JPS58126879A - Optically active piperazine derivative and preventive and remedy for cardiac infarction - Google Patents

Abstract

NEW MATERIAL:The optically active oxirane-containing compound of formulaI[R<1> is H or <=4C straight or branched alkyl; R<2> is <=4C straight or branched alkyl, group of formula II (n is integer of 0-3), cinnamyl, diphenylmethyl, 2-pyridyl or 2-pyrimidinyl]or its nontoxic salt. EXAMPLE:(2R,3R)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)-pi perazin-1- ylcarbonyl}butylcarbamoyl]oxirane-2-carboxylic acid ethyl ester. USE:Preventive and remedy for cardiac infarction. PROCESS:The optically active compound of formulaI(R<1> is R<4>) can be prepared e.g. by reacting the compound of formula III (R<3> is protecting group), etc. with the compound of formula IV, removing the R<3> group from the product, and reacting the resultant compound of formula V with the optically active compound of formula VI (R<4> is <=4C alkyl), etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Technical Field of the Invention) The present invention relates to optically active pyridazine derivatives.

The present invention relates to a method for producing optically active piperazine derivatives.

Furthermore, the present invention relates to a drug for preventing or treating myocardial infarction.

(Technical background) In Japan, the number of myocardial infarction patients tends to increase with the westernization of dietary habits and the increase in the elderly population. This is an extremely important issue from the perspective of maintaining health.

However, prevention and treatment of myocardial infarction is extremely difficult even with modern medicine, and it is difficult to prevent myocardial infarction by administering drugs that alleviate heart failure, arrhythmia, ischemic heart disease, etc. that occur along with myocardial infarction. Currently, it is being used for prevention and treatment. Therefore, there are great expectations for the development of effective drugs for the prevention and treatment of myocardial infarction.

(Object of the Invention) The inventors have continued to search for drugs that exhibit excellent medicinal effects for the prevention and treatment of myocardial infarction, and have synthesized a novel compound represented by the above general formula (1). It was discovered that these compounds exhibit an extremely excellent suppressive effect on myocardial infarction and are highly safe, and the present invention was completed based on this discovery.

(Structure, operation, and effect of the invention) The di-radizine derivative according to the present invention has the following general formula (1
) and non-toxic salts thereof.

■ CH(CH3)2 (1) In the formula, R+ means a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, and R2 means a straight chain or branched alkyl group having up to 4 carbon atoms. A straight chain having a carbon atom or 1] means an integer from 0 to 0. .

That is, the pyradizine derivative according to the present invention has the general formula (
1) The optically active oxirane represented by (2R,3R
) coordination compounds and their non-toxic salts.

Furthermore, the piradzine derivative according to the present invention has the general formula (1
) The optically active oxirane represented by (28,38)
Coordination compounds and their non-toxic salts.

Specific examples of the compound represented by general formula (1) include the following.

(2R1roR) -5-[(S) -3-methyl-1-
(4-methylpiperazin-1-ylcarbonyl)butyl-carbamoyl]oxirane-2-carboxylic acid, (2L
3R)-ro-[(S)-1-(4-ethylbiradin-1-ylcarbonyl)-6-methylbutyl-carpamoyl]oxirane-2-carboxylic acid, (2L3R)-
6-[(S) -1-<4-isobutyl biradin-1-ylcarbonyl)-ro-methylbutyl-carbamoyl]oxirane-2-carboxylic acid, (2)t,roR)-5-C(s)-1 -(4-(4
-methquinphenylmethyl)piperazin-1-ylcarbonyl)-6-methylbutylcarbamoyl]oxirane-2-carboxylic acid, (2R,3R,) -3-[(s) -1-(4-(3
, 4-dimethoxyphenylmethyl)piradin-1-ylcarbonyl)-6-methylbutylcarbamoyl]oxira/-2-carboxylic acid, (2R,5R) -5-[(s) -3-methyl~1-
(4-(2,3,4-trimethoxyphenylmethyl)piradin-1-ylcarbonyl)butylcar/2moyl]oxirane-2-carboxylic acid, (2P1.凭)-6-[(S) -3- Methyl-1-(
4-(3,4,5-)dimethoxyphenylmethyl)bi-ranol-1-ylcarbonyl)butylcar/moyl]oxirane-2-carboxylic acid, (2R,3R) -3-((s) -1-(4- Benzylpiperazin-1-ylcarbonyl)-6-methylbu'
tylcarbamoyl]oxirane-2-carboxylic acid, (2
t1. ．． (2R,3)L) -z, -(: (s) -1-(
4-diphenylmethylbi-radin-1-ylcarbonyl)-6-methylbutylcarbamoyl]oxirane-2
-carboxylic acid, (2R,3R) -3-C(s) -1-(4-(2-
pyridyl)pi is radin-1-ylcarbonyl)-6-methylbutylcarbamoyl]oxirane-2-carboxylic acid, (2R,3R) -3-[(+,) -5-methyl-1
-(4-(2-pyrimidinyl)pizradin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylic acid, (2S, RoS) -5-[(S) -3-methyl-1-
(4-Methylbiradin-1-ylcarbonyl)butyl-carbamoyl]oxirane-2-carboxylic acid, (2S
, 3S) -3-C(s) -1-(4-ethylpyniradin-1-ylcarbonyl)-3-merIF-ruftyrucarbamoyl]oxirane-2-carboxylic acid, (2S
, 3S) -3-C(S) -1-(4-Inbutylbi-glazin-1-ylcarbonyl)-ro-methylbutyl-carbamoyl]oxira/-2-carboxylic acid, (2S, 3S) -3-[ (s) -1-(4-(4-
metquinphenylmethyl)biradin-1-ylcarbonyl)-6-methylbutylcarbamoyl]oxilano-
2-carboxylic acid, (2S, 38) -5-C(S) -1-(4-(3,
4-dimethoxyphenylmethyl)piperazin-1-ylcarbonyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid, (28,38) -5-C(s) -5-methyl-1-
(4-(2,3,4-Trimethquinphenylmethyl)bi-ζ-1-1-lcarbonyl-1-1-1-1-1-1-1-carboxylic acid, (2S,3S)-3-C(s)- 3-methyl-1-
(4-(5,4,5-trimethoxyphenylmethyl)hyperan-1-ylcarbonyl)butylcar/2moyl]oxirane-2-carboxylic acid, (28,38) -3-[(S) -1-(, 4-Benzylpiperazin-1-ylcarbonyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid, (2
8,38) -5-((s) -1-(4-cinnamylpizradin-1-ylcarbonyl)-6-methylbutyrucarbamoyl]oxirane-2-carboxylic acid, (2s, 5s) -3- [(s) -1-(4-diphenylmethylbiradin-1-ylcarbonyl)-6-methylbutyrucarbamoyl]oxirane-2-carboxylic acid, (28,3S) -3-C(s) -1- (4-(2-
(28,58) -5-((s) -3-methyl-1-
(4-(2-pyrimidinyl)pyniradin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylic acid.

