentrated hydrochloric acid (0.1
ml) was stirred in ethanol (1 ml) at room temperature for 60 hours. The crystals precipitated during the reaction were collected by filtration and washed with ethanol.
Ethyl acetate (60 ml) and 2 N sodium hydroxide
(5 ml) was added, stirred, dissolved and separated. The ethyl acetate layer was washed with water (3 times with 10 ml), and 2N hydrochloric acid (0.3 ml) was added.
Concentrated under reduced pressure. Residue is ether / ethanol = 4 /
Wash with the mixed solvent of 1 and dry to give 6- (2-chlorophenyl)
-3-methyl-4- (1-methylguanidin-3-yl) imino-4,5,
6,7-tetrahydroindazole hydrochloride (compound 92) (80
mg) as a colorless solid. mp. 240 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3H, s), 2.69 (1H, dd),
2.92 (5H, m), 3.08 (1H, dd), 3.58 (1H, m), 7.27-7.
43 (2H, m), 7.49 (1H, dd), 7.59 (1H, dd), 7.69 (1
H, broad), 7.80 (2H, broad).

Example 91 (Production of compound 93) 6- (2-chlorophenyl) -3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (1.14 g), 1-amino-3-hydroxy Guanidine p-toluenesulfonate (1.26 g) and concentrated hydrochloric acid (0.44 ml) were stirred in ethanol (12 ml) at 85 ° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added an aqueous solution (20 ml) of ethyl acetate (50 ml), tetrahydrofuran (20 ml), and anhydrous potassium carbonate (1.4 g), followed by shaking and separation. The upper layer was washed with an aqueous solution (10 ml) of anhydrous potassium carbonate (0.7 g) and washed with water (3 times with 10 ml). 2N hydrochloric acid (2.3
ml) and concentrated under reduced pressure. Ether (30 m
A mixed solvent of l) and ethanol (15 ml) was added, and the mixture was stirred at room temperature for 15 hours, and the solidified powder was collected by filtration. This powder was stirred in ethanol (4 ml) at 90 ° C. (bath temperature) for 1 hour, the precipitated crystals were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (12 ml) and stirred at 90 ° C (bath temperature) for 14 hours. After cooling the reaction solution, crystals precipitated during the stirring were collected by filtration, washed with ethanol, dried and dried to give 6- (2-chlorophenyl) -4- (1-
(Hydroxyguanidin-3-yl) imino-3-methyl-4,5,6,
7-tetrahydroindazole hydrochloride (Compound 93) (604
mg) as pale yellow crystals. mp. 234-235 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3H, s), 2.69 (1H, dd),
2.94 (2H, d), 3.08 (1H, dd), 3.57 (1H, m), 7.27-7.
52 (3H, m), 7.60 (1H, dd), 7.98 (2H, broad), 10.66
(1H, s), 10.95 (1H, s).

Example 92 (Production of compound 94) 7- (2,5-dimethylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (100 mg), 1-amino- 3-hydroxyguanidine p-toluenesulfonate (131 mg), concentrated hydrochloric acid
(0.1 ml) was stirred in ethanol (2 ml) at 85 ° C (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate (2
0 ml), tetrahydrofuran (12 ml) and 0.2 N sodium hydroxide (10 ml) were added, shaken and separated. Top layer 0.2
N Wash with sodium hydroxide (5 ml) and wash with water (3 times with 5 ml)
did. 2 N hydrochloric acid (0.5 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was washed with a mixed solvent of ether (4 ml) and ethanol (2 ml), dried and dried with 7- (2,5-dimethylphenyl)-
5- (1-hydroxyguanidin-3-yl) imino-4-methyl-
5,6,7,8-tetrahydroquinoline hydrochloride (compound 94) (12
1 mg) were obtained as yellow crystals. mp. 190-192 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 2.30 (3H, s),
2.79 (1H, m), 2.89 (3H, s), 3.19 (1H, d), 3.39 (3H,
m), 7.00 (1H, d), 7.10 (1H, d), 7.26 (1H, s), 7.8
3 (1H, d), 8.33 (2H, broad), 8.63 (1H, d), 10.40
(1H, broad), 11.15 (1H, broad), 11.34 (1H, broad).

Example 93 (Production of compound 95) 7- (2,3-dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (306 mg), 1-amino-3 -Hydroxyguanidine p-toluenesulfonate (320 mg), concentrated hydrochloric acid
(0.2 ml) in ethanol (6 ml) at 85 ° C (bath temperature) for 2 hours 30
Minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate (30 ml), tetrahydrofuran (20 ml), and 0.2 N sodium hydroxide (25 ml) were added to the residue, and the mixture was shaken and separated. The upper layer was washed with 0.2 N sodium hydroxide (10 ml) and washed with water (10 ml).
3 times). 2 N hydrochloric acid (1 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol and dried to give 7- (2,
3-dichlorophenyl) -5- (1-hydroxyguanidine-3-
Ill) imino-4-methyl-5,6,7,8-tetrahydroquinoline
The hydrochloride (compound 95) (390 mg) was obtained as yellow crystals. mp. 196-198 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.89 (4H, m), 3.27 (1H, dd),
3.47 (2H, m), 3.73 (1H, m), 7.46 (1H, t), 7.62 (2
H, dd), 7.81 (1H, d), 8.34 (2H, broad), 8.63 (1H,
d), 10.40 (1H, broad), 11.15 (1H, broad), 11.45 (1
H, broad).

Example 94 (Production of compound 96) 7- (2,6-dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (153 mg), 1-amino-3 -Hydroxyguanidine p-toluenesulfonate (262 mg), concentrated hydrochloric acid
(0.1 ml) in ethanol (3 ml) at 90 ° C (bath temperature) for 1 hour 30
Minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (15 ml) were added to the residue, and the mixture was shaken and separated. The upper layer was washed with 0.2 N sodium hydroxide (10 ml) and washed with water (10 ml).
3 times). 2 N hydrochloric acid (0.5 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was washed with ether (3 ml) and ethanol (1.5
washed with a mixed solvent of 7- (2,6-dichlorophenyl) -5- (1-hydroxyguanidin-3-yl) imino-4.
-Methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 96) was obtained as pale yellow crystals. mp. 193-195 ℃ decomposition Elemental analysis value C ₁₇ H ₁₇ N ₅ Cl ₂ O ・ 2HCl ・ 3 / 4H ₂ O Calcd. C, 43.94; H, 4.45; N, 15.07 Found C, 43.94; H, 4.63 ^{. N, 14.87 1 H-NMR} (DMSO-d 6) δ: 2.85 (3H, s), 3.07 (1H, dd),
3.26 (1H, d), 3.38 (1H, dd), 4.08 (2H, m), 7.41 (1
H, t), 7.57 (2H, d), 7.78 (1H, d), 8.35 (2H, broa
d), 8.62 (1H, d), 10.38 (1H, broad), 11.13 (1H, br
oad), 11.40 (1H, broad).

Example 95 (Production of compound 97) 7- (2-furyl) -4-methyl-5,6,7,8-tetrahydroquinoline
-5-one (227 mg), 1-amino-3-hydroxyguanidine p
-Toluenesulfonic acid salt (314 mg) and concentrated hydrochloric acid (0.1 ml) were stirred in ethanol (3 ml) at 90 ° C (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was ethyl acetate (30 ml), tetrahydrofuran (20 ml), 0.2 N sodium hydroxide (20 ml)
Was added, and the mixture was shaken and separated. The upper layer was washed with 0.2 N sodium hydroxide (10 ml) and washed with water (3 times with 10 ml). 2 N hydrochloric acid (1 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was stirred in ethanol (3 ml) at 90 ° C. (bath temperature) for 3 hours and cooled. The crystals precipitated during the stirring were collected by filtration, washed with ethanol and dried to give 7- (2-furyl) -5- (1-hydroxyguanidin-3-yl) imino-4-methyl-5,6,7, 8-Tetrahydroquinoline hydrochloride (compound 97) (154 mg) was obtained as pale yellow crystals. mp. 196-198 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (3H, s), 2.96 (1H, dd),
3.23 (2H, m), 3.54 (2H, m), 6.40 (2H, m), 7.61 (1
H, s), 7.79 (1H, d), 8.45 (2H, broad), 8.62 (1H,
d), 10.40 (1H, broad), 11.17 (1H, broad), 11.69 (1
H, broad).

Example 96 (Production of compound 98) 4-methyl-7- (5-methyl-2-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (257 mg), 1-amino acid -3-hydroxyguanidine p-toluenesulfonate (285 mg), concentrated hydrochloric acid
(0.2 ml) was stirred in ethanol (3 ml) at 90 ° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate (3
0 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml) were added, shaken and separated. Top layer 0.2
N Wash with sodium hydroxide (10 ml) and wash with water (3
Times). 2 N hydrochloric acid (1 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was stirred in ethanol (1 ml) at room temperature for 15 hours, and the crystals were collected by filtration, dried and dried with 5- (1-hydroxyguanidin-3-yl) imino-4-methyl-7- (5-methyl- 2-thienyl) -5,6,7,8-tetrahydroquinoline hydrochloride (compound 9
8) (163 mg) was obtained as pale yellow crystals. mp. 210-212 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (3H, s), 2.85 (3H, s),
2.92 (1H, dd), 3.37 (2H, m), 3.54 (2H, m), 6.67 (1
H, m), 6.88 (1H, d), 7.79 (1H, d), 8.43 (2H, broa
d), 8.63 (1H, d), 10.38 (1H, broad), 11.16 (1H, br
oad), 11.62 (1H, broad).

Example 97 (Production of compound 99) 7-phenyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.19 g), aminoguanidine hydrochloride (0.092 g) A mixture of concentrated hydrochloric acid (0.04 ml), water (0.04 ml) and ethanol (20 ml) was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 5-guanidinoimino-7-phenyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (compound 99). ) (0.21 g) as colorless crystals. mp. 300 ° C or higher ¹ H-NMR (DMSO-d ₆ ) δ: 2.45-3.6 (5H, m), 6.26 (1H,
d, J = 9 Hz), 7.0-8.2 (4H, br), 7.20-7.50 (5
H, m), 8.41 (1H, d, J = 9 Hz), 10.94 (1H, s), 11.90
(1H, s).

Example 98 (Production of compound 100) 4-Methyl-7- (3-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (243 mg), aminoguanidine hydrochloride (122 m
g) and concentrated hydrochloric acid (0.2 ml) were heated under reflux in ethanol (3 ml) for 2 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7- (3-thienyl) -5,6,7,8-tetrahydroquinoline. The hydrochloride (Compound 100) (362 mg) was obtained as colorless crystals. mp. 300 ° C or higher ¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (3H, s), 2.90 (1H, dd),
3.36 (4H, m), 7.24 (1H, dd), 7.49 (1H, d), 7.56 (1
H, m), 7.82 (1H, d), 7.90 (4H, broad), 8.64 (1H,
d), 11.65 (1H, broad).

Example 99 (Production of compound 101) 7- (2-chlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (147 mg), aminoguanidine Hydrochloride (63 mg), concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml)
The mixture was stirred at 90 ° C (bath temperature) for 14 hours. Cool the reaction solution,
The precipitated crystals are collected by filtration, washed with ethanol and dried.
-(2-chlorothiophen-3-yl) -5-guanidinoimino-4-
Methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 101) (148 mg) was obtained as colorless crystals. . mp 281-283 ° C. (decomposition) Elemental analysis C ₁₅ H ₁₈ N ₅ Calcd as ClS · 2HCl C, 44.29;. H, 4.46; N, 17.22 Found C, 44.29; H, 4.54;. N, 17.21 1 H -NMR (DMSO-d ₆ ) δ: 2.86 (4H, m),
3.15 (1H, dd), 3.39 (3H, dd)
m), 7.25 (1H, d), 7.55
(1H, d), 7.82 (1H, d), 7.
92 (4H, broad), 8.62 (1H,
d), 11.43 (1H, broad).

Example 100 (Preparation of Compound 102) 7- (2,5-Dichlorothiophen-3-yl) -4-methyl-
5,6,7,8-Tetrahydroquinolin-5-one (218 mg), aminoguanidine hydrochloride (83 mg) and concentrated hydrochloric acid (0.1 ml) were added to ethanol (4 ml) at 100 ° C (bath temperature). Stirred for hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration, washed with ethanol and dried to give 7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6. , 7,8-Tetrahydroquinoline hydrochloride (Compound 102) (250 mg) was obtained as pale yellow crystals. mp. 300 ° C or higher Elemental analysis value C ₁₅ H ₁₅ N ₅ Cl ₂ S ・ 2HCl Calcd. C, 40.83; H, 3.88; N, 15.87 Found C, 40.75; H, 3.64; N, 15.69. ¹ H-NMR (DMSO-d ₆ ) δ: 2.85 (4H, m), 3.12 (1H, dd),
3.36 (3H, m), 7.42 (1H, s), 7.79 (1H, d), 7.90 (4
H, broad), 8.62 (1H, d), 11.44 (1H, broad).

Example 101 (Production of compound 103) 4-methyl-7- (3-thienyl) -5,6,7,8-tetrahydroquinolin-5-one (243 mg), 1-amino-3-hydroxy Guanidine
p-Toluenesulfonic acid salt (393 mg) and concentrated hydrochloric acid (0.2 ml) were stirred in ethanol (3 ml) at 90 ° C. (bath temperature) for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml) were added to the residue.
ml), and the mixture was shaken and separated. The upper layer was washed with 0.2 N sodium hydroxide (10 ml) and washed with water (3 times with 10 ml).
2 N hydrochloric acid (1 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure.
The residue was added with ether (3 ml), stirred at 90 ° C (bath temperature) for 2 hours, cooled, and the crystals were collected by filtration, washed with ethanol, dried and dried with 5- (1-hydroxyguanidine-3- Il) Imino-4-
Methyl-7- (3-thienyl) -5,6,7,8-tetrahydroquinoline hydrochloride (Compound 103) (233 mg) was obtained as pale yellow crystals. mp. 201-202 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (4H, m), 3.35 (4H, m),
7.23 (1H, dd), 7.47 (1H, dd), 7.58 (1H, dd), 7.78
(1H, d), 8.42 (2H, broad), 8.63 (1H, d), 10.40 (1
H, broad), 11.15 (1H, broad), 11.58 (1H, broad).

Example 102 (Production of compound 104) 7- (2-chlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (222 mg), Amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) were stirred in ethanol (4 ml) at 90 ° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml) were added to the residue, and the mixture was shaken and separated. The upper layer was washed with 0.2 N sodium hydroxide (15 ml) and washed with water (10 ml).
3 times). 2 N hydrochloric acid (0.8 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. Add ether (3 ml) to the residue, and add
The mixture was stirred at (bath temperature) for 3 hours, cooled, and the crystals were collected by filtration, washed with ethanol, dried and dried to give 7- (2-chlorothiophen-3-yl) -5- (1-hydroxyguanidine-3- Yl) imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 10
4) (183 mg) was obtained as pale yellow crystals. mp. 199-200 ℃ Decomposition Elemental analysis C ₁₅ H ₁₆ N ₅ ClOS ・ 2HCl ・ 1 / 2H ₂ O Calcd. 16.24. ¹ H-NMR (DMSO-d ₆ ) δ: 2.87 (4H, m), 3.15 (1H, dd),
3.39 (3H, m), 7.25 (1H, d), 7.54 (1H, d), 7.81 (1
H, d), 8.36 (2H, broad), 8.62 (1H, d), 10.40 (1H, b
road), 11.15 (1H, broad), 11.43 (1H, broad).

Example 103 (Preparation of Compound 105) 7- (2,5-Dichlorothiophen-3-yl) -4-methyl-5,6,7,8
-Tetrahydroquinolin-5-one (250 mg), 1-amino-3-
Hydroxyguanidine p-toluenesulfonate (314 m
g) and concentrated hydrochloric acid (0.1 ml) were stirred in ethanol (4 ml) at 105 ° C (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (40 ml), tetrahydrofuran (25 ml), 0.2%
N sodium hydroxide (25 ml) was added, and the mixture was shaken and separated. The upper layer was washed with 0.2 N sodium hydroxide (15 ml),
Washed with water (3 times with 10 ml). 2N Hydrochloric acid (0.8 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was added with ethanol (4 ml), stirred at 90 ° C (bath temperature) for 3 hours, cooled, and the crystals were collected by filtration, washed with ethanol, dried and dried to give 7- (2,5-dichlorothiophene- 3-yl) -5- (1-hydroxyguanidin-3-yl)
Imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 105) (205 mg) was obtained as colorless crystals. mp. 196-197 ° C decomposition ¹ H-NMR (DMSO-d ₆ ) δ: 2.85 (4H, m), 3.14 (1H, dd),
3.35 (3H, m), 7.41 (1H, s), 7.77 (1H, d), 8.40 (2
H, broad), 8.61 (1H, d), 10.40 (1H, broad), 11.16
(1H, broad), 11.41 (1H, broad).

Example 104 (Production of compound 106) 7- (2-chlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (679 mg), 1-amino-3-hydroxyguanidine p-Toluenesulfonic acid salt (917 mg), concentrated hydrochloric acid (0.3
ml) was stirred in ethanol (10 ml) at 90 ° C (bath temperature) for 3 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (40 m
l), tetrahydrofuran (30 ml) and 0.2 N sodium hydroxide (50 ml) were added, and the mixture was shaken and separated. 0.2 N for upper layer
Wash with sodium hydroxide (20 ml) and wash with water (3 times with 15 ml)
did. 2 N hydrochloric acid (2.5 ml) was added to the upper layer, and the mixture was concentrated under reduced pressure. The residue was added with ethanol (10 ml), stirred at 90 ° C. (bath temperature) for 3 hours, cooled, and the crystals were collected by filtration to give 7- (2-chlorophenyl) -5- (1-hydroxyguanidine-3-l. Il) imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 106) (790 mg) was obtained as pale yellow crystals. mp. 185-187 ° C Elemental analysis: C ₁₇ H ₁₈ N ₅ ClO ・ 2HCl ・ 4 / 5H ₂ O Calcd. C, 47.36; H, 5.05; N, 16.24 Found C, 47.56; H, 4.83; N, 15.95 . ¹ H-NMR (DMSO-d ₆ ) δ: 2.89 (4H, m),
3.24 (1H, dd), 3.43 (2H, dd)
m), 3.67 (1H, m), 7.48
(3H, m), 7.61 (1H, dd),
7.81 (1H, d), 8.35 (2H, b
load), 10.39 (1H, broad),
11.14 (1H, broad), 11.44
(1H, broad).

Example 105 (Production of Compound 107) 3-carbamoyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.24 g), aminoguanidine hydrochloride (104 mg) and ethanol ( 2
0 ml) and 6N hydrochloric acid (0.081 ml), and the mixture was heated and stirred at 90 ° C. for 2 hours. After air cooling, the precipitated crystals were ethanol,
Wash sequentially with isopropyl ether, dry and (E)
-3-carbamoyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 107) (0.28 g) was obtained. mp 294 ° C (decomposition). Elemental analysis value: C ₁₆ H ₁₇ N ₅ O ₂ .HCl C, 55.25; H, 5.22;
N, 20.14 Found C, 55.12; H, 5.09;
^{N, 20.04 1 H-NMR (} DMSO-d 6) δ: 2.68 (1H,
dd, J = 12.8 & 16.2 Hz), 3.05-3.
15 (3H, m), 3.3-3.5 (1H, m), 7.
28-7.46 (5H, m), 7.59 (5H, bro)
ad), 8.09 (1H, s), 8.22 (1H, br)
oad).

Reference Example 116 5- (2-chlorophenyl) cyclohexane-1,3-
Phosphorus trichloride (0.62 g) was added to a solution of dione (3.0 g) in chloroform (10 ml).
Stir for 5 hours. Again, phosphorus trichloride (0.62 g) was added, and the mixture was further stirred at 100 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Concentrate under reduced pressure to give 3-chloro-5-
(2-chlorophenyl) -2-cyclohexene-1-
Got on. This was dissolved in ethanol (3 ml), sodium sulfide 9-hydrate (2.0 g) and water (3 ml) were added, and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain 5- (2-chlorophenyl) -3-mercapto-2-cyclohexen-1-one (1.8 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.50-2.80
(4H, m), 3.52 (1H, s), 3.83-4.
01 (1H, m), 6.20 (1H, s), 7.14-
7.43 (4H, m).

Reference Example 117 20% of a solution of 5- (2-chlorophenyl) -3-mercapto-2-cyclohexen-1-one (1.8 g) and chloroacetone (0.7 g) in ethanol (20 ml) was added.
A sodium ethoxide ethanol solution (0.48 g) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue for extraction. Water the organic layer,
The extract was washed successively with a saturated saline solution and dried over magnesium sulfate. Concentrate under reduced pressure to give 5- (2-chlorophenyl) -3-
(2-oxopropylthio) -2-cyclohexene-1
-On (2.3 g) was obtained. mp. 81-82 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 2.52-2.80 (4H, m), 3.76 (2
H, s), 3.79-3.99 (1H, m), 5.85
(1H, s), 7.16-7.43 (4H, m).

Reference Example 118 5- (2-chlorophenyl) -3- (2-oxopropylthio) -2-cyclohexen-1-one (1.0
A solution of g) in xylene (10 ml) was heated at reflux for 7.5 days. After cooling, the reaction solution was subjected to silica gel column chromatography (EtOAc / hexane) to give 6- (2-chlorophenyl) -3-methyl-4,5,5 as an oil.
6,7-Tetrahydrobenzothiophen-4-one (0.07 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H,
s), 2.64-2.92 (2H, m), 3.09 (1
H, dd, J = 11, 17 Hz), 3.35 (1H, d
d, J = 4, 17 Hz), 3.96-4.13 (1H,
m), 6.70 (1H, s), 7.14-7.50 (4
H, m).

Reference Example 119 A solution of 5- (2-thiazolyl) -cyclohexane-1,3-dione (0.93 g) and ammonium acetate (1.1 g) in ethanol (20 ml) was heated under reflux for 13 hours.
The solvent was distilled off under reduced pressure, and aqueous sodium hydrogen carbonate was added.
The aqueous layer was washed with ethyl acetate and concentrated. Ethanol-ethyl acetate (1: 1) was added to the residue, the insolubles were collected by filtration, and concentrated under reduced pressure. Ethanol was added to the residue, insolubles were filtered, and concentrated under reduced pressure to obtain a solid. Add this to ethanol (1
0 ml) and toluene (30 ml), 3-oxobutyraldehyde dimethyl acetal (1.6 g) and powdered 85% potassium hydroxide (0.26 g) were added, and the mixture was heated under reflux. After 30 minutes, powdered 85% potassium hydroxide (0.054 g), and after 1 hour, powdered 85% potassium hydroxide (0.054 g) and 3-oxobutyraldehyde dimethyl acetal (0.063 g), 1 hour 30 minutes After that, powdery 85% potassium hydroxide (0.054 g) was added,
Thereafter, the mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline in that order, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexa).
ne) as crystals after 7- (2-thiazolyl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
ON (0.76 g) was obtained. mp. 88-89 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H,
s), 3.09 (1H, dd, J = 10, 17 Hz),
3.16-3.28 (1H, m), 3.53 (1H, d
d, J = 10, 17 Hz), 3.68 (1H, dd, J)
= 5,17Hz), 3.86-4.06 (1H, m),
7.11 (1H, d, J = 5 Hz), 7.28 (1H,
d, J = 4 Hz), 7.75 (1H, d, J = 4H)
z), 8.50 (1H, d, J = 5 Hz).

