JPH08225531A - Medicine containing quinoline or qyuinazoline derivative and new derivative used therefor - Google Patents

Abstract

PURPOSE: To obtain an anti-inflammatory agent containing quinoline or quinazoline derivative having anti-inflammatory action, low in toxicity and especially useful as a treating agent for arthritis. CONSTITUTION: This anti-inflammatory agent contains a compound of formula I [Y is N or C-G (G is a carbonyl group which may be esterified); R<1> and R<2> are each H, a hydrocarbon residue or a heterocyclic group, etc.; ring A and ring B may have substituent groups; (n) is an integer of 1 to 4; (k) is 0 or 1] or its salt. Especially, a compound having a structure of formula II R<3> and R<4> are independently each an alkoxy) among the compound of formula I is a new compound, e.g. 4-(3,4-dimethoxyphenyl)-2-(N-sec-butyl-N- propylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylic acid ethyl ester. Furthermore, the compound of formula I is obtained by reacting a compound of formula III (Q is an eliminable group) with a compound of formula IV in the presence of a base.

Description

Detailed Description of the Invention

[0001]

This invention relates to anti-inflammatory agents. More specifically, it relates to an anti-inflammatory agent, especially a therapeutic agent for arthritis, which comprises a quinoline or quinazoline derivative or a salt thereof. The present invention further relates to novel quinoline or quinazoline derivatives having anti-inflammatory action.

[0002]

2. Description of the Related Art Arthritis is an inflammatory disease of the joint, and its main diseases include rheumatoid arthritis and related diseases in which inflammation is observed in the joint. In particular, rheumatoid arthritis, which is also called rheumatoid arthritis, is a chronic polyarthritis whose major lesion is inflammatory changes in the synovium of the joint endothelium. Arthritis such as rheumatoid arthritis is progressive and causes joint disorders such as joint deformation and ankylosis.
If they get worse without effective treatment, they often lead to severe disability. Conventionally, in the treatment of these arthritis, steroids such as cortisone and other adrenocortical hormones as drug therapy; nonsteroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin; gold thiomalate and other gold agents, chloroquine preparations, D-penicillamine, etc. , Anti-rheumatic drugs; anti-gout agents such as colchicine; immunosuppressants such as cyclophosphamide, azathioprine, methotrexate, and levamisole have been used.

[0003]

However, these drugs are not effective against severe or long-term side effects that make them difficult to use, their effects are insufficient, or arthritis that has already developed. There was a problem that it was not effective. Therefore, in the clinical field of arthritis, there is still a demand for a drug having low toxicity and excellent in prevention and treatment of arthritis.

[0004]

Various compounds have been conventionally synthesized as quinoline or quinazoline derivatives. Four
Examples of the compound having an aminomethyl group at the 2-position of -phenylquinoline or 4-phenylquinazoline skeleton include 2-dimethylaminomethyl compound and 2-morpholinomethyl compound described in Synthesis, Volume 9, page 718 (1979). And so on, Pharmaco, Vol. 44, page 555.
(1989), 2-alkylaminomethylquinoline derivatives and the like are known. However, there is no disclosure about the anti-inflammatory action of these 4-phenylquinoline or 4-phenylquinazoline derivatives. We have 4
It was found that a compound having an alkylene group substituted with a substituted amino group at the 2-position of -phenylquinoline or 4-phenylquinazoline skeleton has an anti-inflammatory action, particularly an anti-arthritic action, and is useful as a joint destruction inhibitor. Completed the invention. That is, the present invention provides (1) general formula (I):

[0005]

Embedded image

[Wherein Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified).
R ¹ and R ² each represent hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, and R ¹ and R ² are bonded to each other to form a saturated ring. May be. Ring A and ring B may each have a substituent. n represents an integer of 1 to 4, and k represents 0 or 1. ] An anti-inflammatory agent comprising a compound represented by the following or a salt thereof, (2) an alkyl group in which the optionally substituted hydrocarbon residue represented by R ¹ and R ² is substituted (3) The anti-inflammatory agent according to (1), wherein R ¹ and R ² are bonded to each other to form an optionally substituted 5- to 7-membered saturated ring. Agent, (4)
The anti-inflammatory agent according to (1) above, wherein n is 1 or 2.
(5) The anti-inflammatory agent according to (1) above, wherein Y is CG.
(6) The anti-inflammatory agent according to (5) above, wherein G is C _1-6 alkyloxycarbonyl, (7) The anti-inflammatory agent according to (6) above, wherein G is ethoxycarbonyl, (8) Y is a nitrogen atom. (1) The anti-inflammatory agent according to (1) above, wherein (9) the ring A substituent is a lower alkylenedioxy located at the 6- and 7-positions of the quinoline ring or quinazoline ring. (10) The anti-inflammatory agent according to the above (9), wherein the substituent on the A ring is methylenedioxy located at the 6- and 7-positions of the quinoline ring or the quinazoline ring, (11) the A ring is substituted with an alkoxy group. (12) The anti-inflammatory agent according to (1) above, wherein the ring A is substituted with methoxy.
1) The anti-inflammatory agent described above, (13) The A ring is disubstituted with the same or different alkoxy groups, (14) The antiinflammatory agent described above (14), wherein the A ring is disubstituted with methoxy. (13) The anti-inflammatory agent according to (13), wherein the A ring is disubstituted by methoxy at the 6-position and the 7-position of the quinoline ring or the quinazoline ring.
6) The anti-inflammatory agent according to (1) above, wherein the substituent on the B ring is lower alkylenedioxy, (17) The anti-inflammatory agent according to (16), wherein the substituent on the B ring is methylenedioxy.
8) The anti-inflammatory agent according to (1) above, wherein the substituent on the B ring is an alkoxy group, (19) The anti-inflammatory agent according to (18), wherein the substituent on the B ring is methoxy, and (20) the B ring. The anti-inflammatory agent according to (1) above, which is disubstituted with the same or different alkoxy group, the antiinflammatory agent according to (20), wherein (21) ring B is disubstituted with methoxy, and (22) ring B is (1) above, which is disubstituted by methoxy at the 3- and 4-positions
The anti-inflammatory agent according to (1) above, wherein (23) k is 0, and the compound represented by formula (I) is
-(3,4-Dimethoxyphenyl) -2- (N-sec-butyl-N-propylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate ethyl, 4- (3,4-dimethoxyphenyl)- Ethyl 2- (N-tert-butyl-N-ethylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate, 2- (N, N-diethylaminomethyl) -4-
Ethyl (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate or 4- (3,4-dimethoxyphenyl) -2- (N-ethylaminomethyl) -6,
The anti-inflammatory agent according to (1) above, which is 7-dimethoxyquinazoline, (25) the general formula (I ′):

[0007]

[Chemical 4]

[Wherein Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified).
R ¹ and R ² each represent hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, and R ¹ and R ² are bonded to each other to form a saturated ring. May be. R ³ and R ⁴ each independently represent an alkoxy group. Ring B may have a substituent. n represents an integer of 1 to 4, and k represents 0 or 1. Or a salt thereof, (26) the compound according to (25), wherein R ³ and R ⁴ are each methoxy, (27) R ³
And R ⁴ is methoxy at the 6- and 7-positions of the quinoline or quinazoline ring, respectively (25)
The compound according to (25), wherein the substituent on the ring (28) B is an alkoxy group, the compound according to (25), wherein the substituent on the ring (29) B is methoxy, (30).
The compound according to (25) above, wherein ring B is disubstituted with the same or different alkoxy groups, (31) the compound according to (25) above, wherein ring B is disubstituted with methoxy, (3)
2) The compound according to the above (25), wherein the B ring is disubstituted with methoxy at the 3 and 4 positions, and (33) 4-
Ethyl (3,4-dimethoxyphenyl) -2- (N-sec-butyl-N-propylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate, 4- (3,4-dimethoxyphenyl) -2 Ethyl-(N-tert-butyl-N-ethylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate, 2- (N, N-diethylaminomethyl) -4-
Ethyl (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate or 4- (3,4-dimethoxyphenyl) -2- (N-ethylaminomethyl) -6,
The present invention relates to the compound according to (25), which is 7-dimethoxyquinazoline.

Some of the compounds represented by the general formula (I) used in the present invention are novel compounds not described in the literature, and in particular, the compounds represented by the above general formula (I ') are novel compounds. . A description of the above general formulas and the definitions included in the scope of the present invention and preferable examples thereof are described below. In the general formulas (I) and (I ′), the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R ¹ or R ² is an aliphatic hydrocarbon residue or an alicyclic group. Examples thereof include a hydrocarbon residue, an alicyclic-aliphatic hydrocarbon residue, an araliphatic hydrocarbon residue, and an aromatic hydrocarbon residue.

Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, 1 to 1 carbon atoms such as octyl
8 saturated aliphatic hydrocarbon residues, such as ethenyl, 1-
Propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1
-Pentenyl, 2-pentenyl, 3-pentenyl, 4-
Pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5
-Hexinyl, 1-heptynyl, 1-octynyl, and the like, include unsaturated aliphatic hydrocarbon residues having 2 to 8 carbon atoms.

Examples of the alicyclic hydrocarbon residue include saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and 1-cyclopentenyl, 2-cyclo Pentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2 cycloheptenyl, 3-
Examples thereof include unsaturated alicyclic hydrocarbon residues having 5 to 7 carbon atoms such as cycloheptenyl and 2,4-cycloheptadienyl. The alicyclic-aliphatic hydrocarbon residue has 4 to 9 carbon atoms among those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded, for example, cyclopropylmethyl, cyclopropyl Ethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3
-Cyclopentenylmethyl, cyclohexylmethyl, 2
-Cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl,
Examples thereof include cycloheptylmethyl and cycloheptylethyl.