Methyl esters, ethyl esters, n of these compounds
-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, 5ee-butyl ester and tert-butyl ester are also inventive compounds.

From another point of view, the present invention is a method for producing an optically active compound represented by the general formula (1).

The method for producing the compound represented by general formula (1) according to the present invention is as follows.

(a) When R1 in general formula (1) is an alkyl group, general formula (2) (% formula %) (2) (in the formula R31j represents a protecting group for an amine group of an amino acid such as a tert-butoxycarbonyl group) L expressed
- Leucine derivative or its reactive derivative with the general formula (3
) (3) (In the formula, R2 has the same meaning as above.) by reacting with an amine derivative represented by the general formula (4) (4) (In the formula, R2 and R3 have the same meaning as above.) A leucylpiperazine derivative represented by the general formula (5) (5) (wherein R2 has the same meaning as above) obtained by converting the compound represented by In, MORT i et al. (Te
trahedron Vol. 36, p. 87 (1980)] general formula (6) (6) (where R4 is a linear or branched alkyl group having 4 or less carbon atoms) Optically active trans-epoxycono-phosphoric acid monoester represented by (2R,3R)-epoxycono-phosphate monoester or &U (28,38)-epoxysuccinic acid monoester or their reactivity By reacting with a derivative, a compound having an optically active oquinrane represented by the general formula (7) (7) (wherein R2 and R4 have the same meanings as above) is obtained.

Alternatively, the general formula (8) (8) obtained by reacting the optically active trannuevoxysuccinic acid monoester represented by the general formula (6) or its reactive derivative with leucine (wherein R4 has the same meaning as above) The epoxysuccinic acid leucine derivative 1 represented by (indicates the same meaning as above) or its reactive derivative is reacted with an amine derivative represented by the general formula (3) (3) (wherein R2 has the same meaning as above). It is obtained as a compound having an optically active oxirane represented by the general formula (7) (7) (wherein R2 and R4 have the same meanings as above).

Condensation reaction between a compound of general formula (2) and a compound of general formula (3), a condensation reaction between a compound of general formula (5) and a compound of general formula (6), and a compound of general formula (8) The condensation reaction between and the compound of general formula (6) can be carried out using a conventional acid chloride method or by using methylene chloride, It is carried out at room temperature in an organic solvent such as chloroform or tetrahydrofuran.

(b) General formula (9) in which R1 in general formula (1) is a hydrogen atom
) (wherein R2 has the same meaning as above) can be obtained by hydrolyzing the ester group of the compound represented by formula (7).

If desired, sodium, potassium, calcium, magnesium, and further trialkylamines,
Dibenzylamine, N-lower alkyl biba, lysine, α
- Non-toxic salts of phenethylamine, 1-(1-naphthyl)ethylamine, N-benzyl-β-phenethylamine, or non-toxic salts with hydrochloric acid, hydrobromic acid, formic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, etc. It can be done.