Reference Example 120 5- (3-chlorothiophen-2-yl) cyclohexane-1,3-dione (2.0 g), acetic acid (0.90
g) and dicyclohexylcarbodiimide (2.3 g) were added to a solution of dimethylaminopyridine (1.6 g) in dimethylformamide (100 ml), and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue.
The extract was washed successively with an aqueous solution of potassium hydrogen sulfate and water. 1N aqueous sodium hydroxide was added, and the aqueous layer was washed with diethyl ether. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to give 5- (3-
Chlorothiophen-2-yl) -2- (1-hydroxyethylidene) -cyclohexane-1,3-dione (2.
2 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.65 (3H,
s), 2.66 (1H, dd, J = 12, 16 Hz),
2.85 (1H, dd, J = 12, 18 Hz), 2.8
9 (1H, ddd, J = 2, 5, 16 Hz), 3.03
(1H, ddd, J = 2, 5, 18 Hz), 3.71-
3.91 (1H, m), 6.92 (1H, q, J = 5H
z), 7.20 (1H, d, J = 5 Hz).

Reference Example 121 5- (3-chlorothiophen-2-yl) -2- (1-
A solution of (hydroxyethylidene) -cyclohexane-1,3-dione (2.2 g) and hydrazine hydrate (0.45 g) in ethanol (60 ml) was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 6- (3-chlorothiophene- as colorless crystals.
2-yl) -3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.3 g) was obtained. mp. 163-165 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.59 (3H,
s), 2.70 (1H, dd, J = 11, 17 Hz),
2.86 (1H, dd, J = 4, 17 Hz), 2.96
(1H, dd, J = 11, 16 Hz), 3.29 (1
H, dd, J = 4, 16 Hz), 3.84-4.03
(1H, m), 6.91 (1H, d, J = 5 Hz),
7.18 (1H, d, J = 5 Hz).

Reference Example 122 5- (2,5-dichlorophenyl) -cyclohexane-
1,3-dione (5.0 g), ammonium acetate (4.
A solution of 5 g) in ethanol (100 ml) was heated to reflux for 20.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with water and then with toluene, and dried to obtain crystals. This was dissolved in ethanol (50 ml) and toluene (150 ml),
-Oxobutyraldehyde dimethyl acetal (6.1
g) and powdered 85% potassium hydroxide (1.0 g) were added, and the mixture was heated under reflux. 30 minutes later, powdered 85% potassium hydroxide (0.21 g), 1 hour later powdered 85% potassium hydroxide (0.21 g) and 3-oxobutyraldehyde dimethyl acetal (0.24 g), 1 hour 30 minutes After addition of powdered 85% potassium hydroxide (0.21 g),
Refluxed for 1.5 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline in that order, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc / hexan).
e), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 7- (2,5-dichlorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (3 0.7 g) as crystals. mp. 116-117 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.72 (3H,
s), 2.80 (1H, dd, J = 12, 16 Hz),
3.00 (1H, ddd, J = 2, 4, 17 Hz),
3.26 (1H, dd, J = 12, 17 Hz), 3.4
6 (1H, ddd, J = 2, 4, 16 Hz), 3.83
−4.04 (1H, m), 7.12 (1H, d, J = 5)
Hz), 7.21 (1H, dd, J = 2.8 Hz),
7.31 (1H, d, J = 2 Hz), 7.36 (1
H, d, J = 8 Hz), 8.50 (1 H, d, J = 5 H)
z).

Reference Example 123 A solution of 7- (3-chlorothiophen-2-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.74 g) in ethyl acetate (10 ml) was prepared. , Pyridine (0.21 g) and sulfuryl chloride (1.1 g) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (Et.
OAc / hexane) to give 7- (3,5-dichlorothiophen-2-yl) -4-methyl-5,6,7,
8-Tetrahydroquinolin-5-one (0.56 g) was obtained. mp. 109-111 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H,
s), 2.76 (1H, dd, J = 12, 16 Hz),
3.04 (1H, ddd, J = 2, 4, 17 Hz),
3, 24 (1H, dd, J = 11, 17 Hz), 3, 5
1 (1H, ddd, J = 2, 4, 17 Hz), 3.82
-3.99 (1H, m), 6.76 (1H, s), 7.
11 (1H, d, J = 5 Hz), 8.49 (1H, d,
J = 5 Hz).

Reference Example 124 A solution of 2,5-dichlorothiophene (100.0 g) and dichloromethyl methyl ether (165.3 g) in dichloromethane (800 ml) was heated at a temperature range of -10 to -15 ° C for 50 minutes. A solution of titanium chloride (272.7 g) in dichloromethane (160 ml) was added dropwise. 3 at the same temperature
Stirred for 0 minutes and poured the reaction onto ice. The organic layer was washed sequentially with water, aqueous sodium hydrogen carbonate, water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2,5-dichloro-3-formylthiophene (115.0 g) as an oil. Acetone (1000ml)
And sodium hydroxide (28.6 g), water (1200 m
l) A solution of 2,5-dichloro-3-formylthiophene (58.6 g) in acetone (200 ml) was added to the mixture at 0 ° C.
The solution was added over 1.5 hours and stirred at the same temperature for 1 hour.
Acetone was distilled off under reduced pressure, and the crystals were collected by filtration. The crystals are washed with water, dried and dried with 4- (2,5-dichlorothiophene-3).
-Yl) -3-buten-2-one (136.6 g) was obtained. 20% sodium ethoxide ethanol solution (21
1 g) at room temperature with diethyl malonate (99.3 g), followed by 4- (2,5-dichlorothiophene-3-
Il) -3-buten-2-one (136.6 g) was added in small portions. Stir the reaction mixture at room temperature for 30 minutes,
The mixture was heated and stirred for an hour. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (340 ml) was added, and the mixture was heated with stirring at 100 ° C. for 2 hours. After air cooling, add 2.5 M sulfuric acid (340 ml) in 1
The mixture was added over 5 minutes, and heated and stirred at 100 ° C. for 1.5 hours.
After air cooling, the precipitated crystals were collected by filtration, washed successively with ethyl acetate-isopropyl ether (1: 4) and isopropyl ether to give 5- (2,5-dichlorothiophen-3-
Yl) cyclohexane-1,3-dione (78.9 g)
Was obtained as colorless crystals. mp 200 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 2.36-2.61
(4H, m), 3.42-3.62 (1H, m), 5.
51 (1H, s), 6.76 (1H, s), 8.0-1
2.5 (1H, br).

Reference Example 125 A solution of 5- (2,5-dichlorothiophen-3-yl) cyclohexane-1,3-dione (42.0 g) and ammonium acetate (36.9 g) in ethanol (840 ml) was heated for 12 hours. Refluxed. The solvent was distilled off under reduced pressure, water was added to the residue, and the crystals were collected by filtration. The crystals were washed with water and then with toluene and dried to give 1-amino-5- (2,5-dichlorothiophen-3-yl) cyclohexen-3-one (40.3 g). To a solution of 1-amino-5- (2,5-dichlorothiophen-3-yl) cyclohexen-3-one (37.0 g) in ethanol (700 ml) and toluene (1400 ml) was added 3-oxobutyraldehyde dimethyl acetal (46). 0.6 g) and potassium hydroxide (7.7 g) in powder form, and the mixture was heated under reflux. 30 minutes later, powdered potassium hydroxide (1.6 g), 1 hour later, powdered potassium hydroxide (1.6 g) and 3-oxobutyraldehyde dimethyl acetal (3.7 g), 1 hour, 30 minutes later, powdered hydroxide Add potassium (1.6 gl) and then
The mixture was stirred at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure,
Ethyl acetate was added. The extract was washed sequentially with water and a saturated saline solution, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the oil containing crystals was separated from the silica gel column (EtOAc).
/ Hexane) to remove the origin material. The obtained crystals were recrystallized from ethyl acetate-hexane to give 7- (2,2).
5-dichlorothiophen-3-yl) -4-methyl-
5,6,7,8-tetrahydroquinolin-5-one (3
2.6 g) were obtained. mp. 138-140 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H,
s), 2.75 (1H, dd, J = 12, 17 Hz),
2.93 (1H, ddd, J = 2, 4, 16Hz),
3.22 (1H, dd, J = 11, 17 Hz), 3.3
9 (1H, ddd, J = 2, 5, 17 Hz), 3.57
-3.76 (1H, m), 6.72 (1H, s), 7.
11 (1H, d, J = 5 Hz), 8.50 (1H, d,
J = 5 Hz).

Reference Example 126 4-Methyl-7- (3-thienyl) -5,6,7,8-
N-bromosuccinimide (2.3) was added to a solution of tetrahydroquinolin-5-one (2.18 g) in acetic acid (10 ml).
A solution of 2 g) in acetic acid (10 ml) was added, and the mixture was stirred at room temperature for 20 hours under an argon stream. The solvent was distilled off under reduced pressure, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 7- (2-bromothiophene-3-
Yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.74 g) as pale yellow crystals
Also, 7- (2,5-dibromothiophen-3-yl)
-4-Methyl-5,6,7,8-tetrahydroquinolin-5-one (0.53 g) was obtained as pale yellow crystals. 7- (2-Bromothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one: mp 84-85 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s),
2.81 (1H, dd), 2.96 (1H, ddd),
3.28 (1H, dd), 3.42 (1H, ddd),
3.68 (1H, m), 6.88 (1H, d), 7.1
1 (1H, d), 7.31 (1H, d), 8.5 (1
H, d). 7- (2,5-dibromothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
On: mp 130-131 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H,
s), 2.75 (1H, dd), 2.93 (1H, dd)
d), 3.23 (1H, dd), 3.69 (1H, dd)
d), 3.64 (1H, m), 6.87 (1H, d),
7.12 (1H, d), 8.5 (1H, d).

Reference Example 127 5- (2,5-Dichlorothiophen-3-yl) cyclohexane-1,3-dione (3.07 g), 4-dimethylaminopyridine (2.14 g), dicyclohexylcarbodiimide (3.13 g) Acetic acid (1.26 g) was added to a solution of the above) in dimethylformamide (10 ml), and the mixture was stirred at room temperature for 13 hours. Water (30ml) 2N hydrochloric acid (10m
l) was added and extracted with ethyl acetate. Organic layer 0.5
The mixture was extracted with aqueous N sodium hydroxide, the aqueous layer was acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 5- (2,5-dichlorothiophene-
3-yl) -2- (1-Hydroxyethylidene) cyclohexane-1,3-dione (2.5 g) was obtained as yellow crystals. mp 107-108 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.58-2.86
(7H, m), 3.45-3.62 (1H, m), 6.
67 (1H, s).

Reference Example 128 5- (2,5-Dichlorothiophen-3-yl) -2-
(1-hydroxyethylidene) cyclohexane-1,3
-Dione (2.48 g), hydrazine hydrate (0.50 g)
A solution of 8 g) in ethanol (10 ml) was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was washed with diisopropyl ether and 6- (2,5-
Dichlorothiophen-3-yl) -3-methyl-4,
5,6,7-Tetrahydroindazol-4-one (2.15 g) was obtained as pale yellow crystals. mp. 167-168 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.58-2.67
(5H, m), 2.87 (1H, dd), 3.12 (1
H, dd), 3.56-3.73 (1H, m), 6.7.
0 (1H, S).

Reference Example 129 5- (thiophen-3-yl) cyclohexane-1,3
A mixture of -dione (3.83 g), p-toluenesulfonylhydrazide (3.72 g), and ethanol (50 ml) was heated under reflux for 1 hour. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, and treated with 1- [2- (4-methylphenylsulfonyl) hydrazino] -5- (thiophene-3).
-Yl) cyclohexane-3-one (4.5 g) was obtained as colorless crystals. mp. 228-229 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.32-2.4
8 (7H, m), 3.12-3.29 (1H, m),
5.20 (1H, s), 7.09 (1H, dd), 7.
21 (1H, d), 7.42 (2H, d), 7.46-
7.49 (1H, m), 7.72 (2H, d), 8.7
4 (1H, broad), 9.81 (1H, s).

Reference Example 130 1- [2- (4-Methylphenylsulfonyl) hydrazino] -5- (thiophen-3-yl) cyclohexane-
3-one (3.62 g), anhydrous potassium carbonate (3.45 g)
g), a mixture of chloroacetone (1.15 g), sodium iodide (1 g), ethanol (50 ml) and 1,2-dimethoxyethane (20 ml) was heated and stirred at 80 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 4-methyl-7- (thiophene-
3-yl) -5,6,7,8-Tetrahydrocinnolin-5-one (0.8 g) was obtained as yellow crystals. mp. 125-126 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, s),
2.92 (1H, dd), 3.14 (1H, dd),
3.48 (1H, dd), 3.60-3.74 (1H,
m), 3.82 (1H, ddd), 7.08 (2H,
d), 7.43-7.38 (1H, m), 9.13 (1
H, s).

Reference Example 131 5- (2-chlorophenyl) cyclohexane-1,3-
A mixture of dione (5.5 g), p-toluenesulfonyl hydrazide (4.6 g), and ethanol (70 ml) was mixed with 7
Heated to reflux for 0 minutes. After air cooling, the precipitated crystals are collected by filtration,
After washing with ethanol, 5- (2-chlorophenyl) -1
-[2- (4-Methylphenylsulfonyl) hydrazino] cyclohexane-3-one (7.2 g) was obtained as colorless crystals. mp. 235-236 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (1H, d
d), 2.40 (3H, s), 2.49-2.60 (3
H, m), 3.44-3.60 (1H, m), 5.23
(1H, s), 7.23-7.34 (2H, m), 7.
37-7.48 (4H, m), 7.71 (1H, d),
8.79 (1H, broad), 9.83 (1H, br)
oad).

Reference Example 132 5- (2-chlorophenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-3
-One (1.17 g), anhydrous potassium carbonate (1.1
g), chloroacetone (0.335 g), sodium iodide (0.4 g), ethanol (7.5 ml), 1,2
A mixture of -dimethoxyethane (7.5 ml) was heated and stirred at 80 ° C for 4 hours. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography to give 4-methyl-7- (2
-Chlorophenyl) -5,6,7,8-tetrahydrocinnolin-5-one (0.34 g) was obtained as pale yellow crystals. mp. 108-109 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H,
s), 2.88 (1H, dd), 3.09 (1H, dd)
d), 3.49 (1H, dd), 3.79 (1H, dd)
d), 3.93-4.1 (1H, m), 7.22-7.
35 (3H, m), 7.45 (1H, dd), 9.16
(1H, s).

Reference Example 133 5- (2,5-Dichlorothiophen-3-yl) cyclohexane-1,3-dione (5.83 g), p-toluenesulfonylhydrazide (4.3 g), ethanol (5
0 ml) was heated at reflux for 1.5 hours. After air cooling,
The precipitated crystals are collected by filtration, washed with ethanol, and
(2,5-dichlorothiophen-3-yl) -1- [2
-(4-Methylphenylsulfonyl) hydrazino] Cyclohexane-3-one (8.5 g) was obtained as colorless crystals. mp. 255-256 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.17 (1H,
dd), 2.30-2.55 (6H, m), 3.15-
3.31 (1H, m), 5.23 (1H, s), 7.2
0 (1H, s), 7.42 (2H, d), 7.71 (2
H, d), 8.78 (1H, broad), 9.84
(1H, broad).

Reference Example 134 5- (2,5-dichlorothiophen-3-yl) -1-
[2- (4-methylphenylsulfonyl) hydrazino]
Cyclohexane-3-one (1.33 g), anhydrous potassium carbonate (1.14 g), chloroacetone (0.4 g)
g), sodium iodide (0.3 g), methanol (2
5 ml) and 1,2-dimethoxyethane (10 ml) were heated and stirred at 80 ° C. for 3 hours. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography to give 7-
(2,5-Dichlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.51 g) was obtained as colorless crystals. mp. 137-138 ° C ¹ H-NMR (CDCl ₃ ) δ: 2.7 (3H, s),
2.81 (1H, ddd), 3.01 (1H, dd),
3.36 (1H, dd), 3.61-3.75 (2H,
m), 6.74 (1H, s), 9.15 (1H, s).

Reference Example 135 5- (2-chlorophenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-
3-one (1.56 g), anhydrous potassium carbonate (0.72 g)
g), 1-bromobutan-2-one (0.785 g),
A mixture of methanol (30 ml) was stirred at room temperature for 2.5 hours. Anhydrous potassium carbonate (0.72 g) was added, and the mixture was stirred at room temperature for 1.5 hours and heated and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography to give 7- (2-chlorophenyl) -4-ethyl-5,5.
6,7,8-tetrahydrocinnolin-5-one (0.
492 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t),
2.89 (1H, dd), 3.04-3.37 (3H,
m), 3.44 (1H, dd), 3.78 (1H, dd)
d), 3.93-4.07 (1H, m), 7.2-7.
34 (3H, s), 7.45 (1H, dd), 9.19
(1H, s).

Reference Example 136 5- (2,5-Dichlorothiophen-3-yl) cyclohexane-1,3-dione (5.26 g), 4-methoxyphenylsulfonylhydrazide (4.04 g), ethanol (50 ml) The mixture was heated at reflux for 3 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol,
5- (2,5-dichlorothiophen-3-yl) -1-
[2- (4-Methoxyphenylsulfonyl) hydrazino] cyclohexane-3-one (7.1 g) was obtained as pale yellow crystals. mp. 241-242 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.16 (1H,
dd), 2.33-2.60 (3H, m), 3.15-
3.35 (1H, m), 3.85 (3H, s), 5.2
2 (1H, s), 7.14 (2H, d), 7.21 (1
H, s), 7.75 (2H, d), 8.78 (1H, b
load), 9.75 (1H, broad).

Reference Example 137 5- (2,5-dichlorothiophen-3-yl) -1-
[2- (4-Methoxyphenylsulfonyl) hydrazino] cyclohexane-3-one (1.79 g), anhydrous potassium carbonate (0.718 g), methanol (30 ml)
To a mixture of 1-bromobutan-2-one (0.
785 g) was added. The mixture was stirred with heating at room temperature for 2 hours, anhydrous potassium carbonate (1.2 g) was added, and the mixture was stirred with heating for 2 hours.
The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated and the residue was subjected to silica gel column chromatography to give 7- (2,5-dichlorothiophene-3-
Yl) -4-Ethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.26 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H,
t), 2.8 (1H, dd), 3.0 (1H, dd)
d), 3.13 (2H, q), 3.36 (1H, d
d), 3.6-3.76 (2H, m), 6.73 (1
H, s), 9.18 (1H, s).

Reference Example 138 5- (2-chlorophenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-
3-one (1.35 g), anhydrous potassium carbonate (1.19 g)
g), a mixture of 2-bromoacetophenone (0.893 g) and methanol (30 ml) was stirred at 80 ° C for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography to give 7- (2-chlorophenyl) -4-
Phenyl-5,6,7,8-tetrahydrocinnoline-
5-one (0.46 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.90 (1H, d
d), 3.07 (1H, ddd), 3.52 (1H, d
d), 3.88 (1H, ddd), 4.0-4.17.
(1H, m), 7.22-7.38 (5H, s), 7.
43-7.53 (4H, m), 9.20 (1H, s).

Reference Example 139 5- (2-chlorophenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-
3-one (2.74 g), anhydrous potassium carbonate (1.26 g)
g) and methanol (30 ml) were mixed with 1-bromo-3,3,3-trifluoropropan-2-one (1.74 g) at room temperature and stirred at the same temperature for 0.5 hour.
Anhydrous potassium carbonate (1.26 g) was added, the mixture was heated under reflux for 1 hour, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was concentrated. The residue was dissolved in acetic acid (20 ml), concentrated sulfuric acid (1 ml) was added, and the mixture was heated under reflux for 20 minutes. Water (120 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure.
The residue was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate and concentrated. The residue was subjected to silica gel column chromatography to give 7- (2-chlorophenyl)
-4-Trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (1.02 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.01 (1H, d
d), 3.2 (1H, ddd), 3.57 (1H, d
d), 3.98 (1H, ddd), 4.0-4.16
(1H, m), 7.26-7.5 (4H, m), 9.6
4 (1H, s).

Reference Example 140 5- (2,5-dichlorothiophen-3-yl) -1-
[2- (4-methylphenylsulfonyl) hydrazino]
A mixture of cyclohexane-3-one (2.0 g), anhydrous potassium carbonate (0.9 g) and methanol (20 ml) was added to 1-bromo-3,3,3-trifluoropropan-2-one (1 .24 g) and stirred at the same temperature for 0.5 hour. Anhydrous potassium carbonate (1.2 g) was added, the mixture was heated under reflux for 2 hours, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was concentrated. The residue was dissolved in acetic acid (15 ml), concentrated sulfuric acid (0.6 ml) was added, and the mixture was heated under reflux for 30 minutes. Water (120 ml) was added to the reaction solution, concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate, concentrated, and the residue was subjected to silica gel column chromatography to give 7-
(2,5-Dichlorothiophen-3-yl) -4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.867 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.92 (1H, d
d), 3.11 (1H, ddd), 3.49 (1H, d
d), 3.67-3.83 (1H, m), 3.87 (1
H, ddd), 6.76 (1H, s), 9.64 (1
H, s).

Reference Example 141 1-Amino-5- (thiophen-3-yl) cyclohexen-3-one (4.75 g), methyl acetoacetate (1
0 g) was heated at 170 ° C. for 18 hours. After air cooling, ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and treated with 4-methyl-7- (thiophene-3).
-Yl) -1,2,5,6,7,8-Hexahydroquinoline-2,5-dione (1.4 g) was obtained as yellow crystals. mp 300 ° C. or higher ¹ H-NMR (DMSO-d ₆ ) δ: 2.4 (3H,
s), 2.6-2.8 (2H, m), 3.05 (2H,
d), 3.4-3.6 (1H, m), 6.05 (1H,
s), 7.13 (1H, dd), 7.28 (1H,
d), 7.52 (1H, dd), 12.03 (1H, b
load).

Reference Example 142 4-methyl-7- (thiophen-3-yl) -1,2,2
5,6,7,8-Hexahydroquinoline-2,5-dione (0.518 g) in dimethylformamide (5 ml)
To the solution was added 60% sodium hydride (0.08 g) at room temperature, followed by methyl iodide (0.3 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate and 1,4-dimethyl-
7- (thiophen-3-yl) -1,2,5,6,7,
8-hexahydroquinoline-2,5-dione (0.40
5g) were obtained as colorless crystals. mp 156-157 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.53 (3H,
s), 2.72 (1H, dd), 2.88 (1H, dd)
d), 2.99 (1H, dd), 3.3 (1H, dd)
d), 3.46-3.65 (1H, m), 3.58 (3
H, s), 6.33 (1H, s), 7.06 (1H, d
d), 7.1-7.12 (1H, m), 7.39 (1
H, dd).