Examples of the araliphatic hydrocarbon residue include benzyl, phenethyl, 1-phenylethyl and 3-
Phenylalkyl having 7 to 9 carbon atoms such as phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, α-
Examples include naphthylalkyl having 11 to 13 carbon atoms such as naphthylmethyl, α-naphthylethyl, β-naphthylmethyl and β-naphthylethyl. Examples of the aromatic hydrocarbon residue include phenyl and naphthyl (α-naphthyl, β-
Naphthyl) and the like.

In the above general formulas (I) and (I ′), the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ or R ² is, for example, one sulfur atom or nitrogen atom. Or a 5- to 7-membered heterocyclic group containing an oxygen atom, a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, a 5- or 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom A 6-membered heterocyclic group is used, and these heterocyclic groups may be fused with a 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. Specific examples of the heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4
-Pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-
Pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-
Imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-
Thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-
Oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl,
Tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl
Yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1
H-pyrrolo [2,3-b] pyridin-6-yl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo
[4,5-c] Pyridin-2-yl, 1H-imidazo [4,5]
-B] pyrazin-2-yl and the like.

In the above general formulas (I) and (I '), the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² have 1 to 3 substituents at arbitrary positions. May be.

Examples of the substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group and an aromatic heterocyclic group. , A non-aromatic heterocyclic group, a halogen atom, a nitro group, an optionally substituted amino group, an optionally substituted acyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, The carboxyl group which may be esterified is included.

The aliphatic chain hydrocarbon group as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² is a straight chain or branched chain aliphatic hydrocarbon group, Examples thereof include an alkyl group, preferably an alkyl group having 1 to 10 carbon atoms, an alkenyl group, preferably an alkenyl group having 2 to 10 carbon atoms, an alkynyl group and the like. Preferable examples of the alkyl group include, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl, t
ert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like. To be Preferable examples of the alkenyl group include vinyl, allyl, isopropenyl, 1-propenyl and 2-
Methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-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-hexenyl and the like can be mentioned. Preferable examples of the alkynyl group include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like can be mentioned.

The alicyclic hydrocarbon group as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² is a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group. , A cycloalkenyl group, a cycloalkadienyl group and the like. Preferable examples of the cycloalkyl group include cycloalkyl groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2. 2.2] Octyl,
Bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, etc. Is mentioned. A preferred example of the cycloalkenyl group is a cycloalkenyl group having 3 to 7 carbon atoms, such as 2-cyclopentene-1-.
And 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Preferable examples of the cycloalkadienyl group include a cycloalkadienyl group having 5 to 8 carbon atoms such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl and 2,5 -Cyclohexadien-1-yl and the like.

The aryl group as a substituent for the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² means a monocyclic or condensed polycyclic aromatic hydrocarbon group, which is a preferred example. Examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Preferable examples of the aromatic heterocyclic group as the substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1, Aromatic monocyclic heterocyclic groups such as 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuran Nil,
Benzo [b] thienyl, indolyl, isoindolyl, 1
H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl , Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b]. ] Pyridazinyl, pyrazolo
[1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1 , 2,4-
Triazolo [4,3-a] pyridyl, 1,2,4-triazolo
Examples include fused aromatic heterocyclic groups such as [4,3-b] pyridazinyl.

Suitable examples of the non-aromatic heterocyclic group as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² include, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydro. Furyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like can be mentioned. Examples of the halogen atom as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable.

The optionally substituted amino group as the substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² includes, in addition to the amino group, a substituted amino group such as an amino group. An amino group having 1 or 2 alkyl groups having 1 to 10 carbon atoms, alkenyl groups having 1 to 10 carbon atoms, aromatic groups, heterocyclic groups or acyl groups having 1 to 10 carbon atoms as a substituent (eg, methylamino). , Dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-
Methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino and the like).

The acyl group as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² is a formyl group or an alkyl group having 1 to 10 carbon atoms, or 1 to 1 carbon atoms.
A bond of an alkenyl group of 0 or an aromatic group and a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptane) Carbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).

The optionally substituted hydroxy group as the substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² includes a hydroxy group and an appropriate substituent for the hydroxy group, particularly Aryloxy can be mentioned in addition to, for example, alkoxy, alkenyloxy, aralkyloxy, acyloxy, and the like having a group used as a protective group for a hydroxy group. As the alkoxy, alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, (Heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferred. Examples of the alkenyloxy include allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, and the like.
There are 10 types. Examples of the aralkyloxy include phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). As the acyloxy, alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) is preferable. Examples of the aryloxy include phenoxy and 4-chlorophenoxy.

The thiol group which may be substituted as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² includes a thiol group and an appropriate substituent for the thiol group, particularly Examples thereof include those used as protective groups for thiol groups, such as alkylthio, aralkylthio, and acylthio. Examples of the alkylthio include alkylthio having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-
Butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, etc. phenethylthio) and the like. As the acylthio, alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) is preferable.

Examples of the optionally esterified carboxyl group as a substituent of the hydrocarbon residue and the heterocyclic group represented by R ¹ or R ² include, in addition to the carboxyl group, for example, an alkyloxycarbonyl group and aralkyl. Examples thereof include an oxycarbonyl group. Examples of the alkyl group in the alkyloxycarbonyl group include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The aralkyl group in the aralkyloxycarbonyl group means an aryl-alkyl group. Examples of the aryl group include phenyl and naphthyl, which may have the same substituent as the aryl group exemplified as the hydrocarbon group represented by R ¹ or R ^2. Good. The alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, butyl, etc.). Preferable examples of the aralkyl group include benzyl, phenethyl and 3-
Phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like can be mentioned, with preference given to benzyl and phenethyl.

In the above general formulas (I) and (I ′), the hydrocarbon residue represented by R ¹ or R ² and the substituent on the heterocyclic group each further have at least one suitable substituent, Preferably, it may have 1 to 3 substituents, and the substituent is a lower (C _1-8 ) alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl). , Pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.), lower (C _2-10 ) alkenyl groups (eg, ethenyl, 1-propenyl, 2-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-
Octenyl vinyl, etc.),

Lower (C _2-8 ) alkynyl groups (eg ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5
-Hexynyl, 1-heptynyl, 1-octynyl, etc.), a C _3-8 cycloalkyl group (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), C _6-15 aryl group (eg, phenyl,
Naphthyl (eg, 1-naphthyl, 2-naphthyl, etc.), anthryl, phenanthryl, acenaphthylenylphenyl, naphthyl, etc.),

Aromatic heterocyclic groups (eg, furyl, thienyl,
Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
Aromatic monocyclic heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl,
Isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl ,
Phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrroloyl, pyrrolo [2] b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] Pyridyl, imidazo [1,
2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,
Aromatic condensed heterocyclic groups such as 4-triazolo [4,3-b] pyridazinyl),

A non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.), an aralkyl group, preferably C
_6-14 aryl-C _1-4 alkyl group (eg, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl, etc.), amino group, N-monosubstituted amino group (eg, , Methylamino, ethylamino, butylamino, allylamino, cyclohexylamino, phenylamino, acetylamino, propionylamino,
Benzoylamino, nicotinoylamino, etc.), N, N
-Disubstituted amino group (eg, dimethylamino, diethylamino, dibutylamino, diallylamino, N-methyl-N
-Phenylamino etc.), amidino group,

C _1-10 acyl group (eg formyl group, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl , 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.), carbamoyl group, N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (eg, N,
N-dimethylcarbamoyl, N, N-diethylcarbamoyl, piperidinocarbonyl, morpholinocarbonyl, etc.), sulfamoyl group,

N-monosubstituted sulfamoyl groups (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluenesulfamoyl, etc.), N,
N-disubstituted sulfamoyl group (eg, N, N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfonyl, morpholinosulfonyl, etc.), carboxyl group, lower (C _1-5 ) alkoxy Carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxy group,

Lower (C _1-8 ) alkoxy groups (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.), lower (C _3-10 ) alkenyloxy group (eg, allyloxy, crotyloxy) , 2-
Pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.), C _3-7 cycloalkyloxy group (eg, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.) , Aralkyloxy groups, preferably C _6-14 aryl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, 3-phenylpropyloxy, (1-naphthyl) methyloxy, (2-naphthyl) methyloxy, etc. ),

C _6-15 aryloxy group (eg, phenoxy, naphthyloxy (eg, 1-naphthyloxy, 2-naphthyloxy, etc.), anthryloxy, phenanthryloxy, acenaphthylenylphenyloxy, etc.), Mercapto group, lower (C _1-8 ) alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t
ert-butylthio, pentylthio, isopentylthio,
Neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.), C _6-14 aryl-C _1-4 alkylthio group (eg, benzylthio, phenethylthio, etc.), C
_6-14 arylthio group (eg, phenylthio, naphthylthio (eg, 1-naphthylthio, 2-naphthylthio, etc.), anthrylthio, phenanthrylthio, acenaphthylenylphenylthio, naphthylthio, etc.),

Sulfo group, cyano group, azido group, nitro group, nitroso group, halogen (eg, fluorine, chlorine, bromine,
(Iodine) and the like.

Although R ¹ and R ² may combine with each other to form a saturated ring, examples of such —N (R ¹ ) (R ² ) include 1-pyrrolidinyl, 1-imidazolidinyl, 1 -Pyrazolidinyl, 1-piperidinyl, 1-piperazinyl,
4-morpholinyl, 4-thiomorpholinyl, homopiperazin-1-yl and the like can be mentioned. These saturated rings may contain an oxo group or a thioxo group.