Viewed from another point of view, the present invention is a prophylactic and therapeutic agent for myocardial infarction, which contains a compound represented by general formula (1) or a nontoxic salt thereof as an active ingredient.

The usefulness of the compound of general formula (1) and its nontoxic salt in the present invention as a therapeutic agent for myocardial infarction is demonstrated by its excellent preventive and therapeutic effects on experimental myocardial infarction models.

i.e. experimental myocardial infarction in rabbits or dogs.
It shows remarkable preventive and therapeutic effects when administered at a dose of 1 to 400 μ/Icy. For example, a rabbit has 20~
When 200 rv/kg was administered, a clear infarction suppressing effect was observed compared to when no administration was given.

Further, the compound of the present invention was found to be a highly safe substance for living organisms through acute toxicity tests in mice.

The dosage of the compound of general formula (1) and its barotoxic salt in the present invention varies depending on the type of compound and the degree of symptoms of myocardial infarction, but it is usually sufficient to administer about 10 m9 to 1 g per day to the patient. .

When the compound represented by general formula (1) and its salt are used as a therapeutic agent for myocardial infarction, they are usually in the form of a pharmaceutical composition together with a pharmaceutical carrier.

As the carrier, diluents or excipients such as fillers, binders, disintegrants, lubricants, etc., which are commonly used to prepare drugs depending on the usage form, are used.

The dosage form may be any form such as injection, powder, capsule, granule, or tablet.

When used in tablet form, carriers include, for example, lactose, sucrose, chloride, excipients such as lactose, glucose solution, starch, calcium carbonate, crystalline cellulose, and silicic acid, water, ethanol, pro-ξnol, and glucose. , starch liquid, gelatin bath liquid, carboxymethylcellulose,
Binders such as methylcellulose and potassium phosphate, dried starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, monoglyceride stearate, starch, disintegrants such as lactose, stearate, powdered boric acid, solid polyethylene glycol Lubricants that are widely used in this field can be used. Furthermore, it can be made into sugar-coated tablets, gelatin-encapsulated tablets, film-coated tablets, etc., if necessary.

When prepared as an injection, 91% as a diluent.
Examples include water, ethyl alcohol, propylene glycol, holoxyethylene rubitan, and nrubitan ester. At this time, sufficient amounts of salt, glucose, or glycerin may be included to prepare an isodominant bath solution, and conventional solubilizing agents, buffers, soothing agents, preservatives, etc. are required. It may be included depending on the situation.

(Example) A test example showing that the compound mAkatera of the general formula (1) and its non-toxic salt in the present invention shows excellent preventive and therapeutic effects on a myocardial infarction model and is highly safe. The present invention will be specifically explained below. However, the following Examples and Test Examples are not intended to limit the present invention.

Example 1 1e-phthoxycarbonyl-L-leucyl/-monohydrate (24.9 g) and N-hydroxysuccinimide (1
N,N'-dicyclohexylcarbodiimide (1,5,9) was added to a mixture of ethyl acetate (250 ml) under water cooling.
206g) of acetic acid solution (100ml) 16
The liquid was added dropwise and stirred at room temperature for 4 hours. Under water cooling again 1-
A solution of radin (266 g) in xf acetic acid (100 m1i) was added dropwise to (2,3,4-1rimethoxyphenylmethyl)bi, and the mixture was stirred overnight at room temperature. After cooling the reaction mixture with water, the inorganic components were separated in a furnace, and the P solution was washed with aqueous sodium bicarbonate and saturated brine in that order, dried with sodium sulfate, and then the hot medium was distilled off under reduced pressure.
The crude reaction mixture was obtained as a viscous oil. This product was purified by silica gel column chromatography (developing solvent: chloroform, methanol-50:1),
, (s) -3-methyl-1-1:4-(2,3,4-
)rimethoxyphenylmethyl)pi gave tert-butylradin-1-ylcarbonyl]butylcarbamate in the form of a colorless viscous oil at a yield of 46.99% (yield 98%).

NMR(CDC4)δ: 4.56 (IH, m, >N-CHCo-)5
．． 24 (IH, m, -CONH-)6.56
(IH, d, J=-8Hz, aromatic proton) 6.90 (IH, d, J==8Hz
, aromatic protons) ethyl acetate (IDOOml) was introduced with hydrogen chloride on a water-cooled system to saturate it, and the above-obtained (s) -
5-methyl-1-(4-(2,3,4-1-rimethoquinphenylmethyl)bi-radin-1-ylcarbonyl]butylcarbamine1Idtert-butyl(4,6,5,
A solution of 9) in ethyl acetate (250 ml) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and excess hydrogen chloride gas were distilled off under reduced pressure, water was added to the residue, made alkaline with aqueous sodium bicarbonate, extracted with chloroform, the chloroform layer was washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 1-L-leucyl-4-(2,
54.99 (yield: 95) of (xyphenylmethyl)pyrazine was obtained as a yellow viscous oil.