Reference Example 143 1,4-dimethyl-7- (thiophen-3-yl)-
1,2,5,6,7,8-hexahydroquinoline-2,
5-dione (0.518 g), pyridine (0.216
To a solution of g) in ethyl acetate (20 ml) was added sulfuryl chloride (0.405 g) at room temperature. The mixture was stirred at the same temperature for 0.5 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography to give 3-chloro-7- (2-chlorothiophen-3-yl) -1,4-dimethyl-1,2,5,5.
6,7,8-Hexahydroquinoline-2,5-dione (0.195 g) was obtained as colorless crystals. mp 175-176 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.72 (3H,
s), 2.71-2.81 (2H, m), 2.94 (1
H, dd), 3.21 (1H, dd), 3.6-3.7.
5 (1H, m), 3.65 (3H, s), 6.88 (1
H, d), 7.19 (1H, d).

Reference Example 144 1-Amino-5- (2-chlorophenyl) cyclohexen-3-one (6.66 g), methyl acetoacetate (5.
8g) was heated at 170 ° C. for 2.5 hours. Methyl acetoacetate (3 g) was added, and the mixture was further heated for 1.5 hours. After air cooling, the precipitated crystals were collected by filtration and washed with ethanol to give 7- (2-chlorophenyl) -4-methyl-1,
2,5,6,7,8-hexahydroquinoline-2,5-
Dione (0.42 g) was obtained as pale yellow crystals. mp 290-291 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.43 (3H,
s), 2.51-2.62 (1H, m), 2.78-
3.24 (3H, m), 3.74-3.87 (1H,
m), 6.08 (1H, s), 7.28-7.51 (4
H, d), 12.60 (1H, broad).

Example 106 (Production of Compound 108) (±) -7- (2,5-Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,6
7,8-Tetrahydroquinoline hydrochloride (39.0 g) was suspended in methanol (390 ml), and a 28% sodium methoxide methanol solution (34.1 ml) was added dropwise. The mixture was stirred at 50 ° C. for 1 hour and concentrated under reduced pressure. The obtained crystals are washed with water and dried, and (±) -7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline (Compound 108) (32.8 g) was obtained. mp. 250-251 ° C Elemental analysis: C ₁₅ H ₁₅ Cl ₂ N ₅ S · 0.2H ₂ O Calcd. C, 48.45; H, 4.17;
N, 18.83. Found C, 48.38; H, 4.40;
N, 18.74. ¹ H-NMR (CD ₃ OD) δ: 2.70 (3H,
s), 2.74 (1H, dd, J = 13, 18 Hz),
3.02-3.08 (2H, m), 3.13-3.38
(2H, m), 6.97 (1H, s), 7.19 (1
H, d, J = 5 Hz), 8.14 (1 H, d, J = 5 H)
z).

Example 107 (Production of Compounds 109 and 110) (±) -7- (2,5-Dichlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinoline-5 Turn on (1.0 g) CHIRALPAK A
Optical resolution using D (eluted with hexane-ethanol) gave (-)-7- (2,5-dichlorothiophene-
3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.40 g), (+)-7-
(2,5-Dichlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.41 g) was obtained. (-)-7- (2,5-dichlorothiophen-3-yl) -4-methyl-5,6,7,
Dissolve 8-tetrahydroquinolin-5-one (0.35 g) in ethanol (10 ml), add aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.28 ml), water (0.28 ml) and heat for 4 hours Refluxed. The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate.
After concentration under reduced pressure, the residue was dissolved in a small amount of ethanol by heating, and after cooling, the precipitated crystals were filtered off. The mother liquor was concentrated, and the obtained crystals were recrystallized from water to give (-)-7- (2,5-
Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 109) (0.47 g) was obtained as colorless crystals. Calcd As Elemental analysis _{C 15 H 15 C l2 N 5} S · 2HCl · H 2 O. C, 39.23; H, 4.17;
N, 15.25; Cl, 30.88. Found C, 39.06; H, 4.31;
N, 15.25; Cl, 30.69. ¹ H-NMR (DMSO-d ₆ ) was consistent with that of Compound 102.

(+)-7- (2,5-Dichlorothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.36 g) was added to ethanol (10 ml). And dissolved in aminoguanidine hydrochloride (0.
15g), concentrated hydrochloric acid (0.29ml), water (0.29m
l) was added and the mixture was heated under reflux for 4 hours. The solvent is distilled off under reduced pressure,
The residue was dissolved in water and washed with ethyl acetate. After concentration under reduced pressure, the residue was dissolved in a small amount of ethanol by heating, and after cooling, the precipitated crystals were filtered off. The mother liquor was concentrated and the resulting crystals were recrystallized from water to give (+)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7, 8-Tetrahydroquinoline hydrochloride (Compound 110) (0.46 g) was obtained as colorless crystals. Elemental analysis _{C 15 H 15 C l2 N 5} S · 2HCl · 0.5H 2
O as Calcd. C, 40.02; H, 4.03;
N, 15.56. Found C, 39.69; H, 4.17;
N, 15.50. ¹ H-NMR (DMSO-d ₆ ) was consistent with that of Compound 102.

Example 108 (Compounds 111, 112, 1
Preparation of 13) (±) -7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,6
To a solution of 7,8-tetrahydroquinoline (17.4 g) in ethanol (200 ml) was added L-pyroglutamic acid (4.
0 g) in ethanol (20 ml) at 80 ° C. The mixture was gradually returned to room temperature and stirred at room temperature for 6 hours. The crystals are collected by filtration, washed with ethanol, and (+)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline L- Pyroglutamate (11.0 g) was obtained. The crystals were suspended in methanol (200 ml), and a 28% methanol solution of sodium methoxide (4.2 ml) was added.
The solvent was distilled off under reduced pressure. After the obtained crystals were washed with water and dried, they were recrystallized from ethanol. Ethanol (30 ml) was added to the crystals, followed by methanesulfonic acid (3.4 g). Heat to a homogeneous solution and cool. The precipitated crystals are collected by filtration, and (+)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinemethanesulfonic acid Salt (Compound 111) (8.5 g, 99.9% e
e) was obtained. mp. Calcd a 225-229 ° C. Elemental analysis _{C 15 H 15 Cl 2 N 5} S · 2MeSO 3 H. C, 36.43; H, 4.14;
N, 12.49; Cl, 12.65. Found C, 36.61; H, 4.14;
N, 12.39; Cl, 12.57. ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (6H,
s), 2.70-2.94 (1H, m), 2.86 (3
H, s), 2.97-3.26 (2H, m), 3.27.
-3.57 (2H, m), 7.2-8.4 (4H, b
r), 7.41 (1H, s), 7.82 (1H, d, J
= 6 Hz), 8.65 (1H, d, J = 6 Hz), 1
0.80 (1H, s).

A 28% sodium methoxide methanol solution (3 m
l) was added, and the mixture was concentrated and washed with water to obtain (-)-isomer-rich crystals (9.3 g, 78.5% ee). This was recrystallized from ethanol to give (-)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4.
-Methyl-5,6,7,8-tetrahydroquinoline (compound 112) (7.6 g, 99.2% ee) was obtained.
(This compound was confirmed by X-ray crystal structure analysis to have the absolute configuration of the S-configuration.) Mp. 129-133 ° C. ¹ H-NMR (CD ₃ OD) was consistent with that of compound 108.

(-)-7- (2,5-Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-
Ethanol (50 ml) and methanesulfonic acid (3.1) were added to 5,6,7,8-tetrahydroquinoline (6.4 g).
g) was added to make a uniform solution, followed by concentration to obtain crystals.
This was recrystallized from ethanol to give (-)-7- (2,5
-Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 113) (8.1 g,
99.5% ee) was obtained. mp. 229-231 ° C Elemental analysis: C ₁₅ H ₁₅ Cl ₂ N ₅ S.2MeSO ₃ H Calcd. C, 36.43; H, 4.14;
N, 12.49; Cl, 12.65. Found C, 36.50; H, 4.06;
N, 12.34; Cl, 12.62. ¹ H-NMR (DMSO-d ₆ ) was consistent with that of compound 111.

Example 109 (Production of Compound 114) (-)-7- (2,5-Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,6
Methanesulfonic acid (0.37 g) was added to a solution of 7,8-tetrahydroquinoline (0.8 g) in ethanol (20 ml).
And concentrated under reduced pressure. Add water (1 ml) and concentrate,
The precipitated crystals were collected by filtration and washed with ethanol. The crystals are dried and (-)-7- (2,5-dichlorothiophene-3
-Yl) -5-guanidinoimino-4-methyl-5,
6,7,8-Tetrahydroquinoline methanesulfonate monohydrate (Compound 114) (1.0 g) was obtained. mp. 239-241 ° C. Elemental analysis _{C 15 H 15 Cl 2 N 5} S · 2MeSO 3 H · H 2
O as Calcd. C, 35.29; H, 4.36;
N, 12.11. Found C, 35.11; H, 4.27;
N, 12.15. ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (6H,
s), 2.70-2.94 (1H, m), 2.86 (3
H, s), 2.97-3.26 (2H, m), 3.27.
-3.57 (2H, m), 7.2-8.4 (4H, b
r), 7.40 (1H, s), 7.83 (1H, d, J
= 6 Hz), 8.65 (1H, d, J = 6 Hz), 1
0.79 (1H, s).

Example 110 (Preparation of Compound 115) (-)-7- (2,5-Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,6
0.5 M sulfuric acid (3.9 ml) was added to a solution of 7,8-tetrahydroquinoline (0.8 g) in ethanol (20 ml), and the mixture was concentrated under reduced pressure. The crystals are recrystallized from water, washed with ethanol and washed with (-)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-.
5,6,7,8-Tetrahydroquinoline sulfate (Compound 115) (0.8 g) was obtained. mp. 239-242 ° C. Elemental analysis _{C 15 H 15 Cl 2 N 5} S · H 2 SO 4 · 0.5H
₂ O as Calcd. C, 37.90; H, 3.82;
N, 14.73. . Found C, 37.87; H, 3.88; N, 14.56 1 H-NMR (DMSO-d 6) δ: 2.40-3.6
(5H, m), 2.64 (3H, s) 7.0-8.0
(4H, br), 7.37 (1H, s), 7.24 (1
H, d, J = 5 Hz, 8.32 (1H, d, J = 5H)
z), 10.58 (1H, br).

Example 111 (Production of compound 116) (-)-7- (2,5-Dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,6
1.7 M nitric acid (2.3 ml) was added to a solution of 7,8-tetrahydroquinoline (0.8 g) in ethanol (20 ml), and the mixture was concentrated under reduced pressure. The crystals are recrystallized from water to give (-)-
7- (2,5-dichlorothiophen-3-yl) -5
Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline nitrate (Compound 116) (0.92
g) was obtained. mp. 167 ° C (decomposition) Elemental analysis value C ₁₅ H ₁₅ Cl ₂ N ₅ S ・ HNO ₃・ 0.5H ₂
O as Calcd. C, 35.79; H, 3.60;
N, 19.48. Found C, 35.56; H, 3.58;
N, 19.39. ¹ H-NMR (DMSO-d ₆ ) δ: 2.69-3.2
1 (3H, m), 2.83 (3H, s), 3.26-
3.63 (2H, m), 7.2-8.0 (4H, b
r), 7.40 (1H, s), 7.77 (1H, d, J
= 6 Hz), 8.64 (1H, d, J = 6 Hz), 1
0.61 (1H, s).

Example 112 (Preparation of compound 117) 6- (2-Chlorophenyl) -3-methyl-4,5
6,7-tetrahydrobenzothiophen-4-one (0.07 g), aminoguanidine hydrochloride (0.034
g), concentrated hydrochloric acid (0.063 ml), water (0.063 m
l) and a mixture of ethanol (10 ml) was heated to reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzothiophene hydrochloride (Compound 117). (80 m
g) was obtained as colorless crystals.

Mp. 246 ° C. (decomposition) Elemental analysis value C ₁₆ H ₁₆ N ₄ S.HCl.0.5 H ₂ O Calcd. C, 50.80; H, 5.06;
N, 14.81. Found C, 50.60; H, 4.85;
N, 15.01. ¹ H-NMR (DMSO-d ₆ ) δ: 2.45 (3H,
s), 2.73 (1H, dd, J = 12, 17 Hz),
3.0-3, 20 (3H, m), 3.56-3.77
(1H, m), 6.9-8.1 (4H, br), 7.0
3 (1H, s), 7.25-7.66 (4H, m), 1
0.77 (1H, s).

Example 113 (Production of compound 118) 4-Methyl-7- (2-thiazolyl) -5,6,7,8
-Tetrahydroquinolin-5-one (0.68 g), aminoguanidine hydrochloride (0.37 g), concentrated hydrochloric acid (0.7
ml), water (0.7 ml) and ethanol (25 ml) were heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7- (2-thiazolyl)-.
5,6,7,8-Tetrahydroquinoline hydrochloride (compound 118) (0.9 g) was obtained as colorless crystals. mp. 282 ° C. (decomposition) Elemental analysis value C ₁₄ H ₁₆ N ₆ S.3HCl C, 41.04; H, 4.67;
N, 20.51. Found C, 41.13; H, 4.63;
N, 20.74. ¹ H-NMR (DMSO-d ₆ ) δ: 2.88 (3H,
s), 3.19 (1H, dd, J = 9, 18 Hz),
3.37 (1H, dd, J = 5, 17 Hz), 3.46
-3.80 (2H, m), 3.80-4.2 (1H,
m), 7.69 (1H, d, J = 3 Hz), 7.6-
8.5 (4H, br), 7.74 (1H, d, J = 3H
z), 7.89 (1H, d, J = 6 Hz), 8.68
(1H, d, J = 6 Hz), 11.69 (1H, s).

Example 114 (Production of compound 119) 6- (3-Chloro-2-thienyl) -3-methyl-4,
5,6,7-tetrahydroindazol-4-one (1.2 g), aminoguanidine hydrochloride (0.6 g),
A mixture of concentrated hydrochloric acid (1.1 ml), water (1.1 ml) and ethanol (50 ml) was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ethanol. 6- (3-Chloro-2-thienyl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 119) (1.2 g) as colorless crystals. mp. 204 ° C. (decomposition) Elemental analysis value C ₁₃ H ₁₅ ClN ₆ S.2HCl C, 39.46; H, 4.33;
N, 21.24. Found C, 39.49; H, 4.31;
N, 21.06. ¹ H-NMR (DMSO-d ₆ ) δ: 2.48 (3H,
s), 2.69 (1H, dd, J = 10, 17 Hz),
2.85 (1H, dd, J = 10, 16 Hz), 3.0
-3.2 (2H, m), 3.62-3.81 (1H,
m), 6.9-8.4 (4H, br), 7.04 (1
H, d, J = 5 Hz), 7.56 (1H, d, J = 5H)
z), 11.04 (1H, s).

Example 115 (Preparation of Compound 120) 7- (2,5-Dichlorophenyl) -4-methyl-5
6,7,8-tetrahydroquinolin-5-one (1.0
g), a mixture of aminoguanidine hydrochloride (0.43 g), concentrated hydrochloric acid (0.82 ml), water (0.82 ml), and ethanol (30 ml) was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate.
The solvent was distilled off under reduced pressure, and the residue was recrystallized from water to give 7-
(2,5-Dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 120) (1.3 g) was obtained as colorless crystals. mp. 300 ° C. or higher Elemental analysis _{C 17 H 17 Cl 2 N 5} · 2HCl · 0.5H 2
O as Calcd. C, 45.97; H, 4.54;
N, 15.77. Found C, 46.21; H, 4.53;
N, 15.88. ¹ H-NMR (DMSO-d ₆ ) δ: 2.83-3.0
3 (1H, m), 2.88 (3H, s), 3.14-
3.77 (4H, m), 7.43 (1H, dd, J =
2.9 Hz), 7.5-8.4 (4H, br), 7.5
5 (1H, d, J = 9 Hz), 7.76 (1H, d, J
= 2 Hz), 7.83 (1H, d, J = 5 Hz), 8.
63 (1H, d, J = 5 Hz), 11.51 (1H,
s).

Example 116 (Production of Compound 121) 7- (3,5-Dichlorothiophen-2-yl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
ON (0.5 g), aminoguanidine hydrochloride (0.21
g), a mixture of concentrated hydrochloric acid (0.4 ml), water (0.4 ml), and ethanol (15 ml) was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from water.
The obtained crystals are washed with ethanol, and 7- (3,5-dichlorothiophen-2-yl) -5-guanidinoimino-
4-Methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 121) (0.40 g) was obtained as colorless crystals. mp. 184-187 ° C. Elemental analysis _{C 15 H 15 Cl 2 N 5} S · 2HCl · 0.5H
₂ O as Calcd. C, 40.02; H, 4.03;
N, 15.56. Found C, 40.35; H, 3.94;
N, 15.68. ¹ H-NMR (DMSO-d ₆ ) δ: 2.72-2.9
4 (1H, m), 2.83 (3H, s), 3.20-
4.0 (4H, m), 7.24 (1H, s), 7.75
(1H, d, J = 6 Hz), 7.87 (4H, br),
8.60 (1H, d, J = 6 Hz), 11.47 (1
H, s).

Example 117 (Production of compound 122) 7- (3-Methyl-2-thienyl) -4-methyl-5
6,7,8-tetrahydroquinolin-5-one (0.3
To a solution of 8 g) in ethyl acetate (10 ml), pyridine (0.023 g) and sulfuryl chloride (0.3 g) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EtOAc).
/ Hexane) to give 7- (5-chloro-3-methyl-2-thienyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.32 g).
This was dissolved in ethanol (20 ml), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.27 ml),
Water (0.27 ml) was added, and the mixture was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 7- (5-chloro-3-methyl-2-thienyl) -5.
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 122) (0.32
g) was obtained as colorless crystals. mp. 193-196 ° C. Elemental analysis value C ₁₆ H ₁₈ ClN ₅ S.2HCl.H ₂ O Calcd. C, 43.79; H, 5.05;
N, 15.96. Found C, 44.05; H, 5.13;
N, 15.96. ¹ H-NMR (CD ₃ OD) δ: 2,20 (3H,
s), 2.85 (1H, dd, J = 11, 17 Hz),
2.98 (3H, s), 3.26-3.54 (3H,
m), 3.72-3.92 (1H, m), 6.77 (1
H, s), 7.91 (1H, d, J = 6 Hz), 8.5
9 (1H, d, J = 6 Hz).

Example 118 (Production of compound 123) 7- (2-Bromothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g), amino Guanidine hydrochloride (45mg)
To the mixture were added ethanol (2 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was heated and stirred at 90 ° C. for 13 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, and dried to give 7- (2-
(Bromothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 123) (0.14 g) was obtained as pale yellow crystals. mp 243-245 ° C. Elemental analysis value: C ₁₅ H ₁₆ N ₅ BrS.2HCl C, 39.93; H, 4.02;
N, 15.52 Found C, 39.88; H, 4.08;
N, 15.40 ¹ H-NMR (DMSO-d ₆ ) δ: 2.87 (4H,
m), 3.13 (1H, dd), 3.39 (3H,
m), 7.25 (1H, d), 7.70 (1H, d),
7.82 (1H, d), 7.92 (4H, broa
d), 8.64 (1H, d), 11.38 (1H, br)
oad).

Example 119 (Production of Compound 124) 7- (2,5-Dibromothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
ON (0.08 g), aminoguanidine hydrochloride (24 m
g) with ethanol (1 ml) and concentrated hydrochloric acid (0.04 ml)
Was added and stirred at 90 ° C. for 12 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, dried, and dried.
(2,5-Dibromothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 124) (0.09 g) was obtained as pale yellow crystals. . mp 272-273 ° C. Elemental analysis value: C ₁₅ H ₁₅ N ₅ Br ₂ S.2HCl C, 33.99; H, 3.23;
N, 13.21 Found C, 33.99; H, 3.33;
N, 13.12 ¹ H-NMR (DMSO-d ₆ ) δ: 2.84 (4H,
m), 3.10 (1H, dd), 3.33 (3H,
m), 7.49 (1H, s), 7.77 (1H, d),
7.86 (4H, broad), 8.62 (1H,
d), 11.31 (1H, broad).

Example 120 (Preparation of Compound 125) 7- (2-Bromothiophen-3-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.245 g), 1 Ethanol (3 ml) and concentrated hydrochloric acid (0.1 ml) were added to -amino-3-hydroxyguanidine p-toluenesulfonate (262 mg), and the mixture was heated with stirring at 90 ° C for 2 hours. The solvent was distilled off under reduced pressure.
2N aqueous sodium hydroxide (20 ml) was added, and the mixture was extracted with a mixture of ethyl acetate (20 ml) and tetrahydrofuran (20 ml). The organic layer was washed sequentially with 0.2N aqueous sodium hydroxide (20 ml) and water, and then washed with 2N hydrochloric acid (0.8 m
l) was added and concentrated. Ethanol (3 ml) was added to the residue, and the mixture was heated and stirred at 90 ° C. for 3 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, dried, and dried.
(2-bromothiophen-3-yl) -5- (1-hydroxyguanidin-3-yl) imino-4-methyl-
5,6,7,8-Tetrahydroquinoline hydrochloride (Compound 125) (0.215 g) was obtained as pale yellow crystals. mp 197-198 ° C. Elemental analysis value: C ₁₅ H ₁₆ N ₅ BrOS.2HCl C, 38.56; H, 3.88;
N, 14.99 Found C, 38.81; H, 4.16;
N, 15.05 ¹ H-NMR (DMSO-d ₆ ) δ: 2.87 (4
H, m), 3.07-3.46 (4H, m), 7.23.
(1H, d), 7.69 (1H, d), 7.79 (1
H, d), 8.38 (2H, broad), 8.62
(1H, d), 10.40 (1H, broad), 1
1.12 (1H, broad) 11.34 (1H, br)
oad).

Example 121 (Production of compound 126) 7- (2,5-Dibromothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
On (0.07 g), 1-amino-3-hydroxyguanidine p-toluenesulfonate (58 mg) was added with ethanol (1.5 ml) and concentrated hydrochloric acid (0.04 ml), and 9
The mixture was heated and stirred at 0 ° C. for 2 hours. The solvent was distilled off under reduced pressure, 0.2N aqueous sodium hydroxide (10 ml) was added to the residue, and ethyl acetate (30 ml) and tetrahydrofuran (20 ml) were added.
The mixture was extracted with l). The organic layer was washed with water and concentrated by adding concentrated hydrochloric acid (0.02 ml). Ethanol (1 ml) was added to the residue to dissolve, ether (0.2 ml) was added, and the mixture was stirred for 3 hours. The precipitated crystals are collected by filtration, washed with a mixed solvent of ethanol / ether, dried, and dried.
(2,5-dibromothiophen-3-yl) -5- (1
-Hydroxyguanidin-3-yl) imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 126) (0.27 g) was obtained as pale yellow crystals. mp 194-196 ° C (decomposition). Elemental analysis _{C 15 H 15 N 5 Br 2} Calcd as OS · 2HCl. C, 33.71; H, 3.71;
N, 12.28 Found C, 38.79; H, 3.47;
N, 12.13 ¹ H-NMR (DMSO-d ₆ ) δ: 2.70-2.
90 (4H, m), 3.04-3.40 (4H, m),
7.48 (1H, s), 7.70 (1H, d), 8.3
0 (2H, broad), 8.57 (1H, d), 1
0.35 (1H, broad), 11.09 (1H, b
load), 11.19 (1H, broad).