In the general formula (I), when Y is a quinoline derivative represented by CG, examples of the esterified carboxyl group represented by G include an alkyloxycarbonyl group and an aralkyloxycarbonyl group. To be The alkyl group in the alkyloxycarbonyl group is an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
Examples include c-butyl and tert-butyl. Of these, ethyl is preferred. The aralkyl group in the aralkyloxycarbonyl group means an alkyl group having an aryl group as a substituent (arylalkyl group). Examples of the aryl group include aryl groups having 6 to 14 carbon atoms, such as phenyl and naphthyl, which are aryl groups in the optionally substituted hydrocarbon residue represented by R ¹ or R ^2. May have the same substituent as that of. The alkyl group has 1 to 1 carbon atoms.
A lower alkyl group of 6 is preferred. Preferable examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like. Of these, benzyl, phenethyl and the like are preferable.

In the general formula (I), ring A and ring B may have a substituent, and examples of such a substituent include a halogen atom, a nitro group, an optionally substituted alkyl group, and a substituted group. Optionally substituted hydroxy group, optionally substituted thiol group, optionally substituted amino group,
An optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic ring group is used.

Examples of the halogen atom as a substituent of ring A and ring B include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable. The optionally substituted alkyl group as the substituent of the ring A and the ring B may be linear, branched or cyclic having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-
Examples thereof include butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The optionally substituted hydroxy group as the substituent of ring A and ring B has a hydroxy group and an appropriate substituent for the hydroxy group, particularly a group used as a protecting group for the hydroxy group, Examples thereof include aryloxy in addition to alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like. As the alkoxy, alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, (Heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferred. Examples of the alkenyloxy include allyloxy, crotyloxy, 2
-Pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like having 1 to 10 carbon atoms can be used as the aralkyloxy. For example, phenyl-C _1-4 alkyloxy (eg, benzyloxy , Phenethyloxy, etc.). As the acyloxy, alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) is preferable. Examples of the aryloxy include phenoxy and 4-chlorophenoxy.

The thiol group which may be substituted as the substituents of the ring A and the ring B has a thiol group and an appropriate substituent for the thiol group, particularly a group used as a protective group for the thiol group, For example alkylthio,
Examples include aralkylthio and acylthio. The alkylthio is an alkylthio having 1 to 10 carbon atoms.
(For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Etc.) are preferred. Examples of the aralkylthio include phenyl-C _1-4 alkylthio.
(Eg, benzylthio, phenethylthio, etc.). The acylthio is preferably alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, iso-butyrylthio, etc.).

The optionally substituted amino group as the substituent of ring A and ring B is an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, an aromatic group or an acyl group. Or those substituted with two amino groups (—NH ₂ group) (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, Acetylamino, propionylamino, benzoylamino and the like).

The acyl group which may be substituted as a substituent of ring A and ring B includes formyl, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, an aromatic group and a carbonyl group. A bond of (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,
Cycloheptane carbonyl, crotonyl, 2-cyclohexene carbonyl, benzoyl, nicotinoyl and the like).

The aromatic ring group which may be substituted as a substituent of ring A and ring B includes phenyl, naphthyl, anthryl and the like C _6-14 aromatic hydrocarbon residue in addition to pyridyl, furyl and thienyl. And heteroaromatic residues such as imidazolyl and thiazolyl.

The substituents on the A ring and the B ring may be substituted at any position of the respective rings. The substituent on the A ring is preferably located at the 6-position and / or the 7-position of the quinoline ring or the quinazoline ring of the A ring. Further, the substituent on the B ring is preferably the 3-position and / or the 4-position on the B ring.
Located in the place. These substituents may be the same or different, and the number thereof is 1 to 4. When substituents on ring A or ring B are adjacent to each other, linked substituents adjacent, - (CH ₂₎ m- or -O- (C
H ₂ ) _1- O- [wherein m represents an integer of 3 to 5 and l represents an integer of 1 to 3], and the ring may be a carbon atom of a benzene ring. 5 formed with atoms
Includes a 7-membered ring.

In a preferred embodiment in which the substituent on ring A has a substituent, for example, when lower (C _1-3 ) alkylenedioxy is located at the 6- and 7-positions on the quinoline ring or quinazoline ring on ring A, Especially when methylenedioxy is located; when A ring is substituted with the same or different alkoxy group, especially when A ring is substituted with methoxy; A ring is 6-position of quinoline ring or quinazoline ring and Examples thereof include the case where the 7-position is disubstituted with the same or different alkoxy groups, and particularly when the A ring is disubstituted with methoxy at the 6-position and the 7-position of the quinoline ring or the quinazoline ring.

In a preferred embodiment where the ring B substituent has a substituent, for example, the ring B substituent is lower (C
_1-3 ) When it is alkylenedioxy, especially when it is methylenedioxy; when the substituent on the B ring is an alkoxy group, especially when the substituent on the B ring is methoxy; Di-substituted by a group, especially if ring B is di-substituted by methoxy; if ring B is substituted by methoxy at the 3- or 4-positions; ring B by methoxy at the 3- and 4-positions The case where it is disubstituted is mentioned.

The ring A in the general formula (I ') is represented by R ³ and R ^4.
Are substituted with the same or different alkoxy groups represented by. As the alkoxy group represented by R ³ and R ⁴ ,
For example, those exemplified as the alkoxy group as the substituent of the A ring and the B ring in the general formula (I) can be mentioned. When the ring B in the general formula (I ′) is substituted, examples of the substituent include those exemplified as the substituents of the A ring and the B ring in the general formula (I). In the general formula (I), n
Is preferably 1 or 2, and more preferably 1.
In general formula (I), k is preferably 0. The compound represented by the general formula (I) is preferably 4- (3,4-dimethoxyphenyl) -2- (N-sec-butyl-N-propylaminomethyl) -6,7-dimethoxyquinoline-3-.
Ethyl carboxylate (compound of Example 39), 4- (3,4
-Dimethoxyphenyl) -2- (N-tert-butyl-N-
Ethylaminomethyl) -6,7-dimethoxyquinoline-3
-Ethyl carboxylate (compound of example 40), 2- (N,
Ethyl N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (Compound of Example 5) or 4- (3,4-dimethoxyphenyl) -2 -(N-ethylaminomethyl)-
6,7-Dimethoxyquinazoline (Compound of Example 54)
Is. The salts of the compounds represented by the general formulas (I) and (I ') used in the present invention are preferably pharmaceutically acceptable salts, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids. Examples thereof include salts, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include:
For example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Examples thereof include salts with N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
Examples thereof include salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Suitable examples of salts with basic amino acids include, for example, arginine, lysine,
Examples thereof include salts with ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

The compound represented by the general formula (I) used in the present invention is blended with a pharmaceutically acceptable carrier to prepare a solid preparation such as tablet, capsule, granule, powder; or syrup, injection. Can be administered orally or parenterally as a liquid preparation such as. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a solvent in a liquid formulation, a solubilizing agent. , A suspending agent, a tonicity agent, a buffering agent, a soothing agent, etc. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used.

Suitable examples of excipients include lactose,
White sugar, D-mannitol, starch, crystalline cellulose,
Examples include light anhydrous silicic acid. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include bound cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,
Examples thereof include sodium carbonate and sodium citrate. Suitable examples of the suspending agent include, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, surfactants such as glyceryl monostearate; for example, polyvinyl alcohol, Examples thereof include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like. Suitable examples of the buffer include, for example, phosphate,
Buffers such as acetate, carbonate, citrate and the like can be mentioned. Preferred examples of the soothing agent include benzyl alcohol and the like. Suitable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Examples include dehydroacetic acid and sorbic acid. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like. The compound represented by the general formula (I) can be produced, for example, as follows. Ie

[0052]

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[In the formula, Q is a leaving group, and other symbols have the same meanings as described above. In the general formula (II), the leaving group represented by Q is, for example, halogen, preferably chlorine, bromine or iodine, or a hydroxyl group activated by esterification, such as a residue of an organic sulfonic acid ( (Eg, p-toluenesulfonyloxy group, methanesulfonyloxy group, etc.) and diphenylphosphoryloxy group, which is a residue of organic phosphoric acid, dibenzylphosphoryloxy group, dimethylphosphoryloxy group and the like. In method A, (II) was added in the presence of a base (III)
To produce (I). The reaction of (II) and (III) is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine and N, N-dimethyl. Formamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof can be mentioned.

The reaction of (II) and (III) is carried out by sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,
Alkali metal salts such as sodium hydrogen carbonate, pyridine,
It is carried out in the presence of an amine such as triethylamine and N, N-dimethylaniline, and an appropriate base such as sodium hydride and potassium hydride.
About 1 to 5 molar equivalents relative to (II) are preferred. Also,
By using an excess amount of (III), (III) can also be used as a base. This reaction is usually from -20 ° C.
It is carried out at 150 ° C, preferably about -10 ° C to 100 ° C. The quinoline or quinazoline derivative (I) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The starting compound (II) of the present invention can be produced, for example, by the following method.

[0055]

[Chemical 6]

[In the formula, G ′ represents an esterified carboxyl group, and other symbols have the same meanings as described above. In the general formulas (V) and (II-1), examples of the esterified carboxyl group represented by G ′ include the same as the esterified carboxyl group represented by G. In Method B, 2-aminobenzophenone derivative (IV) is reacted with (V) in the presence of acid to produce (II-1).
The reaction of (IV) and (V) is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1, and Examples include alcohols such as 1,2,2-tetrachloroethane, methanol, ethanol and propanol, acetic acid and the like.