N MR (cDc13) δ 1.90 (I H2m, CH2 crystal) 6.96~
4.25 (5H, m, 3NC Dan-) 6.57
(IH, d, J=9Hz, aromatic proton)6
．． 93(II], d, J=9Hz, aromatic proton)C2Ll)-diethyl epoxysuccinate (188
Potassium hydroxide (5,6', ml of ethanol (100ml) was added to a solution of g) in ethanol (100ml) under water cooling with stirring.
l) The solution was added dropwise. - After stirring at night, the precipitate was cooled on ice, taken out, washed with cold ethanol and ether, and dried under reduced pressure. og (yield 81%) 4.

[α), :=-86,4°(C=1,H2O)(2L
3R)-Epoxysuccinic acid monoethyl potassium salt (15
,0,! 9) was dissolved in saturated brine (75 mJ) with stirring under water cooling, concentrated hydrochloric acid (7.6 rrtl) was added, extracted with ethyl acetate (100 rnl), and washed with saturated brine.
A glass filter containing magnesium sulfate is placed in a
N-hydroxysuccinimide (8.7 g) was injected into a reaction vessel in advance.
A solution of N,N'-dicyclohexylcarbodiimide (156 g) in ethyl acetate (60 m/') was added dropwise at 5°C or below, and after stirring at room temperature for 2 hours, 1-L-isoyl-4-(
To the 2,3,4-trimethoxyphenylmethyl)pi, a solution of radin (28.7 g) in ethyl acetate (6 QmJ) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was cooled with water again, the precipitate was separated, and the P solution was washed with heavy distilled water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow viscous oil. This product was purified by silica cell column chromatography (developing phase medium chloroform methanol-50:1) L, (2R,3R) -3-((
s) -3-Methyl-114-(2,5°4-trimethoxyphenylmethyl)piradin-1-ylcarbonyl)butylcarbamoyl]ethyl oquinlane-2-carboxylate as a colorless viscous oil 29. 69 (yield 75%) was obtained.

IR(KBr)CrIL, 1755.16B5.
1630.90ON MR(cDc4) δ; 0.93 (6H, m, (CH-, CH-)
1,15+~1.76 (6H, m, -CH,, Ngong-, -Co2CH,, CH2) 4.76 (IH,
m, -NHHCO2)6.40 (IH, d
, J=8Hz, aromatic proton) 6.73
(IH, d, J=8Hz, aromatic proton) 6.84
(IH, d, J=7Hz, -NHCO-)
.

[α) o--51,9° (c=i,o ethanol)
Example 2 (2FL, 3R) −3-[(s) − obtained in Example 1
Ethyl 3-methyl-1-(4-(2,5,4-trimethoxyphenylmethyl)bi-radin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylate (
14.0g) in ether (50m/) solution of IN(
After adding lifuta (26.8 ml) and stirring, the aqueous layer was separated and evaporated under reduced pressure to obtain (2L3R) -3-((s)
-3-methyl-1-(4-(2,3,4-)rimethoxy/
Phenylmethyl)hiheradi/-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylic acid ethyl dissulfate was obtained as a white powder (yield: 98 cm).

IR(KBr)c77+-': 1745.164
5.895N M R (DMS O-da +D20
) δ0.90 (6H, m, (CH3)2C
H-) 1.22 (3H, t, J-=7Hz
,C02CH2Cf(a)1,! 1-1.75 (
3H1m, -CHJCH-)4.07 (2H,
Q, J=7Hz, -CO2CH=-)4.62
(IH, m, -NHCHCO-)6.62
(1H, d, J=8Hz, aromatic proto/)
6.92 (IH, d, J = 8 Hz, aromatic proton) 8.52 (IH, d, J = 7 Hz,
-NHCO-)[α]o--420″(C=101N
H2S04) Example 3 (2R,3R) -3-[(s) -3-methyl-1-
(4-(2,3,4-trimethoxyphenylmethyl)piperazin-1-ylcarbonyl)butylcarbamoyl]
To a solution of ethyl oxirane-2-carboxylate (14.0 g) in ethanol (100 ml) was added a 0.48N sodium hydroxide-ethanol solution (55.9 ml) under water cooling, and the mixture was stirred at room temperature for 2.5 hours. Ethanol was distilled off under reduced pressure, water was added to separate insoluble components, and the P solution was concentrated to dryness under reduced pressure to obtain (2R,i)-ro-[(S)-3-methyl-
135 g (yield: 98%) of sodium 1-(4-(2,3,4-trinotoquinphenylmethyl)piradin-1-ylcarbonyl)butylcarbamoyl]ochinrane-2-carboxylate was obtained as a pale yellow powder.