Example 122 (Production of compound 127) 6- (2,5-Dichlorothiophen-3-yl) -3-
Methyl-4,5,6,7-tetrahydroindazole-
4-one (0.3 g), aminoguanidine hydrochloride (12
2 mg) and ethanol (5 ml) and concentrated hydrochloric acid (0.1 m
l) was added and the mixture was heated under reflux for 4 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, and dried, to give 6- (2,5).
-Dichlorothiophen-3-yl) -4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 127) (0.41 g) was obtained as pale yellow crystals. mp 300 ° C or higher. Elemental analysis value: C ₁₃ H ₁₄ N ₆ Cl ₂ S.2HCl C, 36.84; H, 4.07;
N, 18.86 Found C, 36.84; H, 4.92;
N, 18.96 ¹ H-NMR (DMSO-d ₆ ) δ: 2.45 (3H,
s), 2.62 (1H, dd), 2.75-3.05
(3H, m), 3.20-3.40 (1H, m) 7.3
3 (1H, s), 7.41 (4H, broad), 1
0.86 (1H, s).

Example 123 (Production of compound 128) 6- (2,5-Dichlorothiophen-3-yl) -3-
Methyl-4,5,6,7-tetrahydroindazole-
4-one (0.211 g), 1-amino-3-hydroxyguanidine hydrochloride (102 mg) and ethanol (4 m
l) and concentrated hydrochloric acid (0.1 ml) were added, and the mixture was heated with stirring at 90 ° C for 4 hours. The solvent was distilled off under reduced pressure, and ethanol (2
ml), and the precipitated crystals were collected by filtration, washed with ethanol and dried, to give 6- (2,5-dibromothiophene-3).
-Yl) -4- (1-hydroxyguanidin-3-yl) imino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 128) (0.225
g) was obtained as pale yellow crystals. mp 190-192 ° C (decomposition). Elemental analysis _{C 13 H 14 N 6 Cl 2} Calcd as OS · 2HCl. C, 34.30; H, 3.76;
N, 18.46 Found C, 34.14; H, 3.75;
N, 18.46 ¹ H-NMR (DMSO-d ₆ ) δ: 2.46 (3
H, s), 2.61 (1H, dd), 2.84-3.0.
3 (3H, m), 3.20-3.40 (1H, m),
7.32 (1H, s), 7.92 (2H, broa
d), 10.10 (1H, broad), 10.60
(1H, broad), 10.77 (1H, broad)
d).

Example 124 (Production of compound 129) 7- (2-Chlorophenyl) -4-methyl-5,6
7,8-tetrahydrocinnolin-5-one (0.21
8 g) and aminoguanidine hydrochloride (94 mg), ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml) were added, and the mixture was heated under reflux for 1.5 hours. After air cooling, the precipitated crystals are collected by filtration, washed with ethanol and dried, and then dried with 7- (2-chlorophenyl).
-5-guanidinoimino-4-methyl-5,6,7,8
-Tetrahydrocinnoline hydrochloride (Compound 129)
(0.255 g) was obtained as crystals. mp 241-243 ° C. Elemental analysis value: C ₁₆ H ₁₇ N ₆ Cl.2HCl C, 47.84; H, 4.77;
N, 20.92 Found C, 47.82; H, 4.61;
N, 20.98 ¹ H-NMR (DMSO-d ₆ ) δ: 2.78 (3
H, s), 2.91 (1H, dd), 3.21-3.34.
(1H, m), 3.40-3.56 (2H, m), 3.
61-3.78 (1H, m) 7.31-7.52 (3H,
m), 7.67 (1H, dd), 8.00 (4H, br)
oad), 9.32 (1H, s).

Example 125 (Preparation of compound 130) 4-Methyl-7- (thiophen-3-yl) -5,6
7,8-tetrahydrocinnolin-5-one (0.19
5 g) and aminoguanidine hydrochloride (94 mg) were added with ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was heated under reflux for 1.5 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol and dried, to give 5-guanidinoimino-4-.
Methyl-7- (thiophen-3-yl) -5,6,7,
8-tetrahydrocinnoline hydrochloride (Compound 130)
(0.26 g) as colorless crystals. mp 278-280 ° C (decomposition). Elemental analysis value: C ₁₄ H ₁₆ N ₆ S.2HCl. C, 43.98; H, 5.01;
N, 21.98 Found C, 43.73; H, 4.91;
N, 21.12 ¹ H-NMR (DMSO-d ₆ ) δ: 2.79 (3
H, s), 2.94 (1H, dd), 3.24-3.61.
(4H, m), 7.27 (1H, d), 7.52-7.5
9 (2H, m), 8.07 (4H, broad),
34 (1H, s), 11.97 (1H, broad).

Example 126 (Preparation of compound 131) 7- (2,5-Dichlorothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydrocinnoline-5
-One (0.203 g), aminoguanidine hydrochloride (8
0mg) in ethanol (6ml) and concentrated hydrochloric acid (0.1m
l) was added and the mixture was heated under reflux for 1.5 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, dried, and dried.
(2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (compound 131) (0.25 g)
Was obtained as crystals. mp 300 ° C or higher. Elemental analysis _{C 14 H 14 N 6 Cl 2} Calcd as S · 2HCl. C, 38.03; H, 3.65;
N, 19.01 Found C, 38.15; H, 3.49;
N, 19.03 ¹ H-NMR (DMSO-d ₆ ) δ: 2.73 (3
H, s), 2.89 (1H, dd), 3.12 (1H,
broad), 3.24-3.41 (3H, m), 7.
40 (1H, s), 7.95 (2H, broad),
9.27 (1H, s), 11.57 (1H, broa
d).

Example 127 (Preparation of Compound 132) 7- (2-Chlorophenyl) -4-phenyl-5,6,7
7,8-tetrahydrocinnolin-5-one (0.23
0 g) and aminoguanidine hydrochloride (84 mg), ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml) were added, and the mixture was heated under reflux for 14 hours. The solvent was distilled off under reduced pressure, and water (10 m
l) was added. The precipitated crystals were collected by filtration and water (10 ml)
And dissolved in 0.2N aqueous sodium hydroxide solution (5 ml)
And extracted with ethyl acetate. The organic layer was washed with water, methanesulfonic acid (100 mg) was added, and the mixture was concentrated under reduced pressure. Acetone (10 ml) was added to the residue, and the crystals were collected by filtration, washed with acetone, dried, and dried with 7- (2-chlorophenyl) -5.
-Guanidinoimino-4-phenyl-5,6,7,8-
Tetrahydrocinnoline methanesulfonate (Compound 1
32) (0.120 g) as crystals. mp 276-278 ° C (decomposition). Calcd As Elemental analysis _{C 23 H 19 N 6 Cl ·} 2CH 3 SO 3 H. C, 47.02; H, 4.72;
N, 14.30 Found C, 47.22; H, 4.68;
N, 14.03 ¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (6
H, s), 2.78 (1H, dd), 3.07 (1H,
dd), 3.35-3.60 (2H, m), 3.75-
3.90 (1H, m), 7.32-7.52 (8H,
m), 7.55 (4H, broad), 7.67 (1
H, s), 9.12 (1H, s), 10.84 (1H,
broad).

Example 128 (Preparation of Compound 133) 7- (2-Chlorophenyl) -4-ethyl-5,6
7,8-tetrahydrocinnolin-5-one (0.28
7 g) and aminoguanidine hydrochloride (122 mg) to which ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml) were added.
Heated to reflux for an hour. The solvent was distilled off under reduced pressure, and water (1
(5 ml), 2N aqueous sodium hydroxide was added, and the precipitated crystals were collected by filtration. The crystals were washed successively with water and ethanol and dried. This was dissolved in acetone (25 ml), and methanesulfonic acid (130 mg) was added. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from methanol-acetone to give 7-
(2-chlorophenyl) -5-guanidinoimino-4-
Ethyl-5,6,7,8-tetrahydrocinnoline methanesulfonate (Compound 133) (0.292 g) was obtained as colorless crystals. mp 244-245 ° C (decomposition). Calcd As Elemental analysis _{C 17 H 19 N 6 Cl ·} 2CH 3 SO 3 H. C, 42.65; H, 5.09;
N, 15.71 Found C, 42.62; H, 4.97;
N, 15.51 ¹ H-NMR (DMSO-d ₆ ) δ: 1.28 (3H,
t), 2.38 (6H, s), 2.80 (1H, d
d), 3.09-3.26 (4H, m), 3.53 (1
H, dd), 3.55-3.70 (1H, m), 7.3.
2-7.53 (3H, m), 7.65 (1H, dd),
7.75 (2H, broad), 9.30 (1H, s),
10.85 (1H, broad).

Example 129 (Preparation of compound 134) 7- (2,5-Dichlorothiophen-3-yl) -4-
Ethyl-5,6,7,8-tetrahydrocinnoline-5
-One (0.195 g), aminoguanidine hydrochloride (7
3mg) in ethanol (3ml) and concentrated hydrochloric acid (0.1m
l) was added and the mixture was heated under reflux for 1 hour. The solvent is distilled off under reduced pressure,
The residue was dissolved in water (10 ml) and washed with ether. The insolubles were removed by filtration, potassium carbonate was added to make the mixture alkaline, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran.
The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixed solvent of acetone-methanol, and methanesulfonic acid (120 mg) was added. The precipitated crystals are collected by filtration, washed with acetone, dried, and dried with 7- (2,5-dichlorothiophen-3-yl) -4-ethyl-5-guanidinoimino-5,6,7,8-tetrahydrofuran. Cinnoline methanesulfonate (Compound 134) (0.206 g) was obtained as colorless crystals. mp 241-242 ° C (decomposition). Calcd As Elemental analysis _{C 17 H 16 N 6 Cl 2} S · 2CH 3 SO 3 H. C, 35.48; H, 4.20;
N, 14.60 Found C, 35.67; H, 4.14;
N, 14.39 ¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (3
H, t), 2.37 (6H, s), 2.80 (1H, d
d), 3.02 (1H, dd), 3.11-3.39
(4H, m), 3.79-3.97 (1H, m), 7.4
0 (1H, s), 7.68 (4H, broad), 9.
24 (1H, s), 10.79 (1H, broad).

Example 130 (Production of Compound 135) 7- (2,5-Dichlorothiophen-3-yl) -4-
A solution of trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.443 g), aminoguanidine hydrochloride (167 mg) in ethanol (10 ml), methanesulfonic acid (0.2 ml), benzene (10
ml) and heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was treated with isopropyl ether-diethyl ether.
After washing with a mixed solvent of ter and dried, 7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline ( Compound 135) (0.160 g) was obtained as colorless crystals. mp 265-266 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (1
H, dd), 3.18-3.45 (4H, m), 6.2.
8 (2H, broad), 7.28 (1H, s), 9.
27 (1H, s).

Example 131 (Production of Compound 136) 7- (2-Chlorophenyl) -4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.335 g), aminoguanidine hydrochloride Salt (165m
g) Ethanol (10 ml) solution, methanesulfonic acid (0.3 ml) and benzene (10 ml) were added, and the mixture was heated under reflux for 80 minutes. The solvent was distilled off under reduced pressure, and the residue was made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in acetone, methanesulfonic acid (0.15 ml) was added, and the precipitated crystals were collected by filtration, washed with acetone, and dried.
7- (2-chlorophenyl) -5-guanidinoimino-
4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline methanesulfonate (Compound 136)
(0.240 g) was obtained as yellow crystals. mp 207-208 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.43 (6
H, s), 2.90 (1H, dd), 3.17 (1H,
dd), 3.41-3.85 (3H, m), 7.31-
7.53 (3H, m), 7.65 (1H, d), 8.0
0 (4H, broad), 9.64 (1H, s), 1
1.31 (1H, broad).

Example 132 (Production of compound 137) 1,4-Dimethyl-7- (thiophen-3-yl)-
1,2,5,6,7,8-hexahydroquinoline-2,
5-dione (0.1 g), aminoguanidine hydrochloride (4
1mg) in ethanol (3ml) and 2N hydrochloric acid (0.2m
l) was added and the mixture was heated under reflux for 4 hours. After concentration under reduced pressure, ethanol (1 ml) was added to the residue, and the precipitated crystals were collected by filtration. The crystals are washed with ethanol and dried to give 1,4-dimethyl-5-guanidinoimino-7- (thiophen-3-
Yl) -1,2,5,6,7,8-Hexahydroquinolin-2-one hydrochloride (Compound 137) (0.125 g)
Was obtained as colorless crystals. mp 156-157 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.45 (3
H, s), 2.6 (1H, dd), 2.91 (1H, d
d), 3.18-3.33 (3H, m), 3.51 (3
H, s), 6.27 (1H, s), 7.3 (1H, d
d), 7.5-7.56 (6H, m), 11.10 (1
H, s).

Example 133 (Production of compound 138) 4-Methyl-7- (thiophen-3-yl) -1,2,2
5,6,7,8-Hexahydroquinoline-2,5-dione (0.155 g), aminoguanidine hydrochloride (73 m
2-ethoxyethanol (2 ml) and 2N hydrochloric acid (0.3 ml) were added to g), and the mixture was heated and stirred at 125 ° C. for 13 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, and dried to give 5-guanidinoimino-4-methyl-7.
-(Thiophen-3-yl) -1,2,5,6,7,8
-Hexahydroquinolin-2-one hydrochloride (Compound 13
8) (0.093 g) was obtained as colorless crystals. mp 300 ° C or higher. Elemental analysis _{C 15 H 17 N 5 OS ·} 2HCl · H 2 Calcd as O. C, 44.34; H, 5.21;
N, 17.24 Found C, 44.36; H, 5.24;
N, 17.34 ¹ H-NMR (DMSO-d ₆ ) δ: 2.47 (3
H, S), 2.64 (1H, dd), 2.77-2.9.
7 (2H, m), 3.08-3.35 (2H, m),
6.16 (1H, s), 7.20 (1H, dd), 7.
40 (1H, dd), 7.49 (4H, broad),
7.54 (1H, dd), 10.98 (1H, s).

Example 134 (Preparation of Compound 139) 7- (2-Chlorophenyl) -4-methyl-1,2,2
5,6,7,8-Hexahydroquinoline-2,5-dione (0.144 g), aminoguanidine hydrochloride (61 m
2-ethoxyethanol (2.5 ml) and concentrated hydrochloric acid (0.1 ml) were added to g), and the mixture was heated with stirring at 135 ° C. for 1 hour.
After air cooling, the precipitated crystals were collected by filtration, washed with methanol and dried, and dried with 7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-1,2,5,6,7,8-hexahydro. Quinolin-2-one hydrochloride (Compound 139)
(0.15 g) as colorless crystals. mp 300 ° C or higher. Elemental analysis value: C ₁₇ H ₁₈ ClN ₅ O.2HCl. C, 49.00; H, 4.84;
N, 16.81 Found C, 49.04; H, 4.89;
N, 16.84 ¹ H-NMR (DMSO-d ₆ ) δ: 2.49 (3H,
S), 2.66 (1H, dd), 2.83 (1H, d
d), 2.97-3.13 (2H, m), 3.45-
3.60 (1H, m), 6.20 (1H, s), 7.2
9-7.61 (8H, m), 10.88 (1H, s).

Example 135 (Preparation of Compound 140) 3-Chloro-7- (2-chlorothiophen-3-yl)
-1,4-dimethyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.098 g), aminoguanidine hydrochloride (32 mg) and 2-ethoxyethanol (1.5 ml) ) And concentrated hydrochloric acid (0.05 ml), and the mixture was heated and stirred at 135 ° C for 1 hour. After air cooling, the precipitated crystals were collected by filtration, washed with methanol, and dried to give 3-chloro-
7- (2-chlorothiophen-3-yl) -5-guanidinoimino-1,4-dimethyl-1,2,5,6,7,
8-Hexahydroquinolin-2-one hydrochloride (Compound 1
40) (0.04 g) as crystals. mp 218-219 ° C. Elemental analysis value C ₁₆ H ₁₇ N ₅ ClOS.HCl.0.5H ₂ O
As Calcd. C, 43.30; H, 4.32;
N, 15.78 Found C, 43.38; H, 4.44;
N, 15.76 ¹ H-NMR (DMSO-d ₆ ) δ: 2.6 (3H,
s), 2.65 (1H, d), 2.94-3.1 (3
H, m), 3.2-3.45 (1H, m), 3.56
(3H, s), 7.25 (1H, d), 7.5 (3H,
broad), 7.54 (1H, d), 7.86 (1
H, broad), 10.72 (1H, broad).

Reference Example 145 5- (2-chlorophenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-3
-One (2.0 g), 2-bromo-4'-chloroacetophenone (1.6 g), anhydrous potassium carbonate (1.8 g)
A mixture of ethanol (50 ml) was heated at reflux for 13 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was subjected to silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-hexane to give 7- (2-chlorophenyl) -4-.
(4-Chlorophenyl) -5,6,7,8-tetrahydrocinnolin-5-one (0.2 g) was obtained as colorless crystals. mp 163-166 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.90 (1H, d
d), 3.06 (1H, ddd), 3.5 (1H, d
d), 3.86 (1H, ddd), 3.98-4.20
(1H, m), 6.8-8.2 (4H, br), 7.1
6-7.52 (8H, m), 9.14 (1H, s).

Reference Example 146 1-Amino-5- (2-chlorophenyl) cyclohexen-3-one (2.0 g) in acetonitrile (50 m
1) To the solution was added phenyl isothiocyanate (1.2 g), and the mixture was heated under reflux for 15 hours. The solvent was distilled off under reduced pressure, and ethanol (20 ml) and hydrazine hydrate (0.55
g) was added and the mixture was heated under reflux for 1 hour. The solvent is distilled off under reduced pressure,
The residue was washed with ethyl acetate to give 6- (2-chlorophenyl) -3-phenylamino-4,5,6,7 as yellow crystals.
-Tetrahydroindazol-4-one (0.8 g) was obtained. mp 272 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.46-2.
57 (1H, m), 2.87 (1H, dd, J = 12,
16Hz), 3.02-3.17 (2H, m), 3.8
-4.1 (1H, m), 6.8-6.92 (1H,
m), 7.2-7.66 (8H, m), 8.01 (1
H, br), 12.53 (1H, br).

Reference Example 147 5- (2-chlorophenyl) -cyclohexane-1,3
-Dione (1.0 g), hydrazine hydrochloride (0.31
A solution of g) in ethanol (10 ml) was heated at reflux for 3 hours. Benzaldehyde (1.5 g) was added, and the mixture was heated under reflux for 4 days. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain crystals. This was recrystallized from ethyl acetate-hexane to give 6- (2-chlorophenyl) -3-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.06 g) as crystals. mp 218-222 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.76-2.88
(2H, m), 3.02 (1H, dd, J = 11, 16
Hz), 3.29 (1H, dd, J =, 4, 16H)
z), 3.96-4.15 (1H, m), 7.18-
7.58 (8H, m), 7.92-8.04 (2H,
m).

Reference Example 148 5- (2-chlorophenyl) cyclohexane-1,3-
Dicyclohexylcarbodiimide (1.0 g) was added to a solution of dione (1.0 g), 4-dimethylaminopyridine (0.82 g) and methoxyacetic acid (0.73 g) in dimethylformamide (40 ml), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and ethyl acetate was added. The insolubles were removed by filtration, and the organic layer was extracted with 1N aqueous sodium hydroxide. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 5- (2-chlorophenyl) -2- (1-hydroxy-2-methoxyethylidene) cyclohexane-1,3-dione (0.8
6g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.44-3.2
(5H, m), 3.51 (3H, s), 3.78-3.
98 (1H, m), 4.76 (2H, s), 7.1-
7.44 (4H, m).

Reference Example 149 5- (2-chlorophenyl) -2- (1-hydroxy-
2-methoxyethylidene) cyclohexane-1,3-dione (0.4 g), hydrazine hydrate (0.072 g)
Was heated to reflux for 1 hour.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give 6- (2-chlorophenyl) -3-.
Methoxymethyl-4,5,6,7-tetrahydroindazol-4-one (0.1 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.56-2.84
(2H, m), 2.96 (1H, dd, J = 6, 16H
z), 3.24 (1H, dd, J = 4, 16 Hz),
3.49 (3H, s), 3.88-4.1 (1H,
m), 4.85 (2H, s), 7.02-7.43 (4
H, S), 8.0 (1H, br).

Reference Example 150 5- (2-chlorophenyl) -2- (1-hydroxyethylidene) cyclohexane-1,3-dione (0.5
g) and benzylhydrazine dihydrochloride (0.39 g) in ethanol (30 ml) were added to triethylamine (0.4 ml).
2 g) and heated under reflux for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate-hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 1-benzyl-6.
-(2-chlorophenyl) -3-methyl-4,5,6
7-tetrahydroindazol-4-one (0.37
g) was obtained as colorless crystals. mp 108-109 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H,
s), 2.61-2.84 (3H, m), 3.11 (1
H, dd, J = 5, 16 Hz), 3.86-4.08
(1H, m), 5.12-5.33 (2H, m), 7.
08-7.43 (9H, m).

Reference Example 151 5- (2-chlorophenyl) -2- (1-hydroxyethylidene) cyclohexane-1,3-dione (1.0
g) and a solution of phenylhydrazine (0.43 g) in ethanol (20 ml) was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 6- (2-chlorophenyl) -3-methyl-2.
-Phenyl-4,5,6,7-tetrahydroindazol-4-one (0.97 g) was obtained as colorless crystals. mp 153-154 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.59 (3H,
s), 2.74 (1H, dd, J = 3, 16 Hz),
2.88 (1H, dd, J = 11, 16 Hz), 3.0
7 (1H, dd, J = 11, 16 Hz), 3.22 (1
H, dd, J = 3, 16 Hz), 3.93-4.13
(1H, m), 7.16-7.64 (9H, m).

Reference Example 152 60% sodium hydride (0.041 g, 3
Suspension) in dimethylformamide (10 ml) was added to 6- (2-chlorophenyl) -3-methyl-4,5,5.
6,7-tetrahydroindazol-4-one (0.4
g) in dimethylformamide (2 ml) was added, and the mixture was stirred at room temperature for 40 minutes. 2-phenylethyl bromide (0.
30 g) and stirred at the same temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give 6- (2-chlorophenyl).
-3-Methyl-1- (2-phenylethyl) -4,5
6,7-tetrahydroindazol-4-one (0.2
2g) as colorless crystals, and 6- (2-chlorophenyl) -3-methyl-2- (2-phenylethyl)-
4,5,6,7-Tetrahydroindazol-4-one (0.2 g) was obtained as an oil. 6- (2-chlorophenyl) -3-methyl-1- (2-
Phenylethyl) -4,5,6,7-tetrahydroindazol-4-one: mp 132-134 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.12 (1H, d
d, J = 5, 16 Hz), 2.37-2.65 (3H,
m), 2.53 (3H, s), 3.09 (2H, t, J
= 6 Hz), 3.57-3.83 (1H, m), 4.1
2-4.23 (2H, m), 6.86-7.97 (2
H, m), 7.05-7.37 (7H, m). 6- (2-chlorophenyl) -3-methyl-2- (2-
Phenylethyl) -4,5,6,7-tetrahydroindazol-4-one: ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H,
s), 2.66-2.74 (2H, m), 2.93 (1
H, dd, J = 11, 16 Hz), 3.12 (2H,
t, J = 7 Hz), 3.19 (1H, dd, J = 4, 1)
6 Hz), 3.84-4.03 (1H, m), 4.22
(2H, t, J = 7 Hz), 6.99-7.18 (2
H, m), 7.12-7.43 (7H, m).