The reaction of (IV) and (V) is carried out in the presence of a Lewis acid such as aluminum chloride or zinc chloride, or an appropriate acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid. About 0.05 to 0.5 molar equivalent is preferable with respect to (IV). This reaction is generally carried out at 20 ° C to 200 ° C, preferably about 30 ° C to 150 ° C. Reaction time is 0.5 to 20
The time is preferably 1 to 10 hours. The compound (II-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0058]

[Chemical 7]

[In the formula, each symbol has the same meaning as described above. In method C, 2-aminobenzophenone derivative (IV) was reacted with acetoacetic acid ester derivative (VI) in the presence of an acid to produce (VII), which was brominated to produce 2-bromomethylquinoline derivative (II-2). To do. The reaction between (IV) and (VI) is carried out in the same manner as in Method B. Bromination of (VII) is carried out in an appropriate solvent by a reaction with N-bromosuccinimide or the like according to a conventional method. Examples of the solvent include halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. The amount of N-bromosuccinimide used is 1 to 2 molar equivalents relative to compound (VII).

This bromination reaction is carried out using benzoyl peroxide,
It is carried out in the presence of a radical reaction initiator such as 2,2′-azobis (isobutyronitrile), and the amount of these radical reaction initiators used is about 0.001 to 0.01 molar equivalents relative to compound (VII). Is preferred. This reaction is usually from 20 ° C to 150 ° C.
C., preferably about 30-100.degree. The reaction time is 0.5 to 20 hours, preferably 1 to 10 hours. The compound (II-2) thus obtained can be separated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like.

[0061]

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[In the formula, Q ′ represents a halogen atom, and other symbols have the same meanings as described above. In formulas (VIII) and (II-3), examples of the halogen atom represented by Q ′ include chlorine, bromine, and iodine.
In method D, 2-aminobenzophenone derivative (IV) is reacted with halogenoacetonitrile derivative (VIII) to give 2
-The halogenomethylquinazoline derivative (II-3) is prepared. The reaction between (IV) and (VIII) is carried out in the presence of an acid using an excess of (VIII) as a solvent. The acid is B
The ones listed in the law are used. The amount of these acids used is about 1 to 5 molar equivalents, preferably 1 to 2 with respect to compound (IV).
It is a molar equivalent. This reaction is generally carried out for 0.5 to 30 hours, preferably 1 to 10 hours. The reaction temperature is usually 20 ° C to 2
The temperature is 00 ° C, preferably 30 ° C to 150 ° C. The quinazoline derivative (II-3) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like.

[0063]

[Chemical 9]

[In the formula, each symbol has the same meaning as described above. In the method E, the 2-aminobenzophenone derivative (IV) is reacted with acetonitrile to prepare a 2-methylquinazoline derivative.
(IX) was prepared, and then (IX) was subjected to a bromination reaction.
-Bromomethylquinazoline derivative (II-4) is prepared. The reaction between (IV) and acetonitrile is carried out in the same manner as in Method D. The bromination of (IX) is carried out in the same manner as the bromination of (VII) in Method C. The quinazoline derivative (II-4) thus obtained can be isolated and purified by a known means such as concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0065]

[Chemical 10]

[In the formula, each symbol has the same meaning as described above. In the F method, the 2-aminobenzophenone derivative (IV) is reacted with the cyanoacetic acid ester derivative (X) to produce the quinazoline derivative (XI). The reaction between (IV) and (X) is carried out in the same manner as in Method D. The quinazoline derivative (XI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0067]

[Chemical 11]

[In the formula, each symbol has the same meaning as described above. In the G method, a 2-aminobenzophenone derivative (IV) is reacted with an acetone dicarboxylic acid ester derivative (XII) to produce a quinoline derivative (XIII). (IV) and
The reaction of (XII) is carried out in the same manner as Method B. The quinoline derivative (XIII) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0069]

[Chemical 12]

[Wherein Y'is a nitrogen atom or CG ',
Other symbols have the same meanings as described above. In method H, compounds (XI) and (X
By subjecting III) to a reduction reaction, the alcohol compound (X
IV) is produced. This reduction reaction can be performed by a method known per se. For example, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, catalytic hydrogenation and the like are used. That is,
This reaction is carried out by treating compounds (XI) and (XIII) with a reducing agent. As the reducing agent, an alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), a metal hydride complex compound such as lithium aluminum hydride, a metal hydride such as sodium hydride, an organic tin compound (hydrogen (Triphenyltin etc.), nickel compounds, metals such as zinc compounds and metal salts, catalytic reduction agents using transition metal catalysts such as palladium, platinum, rhodium and hydrogen, and diborane.
This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,
Halogenated hydrocarbons such as 1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, N, N-dimethylformamide An amide such as the above, or a mixed solvent thereof is appropriately selected and used according to the type of the reducing agent. Reaction temperature is -2
0 ° C to 150 ° C, particularly 0 ° C to 100 ° C is preferable,
The reaction time is about 1 to 24 hours.

[0071]

[Chemical 13]

[In the formula, each symbol has the same meaning as described above. In Method I, compound (XIV) is reacted with a halogenating agent or a sulfonylating agent to produce (II-5). As such a halogenating agent, thionyl chloride, phosphorus tribromide, etc. are preferably used, in which case Q is represented by chlorine or bromine.
(II-5) is produced. This reaction is an appropriate inert solvent
(E.g. benzene, toluene, xylene, chloroform,
It is carried out at −10 to 80 ° C. in a solvent such as dichloromethane or an excess halogenating agent. The amount of the halogenating agent used is 1 to 20 mol with respect to (XIV). As the sulfonylating agent, mesyl chloride, tosyl chloride, benzenesulfonyl chloride and the like are preferably used, and (II-5) in which Q is respectively mesyloxy, tosyloxy and benzenesulfonyloxy is produced. This reaction is carried out in a suitable inert solvent (e.g., benzene, toluene, xylene, ethyl ether, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, etc.) with a base (e.g.,
Triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) at -10 to 30 ° C. The amount of the sulfonylating agent and the base used is 1 to 1.2 mol, respectively, relative to 1 mol of (XIV). When 1 mol of the compound (II-5) in which Q is chlorine, bromine or sulfonyloxy produced as described above is reacted with 1 to 1.5 mol of sodium iodide or potassium iodide, Q is iodine ( II-5) can also be produced. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol or ethanol at 20 to 80 ° C.

[0073]

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[In the formula, n ′ represents 1 or 2, and the other symbols have the same meanings as described above. ] In Method J, the compounds (II-1), (II-2), (II-3) and (II-4) produced by Method B, Method C, Method D, Method E and Method I are used.
And (II-5) are oxidized to produce compound (II-6). This oxidation reaction is carried out according to a conventional method by using an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, peresters,
It is performed using sodium metaperiodate or the like. This oxidation is an organic solvent which is inert under the reaction conditions, for example, a halogenated hydrocarbon (e.g. methylene chloride, chloroform, dichloroethane, etc.) or a hydrocarbon (e.g. benzene,
Toluene, etc., alcohols (methanol, ethanol,
Advantageously, such as propanol). Oxidizer is a compound
1 to 5 molar equivalents relative to (II-1), (II-2), (II-3), (II-4) or (II-5), preferably 1 to
It is carried out using 3 molar equivalents. Reaction temperature is -10 ° C to 15
It is usually 0.5 at a temperature of 0 ° C, preferably about 0 ° C to 100 ° C.
It takes 10 hours. The quinoline 1-oxide or quinazoline 1-oxide derivative (II-6) thus obtained is isolated by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. It can be purified separately. Compound
The compound represented by the quinoline derivative (I-1) of (I) can also be produced by the K method.

[0075]

[Chemical 15]

[In the formula, each symbol has the same meaning as described above. In this method, compound (I-1) is produced by reacting 2-aminobenzophenone derivative (IV) with compound (XV).
This method is performed in the same manner as the method B. The quinoline derivative (I-1) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like. Quinolinecarboxylic acid derivative of compound (I)
(I-3) can also be produced by the L method.

[0077]

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[In the formula, each symbol has the same meaning as described above. ] In this method, quinoline-3-carboxylic acid ester derivative
By subjecting (I-2) to a hydrolysis reaction, a carboxylic acid derivative (I
-3) is manufactured. This hydrolysis reaction is carried out in the presence of an acid or a base in water or a water-containing solvent according to a conventional method. As the solvent, methanol, ethanol, propanol,
Examples thereof include alcohols such as 2-methoxyethanol and ethylene glycol, ethers such as dioxane and tetrahydrofuran, acetic acid, acetonitrile, acetone, 2-butanone, N, N-dimethylformamide and dimethyl sulfoxide. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and the like. Examples of the base include sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and the like. Preferably, an acid or base is used in excess (base: 1 to 10 molar equivalents, acid: 1 to 50 molar equivalents) with respect to compound (I-2). This hydrolysis reaction is usually at -20 ° C to 1
It is carried out at 50 ° C., preferably −10 ° C. to 100 ° C. for 1 to 50 hours. Quinoline derivative thus obtained
(I-3) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound represented by the general formula (I) or a salt thereof used in the present invention has an anti-inflammatory effect, an antipyretic analgesic effect, and an adjuvant arthritis which develops arthritis similar to human rheumatoid arthritis. An excellent anti-arthritic effect was confirmed in the experimental model. Moreover, the toxicity of the compound of the present invention is low, and for example, the compound synthesized in Example 5 is 250 mg / k
No oral death was observed in mice, rats, or the compound synthesized in Example 54 at a dose of 500 mg / kg. Therefore, the object compound of the present invention can be applied to all arthritis in which the joints of mammals including human (eg, mouse, rat, cat, dog, rabbit, cow, pig, etc.) exhibit inflammatory symptoms. The dose of the compound (I) used in the present invention can be variously selected depending on the administration route and the symptoms of the patient to be treated, but usually, per adult, in the case of oral administration, 5 mg to 1000 mg, and in the case of parenteral administration It can be selected from the range of 1 mg to 100 mg.
It can be administered in 1 to 3 divided doses daily.