TR(KBr)CrIL-”: 1620,90O
NMR(DMso-c+a)δ゛0.90 (6H, m, (CHs)gCH-)
1.30-1.70 (3H, m, -C-H2Cp-
)70, -C! (-CH-) 4.70 (I H, m, -NHCH-CO
-)6.64 (IH, d, J=8Hz
, aromatic proton) 6.88 (1H, d,
J=8Hz, aromatic proton) 8.08 (
IH,d, -NHCO-) [α]. Knee 438° (C
-=I N20) Example 4 (2R,3R) -3-[(s) -3-methyl-1-
(4-(2,3,4-toIJ methoxyphenylmethyl)hyherazin-1-ylcarbonyl)phthylcarbamoyl]ethyl oxirane-2-carboxylate (1,049)
Oxalic acid dihydrate (0,
Add a solution of 25,9) in acetone (2 ml), collect the precipitated crystals in F, and dry to give (2L3R) -3-[(S
) -3-Methyl-1-(4-(2,3,4-trimethoxyphenylmethyl)pi is radin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylic acid ethyl oxalate as colorless crystals. 99 g (yield 8
1) Obtained.

m, ρ, 162-133' (decomposition) I R (KBr) CrIL-1: 1750.1640
．． 90ON MR (DMSO-da + , D20
) δ: 0.87 (6H9m, (CH3)KC
H-)1.22 (3H, t, J=7H2,
-co2cH2crI, )1.30-1.70 (s
H, m, -c66n-)4,16 (2H,q
, J -7Hz, -CO2CH2CH3)4.7
2 (IH, m, -NHC!-ICO-)6.
76 (IH, d, J-=8Hz, aromatic proton) 7.05 (IH, d, , ■=
8Hz, aromatic proton) 8.72 (IH,
d, J=8Hz, -NHCHCO-) [α].

Knee 67.6° (C=0.99, N20) Elemental analysis Theoretical value (%) as C28H41N3012:
C: 54.98 H: 6.76 N: 687 Experimental value (%
l: C: 54.80 H6,87N: 6.89 Example 5 (28,38) -Eboxico/・Rir! RJ-l-
Hydroxic acid (hypotassium (1,829) (7
) Ethanol (35 rnl) solution was added dropwise. −
After stirring at night, cool with water, remove the precipitate, add cold ethanol,
After washing with ether and drying under reduced pressure, (2s, 3s)-
4.55 g of epoxysuccinic acid monoethyl potassium salt
(yield 71%).

[α] 332 + 85.26 (C = 1, N20) (
28,38)-epoxysuccinic acid monoethyl potassium salt (422 g) was dissolved in saturated brine (21 rnl) with stirring under water cooling, concentrated hydrochloric acid (2,14 rnl) was added, extracted with ethyl acetate (28 ml), and the saturated After washing with saline,
Through a glass filter containing magnesium sulfate,
N-hydroxysuccinimide (2,459) was filtered and poured into a reaction vessel previously charged. Under water-cooled stirring, 1
A solution of N,N'-dicyclohexylcarbodiimide (4,39@) in ethyl acetate (17 ml) was added dropwise below 5°C, and after stirring at room temperature for 2 hours, 1-L-leucyl-4-(
To the 2,3,4-tritoxyphenylmethyl)pi, a solution of radin (8,079) in ethyl acetate (17 ml) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was cooled on ice again, the precipitate was separated, and the filtrate was washed with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow viscous oil. This product was purified by silica gel column chromatography (developing temperature: chloroform methanol = 50:1) L, (2s).

38) -3-C(s) -3-methyl-1-(4-(
2゜3.41-Rimethoxyphenylmethyl)piperazin-1-ylcarbonyl)butylcarbamoyl]ethyl oxirane-2-carboxylate was obtained as a colorless viscous oil at 7.4.09 (yield: 67%). .

IR(KBr)cv-': 1755.1685
, 1630.90ON MR (DMSO-d, )
δ 0.90 (6H, m, (C horse 2.CH-)t
O8~1.80 (6H, m, -CH2CH-, -
Co2CH2CHx )422 (2H1q
, J = '7.5 Hz, -CO2C-H2-)6.
78 (IH, d, J = BHz, aromatic proton) 7.05 (IH, d, J = 8 Hz,
aromatic proton) 8.72 (IH,d,
J=8Hz, -NI3CO-) [α] name'=+48.
2° (c=i,o ethanol) Example 6 (28.38) −3−[(s) −3 obtained in Example 5
-Methyl-1-(4-(2,3,4-trimethoxyphenylmethyl)py)/-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylate (5
, 20g) in ether (11mz) was added 1N sulfuric acid (6
, 13 ml) and stirred, the aqueous layer was separated and evaporated under reduced pressure to give (2s, ss) -z, -C(s)-3-
Methyl-1-(4-(2,3,4-trimethoxyphenylmethyl)hyhalazin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carbo acid = Chilev sulfate as white powder 3.32 g (yield 95 h) Obtained.

I R(KBr)(:rIl=: 1745,164
5.895N M R (DMS O-da + D20
) δ.