Reference Example 153 60% sodium hydride (0.068 g, 3
Suspension) in dimethylformamide (10 ml) was added to 6- (2-chlorophenyl) -3-methyl-4,5,5.
6,7-tetrahydroindazol-4-one (0.4
g) in dimethylformamide (2 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 40 minutes. 3-Phenylpropyl bromide (0.32 g) was added, and the mixture was stirred at the same temperature for 19 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give 6- (2-chlorophenyl) -3-methyl-1- (3-phenylpropyl).
-4,5,6,7-tetrahydroindazol-4-one (0.20 g) as colorless crystals, and 6- (2-
Chlorophenyl) -3-methyl-2- (3-phenylpropyl) -4,5,6,7-tetrahydroindazol-4-one (0.26 g) was obtained as an oil. 6- (2-chlorophenyl) -3-methyl-1- (2-
Phenylpropyl) -4,5,6,7-tetrahydroindazol-4-one: mp 100-101 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.06-2.24
(2H, m), 2.50 (3H, s), 2.55-2.
82 (5H, m), 2.99 (1H, dd, J = 5, 1
6 Hz), 3.84-4.07 (1H, m), 3.98
(2H, t, J = 7 Hz), 7.07-7.32 (8
H, m), 7.36-7.43 (1H, m). 6- (2-chlorophenyl) -3-methyl-2- (2-
(Phenylpropyl) -4,5,6,7-tetrahydroindazol-4-one: ¹ H-NMR (CDCl ₃ ) δ: 2.08-2.32
(2H, m), 2.49 (3H, s), 2.5-2.7
(4H, m), 2.88 (1H, dd, J = 11, 16
Hz), 3.16 (1H, dd, J = 4, 16Hz),
3.84-4.17 (3H, m), 7.08-7.44
(9H, m).

Reference Example 154 7- (2-Chlorophenyl) -4-methyl-5,6
7,8-tetrahydroquinolin-5-one (272 m
g) was dissolved in benzene (4 ml), m-chloroperbenzoic acid (267 mg) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (70 ml), saturated aqueous sodium bicarbonate (30 m
l), sodium sulfite (100 mg) was added, shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried, and 7- (2-chlorophenyl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
On-1-oxide (205 mg) was obtained as pale yellow crystals. mp 225-226 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H,
s), 2.88-3.15 (3H, m), 3.84-
4.05 (2H, m), 7.12 (1H, d), 7.2
0-7.36 (3H, m), 7.42 (1H, dd),
8.33 (1H, d).

Reference Example 155 7- (2,5-Dichlorothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
Dissolve on (1.09 g) in benzene (15 ml)
m-Chloroperbenzoic acid (0.963 g) was added and the mixture was added at room temperature for 1 hour.
Stirred for hours. Ethyl acetate (150 ml), saturated aqueous sodium hydrogen carbonate (200 ml), sodium sulfite (200
mg), shaken, and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was washed with a mixed solvent of isopropyl ether and ethyl acetate at a ratio of 2: 1 to give 7- (2,5-dichlorothiophen-3-yl) -4-methyl-5,6,7,8-.
Tetrahydroquinolin-5-one-1-oxide (1.
04g) were obtained as yellow crystals. mp 169-170 ° C (recrystallized from ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 2.67 (3H, s),
2.78 (1H, dd), 2.86-3.09 (2H,
m), 3.54-3.70 (1H, m), 3.82 (1
H, ddd), 6.74 (1H, s), 7.13 (1
H, d), 8.33 (1H, d).

Reference Example 156 7- (2-Chlorophenyl) -4-methyl-5,6,
7,8-tetrahydrocinnolin-5-one (1.54
g) was dissolved in benzene (10 ml), m-chloroperbenzoic acid (1.72 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (300 ml), saturated aqueous sodium hydrogen carbonate (300 ml) and sodium sulfite (500 mg) were added, and the mixture was shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 7-
(2-chlorophenyl) -4-methyl-5,6,7,8
-Tetrahydrocinnolin-5-one-1-oxide (478 mg) was obtained as pale yellow crystals. mp 154-155 ° C (recrystallized from ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 2.63 (3H,
s), 2.85-3.01 (2H, m), 3.08 (1
H, dd), 3.89-4.06 (1H, m), 3.7
4 (1H, dd), 7.25-7.47 (4H, m),
8.37, (1H, s) and simultaneously, 7- (2-chlorophenyl) -4-methyl-
5,6,7,8-tetrahydrocinnolin-5-one-
2-oxide (296 mg) was obtained as pale yellow crystals. mp 167-168 ° C (recrystallized from ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 2.66 (3H,
s), 2.85 (1H, dd), 3.03 (1H, dd)
d), 3.20 (1H, dd), 3.41 (1H, dd)
d), 3.91-4.07 (1H, m), 7.25-
7.47 (4H, m), 7.95 (1H, s).

Reference Example 157 5- (2,5-dichlorophenyl) cyclohexane-
1,3-dione (1.19 g), p-toluenesulfonyl hydrazide (0.86 g), ethanol (15 ml)
Was heated at reflux for 2.5 hours. After air cooling, the precipitated crystals were collected by filtration and washed with ethanol to give 5- (2,5-
Dichlorophenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-3-one (1.67 g) was obtained as colorless crystals. mp 256-257 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.23 (1H,
dd), 2.40 (3H, s), 2.45-2.65.
(3H, m), 3.40-3.55 (1H, m), 5.
23 (1H, s), 7.32-7.56 (5H, m),
7.71 (2H, d), 8.00 (1H, br), 9.
85 (1H, s).

Reference Example 158 5- (2,5-dichlorophenyl) -1- [2- (4-
Methylphenylsulfonyl) hydrazino] cyclohexane-3-one (1.65 g), anhydrous potassium carbonate (0.
696 g), methanol (10 ml) and 1,2-dimethoxyethane (8 ml) were added with 1-chloropropan-2-one (0.465 g) and sodium iodide (0.15 g) under ice-cooling. The mixture was stirred at room temperature for 2 hours, anhydrous potassium carbonate (0.64 g) was added, and the mixture was heated and stirred at 80 ° C for 3 hours. The solvent was distilled off under reduced pressure.
0 ml) and water (30 ml) were added, shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 7- (2,5-dichlorophenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.253 g) was obtained as a yellow-brown oil. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H,
s), 2.84 (1H, dd), 3.08 (1H, dd)
d), 3.39 (1H, dd), 3.77 (1H, dd)
d), 3.87-4.04 (1H, m), 7.22-
7.41 (3H, m), 9.16 (1H, s).

Reference Example 159 A solution of 5- (2-chloro-5-methylphenyl) cyclohexane-1,3-dione (3.0 g) and ammonium acetate (2.9 g) in ethanol (50 ml) was heated under reflux for 13 hours. . The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with water and then with toluene and dried to give 1-amino-
5- (2-Chloro-5-methylphenyl) cyclohexen-3-one (2.9 g) was obtained. 1-amino-5-
(2-chloro-5-methylphenyl) cyclohexene-
3-One (2.9 g) was dissolved in ethanol (70 ml) and toluene (120 ml), and 3-oxobutyraldehyde dimethyl acetal (4.1 g) and powdered potassium hydroxide (0.5 g) were added, followed by heating under reflux. 30 minutes later, powdered potassium hydroxide (0.14 g), 1 hour later, powdered potassium hydroxide (0.14 g) and 3-oxobutyraldehyde dimethyl acetal (0.33 g), 1 hour 30
One minute later, powdered potassium hydroxide (0.14 g) was added, and the mixture was stirred at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the residue was subjected to a silica gel column (ethyl acetate-hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 7- (2-chloro-5-methylphenyl). -4-Methyl-5,6,7,8-tetrahydroquinolin-5-one (2.3 g) was obtained. mp 123-124 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H,
s), 2.71 (3H, s), 2.82 (1H, dd,
J = 12, 17 Hz), 3.01 (1H, ddd, J =
2, 4, 17 Hz), 3.28 (1H, dd, J = 1)
2.17 Hz), 3.46 (1H, ddd, J = 2
4,17 Hz), 3.84-4.04 (1H, m),
6.94-7.17 (3H, m), 7.24-7.34
(1H, m), 8.50 (1H, d, J = 5 Hz).

Reference Example 160 A solution of 5- (2-fluoro-5-methylphenyl) cyclohexane-1,3-dione (1.5 g) and ammonium acetate (1.6 g) in ethanol (23 ml) was heated under reflux for 20 hours. . The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with water and then with toluene and dried to give 1-amino-
5- (2-Fluoro-5-methylphenyl) cyclohexen-3-one (1.3 g) was obtained. 1-amino-5-
(2-Fluoro-5-methylphenyl) cyclohexen-3-one (1.3 g) was dissolved in ethanol (35 ml) and toluene (60 ml), and 3-oxobutyraldehyde dimethyl acetal (2.0 g) was added. Potassium (0.32 g) was added and the mixture was heated under reflux. 30 minutes later, powdered potassium hydroxide (0.07 g), 1 hour later, powdered potassium hydroxide (0.07 g) and 3-oxobutyraldehyde dimethyl acetal (0.16 g), 1 hour 3
0 minutes later, powdered potassium hydroxide (0.07 g) was added,
Thereafter, the mixture was stirred at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was applied to a silica gel column (ethyl acetate-hexane). The obtained crystals were treated with ethyl acetate-
Recrystallization from hexane gave 7- (2-fluoro-5-methylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.3 g). mp 92-94 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 2.71 (3H, s), 2.82-3.04 (2
H, m), 3.3-3.5 (2H, m), 3.6-3.
84 (1H, m), 6.88-7.17 (4H, m),
8.50 (1H, d, J = 5 Hz).

Reference Example 16 A solution of 5- (5-chloro-2-methylphenyl) cyclohexane-1,3-dione (2.9 g) and ammonium acetate (2.8 g) in ethanol (50 ml) was heated under reflux for 14 hours. . The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-amino-5-
(5-chloro-2-methylphenyl) cyclohexene-
3-one was obtained. This was dissolved in ethanol (70 ml) and toluene (120 ml), and 3-oxobutyraldehyde dimethyl acetal (4.1 g) and powdered potassium hydroxide (0.57 g) were added, followed by heating under reflux. 30 minutes later, powdered potassium hydroxide (0.14 g), 1 hour later, powdered potassium hydroxide (0.14 g) and 3-oxobutyraldehyde dimethyl acetal (0.33 g), 1 hour 3
0 minutes later, powdered potassium hydroxide (0.14 g) was added,
Thereafter, the mixture was stirred at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the residue was subjected to a silica gel column (ethyl acetate-hexane), and the obtained crystals were recrystallized from diisopropyl ether to give 7- (5-chloro-2-methylphenyl) -4. -Methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) was obtained. mp 125-127 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 2.72 (3H, s), 2.82-2.96 (2
H, m), 3.16-3.46 (2H, m), 3.55
-3.74 (1H, m), 7.08-7.33 (4H,
m), 8.50 (1H, d, J = 5Hz).

Reference Example 16 A solution of 5- (5-fluoro-2-methylphenyl) cyclohexane-1,3-dione (3.0 g) and ammonium acetate (3.1 g) in ethanol (50 ml) was heated under reflux for 14 hours. . The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-amino-5.
-(5-Fluoro-2-methylphenyl) cyclohexen-3-one was obtained. This is ethanol (70 ml),
After dissolving in toluene (120 ml), 3-oxobutyraldehyde dimethyl acetal (4.1 g) and powdered potassium hydroxide (0.57 g) were added, and the mixture was heated under reflux. 30 minutes later, powdered potassium hydroxide (0.14 g), 1 hour later, powdered potassium hydroxide (0.14 g) and 3-oxobutyraldehyde dimethyl acetal (0.33 g), 1 hour, 30 minutes later, powdered hydroxide Potassium (0.14 g) was added, followed by stirring at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the residue was applied to a silica gel column (ethyl acetate-hexane), and the obtained crystals were recrystallized from ethyl acetate-hexane to give 7- (5-fluoro-2-
Methylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.5 g) was obtained. mp 113-114 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 2.71 (3H, s), 2.78-2.98 (2
H, m), 3.24 (1H, dd, J = 11, 16H
z), 3.28-3.44 (1H, m), 3.55-
3.74 (1H, m), 6.82-7.04 (2H,
m), 7.12 (1H, d, J = 5 Hz), 7.07-
7.22 (2H, m), 8.50 (1H, d, J = 5H
z).

Reference Example 163 A solution of 5- (5-chloro-2-methoxyphenyl) cyclohexane-1,3-dione (5.0 g) and ammonium acetate (4.6 g) in ethanol (100 ml) was heated under reflux for 20 hours. . The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-amino-5.
-(5-Chloro-2-methoxyphenyl) cyclohexen-3-one was obtained. Ethanol (120m
1) and dissolved in toluene (210 ml), 3-oxobutyraldehyde dimethyl acetal (6.5 g) and powdered potassium hydroxide (0.92 g) were added, and the mixture was heated under reflux.
30 minutes later, powdered potassium hydroxide (0.19 g), 1 hour later, powdered potassium hydroxide (0.19 g) and 3-oxobutyraldehyde dimethyl acetal (0.52 g)
g) 1 hour and 30 minutes later, powdered potassium hydroxide (0.1
9 g) was added thereto, followed by stirring at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to a silica gel column (ethyl acetate-hexane) to give 7- (5-chloro-2-methoxyphenyl) -4-methyl-5,6,6.
7,8-tetrahydroquinolin-5-one (2.2 g)
Was obtained as colorless crystals. mp 131-133 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H,
s), 2.84 (1H, dd, J = 11, 17 Hz),
2.88-3.03 (1H, m), 3.28 (1H, d
d, J = 11, 17 Hz), 3.41 (1H, ddd,
J = 2, 5, 17 Hz), 3.71-3.92 (1H,
m), 3.82 (3H, s), 6.83 (1H, d, J
= 8 Hz), 7.1 (1H, d, J = 5 Hz), 7.1
6-7.30 (2H, m), 8.49 (1H, d, J =
5 Hz).

Reference Example 164 5- (5-fluoro-2-methoxy) cyclohexane-
1,3-dione (9.5 g), ammonium acetate (8
g) was heated to reflux in ethanol (80 ml) for 1.5 hours. The reaction solution was concentrated under reduced pressure, and water (100 ml) was added to the residue.
Ethyl acetate (150 ml) was added, shaken and separated.
The upper layer was washed with water, concentrated under reduced pressure, the residue was washed with ethyl acetate and dried, and 1-amino-5- (5-fluoro-2-methoxyphenyl) cyclohexane-3-one (8.45
g) was obtained. mp 163-163 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.14 (1H, d
d), 2.28-2.63 (3H, m) 3.43-3.
59 (1H, m), 3.79 (3H, s), 5.00
(1H, s), 6.40 (1H, br), 6.98-
7.15 (3H, m).

Reference Example 165 1-Amino-5- (5-fluoro-2-methoxyphenyl) cyclohexane-3-one (4.5 g), 1,1-
Dimethoxy-3-butanone (7 ml), toluene (70
ml) and ethanol (30 ml) were mixed with 110-1.
Granular potassium hydroxide (1.3 g) with stirring at 15 ° C
Was added. As soon as the potassium hydroxide was dissolved, granular potassium hydroxide (1 g) was added. Thereafter, granular potassium hydroxide (0.25 g) was added three times every 30 minutes. 2 from the start of the reaction
After an hour, 1,1-dimethoxy-3-butanone (3 ml)
Was added, and granular potassium hydroxide (0.25 g) was added, followed by stirring for 1 hour under the same conditions. The reaction solution was concentrated under reduced pressure, and water (30 ml) and ethyl acetate (150 ml) were added to the residue, shaken, and separated. The upper layer is washed with concentrated hydrochloric acid (1.6m
l) was added and concentrated under reduced pressure. The residue was washed with a small amount of ethanol and dried to give 7- (5-fluoro-2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (3.34 g). Obtained. mp 174-175C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.74-2.8
4 (4H, m), 3.10 (1H, dd), 3.35 −
3.60 (2H, m), 3.81-4.00 (4H,
m), 7.00-7.23 (3H, m), 7.76 (1
H, d), 8.77 (1H, d).

Reference Example 166 7- (5-Fluoro-2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (2.13 g) was added to water (20 ml). Anhydrous potassium carbonate (1.5 g) and ethyl acetate (50 ml) were added, shaken and separated. The upper layer was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (15 ml).
An M-boron tribromide-dichloromethane solution (21 ml) was added dropwise. After removing the bath, the mixture was stirred for 2 hours, poured into ice water, added with an excess of aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 7- (5-fluoro-2-hydroxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one ( 0.773 g). mp 222-224 ° C. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 2.71
(3H, s), 2.84-3.03 (2H, m), 3.
30 (1H, dd), 3.46 (1H, dd), 3.7
3-3.87 (1H, m), 6.72-6.90 (3
H, m), 7.14 (1H, d), 8.44 (1H,
d).

Reference Example 167 5- (5-Chloro-2-fluorophenyl) cyclohexane-1,3-dione (2 g) and ammonium acetate (1.9 g) were heated under reflux in ethanol (15 ml) for 15 hours. The reaction solution was concentrated under reduced pressure, and water (30 m
l) and ethyl acetate (150 ml) were added, shaken and separated. The upper layer was washed with water, concentrated under reduced pressure, the residue was washed with ethyl acetate and dried, and 1-amino-5- (5-chloro-2-fluorophenyl) cyclohexane-3-one (1.45)
g) was obtained as yellow crystals. mp 233-234 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.20 (1H, d
d), 2.34-2.53 (2H, m) 2.64 (1
H, dd) 3.39-3.55 (1H, m), 5.02
(1H, s), 6.88 (1H, br), 7.19-
7.50 (3H, m).

Reference Example 168 1-amino-5- (5-chloro-2-fluorophenyl) cyclohexane-3-one (1.33 g), 1,1
-Dimethoxy-3-butanone (2 ml), toluene (2
0-1) and ethanol (9 ml).
Granular potassium hydroxide (0.4g) with stirring at 15 ° C
Was added. As soon as the potassium hydroxide was dissolved, granular potassium hydroxide (0.3 g) was added. Thereafter, granular potassium hydroxide (0.1 g) was added three times every 30 minutes. Two hours after the start of the reaction, 1,1-dimethoxy-3-butanone (1 m
l) was added, and granular potassium hydroxide (0.1 g) was added, followed by stirring for 1 hour under the same conditions. The reaction solution was concentrated under reduced pressure, water (30 ml) and ethyl acetate (100 ml) were added to the residue, and the mixture was shaken and separated. Wash the upper layer with water and concentrate hydrochloric acid (0.5ml)
Was added and concentrated under reduced pressure. The residue was washed with a small amount of ethanol and dried, and 7- (5-chloro-2-fluorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1.05 g) I got mp 179-180 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.79-2.90
(4H, m), 3.16 (1H, dd), 3.43-
3.69 (2H, m), 3.82-3.98 (1H,
m), 7.26-7.47 (2H, m), 7.59 (1
H, dd), 7.75 (1H, d), 8.77 (1H,
d).

Reference Example 169 7- (3-chlorothiophen-2-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (7.07 g), ethylene glycol (6.2 g) , P
-Toluene sulfonic acid (6.9 g)
The resulting solution was heated to reflux for 15 hours while separating water in the same solution. Ethyl acetate (150 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) were added to the reaction solution, and the mixture was shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 7- (3-chlorothiophen-2-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one-ethyleneacetal (7.
3g) were obtained as colorless crystals. mp 117-118 ° C (recrystallized from ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.96 (1H, t),
2.45-2.55 (4H, m) 3.09 (1H, d
d), 3.36 (1H, ddd), 3.64-3.80
(1H, m) 4.15-4.37 (4H, m), 6.9
3 (1H, d), 7.08 (1H, d), 7.18 (1
H, d), 8.36 (1H, d).

Reference Example 170 7- (3-Chlorothiophen-2-yl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one
Ethylene acetal (1.61 g) is dissolved in tetrahydrofuran (16 ml), 1.6M butyllithium and hexane solution (35 ml) while stirring at -60 ° C or lower.
Was added. After stirring at −60 ° C. or lower for 0.5 hour, methyl iodide (1 ml) was added under the same conditions, and the bath was removed.
Stirred for hours. Water (80 ml), ethyl acetate (125 ml) and hexane (100 ml) were added to the reaction solution, and the mixture was shaken and separated. The upper layer was washed with aqueous sodium sulfite and then with water, and concentrated under reduced pressure to obtain a pale green candy (1.47 g). This was dissolved in 1,2-dimethoxyethane (12 ml), 2N hydrochloric acid (6 ml) was added, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was washed with ethanol and dried, and 7- (3-chloro-5-methylthiophen-2-yl) -4-methyl-5,6,7,8-tetrahydroquinoline- 5-one hydrochloride (1.03 g) was obtained as pale yellow crystals. mp 192-193 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (3H,
s), 2.77 (3H, s), 2.94-2.98 (2
H, m), 3.44 (1H, dd), 3.59 (1H,
dd), 3.90-4.08 (1H, m), 6.78.
(1H, s), 7.72 (1H, d), 8.76 (1
H, d).

Reference Example 171 A mixture of 5- (2-chloro-5-methylphenyl) cyclohexane-1,3-dione (2.37 g), p-toluenesulfonylhydrazide (2 g), and ethanol (20 ml) was prepared in 3.5. Heated to reflux for an hour. After air cooling, the precipitated crystals were collected by filtration and 5- (2-chloro-5-methylphenyl)
-1- [2- (4-Methylphenylsulfonyl) hydrazino] cyclohexane-3-one (3.67 g) was obtained as pale yellow crystals. mp 256-257 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.21 (1H, d
d), 2.29 (3H, s) 2.36-2.50 (6
H, m), 3.42-3.57 (1H, m), 5.24
(1H, s), 7.07 (1H, dd), 7.28 (1
H, s), 7.30 (1H, d), 7.42 (2H,
d), 7.72 (2H, d), 8.78 (1H, b
r), 9.83 (1H, br).

Reference Example 172 5- (2-chloro-5-methylphenyl) -1- [2-
A mixture of (4-methylphenylsulfonyl) hydrazino] cyclohexane-3-one (2.03 g), anhydrous potassium carbonate (1.73 g), and methanol (20 ml) was stirred at room temperature for 30 minutes. To this mixture, 1,2-dimethoxyethane (10 ml), bromoacetone (0.89
1 g), and the mixture was heated and stirred at 80 ° C. for 4.5 hours. The solvent was distilled off under reduced pressure, and ethyl acetate (200 ml) and water (30 ml) were added to the residue, followed by shaking and separation. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 7- (2-chloro-5-methylphenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.804 g) was obtained as brown crystals. As obtained. mp 65-70 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s),
2.71 (3H, s), 2.86 (1H, dd), 3.
07 (1H, ddd), 3.41 (1H, dd), 3.
76 (1H, ddd), 3.88-4.03 (1H,
m), 7.06 (1H, dd), 7.13 (1H,
s), 7.32 (1H, dd), 9.15 (1H,
s).

Reference Example 173 A mixture of 5- (5-fluoro-2-methylphenyl) cyclohexane-1,3-dione (2.2 g), p-toluenesulfonylhydrazide (2 g), and ethanol (20 ml) was added in 2.5 parts. Heated to reflux for an hour. After air cooling, the precipitated crystals were collected by filtration and washed with ethanol to give 5- (3-fluoro-6-methylphenyl) -1- [2- (4-methylphenylsulfonyl) hydrazino] cyclohexane-3-.
On (1.64 g) was obtained as colorless crystals. mp 241-242 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.15 (1H, d
d), 2.24 (3H, s), 2.27-1.60 (6
H, m), 3.20-3.37 (1H, m), 5.23
(1H, s), 6.88-6.98 (1H, m), 7.
12-7.22 (2H, m), 7.42 (2H, d),
7.72 (2H, d), 8.73 (1H, br), 9.
82 (1H, br).