Next, the test method for supporting the pharmacological action of the compound (I) or salts thereof used in the present invention and the results thereof will be shown. Test Example 1: Effect on Rat Adjuvant Arthritis Freund's complete adjuvant (0.5% tuberculosis killed liquid paraffin suspension) in the right hind footpad of male Lewis rats (7 weeks old, CLEA Japan, Inc.). It was sensitized by injecting 05 ml. A test drug (12.5 mg / kg) was suspended in 0.5% methylcellulose and orally administered once a day for 14 days immediately before sensitization (day 0). Immediately before sensitization (Day 0) and day 14 (Day
In 14), the volume of the left hind limb and the body weight were measured, and the foot pad expansion inhibition rate (%) and the body weight increase rate (%) of the non-sensitized rat were obtained. Results are expressed as the mean ± SE of each group (N = 6) Dun
Nett's test was used for comparison and verification. A risk rate of less than 5% was considered significant. As shown in Table 1, the compound of the present invention was effective in suppressing the edema of the foot pads and improving the general symptoms observed in weight gain.

[0081]

[Table 1]

[0082]

EXAMPLES The present invention will be described in more detail below with reference to reference examples and examples, but the present invention is not limited thereto. Reference Example 1 2-Amino-4,5-ethylenedioxy-3 ', 4'-dimethoxybenzophenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml) were added to concentrated sulfuric acid.
(0.3 ml) and stirred at 100 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was poured into water and 2NN.
It was made alkaline with aOH and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. From the portion eluted with chloroform-ethyl acetate (7: 3, v / v), 2-chloromethyl-6,7-ethylenedioxy-4- (3,4-dimethoxyphenyl) quinoline-
3-Carboxylic acid ethyl ester (5.5 g, 60%) was obtained. Recrystallized from acetone. Colorless prism crystals. Melting point 1
97-198 ° C.

Reference Examples 2 to 7 In the same manner as in Reference Example 1, the compounds in Table 2 were obtained.

[0084]

[Table 2]

Reference Example 8 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, ethyl acetoacetate and acetic acid, and treated in the same manner as in Reference Example 1 to prepare 4- (3 , 4-Dimethoxyphenyl) -6,7-dimethoxy-2-methylquinoline-3-carboxylic acid ethyl ester (83%) was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 147
~ 148 ° C.

Reference Example 9 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-methylquinoline-3-carboxylic acid ethyl ester
(411 mg), N-bromosuccinimide (214 mg), 2,
A mixture of 2'-azobis (isobutyronitrile) (10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. After the reaction mixture was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Chloroform-ethyl acetate (10: 1, v / v)
2-Bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3
-Carboxylic acid ethyl ester (285 mg, 58%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 135-136 ° C.

Reference Example 10 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, propyl acetoacetate and acetic acid, and treated in the same manner as in Reference Example 1 to prepare 4- (3 , 4-Dimethoxyphenyl) -6,7-dimethoxy-2-methylquinoline-3-carboxylic acid propyl ester (79%) was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 153-155 [deg.] C.

Reference Example 11 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, butyl acetoacetate and acetic acid, and treated in the same manner as in Reference Example 1 to prepare 4- (3 , 4-Dimethoxyphenyl) -6,7-dimethoxy-2-methylquinoline-3-carboxylic acid butyl ester (53%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
119-120 ° C.

Reference Example 12 In the same manner as in Reference Example 9, 2-bromomethyl-4- (3,4-
Dimethoxyphenyl) -6,7-dimethoxyquinoline-3
-Carboxylic acid propyl ester (48%) was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 144-145 [deg.] C.

Reference Example 13 In the same manner as in Reference Example 9, 2-bromomethyl-4- (3,4)
-Dimethoxyphenyl) -6,7-dimethoxyquinoline-
Obtained 3-carboxylic acid butyl ester (56%). Recrystallized from ethyl acetate-ether. Colorless prism crystals. Melting point 160-161 [deg.] C.

Reference Example 14 Powdered aluminum chloride (6.7 g) was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (8.0 g) and chloroacetonitrile (25 ml) at 100 ° C.
Stirred for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO
₄ ) After that, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. Chloroform-ethyl acetate (10:
1, v / v), 2-chloromethyl-4-
(3,4-Dimethoxyphenyl) -6,7-dimethoxyquinazoline (4.9 g, 52%) was obtained. Recrystallized from acetone. Colorless prism crystals. 183-184 ° C.

Reference Example 15 2-Amino-4,5,3 ', 4'-tetramethoxybenzophenone (6.3 g) and cyanoacetic acid methyl ester (23 m
l) Powdered aluminum chloride (5.3g) was added to the mixture of 10
Stir at 0 ° C. for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (Mg
After SO ₄ ) the solvent was evaporated and the residue was subjected to silica gel column chromatography. Hexane-ethyl acetate (4:
4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline-2-acetic acid methyl ester was obtained from the portion eluted with 1, v / v). Recrystallized from acetone. Colorless needles. Melting point 152-153 [deg.] C.

Reference Example 16 4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline-2-acetic acid methyl ester (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran
Methanol (15 ml) was added dropwise to a mixture of (80 ml) under reflux. The mixture was stirred under reflux for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
It was distilled off (MgSO ₄₎ and the solvent to give 4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethyl) 6,7-dimethoxyquinazoline (3.0 g, 81%). Recrystallized from ethyl acetate. Colorless needles. Melting point 165-166 [deg.] C.

Reference Example 17 Phosphorus tribromide (PBr ₃ ) (0.95 g) was added to 4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethyl) -6,7-
A solution of dimethoxyquinazoline (2.6 g) in benzene (50 ml) was added dropwise at room temperature. The mixture was stirred at 75 ° C for 1 hr, poured into ice water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. Chloroform layer washed with water and dried
After (MgSO ₄ ), the solvent was distilled off, and the residue was subjected to silica gel column chromatography, chloroform-ethyl acetate.
2- (2-Bromoethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline (1.1 g, 37%) was obtained from the portion eluted with (3: 1, v / v). . Recrystallized from ethyl acetate. Colorless needles. Melting point 166-167 [deg.] C.

Reference Example 18 In the same manner as in Reference Example 1, ethyl 6-chloro-2-chloromethyl-4- (4-chlorophenyl) quinoline-3-carboxylate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 140-141 [deg.] C.

Reference Example 19 In the same manner as in Reference Example 1, 2-chloromethyl-4- (4-
Obtained ethyl chlorophenyl) -6,7-dimethoxyquinoline-3-carboxylate. Recrystallized from ethanol. Colorless prism crystals. Melting point 153-154 [deg.] C.

Reference Example 20 In the same manner as in Reference Example 1, 2-chloromethyl-4- (4-
Fluorophenyl) -6,7-dimethoxyquinoline-3-
Obtained ethyl carboxylate. Recrystallized from ethanol.
Colorless prism crystals. Melting point 147-148 [deg.] C.

Reference Example 21 In the same manner as in Reference Example 1, 2-chloromethyl-4- (3,4)
-Dichlorophenyl) -6,7-dimethoxyquinoline-3
-Ethyl carboxylate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 159-160 [deg.] C.

Reference Example 22 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
A mixture of (3.0 g), metachloroperbenzoic acid (85%, 2.3 g) and methanol (40 ml) was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The chloroform layer is washed with water and dried (MgS
After O ₄ ) the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. From the portion eluted with chloroform-ethyl acetate (6: 4, v / v), 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate ethyl 1-oxide ( 2.
0 g, 65%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 193-194
° C.

Reference Example 23 2-Amino-4,5,3 ', 4'-tetramethoxybenzophenone (50.0 g), diethyl acetone dicarboxylate (3
A mixture of 5.0 g) and acetic acid (400 ml) was added with concentrated sulfuric acid (1.5 m).
l) was added and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform.
The chloroform layer was washed with water, dried and the solvent was distilled off under reduced pressure after (MgSO _4), the crystal remaining was recrystallized from acetone, 4
-(3,4-dimethoxyphenyl) -6,7-dimethoxy-
3-Ethoxycarbonylquinoline-2-ethyl acetate (4
8.8 g, 64%) was obtained. Colorless prism crystals. Melting point 146-
147 ° C.

Reference Example 24 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-ethoxycarbonylquinoline-2-ethyl acetate
A solution of (5.8 g) in tetrahydrofuran (100 ml) was added dropwise to a suspension of lithium aluminum hydride (0.455 g) in tetrahydrofuran (50 ml) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour, water (2.5 ml) was added dropwise, and the mixture was stirred for another 30 minutes.
Stir for a minute. The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 4- (3,4-dimethoxyphenyl) -2 was eluted from the portion eluted with chloroform-ethyl acetate (1: 1, v / v).
Obtained ethyl-(2-hydroxyethyl) -6,7-dimethoxyquinoline-3-carboxylate (1.75 g, 33%).
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 150-151 [deg.] C.

Reference Example 25 Phosphorus tribromide (1.0 g) was added to ethyl 4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethyl) -6,7-dimethoxyquinoline-3-carboxylate ( 1.7 g) benzene
(50 ml) was added dropwise to the solution at room temperature. The mixture was stirred at 80 ° C. for 1 hr, poured into ice water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The chloroform layer was washed with water and dried was distilled off (MgSO ₄₎ the solvent under reduced pressure,
The residue was subjected to silica gel column chromatography. From the portion eluted with chloroform-ethyl acetate (1: 1, v / v), ethyl 2- (2-bromoethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate ( 0.49 g, 26%) was obtained. Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 132
-133 ° C.