0.88 (6H, m, (C shell,), CH
-) 1.24 (3H, +, J=7Hz
, -Co2CH2CH,)16~1.75 (5H
,m,-(JjzCH-)4.24 (2H,
q, J=7Hz, -CO□Csu2-)4.84
(I H, m, -NHC!-UCO-)6.9
2 (IH, d, J=9Hz, aromatic proton) 7.22 (IH, d, J=9H
z, aromatic proton) 8.84 (IH, d
, J =8Hz, -NHCO-)[α,]o=+
47.3° (C21.OH2O) Example 7 (2S, 38)-ro-((S) -5-methyl-1-(
A solution of ethyl 4-(2,3,4-)rimethquinphenylmethyl)piperazi/-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylate (1,04 g) in ethanol (7,5 ml) was added under water cooling. .48 N-
Sodium hydroxide-ethanol solution (4.15ml)
was added and stirred at room temperature for 2.5 hours. Ethanol was distilled off under reduced pressure, water was added and insoluble components were separated in a furnace, and solution F was concentrated to dryness under reduced pressure (2S, 3S) -3-[(s)-6-
Sodium methyl-1-(4-(2,3,4-trimethoxyphenylmethyl)piradin-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylate as pale yellow powder 1,009 (yield 97 %)Obtained.

IR(KBr)c+a-1: 1625,895N
MR(DMSO-da)δ: 0.86 (6H, m, (CH3)2CH-
)120-1.70 (3H, m, -CH2CH-)
-(Le-CH-) 4.75 (I H, m, -NHCH-CO-
) 6.72 (1H, d, J = 8 Hz, aromatic proton) 6.96 (IH, d, J = 8
Hz, aromatic proton) 8.12 (IH, d
, -NHCO-) (α), -, +29.3° (C=0
．． 99 H2O) Example 8 (28,38) -5-((s) -3-methyl-1-
(4-(2,3,4-)rimethoxyphenylmethyl)hyhalazin-1-ylcarbonyl)butylcarbamoyl]
Oxalic acid dihydrate (0,2
5 g) of acetoy (2 m/) is added, the precipitated crystals are separated, and dried to form (28,38) -3-((s
) -s-Methyl-1-(4-(2,3゜4-trimethoxyphenylmethyl)pyR7) :y-1-ylcarbonyl)butylcarbamoyl]oxirane-2-carboxylic acid ethyl oxalate as colorless crystals as 1.03 g
(Yield 84%) Great.

mp, 132.5-133.5°C (decomposition) I R
1755,1640,90O NMR (DMSOda + H2O) δ: 0.88
(6H, m, (CH3)2CH-)
'1, 24 (5H, t, J =
7 Hz, -co2cH2c1. i, )4.20
(2H, q, J==7Hz, -co2cl(,
c) (314,80(IH,m, -NHCHCO-
)6.81 (IH, d, J = 8Hz, aromatic proton) 7.10 (IH, d, J
=8Hz, aromatic proton )8.72 (1
H, d, J = 8Hz, -NHCHCO-) [α),
=+46.26 (C=1.01, H, O1 elemental analysis Theoretical value as C24H41N3012 (%l
: C, 54, 98 H: 6.76 N: 6.87 Experimental value (ch): C: 54.87 H: 6.69 N: 6
．． 76 Example 9 tert-1+' Toxycarbonyl-L-leucine
Monohydrate (12,5,9) and N-hydroxyconophosphate imide (5.76 g) were added to a solution of ethyl acetate (150 m/liter) under water cooling, and N'-dicyclohexylcarbodiimide (103) was added to the solution. A solution of ethyl acetate (40 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours.
-pyrimidinyl) by adding radin (8.21 g),
Stir overnight at room temperature. The precipitate was separated, and the p solution was washed successively with aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude reaction mixture. This product was purified by silica gel column chromatography (developing solvent: methylene chloride: methanol = 10:1 J) (sl -5-
Methyl-1-[4-(2-pyrimidinyl)piperazine-
tert-butyl 1-ylcarbonylcobnalcarbamate in 15.4. ! i+ (yield: 710 cm) was obtained.

I R(neatlcm-'; 1710.16g0
,1590,80ONMR(CDC4)δ; 1.00 (6H,m, (CH3)2CH-
)1,5 (9H,s, (CHsls C
-11,4~1.8 (3H,m, -CH2-
CT(-)4.84~5.47 (2H, br, -C
ONH-, -NH-CH-CO-)6.8, 8.68
(3H, m, aromatic proton) Hydrogen chloride gas was introduced into water-cooled ethyl acetate (200 ml) to saturate it to give the above-obtained (sl-3-methyl-1-(4-(2-pyrimidinyl)piperazine-1). -ylcarbonyl]funalcarhamic acid tert-7'nal (13.3 g)' was added little by little and stirred for 60 minutes. The solvent and hydrogen chloride were distilled off under reduced pressure, and 200 ml of water was added to the white powder obtained. After dissolving and washing with ethyl acetate, add sodium bicarbonate solution and adjust the pH.
8, add food Ia, k and add ethyl acetate to 100+++l
The mixture was extracted 6 times, dried over Glauber's salt, and the solvent was distilled off under reduced pressure to obtain 1-
976 g (quantitative yield) of L-isoyl-4-(2-pyriminyl)viverane was obtained.