Reference Example 174 5- (5-fluoro-2-methylphenyl) -1- [2
-(4-Methylphenylsulfonyl) hydrazino] cyclohexane-3-one (1.63 g), anhydrous potassium carbonate (1.45 g), methanol (20 ml), 1,2-
To a mixture of dimethoxyethane (10 ml) was added 1-
Bromopropan-2-one (0.75 g) was added. The mixture was stirred at room temperature for 2 hours and heated and stirred at 80 ° C. for 5 hours. The solvent was distilled off under reduced pressure, ethyl acetate (70 ml) and water (30 ml) were added to the residue, and the mixture was shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 7- (5-fluoro-2-methylphenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.265 g) was yellow-brown. Obtained as crystals. mp 127-128 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s),
2.71 (3H, s), 2.85 (1H, dd), 2.
98 (1H, dd), 3.36 (1H, dd), 3.
62-3.77 (2H, m), 6.87-7.02 (2
H, m), 7.20 (1H, dd), 9.16 (1H,
s).

Reference Example 175 5- (5-chloro-2-fluorophenyl) cyclohexane-1,3-dione (2.04 g), p-toluenesulfonylhydrazide (1.67 g), ethanol (15
ml) of the mixture was heated at reflux for 2.5 hours. After air cooling, the precipitated crystals were collected by filtration, washed with ethanol, and treated with 5- (5
-Chloro-2-fluorophenyl) -1- [2- (4-
Methylphenylsulfonyl) hydrazino] cyclohexane-3-one (2.08 g) was obtained as colorless crystals. mp 244-245 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.23 (1H, d
d), 2.40 (3H, s), 2.43-2.60 (3
H, m), 3.32-3.47 (1H, m), 5.23
(1H, s), 7.19-7.49 (5H, m), 7.
72 (2H, d), 8.79 (1H, br), 9.85
(1H, s).

Reference Example 176 5- (5-chloro-2-fluorophenyl) -1- [2
-(4-Methylphenylsulfonyl) hydrazino] cyclohexane-3-one (2.0 g), anhydrous potassium carbonate (1.68 g), methanol (20 ml), and 1,2-dimethoxyethane (10 ml) were ice-cooled. Lower 1-bromopropan-2-one (0.87 g) was added. The mixture was stirred at room temperature for 2 hours, and heated and stirred at 80 ° C. for 6 hours. The solvent was distilled off under reduced pressure, ethyl acetate (70 ml) and water (30 ml) were added to the residue, and the mixture was shaken and separated. The upper layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 7- (5-chloro-2-fluorophenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.338 g) was yellow-brown. Obtained as crystals. mp 124-125 ° C (recrystallized from ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s),
2.93 (1H, dd), 3.05 (1H, dd),
3.48 (1H, dd), 3.68-3.85 (2H,
m), 7.02-7.10 (1H, m), 7.24-
7.31 (2H, m), 9.16 (1H, s).

Reference Example 177 5- (2,5-dichlorophenyl) cyclohexane-
Dicyclohexylcarbodiimide (1.3 g) was added to a solution of 1,3-dione (1.5 g), 4-dimethylaminopyridine (1.1 g) and acetic acid (0.63 g) in dimethylformamide (60 ml), and the mixture was added at room temperature for 36 hours. Stirred. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
Extracted with 1N aqueous sodium hydroxide. The aqueous layer was filtered, and the insoluble matter was removed by filtration. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure.
(2,5-dichlorophenyl) -2- (1-hydroxyethylidene) cyclohexane-1,3-dione (1.4
g) was obtained. Dissolve this in ethanol (30 ml)
Hydrazine hydrate (0.26 g) was added, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give 6- (2,5-dichlorophenyl) -3-
Methyl-4,5,6,7-tetrahydroindazole-
4-one (1.2 g) was obtained as colorless crystals. mp 184-186 <0> C. ¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H, s),
2.66-2.82 (2H, m), 2.92 (1H, d
d, J = 12, 16 Hz), 3.20 (1H, dd, J)
= 4, 16 Hz), 3.83-4.03 (1H, m),
7.16-7.37 (4H, m).

Reference Example 178 Sodium hydroxide (4.0 g) was dissolved in water (500 ml), acetone (100 ml) and then 2,5-dichlorobenzaldehyde (15.9 g) were added, and the mixture was stirred at room temperature for 1 hour. Acetone was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and concentrated under reduced pressure to obtain 4- (2,5-dichlorophenyl) -3-buten-2-one (19.0 g). Ethanol (150 ml) and diethyl malonate (14.6) were added to a 20% sodium ethoxide ethanol solution (6.2 g) at room temperature.
g) was added and then 4- (2,5-dichlorophenyl) -3-buten-2-one (19.0 g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling, the solvent was distilled off, and water was added to the residue.
The aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (50 ml) was added, and the mixture was heated under reflux for 2 hours, air-cooled,
2.5 M sulfuric acid (50 ml) was added over 15 minutes,
Heated to reflux for an hour. After air cooling, the precipitated crystals are collected by filtration,
After washing with water and toluene sequentially, 5- (2,5-dichlorophenyl) cyclohexane-1,3-dione (9.9
g) was obtained as colorless crystals. mp 187 ° C (decomposition). ¹ H-NMR (CDCl ₃ ) δ: 2.42-2.70
(4H, m), 3.71-3.89 (1H, m), 5.
54 (1H, s), 7.16-7.43 (3H, m).

Reference Example 179 Sodium hydroxide (3.0 g) was dissolved in water (100 ml), and acetone (80 ml) was added.
A solution of methoxybenzaldehyde (11.8 g) in acetone (30 ml) was added dropwise. The reaction was stirred at room temperature for 2 hours. Acetone was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 4- (5-chloro-2-methoxyphenyl) -3-.
Buten-2-one (6.8 g) was obtained. To a 20% sodium ethoxide ethanol solution (2.3 g) was added diethyl malonate (5.4 g) at room temperature, followed by 4- (5-
Chloro-2-methoxyphenyl) -3-buten-2-one (6.8 g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (18 ml) was added and 2
Heated to reflux for an hour. After air cooling, 2.5M sulfuric acid (18ml)
Was added over 15 minutes, and the mixture was heated under reflux for 15 minutes. After air cooling,
The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5- (5-chloro-2-methoxyphenyl) cyclohexane-1,3-dione (7.3 g) as amorphous. ¹ H-NMR (CDCl ₃ ) δ: 2.5-2.95 (4
H, m), 3.4-3.88 (1H, m), 3.80
(3H, s), 5.61 (1H, s), 6.38 (1
H, br), 6.77-7.28 (3H, m).

Reference Example 180 A 1.6 M butyllithium hexane solution (55.5 ml) was added dropwise to a solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran at -78 ° C. Stir at the same temperature for 30 minutes, and add dimethylformamide (6.8
g) in tetrahydrofuran (20 ml) was added dropwise. The temperature was spontaneously raised to 0 ° C., and ice water was added to the reaction solution.
The reaction solution was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-fluoro-2-methylbenzaldehyde (11.5 g) as an oil. Acetone (80m
l), sodium hydroxide (3.7 g), water (100 m
A solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml) was added dropwise to the mixture of 1) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Acetone was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, concentrated under reduced pressure to give 4- (5-fluoro-2).
-Methylphenyl) -3-buten-2-one (13.4)
g) was obtained. Diethyl malonate (14.0 g) was added to a 20% sodium ethoxide ethanol solution (5.9 g) at room temperature.
g) was added and then 4- (5-fluoro-2-methylphenyl) -3-buten-2-one (13.4 g) was added in small portions. Stir the reaction mixture at room temperature for 30 minutes,
The mixture was heated and stirred for an hour. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (46 ml) was added, and the mixture was heated under reflux for 2 hours.
After air cooling, 2.5 M sulfuric acid (46 ml) was added over 10 minutes, and the mixture was heated under reflux for 30 minutes. After air cooling, the precipitated crystals are collected by filtration, washed successively with water and isopropyl ether, and
-(5-Fluoro-2-methylphenyl) cyclohexane-1,3-dione (8.6 g) was obtained as colorless crystals. mp 175-176 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s),
2.27-2.56 (4H, m), 2.5-4.3 (1
H, br), 3.44-3.63 (1H, m), 5.5.
5 (1H, s), 6.77-7.01 (2H, m),
7.09-7.17 (1H, m).

Reference Example 181 4-fluorotoluene (21.5 g), dichloromethyl methyl ether (56.1 g) in dichloromethane (16
0 ml) solution at room temperature was added dropwise a solution of titanium tetrachloride (92.6 g) in dichloromethane (50 ml). 5 at the same temperature
Stirred for hours and poured the reaction onto ice. Water the organic layer,
Wash sequentially with aqueous sodium bicarbonate, water and saturated saline,
Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and about 1: 7 of 2-fluoro-5-methylbenzaldehyde and 5-fluoro-2-methylbenzaldehyde as oily substances.
A mixture (28.1 g) was obtained. Acetone (160ml)
To a mixture of sodium hydroxide (6.4 g) and water (200 ml) at 0 ° C. at about 1: 7 mixture (28.1 g) of 2-fluoro-5-methylbenzaldehyde and 5-fluoro-2-methylbenzaldehyde. Was added dropwise and stirred at the same temperature for 1 hour. 1N hydrochloric acid (160
ml) and acetone was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated saline, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give 4- (2
-Fluoro-5-methylphenyl) -3-butene-2-
On (18.2 g) was obtained. To a 20% sodium ethoxide ethanol solution (1.4 g) at room temperature was added diethyl malonate (3.3 g), followed by 4- (2-fluoro-
5-methylphenyl) -3-buten-2-one (3.5
g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2
M sodium hydroxide (11 ml) was added, and the mixture was heated under reflux for 2 hours. After air cooling, 2.5 M sulfuric acid (11 ml) was added over 5 minutes, and the mixture was heated under reflux for 30 minutes. After air cooling, the precipitated crystals were collected by filtration and washed sequentially with water and isopropyl ether to give 5- (2-fluoro-5-methylphenyl) cyclohexane-1,3-dione (1.6 g) as colorless crystals. Was. mp 174 ° C (decomposition). ¹ H-NMR (CDCl ₃ -DMSO-d ₆ ) δ: 2.3
1 (3H, s), 2.47-2.93 (4H, m),
3.48-3.68 (1H, m), 5.56 (1H,
s), 6.77-7.30 (1H, br), 6.86-
7.07 (3H, m).

Reference Example 182 4-chlorotoluene (25.0 g), dichloromethyl methyl ether (45.4 g) in dichloromethane (160
ml) solution at room temperature was added dropwise a solution of titanium tetrachloride (74.9 g) in dichloromethane (40 ml). 15 at the same temperature
Stirred for hours and poured the reaction onto ice. Water the organic layer,
Wash sequentially with aqueous sodium bicarbonate, water and saturated saline,
Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give crude 2-chloro-5- as an oil.
Methylbenzaldehyde (18.3 g) and 5-chloro-
2-Methylbenzaldehyde (4.1 g) was obtained, respectively. Acetone (160 ml) and sodium hydroxide (2.
6 g) and water (160 ml) were added dropwise with a solution of crude 2-chloro-5-methylbenzaldehyde (18.3 g) in acetone (30 ml) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour.
Acetone is distilled off under reduced pressure, and the residue is extracted with ethyl acetate.
The organic layer was washed sequentially with water and saturated saline, and concentrated under reduced pressure.
4- (2-Chloro-5-methylphenyl) -3-buten-2-one (18.9 g) was obtained as an oil. 20%
To a sodium ethoxide ethanol solution (4.3 g) at room temperature was added diethyl malonate (10.1 g).
4- (2-Chloro-5-methylphenyl) -3-buten-2-one (18.9 g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (33ml)
Was added and the mixture was heated under reflux for 2 hours. After air cooling, 2.5 M sulfuric acid (33 ml) was added over 15 minutes, and the mixture was heated under reflux for 30 minutes. After air cooling, the precipitated crystals were collected by filtration, washed successively with water and isopropyl ether, and washed with 5- (2-chloro-5-methylphenyl) cyclohexane-1,3-dione (7.
8g) were obtained as colorless crystals. mp 186-188 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H,
s), 2.38-2.72 (4H, m), 3.2-5.
4 (1H, br), 3.73-3.93 (1H, m),
5.55 (1H, s), 7.01 (1H, d, J = 8H)
z), 7.03 (1H, s), 7.26 (1H, d, J
= 8Hz). Also, acetone (80 ml) and sodium hydroxide (1.
2g) and water (80 ml) at 0 ° C with 5-chloro-2.
-Methylbenzaldehyde (4.1 g) in acetone (1
0 ml) solution was added dropwise and stirred at the same temperature for 1 hour. Acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in that order, concentrated under reduced pressure,
(5-chloro-2-methylphenyl) -3-butene-2
The -one (5.5 g) was obtained as an oil. To a 20% sodium ethoxide ethanol solution (9.5 g) was added diethyl malonate (4.5 g) at room temperature, followed by 4- (5
-Chloro-2-methylphenyl) -3-buten-2-one (5.5 g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (15 ml) was added and 2
Heated to reflux for an hour. After air cooling, 2.5M sulfuric acid (15ml)
Was added over 15 minutes, and the mixture was heated under reflux for 30 minutes. After air cooling,
The precipitated crystals were collected by filtration and washed sequentially with water and isopropyl ether to give 5- (5-chloro-2-methylphenyl) cyclohexane-1,3-dione (2.9 g) as colorless crystals. mp 180-181 ° C. ¹ H-NMR (CDCl ₃ -DMSO-d ₆ ) δ: 2.3
1 (3H, s), 2.35-2.84 (4H, m),
3.37-3.73 (1H, m), 5.56 (1H,
s), 6.9-7.43 (1H, br), 7.08-
7.26 (3H, m).

Reference Example 183 Sodium hydroxide (3 g) was dissolved in water (200 ml), and acetone (80 ml) was added.
Methoxybenzaldehyde (10 g) in acetone (25
ml) solution was added dropwise. The reaction was stirred at room temperature for 4 hours. Acetone was distilled off under reduced pressure, and extracted with ethyl acetate.
The organic layer was washed successively with water and saturated saline, and concentrated under reduced pressure to give 4- (5-fluoro-2-methoxyphenyl) -3.
-Buten-2-one (13 g) was obtained. To a 20% sodium ethoxide ethanol solution (21.4 g) at room temperature was added diethyl malonate (11.2 g).
(5-Fluoro-2-methoxyphenyl) -3-buten-2-one (13 g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling,
The solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (50 ml) was added, and the mixture was heated under reflux for 2 hours. After air cooling, 2.5M sulfuric acid (50
ml) was added over 15 minutes, and the mixture was heated under reflux for 15 minutes. After air cooling, the precipitated crystals were washed with ethyl acetate, and the 5- (5-
Fluoro-2-methoxyphenyl) cyclohexane-
1,3-dione (9.6 g) was obtained as pale yellow crystals. mp 160-161 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.3-2.66
(4H, m), 3.5-3.66 (1H, m), 3.8
0 (3H, s), 5.29 (1H, s), 6.96-
7.17 (3H, m), 11.20 (1H, br).

Reference Example 184 Anhydrous tetrahydrofuran (100 ml) was added to a 1.6 M butyllithium hexane solution (32 ml), and 2,2,2
6,6-Tetramethylpiperidine (8.4 ml) was added to -7.
The solution was added dropwise at 0 ° C or lower. Then, 1-chloro-4-fluorobenzene (6.5 g) in anhydrous tetrahydrofuran (2
0 ml) solution was added dropwise, and the mixture was stirred at -70 ° C or lower for 2 hours. A solution of dimethylformamide (6.5 g) in tetrahydrofuran (15 ml) was added dropwise, and the temperature was spontaneously raised to 0 ° C. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-chloro-2-fluorobenzaldehyde (5.1 g) as an oil. Acetone (22 ml) and sodium hydroxide (0.8
3g) and water (55 ml) at room temperature in 5-chloro-2.
A solution of -fluorobenzaldehyde (3.5 g) in acetone (20 ml) was added dropwise, and the mixture was stirred at the same temperature for 15 hours.
Acetone was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and concentrated under reduced pressure to give 4
-(5-Chloro-2-fluorophenyl) -3-buten-2-one (4.3 g) was obtained. To a 20% sodium ethoxide ethanol solution (7.4 g) at room temperature was added diethyl malonate (3.6 g), followed by 4- (5-chloro-2-fluorophenyl) -3-buten-2-one (4 g). 0.3 g) was added in small portions. Reaction mixture at room temperature
The mixture was stirred for 0 minutes and heated and stirred for 2 hours. After air cooling, the solvent was distilled off, water was added to the residue, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (17 ml) was added, and the mixture was heated under reflux for 1 hour. After air cooling, 2.5 M sulfuric acid (17 ml) was added over 10 minutes, and the mixture was heated under reflux for 30 minutes. After air cooling, the precipitated crystals were collected by filtration, washed successively with water and isopropyl ether to give 5- (5-chloro-2-fluorophenyl) cyclohexane-1,3-dione (4.1 g) as pale yellow crystals. Obtained. mp 176-177 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.33-2.7
2 (4H, m), 3.43-3.65 (1H, m),
5.30 (1H, s), 7.18-7.39 (2H,
m), 7.47-7.52 (1H, m), 10.78
(1H, br).

Example 136 (Production of compounds 141 and 142) (±) -7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride ( 3.0 g) of methanol (50
ml) solution was added with a 28% sodium methoxide methanol solution (2.7 g). The mixture was stirred at 50 ° C. for 1 hour, and the solvent was distilled off under reduced pressure. Water was added, the precipitated crystals were washed with water, dried and dried (±) -7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,6.
7,8-Tetrahydroquinoline was obtained. (±) -7-
To a solution of (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline (2.3 g) in ethanol (10 ml), ethanol of L-pyroglutamic acid (0.81 g) (5ml)
The solution was added at 80 ° C. The mixture was gradually returned to room temperature and stirred for 6 hours. The crystals are collected by filtration, washed with ethanol, and (+)-7-
(2,5-Dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline L-pyroglutamate (1.61 g) was obtained. The crystals were recrystallized from ethanol, suspended in methanol, and treated with a 28% sodium methoxide methanol solution (0.1%).
5 g) was added, and the solvent was distilled off under reduced pressure. After the obtained crystals were washed with water and dried, they were recrystallized from acetonitrile. The crystals were dissolved in ethanol (10 ml), and methanesulfonic acid (0.12 g) was added, followed by concentration. The obtained crystals were recrystallized from ethanol to give (+)-7-
(2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 141) (0.25 g,
99.8% ee) was obtained. mp. 248 ° C (decomposition). Calcd As Elemental analysis _{C 17 H 17 Cl 2 N 5} · 2MeSO 3 H. C, 41.16; H, 4.54;
N, 12.63; Cl, 12.79. Found C, 41.16; H, 4.42;
N, 12.40; Cl, 12.51. ¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (6
H, s), 2.58-2.96 (1H, m), 2.73.
(3H, s), 2.97-4.2 (4H, m), 7.2
−8.4 (4H, br), 7.38-7.80 (4H,
m), 8.45 (1H, d, J = 6 Hz), 10.64
(1H, s). A 28% methanol solution of sodium methoxide (1.5 g) was added to the mother liquor and the washing solution separated with L-pyroglutamic acid, and the mixture was concentrated and then washed with water to obtain crystals (1.9 g) rich in (-)-isomer. . This was dissolved in ethanol (10 ml), and D-pyroglutamic acid (0.68 g) was added.
Heat and concentrate as a homogeneous solution. The residue was recrystallized from ethanol to give (-)-7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,6.
7,8-Tetrahydroquinoline D-pyroglutamate (1.0 g) was obtained. The crystals were suspended in methanol, and a 28% sodium methoxide methanol solution (0.
8 g) was added, and the solvent was distilled off under reduced pressure. After the obtained crystals were washed with water and dried, they were dissolved in ethanol (10 ml), and methanesulfonic acid (0.41 g) was added, followed by concentration. The obtained crystals are recrystallized from ethanol,
(-)-7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 142)
(0.31 g, 99.0% ee) was obtained. mp. 258 ° C (decomposition). Calcd As Elemental analysis _{C 17 H 17 Cl 2 N 5} · 2MeSO 3 H. C, 41.16; H, 4.54;
N, 12.63; Cl, 12.79. Found C, 40.97; H, 4.55;
N, 12.31; Cl, 12.71. ¹ H-NMR (DMSO-d ₆ ) was consistent with that of compound 141.

Example 137 (Production of compounds 143 and 144) (±) -7- (3,5-dichlorothiophen-2-yl) -5-guanidinoimino-4-methyl-5,6,6
To a solution of 7,8-tetrahydroquinoline hydrochloride (3.0 g) in methanol (30 ml) was added a 28% sodium methoxide methanol solution (3 g). The mixture was stirred at 50 ° C. for 1 hour, and the solvent was distilled off under reduced pressure. Water was added, the precipitated crystals were washed with water, dried and dried (±) -7- (3,5-dichlorothiophen-2-yl) -5-guanidinoimino-4-.
Methyl-5,6,7,8-tetrahydroquinoline was obtained. (±) -7- (3,5-dichlorothiophene-2-
Yl) -5-guanidinoimino-4-methyl-5,6,
L-pyroglutamic acid (0.56 g) was added to a solution of 7,8-tetrahydroquinoline (1.6 g) in ethanol (10 ml).
A solution of g) in ethanol (2 ml) was added at 80 ° C. The mixture was gradually returned to room temperature and stirred at room temperature for 6 hours. The crystals are collected by filtration, washed with ethanol, and (+)-7- (3,5-dichlorothiophen-2-yl) -5-guanidinoimino-4.
-Methyl-5,6,7,8-tetrahydroquinoline L
-Pyroglutamate (1.2 g) was obtained. The crystals were recrystallized from ethanol and suspended in methanol.
8% sodium methoxide methanol solution (0.6 g)
Was added and the solvent was distilled off under reduced pressure. The obtained crystals were washed with water and dried, dissolved in ethanol (10 ml), and concentrated by adding methanesulfonic acid (0.098 g). The obtained crystals were recrystallized from ethanol to give (+)-7-
(3,5-dichlorothiophen-2-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 143)
(0.1 g, 99.6% ee) was obtained. mp. 168-172 ° C. Calcd As Elemental analysis _{C 15 H 15 Cl 2 N 5} S · 2MeSO 3 H. C, 36.43; H, 4.14;
N, 12.49. Found C, 36.54; H, 4.10;
N, 12.66. ¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (6
H, s), 2.67-2.92 (1H, m), 2.80.
(3H, s), 3.02-4.12 (4H, m), 7.
24 (1H, s), 7.4-8.1 (4H, br),
7.68 (1H, d, J = 5 Hz), 8.58 (1H, d, J = 5 Hz)
d, J = 5 Hz), 10.72 (1H, s). A 28% methanol solution of sodium methoxide (0.8 g) was added to the mother liquor and the washing liquid separated with L-pyroglutamic acid, and after concentration, the mixture was washed with water to obtain (-)-isomer-rich crystals (1.3 g). . This is dissolved in ethanol and D-
Pyroglutamic acid (0.46 g) was added and heated to form a uniform solution. After cooling, the precipitated crystals were collected by filtration and (-)-7
-(3,5-dichlorothiophen-2-yl)-5-
Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline D-pyroglutamate was obtained. The crystals were suspended in methanol, a 28% sodium methoxide methanol solution (0.8 g) was added, and the solvent was distilled off under reduced pressure. After the obtained crystals were washed with water and dried, they were dissolved in ethanol (10 ml), and then methanesulfonic acid (0.32 g) was added and concentrated. The obtained crystals were recrystallized from ethanol to give (-)-7- (3,5-dichlorothiophen-2-yl) -5-guanidinoimino-
4-methyl-5,6,7,8-tetrahydroquinoline methanesulfonate (compound 144) (0.39 g, 9
9.6% ee) was obtained. mp. 172-176 ° C. Calcd As Elemental analysis _{C 15 H 15 Cl 2 N 5} S · 2MeSO 3 H. C, 36.43; H, 4.14;
N, 12.49. Found C, 36.63; H, 3.94;
N, 12.32. ¹ H-NMR (DMSO-d ₆ ) was consistent with that of compound 143.