Reference Example 26 A mixture of benzyl 4-bromobutanoate (58.6 g), diethylamine (58.3 g) and dichloromethane (1000 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water, dried and the solvent was distilled off under reduced pressure after (MgSO _4), the residue was subjected to silica gel column chromatography. Benzyl 4- (N, N-diethylamino) butanoate (33.8 g, 60%) was obtained from the portion eluted with ethyl acetate. NMR
(δ ppm in CDCl ₃ ): 0.99 (6H, t, J = 7.2H
z), 1.78 (2H, quintet, J = 7.2Hz), 2.39 (2
H, t, J = 7.2Hz), 2.49 (4H, q, J = 7.2Hz),
5.11 (2H, s), 7.30-7.41 (5H, m).

Reference Example 27 In the same manner as in Reference Example 26, benzyl 5- (N, N-diethylamino) pentanoate was obtained. NMR (δ ppm in
CDCl ₃ ): 0.99 (6H, t, J = 7.0Hz), 1.40-
1.78 (4H, m), 2.33-2.50 (4H, m), 2.49
(4H, q, J = 7.0Hz), 5.11 (2H, s), 7.30-7.
40 (5H, m).

Reference Example 28 Benzyl 4- (N, N-diethylamino) butanoate (33.
8g), palladium-carbon (5%, 7g) and ethanol
The mixture (500 ml) was subjected to catalytic reduction reaction at room temperature and 1 atm. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and 4- (N,
N-diethylamino) butanoic acid (16.2 g, 75%) was obtained. Melting point 45-47 [deg.] C. NMR (δ ppm in CDCl ₃ ):
1.30 (6H, t, J = 6.6Hz), 1.92 (2H, quintet,
J = 6.6Hz), 2.52 (2H, t, J = 6.6Hz), 2.95
(2H, t, J = 6.6Hz), 2.99 (4H, q, J = 6.6Hz).

Reference Example 29 In the same manner as in Reference Example 28, 5- (N, N-diethylamino) pentanoic acid was obtained. NMR (δ ppm in CDC
l ₃ ): 1.26 (6H, t, J = 7.2Hz), 1.53-1.85
(4H, m), 2.29 (2H, t, J = 6.0Hz), 2.90 (2
H, t, J = 6.0 Hz), 3.06 (4H, q, J = 6.0 Hz).

Reference Example 30 To a suspension of 4- (N, N-diethylamino) butanoic acid (10.0 g) in tetrahydrofuran (400 ml) was added N, N'-carbonyldiimidazole (11.2 g) and the mixture was stirred at room temperature for 6 hours. Stir the time. Then, malonic acid monoethyl ester magnesium salt (Mg (OCOCH ₂ COOC ₂ H ₅ ) ₂ ] (19.8 g) was added and stirred at room temperature for 14 hours.The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried (MgSO ₄ ), then the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with chloroform-methanol (5: 1, v / v). From this, ethyl 6- (N, N-diethylamino) -3-oxohexanoate (7.6 g, 53%) was obtained.
ppm in CDCl ₃ ): 1.00 (6H, t, J = 7.0Hz),
1.28 (3H, t, J = 7.2Hz), 1.75 (2H, quintet,
J = 7.2Hz), 2.36-2.64 (8H, m), 3.46 (2
H, broad s), 4.19 (2H, q, J = 7.2Hz).

Reference Example 31 In the same manner as in Reference Example 30, ethyl 7- (N, N-diethylamino) -3-oxoheptanoate was obtained. NMR (δ
ppm in CDCl ₃ ): 1.01 (6H, t, J = 7.0Hz),
1.28 (3H, t, J = 7.2Hz), 1.38-1.70 (4
H, m), 2.36-2.60 (8H, m), 3.43 (2H, s), 4.
19 (2H, q, J = 7.2Hz).

Example 1 Oily sodium hydride (60%, 0.27 g) was added to morpholine.
(0.537 g) N, N-dimethylformamide (20 ml)
The mixture was added to the solution and stirred at room temperature for 15 minutes. Then, 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7
Ethyl dimethoxyquinoline-3-carboxylate (2.5 g)
Was added. The mixture was stirred at 100 ° C. for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. The residual crystals were collected by filtration and recrystallized from ethanol to give ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate (1.9 g, 68%). Obtained. Colorless prism crystals. 146-147 ° C.

Example 2 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
(1.0 g), piperazine (1.15 g) and methanol (1
5 ml) was stirred at room temperature for 36 hours. The reaction mixture was concentrated under reduced pressure and 6N HCl (30 ml) was added to the residue.
Was added and washed with dichloromethane. Aqueous layer is 2N Na
It was neutralized with OH and extracted with dichloromethane. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4). The residual crystals were collected by filtration and recrystallized from dichloromethane-hexane to give ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperazinomethylquinoline-3-carboxylate (0.43 g, 39%). Colorless prism crystals. Melting point 192-193 [deg.] C.

Example 3 Oily sodium hydride (60%, 0.753 g) was added to thiomorpholine (1.8 g) in N, N-dimethylformamide (50 m).
l) Add to the solution and stir for 15 minutes at room temperature. Then, 2-
Chloromethyl-4- (3,4-dimethoxyphenyl) -6,
Ethyl 7-dimethoxyquinoline-3-carboxylate (6.0
g) was added. The mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
After (MgSO ₄ ), the solvent was distilled off. The residue was subjected to silica gel column chromatography, and 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-thio was extracted from the portion eluted with chloroform-ethyl acetate (7: 3, v / v). Ethyl morpholinomethylquinoline-3-carboxylate (1.4 g, 4
2%). Recrystallized from ethanol. Colorless prism crystals. Melting point 148-149 [deg.] C.

Example 4 Oily sodium hydride (60%, 0.466 g) was added to a solution of N-methylhomopiperazine (1.23 g) in N, N-dimethylformamide (40 ml), and the mixture was stirred at room temperature for 15 minutes.
Then ethyl 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (4.0 g) was added. The mixture was stirred at 100 ° C. for 3.5 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (5: 1, v / v) to give 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[( Ethyl 4-methylhomopiperazino) methyl] quinoline-3-carboxylate (1.0 g, 22%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 157-159 [deg.] C.

Example 5 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
(4.0 g), diethylamine (1.28 g) and methanol
The mixture (45 ml) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with dichloromethane. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4).
The residue was subjected to silica gel column chromatography,
From the portion eluted with ethyl acetate, 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl)-
Ethyl 6,7-dimethoxyquinoline-3-carboxylate
(0.51 g, 18%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 130-131 [deg.] C.

Example 6 Ethyl 2-chloromethyl-6,7-dimethoxy-4- (4-methoxyphenyl) quinoline-3-carboxylate (2.0
A mixture of g), morpholine (2.5 g) and methanol (30 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, washed with water was added dichloromethane to the residue, and the mixture was dried (MgSO _4). The crystals obtained by distilling off the solvent were collected by filtration and recrystallized from ethanol to give 6,7-dimethoxy-4.
Obtained ethyl-(4-methoxyphenyl) -2-morpholinomethylquinoline-3-carboxylate (1.65 g, 74%). Colorless prism crystals. Melting point 165-166 [deg.] C.

Example 7 In the same manner as in Example 6, 6,7-dimethoxy-4- (4-
Methoxyphenyl) -2-piperidinomethylquinoline-
Obtained ethyl 3-carboxylate. Recrystallized from ethanol. Colorless prism crystals. Melting point 129-130 [deg.] C.

Example 8 Ethyl 2-chloromethyl-6,7-dimethoxy-4- (2-methoxyphenyl) quinoline-3-carboxylate (1.0
After stirring a mixture of g), morpholine (1.25 g) and ethanol (13 ml) at room temperature for 3 days, the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 6,7-dimethoxy-4- ( Ethyl 2-methoxyphenyl) -2-morpholinomethylquinoline-3-carboxylate (0.76 g, 68
%). Colorless prism crystals. Melting point 153-154 [deg.] C.

Example 9 In the same manner as in Example 6, ethyl 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2-morpholinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless needles. Melting point 174-175 [deg.] C.

Example 10 In the same manner as in Example 6, ethyl 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 158-160
° C.

Example 11 In the same manner as in Example 6, ethyl 4- (3,4-dimethoxyphenyl) -6,7-diethoxy-2-morpholinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 147-148 [deg.] C.

Example 12 In the same manner as in Example 6, ethyl 4- (3,4-dimethoxyphenyl) -6,7-diethoxy-2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 154-155 [deg.] C.

Example 13 In the same manner as in Example 6, ethyl 6-chloro-2-morpholinomethyl-4-phenylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 161-163 [deg.] C.