IR(KBr)cIn-'; 2960-2940.
1630, 1590゜0O NMR (CDC131δ; 0.99 (6H, m, (CH312CH-
)1.4 (3H,m, -CH,-(!:H-
)1,70 (2H, m, NH2-)-N
H-Ra-CO-) 6.75-8.59 (3H, m, aromatic proton) (2R,3R1-epoxysuccinic acid monoether,
1-L-o-4-(2-pyrimidinyl)piperazine J: (2R,3R)-3 in the same manner as in Example 1
-[(s) -3-Methyl-1-(4-(2-pyriminyl)biradin-1-ylcarbonyl)funalcarbamoyl]ethyl oxirane-2-carboxylate was obtained.

IR(KBrlCIrL-': 1745,163
0,1583,900°0O NMR(CDCIls)δ.

0.84-1. Gi4 (6H, m, (CH3)2
cH-)1.28 (3H,t, J=7H
z, -Co2CH2CH,)1.36-1.72
(3H,m, -CH2CH-)4.19
(2H, q, J=7Hz, -CO2C浵CH,
) ■ 4.94 (IH, m, -NHCHCO-
)6.45 (IH, m, aromatic proton)
6.77 (IH, d, J=8Hz, -NdanC0
-) 8.20 (2H, m, aromatic proton) "α), -52" (C = 1.0. CHCl3
) Example 10 (2R,3Rl -3-C(s) -3-methyl-1-
(4-(2-pyrimidinyl)bixradin-1-ylcarbonyl)butylcarbamoyl]ethyl oxirane-2-carboxylate was hydrolyzed with sodium hydroxide in the same manner as in Example 2, and f2R,3R)-RO-C( sl-3-methyl-1-(4-(2-pyrimidinyl)hyhalazine-1
-ylcarbonyl)phtercarbamoyl]oxirane-
Sodium 2-carboxylate was obtained.

IR (KBr 1cm-': 1680-1600
．． 1590.90ONMR (DMSO-d,) 0.90 (6H, m, fcH3)2cH
-)1.51 (3H,m, -CH2 and H-
) ■ 4.83 (IH, m, -NHHC
O-)6.67 (IH,m, aromatic proton
)8.40 (3H, m, aromatic proton, -N, HCO-)[α]D-44° (C=1.
0, HtO) Example 11 (2S, 381-epoxysuccinic acid monoether and 1-
(2S,3S)-5-((s
) -3-methyl-1-(4-(2-pyriminyl)biperan-1-ylcarbonyl)funalcarpamoyl]
Ethyl oxirane-2-carboxylate was obtained.

IR(KBr)cIrL-': 1745,1630
,1583.900゜0O NMR (CDC4) δ: 0.84-1.04 (6H,m, (CH,J,C
H-) 1.28 (5H, t, J = 7
Hz, -Co2CH2CH5)■ 1.36~1.72 (3H,m, -CH,CH
-14, 19 (2H, q, J" 7Hz, -
CO2CH2CH3)4.94 (IH,m,
-NHCHCO-)6.45 (IH,m,
aromatic proton) 6.95 (IH, d, J
=8Hz, -NdanCO-)8.20 (2H
, m, aromatic proton) [α] + 78° (C = 1.0
, CHCl3) Example 12 (2S,3S)-3-C(s)-3-methyl-1-(4
-(2-pyrimidinyl)biradin-1-ylcarbonyl)bunalcarbamoyl]oxirane-2-carboxylic acid ether was hydrolyzed with sodium hydroxide in the same manner as in Example 7, and (2S, filter 5)-3-[ (81-3-methyl-1-(4-(2-pyrimidinyl)hiheracin-1-ylcarbonyl)bunalcarbamoyl]oxirane-2-
Sodium carboxylate was obtained.

IR(KBr)cn-': 1680-1600.1
580.89ONMR (DMSO-da) 0.91 (6H,m, (CH,),CH-
) 1.51 (3H, m, - Tsutomu"u->4.8
6 (IH, m, -NHHCO2)6.69
(IH, m, aromatic proton) 8.29
(IH, d, J=8Hz, -NHCO-)8.
41 (2H, m, aromatic proton) [α]ゎ+
68° (C = 1.0.H2O) A white male rabbit weighing around 2 kg was anesthetized with bendoparby: sodium tar (35 da/kg, i, v, l), then the chest was opened under artificial respiration and the left anterior descending artery ( The entire heart was ligated from the origin (approximately 711111 lower part).After 24 hours, the heart was removed and sliced into myocardial k 2 im thick slices from the apex to the ligated area, and the infarct focus was stained using a phosphorylase reaction to determine necrosis. The area ratio of the area was calculated.
9. i, v,), from immediately after ligation to 1 hour later (T
/ 4 m9/ki? / hr, infusion), 2 hours after ligation k (T/8'%'/kl?, i, v,) and 3 hours after ligation (9, i, v, at 'r/8m9/'
It was administered to l. The administered drug was used as a physiological saline solution. The control group received only physiological saline. (Total dose of T) As a result, as shown in Table 1, the control group without drug administration showed a necrosis rate of 141cm, whereas the necrosis rate in the drug-administered group of the present invention was 98 to 113cm. A remarkable effect on suppressing necrosis was observed.