Example 138 (Preparation of compound 145) 7- (2-Chlorophenyl) -4- (4-chlorophenyl) -5,6,7,8-tetrahydrocinnoline-5
ON (0.18 g), aminoguanidine hydrochloride (65 m
g) in ethanol (10 ml) was added to concentrated hydrochloric acid (0.12
ml) and water (0.12 ml), and the mixture was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, and the residue was made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-methanol). The obtained crystals were dissolved in 1N hydrochloric acid (1 ml) and concentrated. The residue was recrystallized from ethanol-ethyl acetate to give 7
-(2-chlorophenyl) -4- (4-chlorophenyl) -5-guanidinoimino-5,6,7,8-tetrahydrocinnoline hydrochloride (compound 145) (0.13
g) was obtained as colorless crystals. mp 196 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.72-3.
01 (1H, m), 3.06-28 (1H, m), 3.
3-52 (2H, m), 3.72-3.99 (1H,
m), 6.0-8.6 (4H, broad), 7.28.
-7.77 (8H, s), 9.12 (1H, s), 1
1.62 (1H, s).

Example 139 (Production of compound 146) 6- (2-Chlorophenyl) -3-phenylamino-
4,5,6,7-tetrahydroindazol-4-one (0.4 g), aminoguanidine hydrochloride (0.16
g), concentrated hydrochloric acid (0.31 ml), water (0.31 ml),
A mixture of ethanol (20 ml) was heated at reflux for 6 hours. The solvent was distilled off under reduced pressure, and the residue was made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in ethanol, concentrated by adding 1N hydrochloric acid (5 ml), and the precipitated crystals were recrystallized from ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-3-phenylamino-phenyl.
4,5,6,7-Tetrahydroindazole hydrochloride (Compound 146) (0.23 g) was obtained as colorless crystals. mp. 208-210 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.72 (1
H, dd), 2.86-3.16 (3H, m), 3.6.
-3.9 (1H, m), 6.6-8.5 (4H, b
r), 6.84 (1H, t), 7.20-7.63 (9
H, m), 10.68 (1H, s).

Example 140 (Production of compound 147) 6- (2-Chlorophenyl) -3-phenyl-4,5
6,7-tetrahydroindazol-4-one (0.0
5 g), a mixture of aminoguanidine hydrochloride (0.021 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml), and ethanol (5 ml) was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 6-
(2-chlorophenyl) -4-guanidinoimino-3-
Phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 147) (0.04 g) was obtained as colorless crystals. mp. 185 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.73 (1
H, dd, J = 12, 16 Hz), 2.96-3.12
(3H, m), 3.6-3.9 (1H, m), 6.6
8.4 (4H, br), 7.16-7.8 (9H,
m), 10.97 (1H, s).

Example 141 (Production of compound 148) 6- (2-Chlorophenyl) -3-methoxymethyl-
4,5,6,7-tetrahydroindazol-4-one (0.1 g), aminoguanidine hydrochloride (0.046
g), concentrated hydrochloric acid (0.086 ml), water (0.086 m
l), a mixture of ethanol (10 ml) was heated to reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
The organic layer was washed with water and concentrated under reduced pressure. The residue was treated with 1N hydrochloric acid (1
ml) and concentrated. The obtained crystals were recrystallized from ethanol-ethyl acetate to give 6- (2-chlorophenyl) -4-guanidinoimino-3-methoxymethyl-.
4,5,6,7-Tetrahydroindazole hydrochloride (Compound 148) (0.06 g) was obtained as colorless crystals. mp. 210-212 ° C. Elemental analysis value As C ₁₆ H ₁₉ ClN ₆ O.2HClCalcd. C, 45.78; H, 5.04;
N, 20.02. Found C, 45.70; H, 5.08;
N, 19.89. ¹ H-NMR (DMSO-d ₆ ) δ: 2.69 (1
H, dd, J = 12, 16 Hz), 2.89-3.12
(3H, m), 3.3 (3H, s), 3.51-3.7
6 (1H, m), 4.69 (2H, s), 6.9-8.
4 (4H, br), 7.26-7.65 (4H, m),
10.97 (1H, s).

Example 142 (Preparation of compound 149) 1-benzyl-6- (2-chlorophenyl) -3-methyl-4,5,6,7-tetrahydroindazole-4-
ON (0.3 g), aminoguanidine hydrochloride (0.11
g), concentrated hydrochloric acid (0.21 ml), water (0.21 ml),
A mixture of ethanol (20 ml) was heated at reflux for 18 hours. The solvent was distilled off under reduced pressure.
Recrystallized from water to give 1-benzyl-6- (2-chlorophenyl) -4-guanidinoimino-3-methyl-4,
5,6,7-Tetrahydroindazole hydrochloride (Compound 149) (0.37 g) was obtained as colorless crystals. mp. 151-153 ° C. Elemental analysis _{C 22 H 23 ClN 6 · 2HCl} · 0.5H 2 O
As Calcd. C, 58.41; H, 5.57;
N, 18.58. Found C, 58.73; H, 5.46;
N, 18.39. ¹ H-NMR (DMSO-d ₆ ) δ: 2.41 (3
H, s), 2.69 (1H, dd), 2.81-3.7.
4 (4H, m), 5.14-5.36 (2H, m),
6.8-7.65 (4H, br), 7.08-7.63
(9H, m), 10.70 (1H, s).

Example 143 (Preparation of compound 150) 6- (2-Chlorophenyl) -3-methyl-2-phenyl-4,5,6,7-tetrahydroindazole-4-
ON (0.6 g), aminoguanidine hydrochloride (0.24
g), concentrated hydrochloric acid (0.45 ml), water (0.45 ml),
A mixture of ethanol (20 ml) was heated at reflux for 12 hours. The solvent was distilled off under reduced pressure.
Recrystallized from water to give 6- (2-chlorophenyl) -4-
Guanidinoimino-3-methyl-2-phenyl-4,
5,6,7-Tetrahydroindazole hydrochloride (Compound 150) (0.73 g) was obtained as colorless crystals. mp. 192-194 ° C. Elemental analysis value As C ₂₁ H ₂₁ ClN ₆ .HCl.H ₂ O, Calcd. C, 56.38; H, 5.41;
N, 18.79. Found C, 56.57; H, 5.41;
N, 18.76. ¹ H-NMR (DMSO-d ₆ ) δ: 2.52 (3H,
s), 2.73 (1H, dd), 2.95 (1H, d
d), 3.0-3.2 (1H, m), 3.25-3.5
2. (1H, m), 3.57-3.8 (1H, m),
8-8.4 (4H, br), 7.26-7.75 (9
H, m), 10.9 (1H, br).

Example 144 (Production of compound 151) 6- (2-Chlorophenyl) -3-methyl-1- (2-
Phenylethyl) -4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.055 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml), ethanol (15 ml) of the mixture
The mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-3-methyl-1- (2
-Phenylethyl) -4,5,6,7-tetrahydroindazole hydrochloride (Compound 151) (0.07 g) was obtained as colorless crystals. mp. 152-154 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.33-2.
7 (3H, m), 2.42 (3H, s), 2.83-
2.92 (1H, m), 3.01 (2H, t), 3.2
8-3.55 (1H, m), 4.21 (2H, m),
6.2-8.4 (4H, br), 6.97-7.5 (9
H, m), 10.72 (1H, s).

Example 145 (Preparation of compound 152) 6- (2-Chlorophenyl) -3-methyl-2- (2-
Phenylethyl) -4,5,6,7-tetrahydroindazol-4-one (0.20 g), aminoguanidine hydrochloride (0.073 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml), ethanol (15 ml) was heated at reflux for 12 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 6- (2-chlorophenyl) -4-guanidinoimino-3-methyl-2-methyl.
(2-Phenylethyl) -4,5,6,7-tetrahydroindazole hydrochloride (compound 152) (0.17 g)
Was obtained as colorless crystals. mp. 185 ° C (decomposition). Elemental analysis value: C ₂₃ H ₂₅ ClN ₆ .HCl.0.5 H ₂ O Calcd. C, 59.23; H, 5.83;
N, 18.02. Found C, 59.36; H, 5.75;
N, 17.89. ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 2.66 (1H, dd), 2.8-3.15 (3
H, m), 3.06 (2H, t), 3.5-3.7 (1
H, m), 4.27 (2H, t), 6.2-8.0 (4
H, br), 7.05-7.63 (9H, m), 10.
71 (1H, s).

Example 146 (Production of compound 153) 6- (2-Chlorophenyl) -3-methyl-1- (3-
Phenylpropyl) -4,5,6,7-tetrahydroindazol-4-one (0.11 g), aminoguanidine hydrochloride (0.048 g), concentrated hydrochloric acid (0.073 m
l), water (0.073 ml), ethanol (10 ml)
Was heated to reflux for 8 hours. The solvent is distilled off under reduced pressure,
The obtained crystals were recrystallized from ethanol to give 6- (2-
(Chlorophenyl) -4-guanidinoimino-3-methyl-1- (3-phenylpropyl) -4,5,6,7-tetrahydroindazole hydrochloride (Compound 153) (0.
12 g) were obtained as colorless crystals. mp. 210 ° C (decomposition). Elemental analysis value C ₂₄ H ₂₇ ClN ₆ .HCl.0.5 H ₂ O Calcd. C, 60.00; H, 6.08;
N, 17.49. Found C, 60.11; H, 6.00;
N, 17.65. ¹ H-NMR (DMSO-d ₆ ) δ: 1.92-2.1
3 (2H, m), 2.3-2.76 (3H, m), 2.
4 (3H, s), 2.8-3.1 (3H, m), 3.5
3-3.74 (1H, m), 3.83-4.16 (2
H, m), 6.6-8.4 (4H, br), 7.08-
7.65 (9H, m), 10.81 (1H, s).

Example 147 (Preparation of compound 154) 6- (2-Chlorophenyl) -3-methyl-2- (3-
(Phenylpropyl) -4,5,6,7-tetrahydroindazol-4-one (0.25 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.16 ml), water (0.16 ml), ethanol (15 ml) was heated at reflux for 8 hours. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol-water to give 6- (2-chlorophenyl) -4-guanidinoimino-3-methyl-2-methyl.
(3-phenylpropyl) -4,5,6,7-tetrahydroindazole hydrochloride (compound 154) (0.24
g) was obtained as colorless crystals. mp. 170-180 ° C. Elemental analysis value C ₂₄ H ₂₇ ClN ₆ .HCl.0.5 H ₂ O Calcd. C, 60.00; H, 6.08;
N, 17.49. Found C, 60.35; H, 5.85;
N, 17.38. ¹ H-NMR (DMSO-d ₆ ) δ: 1.96-2.1
7 (2H, m), 2.38-2.77 (3H, m),
2.51 (3H, s), 2.8-3.12 (3H,
m), 3.2-3.74 (1H, m), 3.93-4.
23 (2H, m), 6.6-8.4 (4H, br),
7.13-7.63 (9H, m), 10.74 (1H,
s).

Example 148 (Preparation of compound 155) 7- (2,5-Dichlorothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydrocinnoline-5
-One (145 mg), 1-amino-3-hydroxyguanidine hydrochloride (61 mg) in ethanol (3 ml),
Concentrated hydrochloric acid (0.05 ml) was added, and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol-acetone to give 7- (2,5-dichlorothiophen-3-yl) -5- (1-hydroxyguanidine-3-.
Il) Imino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 155) (80 mg) was obtained as off-white crystals. mp 176-178 ° C. Elemental analysis _{C 14 H 16 N 6 Cl 2} OS · 2HCl · 0.5H
₂ O as Calcd. C, 35.99; H, 3.57;
N, 17.99. Found C, 35.90; H, 3.84;
N, 17.72. ¹ H-NMR (DMSO-d ₆ ) δ: 2.77 (3H,
S), 2.84-3.42 (5H, m), 7.40 (1
H, S), 8.49 (2H, br), 9.31 (1H,
s), 11.27 (1H, br), 11.73 (1H,
br).

Example 149 (Preparation of compound 156) 7- (2-Chlorophenyl) -4-methyl-5,6
7,8-tetrahydrocinnolin-5-one (101 m
g), 1-amino-3-hydroxyguanidine hydrochloride (48 mg) was added to ethanol (2 ml), concentrated hydrochloric acid (0.0%).
5 ml) and stirred at 90 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol and dried.
-(2-chlorophenyl) -5- (1-hydroxyguanidin-3-yl) imino-4-methyl-5,6,7,
8-tetrahydrocinnoline hydrochloride (compound 156)
(110 mg) was obtained as off-white crystals. mp 210 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.76 (3H,
S), 2.88 (1H, dd), 3.23 (1H, dd)
d), 3.36-3.68 (3H, m), 7.31-
7.54 (3H, m), 7.63 (1H, dd), 8.
45 (2H, br), 9.27 (1H, s), 11.2
0 (1H, br), 11.58 (1H, br).

Example 150 (Preparation of Compound 157) 7- (2-Chlorophenyl) -4-methyl-5,6
7,8-tetrahydroquinolin-5-one-1-oxide (0.23 g), aminoguanidine hydrochloride (100 m
g), ethanol (6 ml) and concentrated hydrochloric acid (0.1 ml) were added, and the mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and the crystals were collected by filtration and dried to give 7- (2-chlorophenyl) -5-.
Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline-1-oxide hydrochloride (compound 15
7) (220 mg) was obtained as colorless crystals. mp 202-203 ° C. Elemental analysis value: C ₁₇ H ₁₈ N ₅ Cl.HCl.H ₂ O: Calcd. C, 51.27; H, 5.31;
N, 17.58. Found C, 51.02; H, 5.29;
N, 17.34. ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (3H,
s), 2.74-2.96 (2H, m), 3.18 (1
H, br), 3.45-3.65 (2H, m), 7.2
7-7.51 (4H, m), 7.60 (1H, d),
7.74 (4H, br), 8.23 (1H, d), 1
1.20 (1H, br).

Example 151 (Production of compound 158) 7- (2,5-Dichlorothiophen-3-yl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
Ethanol (8 ml) and concentrated hydrochloric acid (0.15 ml) were added to on-1-oxide (426 mg) and aminoguanidine hydrochloride (159 mg), and the mixture was stirred at 105 ° C. for 2 hours. The reaction solution was cooled to room temperature, and the crystals were collected by filtration and dried.
(2,5-Dichlorothiophen-3-yl) -5-guanidineimino-4-methyl-5,6,7,8-tetrahydroquinoline-1-oxide hydrochloride (Compound 158)
(480 mg) as colorless crystals. mp 300 ° C or higher. ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (3
H, s), 2.69-3.60 (5H, m), 7.31.
(1H, d), 7.38 (1H, s), 7.69 (4
H, br), 8.27 (1H, d), 11.10 (1
H, br).

Example 152 (Preparation of compound 159) 7- (2-Chlorophenyl) -4-methyl-5,6,6
7,8-tetrahydrocinnolin-5-one-1-oxide (173 mg), aminoguanidine hydrochloride (73 m
g) in ethanol (4 ml), concentrated hydrochloric acid (0.07 ml)
Was added and stirred at a bath temperature of 90 ° C. for 3.5 hours. The reaction solution was cooled to room temperature, the crystals were collected by filtration and dried, and 7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,5 was obtained.
6,7,8-Tetrahydrocinnoline-1-oxide hydrochloride (Compound 159) (195 mg) was obtained as colorless crystals. mp 283-284 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.59 (3H,
s), 2.83 (1H, dd), 2.94 (1H, d)
d), 3.18-3.25 (1H, m), 3.26-
3.48 (1H, m), 3.50-3.70 (1H,
m), 7.30-7.63 (4H, m), 7.89 (4
H, br), 8.50 (1H, s) 11.57 (1H,
br).

Example 153 (Preparation of compound 160) 7- (2-Chlorophenyl) -4-methyl-5,6
7,8-tetrahydrocinnolin-5-one-2-oxide (116 mg), aminoguanidine hydrochloride (49 m
g) with ethanol (3 ml), concentrated hydrochloric acid (0.05 ml)
Was added and stirred at a bath temperature of 100 ° C. for 3 hours. The reaction solution was cooled to room temperature, and the crystals were collected by filtration and dried, and 7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,6.
7,8-Tetrahydrocinnoline-2-oxide hydrochloride (Compound 160) (116 mg) was obtained as colorless crystals. mp 249-250 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (3H,
s), 2.78 (1H, dd), 2.89-2.97
(1H, m), 3.08-3.22 (1H, m), 3.
28 (1H, d), 3.53-3.73 (1H, m),
7.30-7.63 (4H, m), 7.74 (4H, b
r), 8.35 (1H, s) 11.00 (1H, b
r).

Example 154 (Production of compound 161) 7- (2,5-Dichlorophenyl) -4-methyl-5,
6,7,8-tetrahydrocinnolin-5-one (24
6 mg), aminoguanidine hydrochloride (98 mg), ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and a bath temperature of 1
Stirred at 10 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, the crystals were collected by filtration and dried, and 7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,6.
7,8-tetrahydrocinnoline hydrochloride (compound 16
1) (215 mg) was obtained as off-white crystals. mp 256-258 ° C. Elemental analysis value: C ₁₆ H ₁₆ N ₆ Cl ₂ .2HCl. C, 44.06; H, 4.16;
N, 19.27. Found C, 43.98; H, 4.18;
N, 19.13. ¹ H-NMR (DMSO-d ₆ ) δ: 2.74 (3H,
s), 2.93 (1H, dd), 3.15-3.70.
(4H, m), 7.44 (1H, dd), 7.56 (1
H, d), 7.77 (1H, d), 7.96 (4H, b
r), 9.28 (1H, s), 11.59 (1H, b
r).

Example 155 (Preparation of compound 162) 7- (2-Chloro-5-methylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g), amino Guanidine hydrochloride (0.51 g)
Concentrated ethanol (0.96m) in ethanol (30ml) solution
l) and water (0.96 ml) were added and the mixture was heated under reflux for 5 hours.
The solvent was distilled off under reduced pressure, and the precipitated crystals were recrystallized from ethanol to give 7- (2-chloro-5-methylphenyl) -5.
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 162) (1.5
g) was obtained as colorless crystals. mp 240-243 ° C. Elemental analysis _{C 18 H 20 N 5 Cl ·} 2HCl · 0.3H Calcd the ₂ O. C, 51.45; H, 5.42;
N, 16.67. Found C, 51.60; H, 5.68;
N, 16.53. ¹ H-NMR (DMSO-d ₆ ) δ: 2.35 (3H,
s), 2.77-3.04 (1H, m), 2.91 (3
H, s), 3.15-3.33 (1H, m), 3.39.
-3.75 (3H, m), 7.16 (1H, d, J = 8
Hz), 7.36 (1H, d, J = 8 Hz), 7.48
(1H, s), 7.5-8.4 (4H, br), 7.8
6 (1H, d, J = 6 Hz), 8.65 (1H, d, J
= 6 Hz), 11.44 (1H, s).

Example 156 (Preparation of compound 163) 7- (2-Fluoro-5-methylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g), amino Guanidine hydrochloride (0.54 g)
Hydrochloric acid (1.0 ml) in ethanol (30 ml) solution
And water (1.0 ml) were added, and the mixture was heated under reflux for 7 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water. After washing with ethyl acetate, the aqueous layer was made alkaline with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol, concentrated by adding 1N hydrochloric acid (10 ml), and the precipitated crystals were recrystallized from ethanol to give 7- (2-fluoro-5-methylphenyl) -5-
Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 163) (1.4 g)
Was obtained as colorless crystals. mp 230-235 ° C. Elemental analysis C ₁₈ Calcd as H ₂₀ FN ₅ · 2HCl. C, 54.28; H, 5.57;
N, 17.58. Found C, 54.10; H, 5.50;
N, 17.27. ¹ H-NMR (DMSO-d ₆ ) δ: 2.32 (3H,
s), 2.75-3.02 (1H, m), 2.87 (3
H, s), 3.21 (1H, dd, J = 4, 18H)
z), 3.31-3.63 (3H, m), 7.06-
7.27 (2H, m), 7.4 (1H, d, J = 7H
z), 7.5-8.4 (4H, br), 7.84 (1
H, d, J = 6 Hz), 8.63 (1H, d, J = 6H)
z), 11.54 (1H, s).

Example 157 (Preparation of compound 164) 7- (5-Chloro-2-methylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g), amino Guanidine hydrochloride (0.46 g)
Concentrated ethanol (0.9 ml) in ethanol (30 ml) solution
And water (0.9 ml) were added, and the mixture was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, and washed with ethyl acetate. The aqueous layer was made alkaline by adding aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Concentrate under reduced pressure, dissolve the residue in ethanol, and add 1N hydrochloric acid (10 ml).
And concentrated. The precipitated crystals were recrystallized from ethanol to give 7- (5-chloro-2-methylphenyl) -5.
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (compound 164) (1.4
g) was obtained as colorless crystals. mp 215-220 ° C. Elemental analysis _{C 18 H 20 N 5 Cl ·} 2HCl · 0.3H Calcd the ₂ O. C, 51.45; H, 5.42;
N, 16.67. Found C, 51.49; H, 5.57;
N, 16.44. ¹ H-NMR (DMSO-d ₆ ) δ: 2.32 (3H,
s), 2.68-3.03 (1H, m), 2.87 (3
H, s), 3.13-3.65 (4H, m), 7.12.
-7.38 (2H, m), 7.54 (1H, s), 7.
6-8.45 (4H, br), 7.87 (1H, d, J
= 6 Hz), 8.66 (1H, d, J = 6 Hz), 1
1.48 (1H, s).