Example 14 Ethyl 2-chloromethyl-4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (3.0 g), morpholine (2.76 g) and A mixture of ethanol (50 ml) -dichloromethane (5 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure,
Dichloromethane (50 ml) was added to the residue. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4). The residue was subjected to silica gel column chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) to give 4- (3-isopropoxy-4-methoxyphenyl).
An oily product of ethyl-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate was obtained. This oily substance was dissolved in ethanol (20 ml), an ethanol solution of hydrogen chloride (23%, 1.05 g) was added, and the mixture was stirred at room temperature for 10 min. The solvent was distilled off under reduced pressure, and the crystals were collected by filtration. Recrystallized from ethanol-ether to give 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylic acid ethyl hydrochloride.
(1.62 g, 45%) was obtained. Colorless crystals. Melting point 185-1
88 ° C. Elemental analysis Calculated as C ₂₉ H ₃₇ N ₂ O ₇ Cl · H ₂ O: C, 60.15; H, 6.79; N, 4.84 Analytical value: C, 60.51; H, 6.58 N, 4.73

Example 15 In the same manner as in Example 14, 4- (3-isopropoxy-
Ethyl 4-methoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylic acid hydrochloride was obtained. Recrystallized from ethanol-ether. Colorless crystals. Melting point 207-210 [deg.] C. Elemental analysis Calculated as C ₃₀ H ₃₉ N ₂ O ₆ Cl · 1 / 2H ₂ O: C, 63.43; H, 7.10; N, 4.93 Analytical value: C, 63.15; H, 7 .02; N, 4.80

Example 16 In a similar manner to Example 14, 2- (N, N-dipentylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7
-Ethyl dimethoxyquinoline-3-carboxylate dihydrochloride was obtained. Recrystallized from dichloromethane-ethyl acetate.
Yellow powder. Melting point 93-95 [deg.] C. Elemental analysis Calculated as C ₃₃ H ₄₈ N ₂ O ₆ Cl ₂ · 3 / 2H ₂ O: C, 59.45; H, 7.71; N, 4.20 Analytical value: C, 59.58; H, 7.88; N, 4.14

Example 17 In the same manner as in Example 1, ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 148-149 [deg.] C.

Example 18 In the same manner as in Example 1, ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-pyrrolidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 139-14
0 ° C.

Example 19 2-Bromomethyl-4- (3,4-dimethoxyphenyl)
A mixture of -6,7-dimethoxyquinoline-3-carboxylic acid propyl ester (1.5g), piperidine (1.27g) and dichloromethane (30ml) was stirred at room temperature for 2 days. The reaction mixture was washed with water and freed from dried (MgSO ₄₎ and the solvent. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (10: 1, v / v) to give 4- (3,4-dimethoxyphenyl) -6,7.
-Dimethoxy-2-piperidinomethylquinoline-3-carboxylic acid propyl ester (0.8 g, 53%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 129-131 [deg.] C.

Example 20 In the same manner as in Example 19, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylic acid butyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 154
~ 155 ° C.

Examples 21 to 28 The compounds of Table 3 were obtained in the same manner as in Example 5.

[0130]

[Table 3]

1) Hemihydrate. 2) 1/4 hydrate. 3) Amorphous solid. NMR (δ ppm in CDCl ₃ ): 0.9
7 (3H, t, J = 7Hz), 3.59 (4H, s), 3.78 (3H,
s), 3.88 (3H, s), 3.97 (3H, s), 3.99 (2H, q,
J = 7Hz), 4.04 (3H, s), 4.13 (2H, s), 6.84
-7.02 (4H, m), 7.10-7.40 (10H, m), 7.4
2 (1H, s).

Example 29 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
-6,7-Dimethoxyquinazoline (2.0 g), piperidine
(2.27 g) and ethanol (40 ml) -dichloromethane
The mixture (10 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (50 ml).
Was added. Dichloromethane layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off. The residue was subjected to silica gel column chromatography, and chloroform-ethyl acetate (1: 1, v
/ (V) eluate to give 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinazoline (1.46 g, 65%). Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 130-132
° C.

Example 30 In the same manner as in Example 29, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-morpholinomethylquinazoline was obtained. Recrystallized from ethyl acetate-hexane.
Colorless prism crystals. 148-150 ° C.

Example 31 In the same manner as in Example 29, 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-
Dimethoxyquinazoline was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 111-113
° C.

Example 32 In a similar manner to Example 29, 2-bromomethyl-4-
2- (N-Ethyl-N-propylaminomethyl) -4 was obtained by the reaction of ethyl (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate with N-ethyl-N-propylamine. Obtained ethyl-(3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate. Recrystallized from ethyl acetate-hexane.
Colorless prism crystals. Melting point 105-106 [deg.] C.

Example 33 2- (2-Bromoethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline (0.486)
A mixture of g), diethylamine (0.41 g) and dichloromethane (10 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4). The residue was subjected to silica gel column chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) to give 2- [2- (N, N-diethylamino).
Ethyl] -4- (3,4-dimethoxyphenyl) -6,7-
Dimethoxyquinazoline (0.040 g, 8%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 164-166 [deg.] C.

Example 34 Ethyl 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (3.0 g), N-methyl-N-cyclohexylamine (2 A mixture of 0.28 g) and ethanol (45 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer is washed with water,
Drying was distilled off (MgSO ₄₎ and the solvent. The residue was subjected to silica gel column chromatography, and 2- (N-cyclohexyl-N-methylaminomethyl) -4- (3,4-dimethoxyphenyl)-was extracted from the portion eluted with chloroform.
Ethyl 6,7-dimethoxyquinoline-3-carboxylate (2.80 g, 80%) was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 172-174 [deg.] C.

Examples 35 to 41 In the same manner as in Example 34, the compounds shown in Table 4 were obtained.

[0139]

[Table 4]

Example 42 In the same manner as in Example 14, 2-chloromethyl-4- (3
-Isopropoxy-4-methoxyphenyl) -6,7-
2- (N, N-diethylaminomethyl) -4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylic acid was obtained by reacting ethyl dimethoxyquinoline-3-carboxylate with diethylamine. Ethyl acid dihydrochloride was obtained. Recrystallized from ethyl acetate-ether. Yellow powder. Melting point 122-124 [deg.] C. Elemental analysis Calculated as C ₂₉ H ₄₀ N ₂ O ₆ Cl ₂ .1 / 2H ₂ O: C, 58.78; H, 6.97; N, 4.73 Analytical value: C, 58.84; H, 7.00; N, 4.69

Example 43 In a manner analogous to Example 33, 6-chloro-4- was prepared by reacting ethyl 6-chloro-2-chloromethyl-4- (4-chlorophenyl) quinoline-3-carboxylate with diethylamine. Ethyl (4-chlorophenyl) -2- (N, N-diethylaminomethyl) quinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 132-133 [deg.] C.

Example 44 In a manner similar to Example 33, the reaction of ethyl 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylate with diethylamine gave 6-chloro-2- (N, N).
-Diethylaminomethyl) -4-phenylquinoline-3
-Ethyl carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 107-108 [deg.] C.

Example 45 In a manner similar to Example 33, 2-chloromethyl-4- (3,
4-dichlorophenyl) -6,7-dimethoxyquinoline-
Reaction of ethyl 3-carboxylate with diethylamine gives 4- (3,4-dichlorophenyl) -2- (N, N-diethylaminomethyl) -6,7-dimethoxyquinoline-3.
-Ethyl carboxylate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 157-158 [deg.] C.

Example 46 In the same manner as in Example 33, 2-chloromethyl-4- (4
-Chlorophenyl) -6,7-dimethoxyquinoline-3-
By the reaction of ethyl carboxylate with diethylamine, 4
Obtained ethyl-(4-chlorophenyl) -2- (N, N-diethylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate. Recrystallized from ethyl acetate-hexane.
Colorless prism crystals. Melting point 82-83 [deg.] C.

Example 47 In the same manner as in Example 33, 2-chloromethyl-4- (4
-Fluorophenyl) -6,7-dimethoxyquinoline-3
-By reaction of ethyl carboxylate with diethylamine,
Obtained ethyl 4- (4-fluorophenyl) -2- (N, N-diethylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 102-103 [deg.] C.

Example 48 In the same manner as in Example 33, 2-chloromethyl-4- (4
-Methoxyphenyl) -6,7-dimethoxyquinoline-3
-By reaction of ethyl carboxylate with diethylamine,
Obtained ethyl 2- (N, N-diethylaminomethyl) -6,7-dimethoxy-4- (4-methoxyphenyl) quinoline-3-carboxylate. . Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 118-119 [deg.] C.

Example 49 2-Amino-4,5,3 ', 4'-tetramethoxybenzophenone hydrochloride (7.7 g), 6- (N, N-diethylamino)
A mixture of ethyl-3-oxohexanoate (5.0 g) and ethanol (100 ml) was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The chloroform layer was washed with saturated aqueous sodium bicarbonate and water, was distilled off dried (MgSO ₄₎ the solvent under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-methanol (20: 1, v / v).
2- [3- (N, N-diethylamino)
Propyl] -4- (3,4-dimethoxyphenyl) -6,7
-Ethyl dimethoxyquinoline-3-carboxylate (1.51
g, 14%). Recrystallized from ethanol-hexane. Colorless prism crystals. Melting point 96-98 [deg.] C.

Example 50 2-Amino-4,5,3 ', 4' was prepared in the same manner as in Example 49.
-Tetramethoxybenzophenone hydrochloride and 7- (N, N-
2- [4- (N, N-diethylamino) butyl] by reaction with diethylamino) -3-oxoheptanoate ethyl
Ethyl -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 17
1-172 ° C.

Example 51 Ethyl 2- (2-bromoethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (0.45 g), diethylamine (0.326 g) and A mixture of dichloromethane (10 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water and distilled off dried (MgSO ₄₎ the solvent under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (20:
1, v / v) to elute 2- [2- (N, N-diethylamino) ethyl] -4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
(0.113 g, 26%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 76-78 [deg.] C.

Example 52 In a manner similar to Example 33, 2-chloromethyl-4- (3,
4-Dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate ethyl 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl)-by reaction of 1-oxide with diethylamine Ethyl 6,7-dimethoxyquinoline-3-carboxylic acid 1-oxide was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 143-144 [deg.] C.

Example 53 In a manner similar to Example 33, 2-chloromethyl-4- (3,
4- (3,4-dimethoxyphenyl) -2- by reaction of ethyl 4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate with diisopentylamine
Obtained ethyl (N, N-diisopentylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 1
14-115 ° C.