Test example 2 acute toxicity test ddN male mice weighing 20 to 28 g were used.

The drug was administered via the tail vein.

As a result, as shown in Table 1, it was confirmed that the drug of the present invention is highly safe.

Table 1 However, compound 1 (2R,3R) -3-C(s)
-3-methyl-1-(4-(2,3,4-)rimethquinphenylmethyl)pi is radin-1-ylcarbonyl)
Butylcarbamoyl] Okinra/-2-carboxylic acid ethyl 1/2 sulfate compound 2 (2R,3R) -3-(: (s)
-3-Methyl-1-(4-(2,3,4-)rimethoxyphenylmethyl)piradin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid sodium compound 3 (28,38) -3 - [(s) 3
-Methyl-1-(4-(2,3,4-)rimethoxyphenylmethyl)pizradin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid ethyl 2
Sulfate compound 4 (2S, 3S) -3-C(s) -3
-Methyl-1-(4-(2,3,4-)rimethoxyphenylmethyl)bi-radin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid sodium compound 5 (2R,l) -3-( (S) -3-
Methyl-1-(4-(2-pyriminidyl)pyhalazin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid sodium compound 6 (2s, ss) -3-[: (s)
-3-Methyl-1-(4-(2-pyrimidinyl)piperazin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid sodium Example 13 Formulation example (tablet) The following ingredients were contained in 1 tablet (220m9) Film-coated tablets containing

(2R, 3R) -3-[(s) -3-methyl-1-
Sodium (4-(2,3,4-)rimethoxyphenylmethyl)piperazin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylate
50■ Lactose
100rv crystalline cellulose
50m9 Magnesium Stearate
1m9 Hydroquine Propyl Methyl Cellulose
15■Hydroxypropylcellulose
4. Other compounds used as active ingredients in the present invention can also be made into film-coated tablets using the same formulation.

Example 14 Formulation example (granules) 1 g of granules contains the middle and lower symbols.

(2s,5s)-s-4(s)-3-methyl-1-(4
-(2,3,4-trimethoxyphenylmethyl)piradin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid ethyl'/2 Sulfate 200
m9 lactose
500 ■ Corn starch 300
m9 Other compounds used as active ingredients in the present invention can also be made into granules using the same formulation.

(2R,3R)-3-[:(s)-1-methyl-1-(
4-(2,3,4-trimethoxyphenylmethyl)piperazin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid ethyl disulfate
20 - Add sterile distilled water to the above ingredients to make 1 CJtnl.

) Contains 1 ampule of the number indicated below.

(2s,3s)-s-((s)-s-methyl-1-(4
-(2-pyriminidyl)pi is radin-1-ylcarbonyl)butylcarbamoyldioxirane-2-carboxylic acid sodium 100 phosphoric acid-potassium hydrogen buffer (0.4M solution) 1m/m/above example Sterile distilled water 10m
Add so that it becomes 1.

Other compounds used as active ingredients in the present invention can also be made into injections using the same formulation.

Applicant: Nippon Chemifa Co., Ltd. Agent: Patent Attorney Minoru Saka

Claims (6)

[Claims] (1) General formula (1) having optically active oxirane
Compounds represented by and non-toxic salts thereof. However, R1 in the formula means a hydrogen atom or a linear or branched alkyl group having 4 or less carbon atoms, R2H means a straight chain or branched alkyl group having 4 or less carbon atoms, and n is means an integer from 0 to 3. (2) The coordination of optically active oxirane is (2R,,3FL
) and its non-toxic salts. (3) The compound and its nontoxic salts according to claim 1, characterized in that the optically active oxirane has a (28,58) coordination. (4) General formula (1) having optically active oxirane
A prophylactic and therapeutic agent for myocardial infarction, which contains a compound represented by the formula or a non-toxic salt thereof as an active ingredient. However, R1 in the formula means a hydrogen atom or a straight-chain or branched alkyl group having 4 or less carbon atoms, and R1
2 is a straight chain 1° with up to 4 carbon atoms (5) The coordination of optically active oxirane is (2FL, 3R)
A preventive and therapeutic agent for myocardial infarction, which contains the compound according to claim 4 or a nontoxic salt thereof as an active ingredient. (6) The coordination of optically active oxirane is (28,38
) A prophylactic and therapeutic agent for myocardial infarction, which contains the compound according to claim 4 or a non-toxic salt thereof as an active ingredient.