Example 158 (Production of compound 165) 7- (5-Fluoro-2-methylphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g), amino Guanidine hydrochloride (0.54 g)
Hydrochloric acid (1.0 ml) in ethanol (30 ml) solution
And water (1.0 ml) were added, and the mixture was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, and washed with ethyl acetate. The aqueous layer was made alkaline by adding aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Dissolve the residue in ethanol and add 1N hydrochloric acid (10ml)
And concentrated, and the precipitated crystals are recrystallized from ethanol to give 7- (5-fluoro-2-methylphenyl) -5.
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 165) (1.4
g) was obtained as colorless crystals. mp 202-205 ° C. Elemental analysis _{C 18 H 20 N 5 F ·} 2HCl · 0.5H Calcd the ₂ O. C, 53.08; H, 5.69;
N, 17.19. Found C, 53.33; H, 5.87;
N, 16.94. ¹ H-NMR (DMSO-d ₆ ) δ: 2.31 (3H,
s), 2.72-3.03 (1H, m), 2.90 (3
H, s), 3.13-3.57 (4H, m), 6.93.
−7.06 (1H, m), 7.17-7.4 (2H,
m), 7.5-8.4 (4H, br), 7.85 (1
H, d, J = 6 Hz), 8.65 (1H, d, J = 6H)
z), 11.39 (1H, s).

Example 159 (Production of compound 166) 7- (5-Chloro-2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g), amino Guanidine hydrochloride (0.44 g)
Concentrated ethanol (0.83m
l) and water (0.83 ml) were added, and the mixture was heated under reflux for 7 hours.
The solvent was distilled off under reduced pressure, the residue was dissolved in water, and washed with ethyl acetate. The aqueous layer was made alkaline by adding aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Dissolve the residue in ethanol and add 1N hydrochloric acid (10m
l), and the mixture was concentrated. The precipitated crystals were recrystallized from ethanol to give 7- (5-chloro-2-methoxyphenyl).
-5-guanidinoimino-4-methyl-5,6,7,8
-Tetrahydroquinoline hydrochloride (compound 166) (1.
2g) were obtained as colorless crystals. mp 205-209 ° C. Elemental analysis _{C 18 H 20 N 5 OCl ·} 2HCl · 0.5H 2 O
As Calcd. C, 48.96; H, 5.30;
N, 15.86. Found C, 49.18; H, 5.38;
N, 15.50. ^{1 H-NMR (DMSO-d} 6) δ: 2.73-2.97
(1H, m), 2.85 (3H, s), 3.07-3.
65 (4H, m), 3.82 (3H, s), 7.09
(1H, d, J = 9 Hz), 7.35 (1H, dd, J
= 3.9 Hz), 7.47 (1H, d, J = 3 Hz),
7.63-8.25 (4H, br), 7.79 (1H,
d, J = 6 Hz), 8.6 (1 H, d, J = 6 Hz),
11.38 (1H, s).

Example 160 (Production of Compound 167) 1 M Boron tribromide in dichloromethane (12.3 ml)
Then, a solution of 7- (5-chloro-2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.2 g) in dichloromethane (30 ml) was added to 0%.
It was added dropwise at ° C. The reaction was stirred at room temperature for 1.5 hours,
An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 7- (5-chloro-2-hydroxyphenyl) -4-methyl-5,6,6.
7,8-Tetrahydroquinolin-5-one was obtained. 7-
(5-Chloro-2-hydroxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one and aminoguanidine hydrochloride (0.53 g), ethanol (30 ml), concentrated hydrochloric acid (1. 0ml) and water (1.0m
l) was added and the mixture was heated under reflux for 4 hours. The solvent is distilled off under reduced pressure,
The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was made alkaline by adding aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, the residue was dissolved in ethanol, and 1N hydrochloric acid (10 ml) was added, followed by concentration.
The precipitated crystals were recrystallized from ethanol to give 7- (5-
Chloro-2-hydroxyphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 167) (1.1 g) was obtained as colorless crystals. mp 202 ° C. (Decomposition) Elemental analysis _{C 17 H 18 N 5 OCl ·} 2HCl · 0.5H 2 O
As Calcd. C, 47.96; H, 4.97;
N, 16.45. Found C, 48.01; H, 5.00;
N, 16.28. ¹ H-NMR (DMSO-d ₆ ) δ: 2.76-3.0
(1H, m), 2.89 (3H, s), 3.06-3.
57 (4H, m), 6.96 (1H, d, J = 8H
z), 7.16 (1 H, dd, J = 2.8 Hz), 7.
36 (1H, d, J = 2 Hz), 7.4-8.5 (4
H, br), 7.86 (1H, d, J = 6 Hz), 8.
64 (1H, d, J = 6 Hz), 10.22 (1H, b
r), 11.42 (1H, s).

Example 161 (Preparation of compound 168) 7- (5-Fluoro-2-methoxyphenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1.2 g) , Aminoguanidine hydrochloride (0.
477 g) in ethanol (15 ml) and concentrated hydrochloric acid (0.1
ml) and stirred at a bath temperature of 110 ° C. for 2 hours. The reaction solution was cooled to room temperature, the crystals were collected by filtration and dried, and 7- (5-fluoro-2-methoxyphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride was used. (Compound 168) (1.4 g) was obtained as colorless crystals. mp 300 ° C or higher. Elemental analysis C ₁₈ H ₂₀ N ₅ Calcd as 0F · 2HCl. C, 52.18; H, 5.35;
N, 16.90. Found C, 51.98; H, 5.22;
N, 16.90. ¹ H-NMR (DMSO-d ₆ ) δ: 2.77-2.9
2 (4H, m), 3.16 (1H, dd), 3.33-
3.61 (3H, m), 3.81 (3H, s), 7.0
1-7.15 (2H, m), 7.28-7.33 (1
H, m), 7.82 (1H, d), 7.91 (4H, b
r), 8.62 (1H, d), 11.42 (1H, b
r).

Example 162 (Preparation of compound 169) 7- (5-Fluoro-2-hydroxyphenyl) -4-
Methyl-5,6,7,8-tetrahydroquinoline-5
ON (0.75 g), aminoguanidine hydrochloride (0.3
33g) in ethanol (8ml), concentrated hydrochloric acid (0.5m
l) was added and the mixture was stirred at a bath temperature of 110 ° C for 2.5 hours. The reaction solution was cooled to room temperature, the crystals were collected by filtration and dried, and 7- (5-fluoro-2-hydroxyphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride was used. (Compound 169) (1 g) was obtained as pale yellow crystals. mp 264-266 ° C. Elemental analysis C ₁₇ H ₁₈ N ₅ Calcd as 0F · 2HCl. C, 51.01; H, 5.04;
N, 17.50. Found C, 50.71; H, 5.06;
N, 17.59. ¹ H-NMR (DMSO-d ₆ ) δ: 2.78-2.9
2 (4H, m), 3.09-3.23 (1H, m),
3.26-3.60 (3H, m), 6.88-7.00
(2H, m), 7.17 (1H, dd), 7.80 (1
H, d), 7.81 (4H, br), 8.62 (1H,
d), 9.80 (1H, br), 11.24 (1H,
s).

Example 163 (Production of compound 170) Concentrated sulfuric acid (40 ml) was added dropwise to a solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) under ice-cooling. Subsequently, a solution of chromic anhydride (9.3 g) in acetic anhydride (40 ml) was added dropwise over 2 hours. Stir at the same temperature for 1 hour and add to ice water. The mixture was extracted with diethyl ether, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml).
Water (4 ml) and concentrated sulfuric acid (4 ml) were added and 100 minutes for 30 minutes.
The mixture was heated and stirred at ℃. After air cooling, the reaction solution was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give 2-chloro-5-fluorobenzaldehyde (1.
6 g) were obtained. By repeating the same reaction, 2-chloro-5
-Fluorobenzaldehyde (1.2 g) was obtained. Sodium hydroxide (0.78 g) was dissolved in water (55 ml) and acetone (55 ml) was added, followed by 2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 g).
ml) solution was added dropwise. The reaction was stirred at room temperature for 2 hours. Acetone was distilled off under reduced pressure, and extracted with ethyl acetate.
The organic layer was washed successively with water and saturated saline and concentrated under reduced pressure to give 4- (2-chloro-5-fluorophenyl) -3-.
Buten-2-one (0.24 g) was obtained. To a 20% sodium ethoxide ethanol solution (0.43 g) at room temperature was added diethyl malonate (0.2 g).
(2-chloro-5-fluorophenyl) -3-butene-
2-one (0.24 g) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and heated under reflux for 2 hours. After air cooling, the solvent was distilled off, the residue was dissolved in water, and the aqueous layer was washed with ethyl acetate and concentrated. 2M sodium hydroxide (0.7m
l) was added and the mixture was heated under reflux for 2 hours. After air cooling, 2.5 M sulfuric acid (0.7 ml) was added, and the mixture was heated under reflux for 15 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5- (2-chloro-5-fluorophenyl) cyclohexane-1,3-dione (0.17 g) as an oil. A solution of 5- (5-chloro-2-fluorophenyl) cyclohexane-1,3-dione (0.17 g) and ammonium acetate (0.16 g) in ethanol (10 ml) was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (3.5 ml) and toluene (6 ml), and 3-oxobutyraldehyde dimethyl acetal (0.21 g) and powdered potassium hydroxide (34 mg) were added, followed by heating under reflux. . 30 minutes later, powdered potassium hydroxide (0.07 g), 1 hour later, powdered potassium hydroxide (0.07 g) and 3-oxobutyraldehyde dimethyl acetal (17 mg), 1 hour and 30 minutes later, powdered potassium hydroxide (0.07 g) 0.07 g), and then stirred at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-hexane) to give 7- (2-chloro-5-fluorophenyl) -4-methyl-5,6,6.
7,8-Tetrahydroquinolin-5-one was obtained. 7-
(2-chloro-5-fluorophenyl) -4-methyl-
To a solution of 5,6,7,8-tetrahydroquinolin-5-one in ethanol (10 ml), aminoguanidine hydrochloride (0.041 g), concentrated hydrochloric acid (0.078 ml) and water (0.078 ml) were added, and the mixture was added. Was heated at reflux for 4 hours. The solvent was distilled off under reduced pressure, water was added, and the aqueous layer was washed with ethyl acetate. The aqueous layer was made alkaline by adding aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid (1 ml) and concentrated. The obtained crystals were recrystallized from ethanol-ethyl acetate to give 7- (2-chloro-5-fluorophenyl)-
5-guanidinoimino-4-methyl-5,6,7,8-
Tetrahydroquinoline hydrochloride (Compound 170) (0.0
5g) were obtained as colorless crystals. mp. 268 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.76-3.05
(1H, m), 2.84 (3H, s), 3.13-3.
75 (4H, m), 7.0-8.4 (4H, br),
7.2-7.34 (1H, m), 7.52-7.66
(2H, m), 7.76 (1H, d, J = 6 Hz),
8.6 (1H, d, J = 6 Hz), 11.36 (1H,
s).

Example 164 (Preparation of compound 171) 7- (5-Chloro-2-fluorophenyl) -4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (0.6 g) , Aminoguanidine hydrochloride (0.2
33 g) in ethanol (10 ml) and concentrated hydrochloric acid (0.1 m
l) was added and the mixture was stirred at a bath temperature of 110 ° C for 2 hours. The reaction solution was cooled to room temperature, the crystals were collected by filtration and dried, and 7- (5-chloro-2-fluorophenyl) -5-guanidinoimino-4 was obtained.
-Methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 171) (0.6 g) was obtained as colorless crystals. mp 300 ° C or higher. Elemental analysis value: C ₁₆ H ₁₆ N ₆ ClF. C, 45.79; H, 4.32;
N, 20.02. Found C, 45.74; H, 4.36;
N, 19.88. ¹ H-NMR (DMSO-d ₆ ) δ: 2.88 (3H,
s), 2.95 (1H, dd), 3.23 (1H, d
d), 3.39-3.70 (3H, m), 7.26-
7.48 (2H, m), 7.70 (1H, dd) 7.8
5 (1H, d), 7.96 (4H, br), 8.63
(1H, d), 11.60 (1H, s).

Example 165 (Preparation of compound 172) 7- (3-Chloro-5-methylthiophen-2-yl)
-4-Methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1 g) and aminoguanidine hydrochloride (0.366 g) were added with ethanol (12 ml) and concentrated hydrochloric acid (0.1 ml), followed by bathing. The mixture was stirred at a temperature of 110 ° C. for 3 hours.
The reaction solution was cooled to room temperature, and the crystals were collected by filtration and dried.
(3-chloro-5-methylthiophen-2-yl) -5
-Guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 172) (1.17
g) was obtained as colorless crystals. mp 198-200 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.42 (3H,
s), 2.79 (1H, dd), 2.85 (3H,
s), 3.26 (1H, dd), 3.40-3.46.
(2H, m), 3.64-3.78 (1H, m). 6.
80 (1H, s), 7.80 (1H, d), 8.91
(4H, br), 8.62 (1H, d), 11.46
(1H, br).

Example 166 (Preparation of compound 173) 7- (2-Chloro-5-methylphenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.4 g) Aminoguanidine hydrochloride (0.164
g) in ethanol (8 ml), concentrated hydrochloric acid (0.15 ml)
Was added and stirred at a bath temperature of 110 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, the crystals were collected by filtration and dried, and 7- (2-chloro-5-methylphenyl) -5-guanidinoimino-4 was used.
-Methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 173) (0.261 g) was obtained as pale-white crystals. mp 240-242 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.34 (3H,
s), 2.76 (3H, s), 2.88 (1H, d
d), 3.13-3.36 (4H, m), 7.16 (1
H, d), 7.37 (1H, d), 7.49 (1H,
s), 7.97 (4H, br), 9.30 (1H,
s), 11.57 (1H, br).

Example 167 (Production of compound 174) 7- (5-Fluoro-2-methylphenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.265 g) Aminoguanidine hydrochloride (0.1
2g) and ethanol (3ml), concentrated hydrochloric acid (0.15m
l) was added and the mixture was stirred at a bath temperature of 110 ° C for 3.5 hours. The reaction solution was cooled to room temperature, and the crystals were collected by filtration and dried, and 7- (5-
Fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 174) (0.33 g) was obtained as blue-grey crystals. mp 240 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 2.73-2.90 (4H, m), 3.17-
3.50 (4H, m), 6.96-7.06 (1H,
m), 7.21-7.36 (2H, m), 8.02 (4
H, br) 9.35 (1H, s), 11.66 (1H,
s).

Example 168 (Preparation of compound 175) 7- (5-Chloro-2-fluorophenyl) -4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.33 g), amino Guanidine hydrochloride (0.13
3g) in ethanol (4ml), concentrated hydrochloric acid (0.1ml)
Was added and the mixture was stirred at a bath temperature of 110 ° C. for 2 hours. The reaction solution was cooled to room temperature, and the crystals were collected by filtration, dried, and treated with 7- (5-chloro-
2-fluorophenyl) -5-guanidinoimino-4-
Methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 175) (0.345 g) was obtained as blue-grey crystals. mp 300 ° C or higher. Elemental analysis value: C ₁₆ H ₁₆ N ₆ ClF. C, 45.79; H, 4.32;
N, 20.02. Found C, 45.74; H, 4.36;
N, 19.88. ¹ H-NMR (DMSO-d ₆ ) δ: 2.77 (3H,
s), 2.96 (1H, dd), 3.17-3.60.
(4H, m), 7.27-7.48 (2H, m), 7.
71 (1H, dd), 8.03 (4H, br), 9.3
3 (1H, s), 11.78 (1H, br).

Example 169 (Production of compound 176) 6- (2,5-Dichlorophenyl) -3-methyl-4,
5,6,7-tetrahydroindazol-4-one hydrochloride (1.1 g), aminoguanidine hydrochloride (0.49
g) in ethanol (30 ml) was added to concentrated hydrochloric acid (0.9
ml) and water (0.9 ml), and the mixture was heated under reflux for 5 hours.
The solvent was distilled off under reduced pressure, and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethanol-water to give 6- (2,5-dichlorophenyl) -4-guanidinoimino-3-methyl-4,5,5.
6,7-tetrahydroindazole hydrochloride (compound 17
6) (1.2 g) was obtained as colorless crystals. mp 287 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 2.35-3.2
2 (4H, m), 2.48 (3H, s), 3.40 −
3.68 (1H, m), 6.6-8.4 (4H, b
r), 7.39 (1 H, dd, J = 2.8 Hz), 7.
54 (1H, d, J = 8 Hz), 7.72 (1H, d,
J = 2 Hz), 10.9 (1H, s).

A Na-H exchange inhibitor containing the compound represented by the general formula (I) or a salt thereof according to the present invention as an active ingredient (eg, a therapeutic agent for ischemic heart disease such as myocardial infarction and arrhythmia). Can be produced, for example, by the following formulation. After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.

[0399] 2/3 of (1), (2), (3), (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Formulation Example 3 The compound 64 (500 mg) obtained in Example 63 was dissolved in 50 ml of Japanese Pharmacopoeia distilled water for injection, and the Japanese Pharmacopoeia distilled water for injection was added to make 100 ml. The solution is filtered under sterile conditions, then 1 ml each of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.

Formulation Example 4 Compound 64 (5 g) obtained in Example 63 was dissolved in 50 ml of distilled water for injection in Japan Pharmaceutical Co., and then distilled water for injection in Japan was added to make 100 ml. This solution is filtered under sterile conditions,
Next, 1 ml of this solution is taken, filled in an injection vial under sterile conditions, freeze-dried and sealed.

Test Example 1 Male Wistar rats (350-450 g) were anesthetized with pentobarbital Na (50 mg / kg, ip). Using a disposable syringe, previously filled with 1.5 ml of 3.8% citric acid solution, 8.5 m from the abdominal aorta
l blood was collected. Blood is centrifuged at 3000 rpm for 5 seconds, and platelet rich plasm
a: PRP). Automatic blood cell counter (Sysmex 2
The platelet count of PRP was measured using 500, Toa Medical Electronics Co., Ltd. and diluted with physiological saline to 40 × 10 ⁴ per μl. For platelet expansion, a platelet aggregometer (hema tracer, Niko Bioscience) was used. 200
μl of PRP was dispensed into a cuvette and stirred at 37 ° C. while stirring sodium propionate solution (Na propionate 13).
5, glucose 10, Hepes 20, CaCl ₂ 1, MgCl ₂
1, unit: mM, pH 6.7) was added in an amount of 600 μl.
The change in transmitted light of PRP, which is an indicator of platelet swelling, was output to a pen recorder. The test compound was added 3 minutes before adding the sodium propionate solution. All test compounds were dissolved in dimethyl sulfoxide (DMSO) and used in the experiments. The final DMSO concentration was 1%. The value of the transmitted light 1 minute after the addition of the sodium propionate solution was used for analysis. 1% DMSO and a known N represented by the following formula:
The difference in transmitted light obtained during treatment with HOE-642 (10 ⁻⁵ M), which is an aH exchange inhibitor, was defined as 100%, and the inhibition rate of increase in transmitted light by the test compound was calculated. The results are shown in Table 1 as suppression rates. From this, the compound of the present invention is Na-
It is clear that it exhibits an H exchange inhibitory effect.

Embedded image

[0403]

[Table 1]

[0404]

According to the present invention, there is provided a Na-H exchange inhibitor useful as a therapeutic agent for ischemic heart diseases such as myocardial infarction and arrhythmia.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/343 A61K 31/34 602 4C204 31/381 31/38 601 31/404 31/40 607 31/4155 31/415 603 31/416 604 31/42 31/42 31/4725 31/47 605 31/502 31/50 602 31/505 31/505 C07D 215/38 C07D 215/38 231/56 231/56 FB A 237/28 237/28 239/72 239/72 261/20 261/20 307/79 307/79 307/84 307/84 333/54 333/54 401/04 213 401/04 213 405/04 215 405 / 04 215 407/04 307 407/04 307 409/04 209 409/04 209 215 215 307 307 417/04 417/04 F term (reference) 4C031 JA01 4C037 PA11 QA07 4C056 AA01 AB01 AC01 AD03 AE03 FA03 FB12 FC01 406 BB01 CC31 CC51 CC76 CC94 DD06 DD12 DD14 EE01 4C086 AA01 AA03 BC28 BC46 GA02 GA03 GA07 GA10 MA04 NA14 ZA15 ZA36 ZC02 4C204 BB01 CB03 EB03 FB03 GB07 GB28 GB32

Claims (26)

[Claims] (1) Formula (1) [In the formula, ring A is a 5- or 6-membered aromatic heterocyclic ring which may be substituted, and ring B is 5 or 6 which may be substituted.
R ¹ represents a hydrogen atom, a hydroxyl group or a lower alkyl group, and n represents 0 or 1. Or a salt thereof. 2. The compound according to claim 1, or a prodrug thereof. 3. A compound of the formula [The symbols in the formula are as defined in claim 1. Or a salt thereof. 4. A compound of the formula [The symbols in the formula are as defined in claim 1. Or a salt thereof. 5. The compound according to claim 1, wherein the aromatic heterocyclic ring is an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. 6. The compound according to claim 1, wherein the ring A is an optionally substituted pyridine ring, pyridazine ring, pyrrole ring, pyrazole ring, furan ring, thiophene ring, isoxazole ring or pyrimidine ring. 7. The compound according to claim 1, wherein the ring B is a pyridine ring, a pyrrole ring, a furan ring, a thiophene ring or a benzene ring, each of which may be substituted. 8. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom. 9. The compound according to claim 1, wherein n is 1. (10) (S)-(-)-7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4
-Methyl-5,6,7,8-tetrahydroquinoline or a salt thereof. (11) (±) -7- (2,5-dichlorothiophen-3-yl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof. (S)-(-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydroquinoline or a salt thereof. 13. The (±) -7- (2-chlorophenyl)-
5-guanidinoimino-4-methyl-5,6,7,8-
Tetrahydroquinoline or a salt thereof. (14) (±) -7- (2,5-dichlorophenyl) -5-guanidinoimino-4-methyl-5,6,
7,8-tetrahydrocinnoline or a salt thereof. 15. A (±) -7- (5-chloro-2-methylphenyl) -5-guanidinoimino-4-methyl-5.
6,7,8-tetrahydroquinoline or a salt thereof. (16) (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-
5,6,7,8-tetrahydroquinoline or a salt thereof. (17) (±) -7- (2-chloro-5-fluorophenyl) -5-guanidinoimino-4-methyl-
5,6,7,8-tetrahydroquinoline or a salt thereof. (18) (±) -7- (5-chloro-2-fluorophenyl) -5-guanidinoimino-4-methyl-
5,6,7,8-tetrahydroquinoline or a salt thereof. (19) (±) -7- (5-fluoro-2-methylphenyl) -5-guanidinoimino-4-methyl-
5,6,7,8-tetrahydrocinnoline or a salt thereof. 20. (±) -7- (5-Chloro-2-fluorophenyl) -5-guanidinoimino-4-methyl-
5,6,7,8-tetrahydrocinnoline or a salt thereof. 21. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 22. The composition according to claim 21, which is a Na-H exchange inhibitor. 23. The method according to claim 2, which is an agent for preventing or treating ischemic heart disease.
The composition of claim 1. 24. The composition according to claim 23, wherein the ischemic heart disease is myocardial infarction or arrhythmia. (25) The composition according to the above (21), which is an agent for preventing or treating heart failure. 26. A compound of the formula (II) [In the formula, ring A is a 5- or 6-membered aromatic heterocyclic ring which may be substituted, and ring B is 5 or 6 which may be substituted.
And n represents 0 or 1; Compound or a salt thereof of the formula _{(III) H 2 N-N} = C (NH 2) (NHR 1) [Formula represented by], R ¹ is a hydrogen atom, a hydroxyl group or a lower alkyl group. Or a salt thereof, which is represented by the formula (I): [The symbols in the formula are as defined above. Or a salt thereof.