Example 54 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
-6,7-Dimethoxyquinazoline (10.0 g), ethylamine (70% aqueous solution, 206 g) and ethanol (200
ml) -dichloromethane (200 ml) mixture at room temperature 13
Stir the time. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Dichloromethane layer was washed with water, dried the solvent was removed under reduced pressure (MgSO _4), and the residue was subjected to silica gel column chromatography. 2-from the part eluted with chloroform-ethanol (5: 1, v / v)
(N-Ethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline (5.7 g, 55
%). Recrystallized from ethanol. Colorless prism crystals. Melting point 128-130 [deg.] C.

Example 55 In a manner similar to Example 34, 2-chloromethyl-4- (3,
4- (3,4-dimethoxyphenyl) -2- (N- by reaction of ethyl 4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate with N-methylaniline.
Ethyl methyl-N-phenylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate was obtained. Recrystallized from dichloromethane-hexane. Colorless prism crystals. Melting point 194-196 [deg.] C.

Example 56 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
A mixture of -6,7-dimethoxyquinazoline (1.78g), tert-butylamine (17.4g) and dichloromethane (40ml) was stirred at room temperature for 13 hours. The reaction mixture was washed with water, dried and concentrated (MgSO ₄₎ after under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with dichloromethane-ethanol (30: 1, v / v).
2- (tert-butylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline (0.77)
g, 40%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 120-122 [deg.] C.

Example 57 In a manner similar to Example 56, 2-chloromethyl-4- (3,
4- (dimethoxyphenyl) -6,7-dimethoxyquinazoline and sec-butylamine give 2- (sec-butylaminomethyl) -4- (3,4-dimethoxyphenyl)
-6,7-Dimethoxyquinazoline was obtained. Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 118
-120 ° C.

Example 58 In a similar manner to Example 56, 2-chloromethyl-4- (3,
By reacting 4-dimethoxyphenyl) -6,7-dimethoxyquinazoline with N-methylaniline, 4- (3,4-
Dimethoxyphenyl) -6,7-dimethoxy-2- (N-
Methyl-N-phenylaminomethyl) quinazoline was obtained. Recrystallized from ethanol. Colorless needles. Melting point 14
1-143 ° C.

Example 59 In a similar manner to Example 56, 2-chloromethyl-4- (3,
2-anilinomethyl-4 was obtained by the reaction of 4-dimethoxyphenyl) -6,7-dimethoxyquinazoline with aniline.
-(3,4-Dimethoxyphenyl) -6,7-dimethoxyquinazoline was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 199-200 [deg.] C.

Example 60 2-Chloromethyl-4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
A mixture of (1.0 g), 2- (methylamino) pyridine (0.95 g) and 2-methoxyethanol (30 ml) was stirred under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure,
Water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated (MgSO ₄₎ after under reduced pressure. The residue was subjected to silica gel column chromatography, and 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-from the portion eluted with hexane-ethyl acetate (3: 2, v / v). Ethyl [N-methyl-N- (2-pyridyl) aminomethyl] quinoline-3-carboxylate (0.1 g, 9%) was obtained. Recrystallized from dichloromethane-ethanol. Pale yellow prism crystal. Melting point 174-175 [deg.] C.

Example 61 A solution of diphenylamine (0.497 g) in N, N-dimethylformamide (10 ml) was added with sodium hydride (oiliness, 60 ml).
%, 0.129 g) was added and the mixture was stirred at room temperature for 20 minutes. Then, 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline (1.0 g) was added,
Stir at 100 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
After (MgSO ₄ ), it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 2- (N, N-diphenylaminomethyl) -4- (3,4-) was extracted from the portion eluted with ethyl acetate-hexane (1: 1, v / v). Dimethoxyphenyl) -6,7-dimethoxyquinazoline (0.27 g, 20%)
I got Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 215-216 [deg.] C.

[0160]

According to the present invention, there is provided an anti-inflammatory agent containing a quinoline or quinazoline derivative. The anti-inflammatory agent of the present invention is particularly effective as a therapeutic agent for arthritis.
The anti-inflammatory agent of the present invention has low toxicity and can be safely administered. Furthermore, according to the present invention, a novel quinoline or quinazoline derivative having an anti-inflammatory action is provided.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area C07D 491/056 7019-4C C07D 491/056

Claims (33)

[Claims] 1. A compound represented by the general formula (I): [In the formula, Y represents a nitrogen atom or C-G (G represents an optionally esterified carboxyl group), R ¹ and R ² are each hydrogen, or an optionally substituted hydrocarbon residue. Or a heterocyclic group which may be substituted, R
¹ and R ² may combine with each other to form a saturated ring.
Ring A and ring B may each have a substituent.
n represents an integer of 1 to 4, and k represents 0 or 1. ] Or a salt thereof. 2. The anti-inflammatory agent according to claim 1, wherein the optionally substituted hydrocarbon residue represented by R ¹ and R ² is an optionally substituted alkyl group. 3. The anti-inflammatory agent according to claim 1, wherein R ¹ and R ² are bonded to each other to form an optionally substituted 5- to 7-membered saturated ring. 4. The anti-inflammatory agent according to claim 1, wherein n is 1 or 2. 5. The anti-inflammatory agent according to claim 1, wherein Y is CG. 6. The anti-inflammatory agent according to claim 5, wherein G is C _1-6 alkyloxycarbonyl. 7. G is ethoxycarbonyl.
The anti-inflammatory agent as described above. 8. The anti-inflammatory agent according to claim 1, wherein Y is a nitrogen atom. 9. The anti-inflammatory agent according to claim 1, wherein the substituent on the A ring is a lower alkylenedioxy located at the 6- and 7-positions of the quinoline ring or the quinazoline ring. 10. The anti-inflammatory agent according to claim 9, wherein the substituent on the A ring is methylenedioxy located at the 6- and 7-positions of the quinoline ring or the quinazoline ring. 11. The anti-inflammatory agent according to claim 1, wherein ring A is substituted with an alkoxy group. 12. The anti-inflammatory agent according to claim 11, wherein ring A is substituted with methoxy. 13. The anti-inflammatory agent according to claim 1, wherein ring A is disubstituted with the same or different alkoxy groups. 14. The anti-inflammatory agent according to claim 1, wherein ring A is disubstituted with methoxy. 15. The anti-inflammatory agent according to claim 14, wherein ring A is disubstituted by methoxy at the 6- and 7-positions of the quinoline ring or quinazoline ring. 16. The anti-inflammatory agent according to claim 1, wherein the substituent on the B ring is lower alkylenedioxy. 17. The anti-inflammatory agent according to claim 16, wherein the substituent on the B ring is methylenedioxy. 18. The anti-inflammatory agent according to claim 1, wherein the substituent on the B ring is an alkoxy group. 19. The anti-inflammatory agent according to claim 18, wherein the substituent on the B ring is methoxy. 20. The anti-inflammatory agent according to claim 1, wherein ring B is disubstituted with the same or different alkoxy groups. 21. The anti-inflammatory agent according to claim 20, wherein ring B is disubstituted with methoxy. 22. The anti-inflammatory agent according to claim 1, wherein ring B is disubstituted with methoxy at the 3- and 4-positions. 23. The anti-inflammatory agent according to claim 1, wherein k is 0. 24. A compound represented by the formula (I) is 4- (3,4-dimethoxyphenyl) -2- (N-sec-butyl-N-propylaminomethyl) -6,7-dimethoxyquinoline- Ethyl 3-carboxylate, 4- (3,4-dimethoxyphenyl) -2- (N-tert-butyl-N-ethylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylate, 2- (N , N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-
The anti-inflammatory agent according to claim 1, which is ethyl carboxylate or 4- (3,4-dimethoxyphenyl) -2- (N-ethylaminomethyl) -6,7-dimethoxyquinazoline. 25. The general formula (I ′): [In the formula, Y represents a nitrogen atom or C-G (G represents an optionally esterified carboxyl group), R ¹ and R ² are each hydrogen, or an optionally substituted hydrocarbon residue. Or a heterocyclic group which may be substituted, R
¹ and R ² may combine with each other to form a saturated ring.
R ³ and R ⁴ each independently represent an alkoxy group.
Ring B may have a substituent. n represents an integer of 1 to 4, and k represents 0 or 1. ] The compound or its salt represented by these. 26. The compound according to claim 25, wherein R ³ and R ⁴ are each methoxy. 27. The compound of claim 25, wherein R ³ and R ⁴ are methoxy located at the 6- and 7-positions of the quinoline ring or quinazoline ring, respectively. 28. The compound according to claim 25, wherein the substituent on the B ring is an alkoxy group. 29. The compound according to claim 25, wherein the substituent on the B ring is methoxy. 30. The compound according to claim 25, wherein ring B is disubstituted with the same or different alkoxy groups. 31. The compound of claim 25, wherein ring B is disubstituted with methoxy. 32. The compound of claim 25, wherein ring B is disubstituted with methoxy at the 3 and 4 positions. 33. 4- (3,4-dimethoxyphenyl)-
2- (N-sec-butyl-N-propylaminomethyl)-
Ethyl 6,7-dimethoxyquinoline-3-carboxylate, 4- (3,4-dimethoxyphenyl) -2- (N-tert-butyl-N-ethylaminomethyl) -6,7-dimethoxyquinoline-3-carboxylic acid Ethyl acid salt, 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-
26. The compound according to claim 25, which is ethyl carboxylate or 4- (3,4-dimethoxyphenyl) -2- (N-ethylaminomethyl) -6,7-dimethoxyquinazoline.