JPH0155272B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD OF THE INVENTION The present invention relates to novel acid amide derivatives. The present invention also relates to a method for producing a novel acid amide derivative. Furthermore, the present invention relates to a drug for preventing or treating myocardial infarction. (Technical background) In Japan, there is a tendency for the number of patients with myocardial infarction to increase with the westernization of dietary habits and the increase in the elderly population. Therefore, prevention and treatment of myocardial infarction are extremely important issues from the perspective of maintaining the health of the nation. However, prevention and treatment of myocardial infarction is extremely difficult even with modern medicine. Currently, it is being used for the prevention and treatment of diseases. 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 their search for a drug that exhibits excellent medicinal effects for the prevention and treatment of myocardial infarction, and have synthesized a novel compound represented by the above general formula (). The inventors have discovered that these compounds exhibit an extremely excellent inhibitory effect on myocardial infarction and are also highly safe, and have completed the present invention based on this discovery. (Structure of the Invention) The novel acid amide derivative according to the present invention is a compound represented by the following general formula (). However, R ¹ in the formula means a hydrogen atom, an alkali metal atom, or a linear or branched alkyl group having 4 or less carbon atoms, n means an integer from 0 to 2, and m is 1. means an integer between 3 and 3. Specific examples of the compound represented by the general formula () include trans-3-[(s)1-1(4-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid, trans-3 -[(s)-1-(3-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]
Oxirane-2-carboxylic acid, trans-3-
[(s)-1-(3,4-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid, trans-3-[(s)
-1-(4-methoxyphenylmethylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid, trans-3-[(s)-3
-Methyl-1-(3,4,5-trimethoxyphenylcarbamoyl)butylcarbamoyl]oxirane-2-carboxylic acid, trans-3-[(s)-
1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]
Examples include oxirane-2-carboxylic acid, and methyl esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters, isobutyl esters, sec-butyl esters, and tert-butyl esters of these compounds. In addition, the above acid amide derivatives can be added to sodium, potassium, calcium, magnesium, and non-toxic compounds such as trialkylamine, dibenzylamine, N-lower alkylpiperidine, N-benzyl-β-phenethylamine, etc. in a conventional manner if desired. It can be salt. Furthermore, the preventive and therapeutic agent for myocardial infarction according to the present invention includes an acid amide derivative represented by the above chemical structural formula () (in which R ¹ , n and m have the same meanings as above); The active ingredient is at least one compound from the group consisting of non-toxic salts thereof. (Production method) The production method of the compound represented by the general formula () according to the present invention is as follows. (a) When R ¹ in general formula () is an alkyl group (a) General formula () (In the formula, R ² represents a protecting group for the amino group of an amino acid such as a tert-butoxycarbonyl group.) A leucine derivative or its reactive derivative represented by the general formula () (In the formula, n and m have the same meanings as above.) By reacting with an amine derivative represented by the general formula () (In the formula, n, m and R ² have the same meanings as above.) After forming a compound represented by the formula (), the protecting group is removed by a conventional method to obtain the general formula () (In the formula, n and m have the same meanings as above.) A leucylamide derivative represented by the general formula () (In the formula, R ³ represents an alkyl group having 1 to 4 carbon atoms and which may be branched.) (In the formula, n, m, and R ³ have the same meanings as above.) It is obtained as a compound represented by the following formula. (b) General formula () (In the formula, R ³ has the same meaning as above.) General formula () obtained by reacting a trans-epoxysuccinic acid monoester represented by or a reactive derivative thereof with leucine (In the formula, R ³ has the same meaning as above.) The epoxysuccinic acid leucine conductor or its reactive derivative represented by the general formula () (In the formula, n and m have the same meanings as above.) By reacting with an amine derivative represented by the general formula () (In the formula, n, m and R ³ have the same meanings as above.) It is obtained as a compound represented by the following formula. Condensation reaction between a compound of general formula () and a compound of general formula (), a condensation reaction between a compound of general formula () and a compound of general formula (), and a compound of general formula () and a compound of general formula () The condensation reaction can be carried out using the usual acid chloride method or in the presence of a known condensing agent such as N-hydroxysuccinimide and N,N'-dicyclohexycarbodiimide in an organic solvent such as methylene chloride, chloroform, or tetrahydrofuran at room temperature. It is carried out in The compound represented by the general formula () can be easily converted into the corresponding carboxylic acid by alkaline hydrolysis using a conventional method. (b) General formula () in which R ¹ is a hydrogen atom (In the formula, n and m have the same meanings as above.) The compound represented by the formula (2) can be obtained by hydrolyzing the ester group of the compound represented by the general formula (), and if desired, by a conventional method. It is then converted into a non-toxic salt. (Applications) From another point of view, the present invention is a prophylactic and therapeutic agent for myocardial infarction, which contains a compound represented by the general formula () as an active ingredient. The pharmacological effects, dosage and administration method, toxicity, etc. are shown below. (b) Pharmacological effect The compound of general formula () and its non-toxic salt in the present invention are useful as therapeutic agents for myocardial infarction because they have excellent preventive and therapeutic effects in experimental myocardial infarction models. will be shown. That is, when administered at a dose of 1 to 400 mg/Kg to experimental myocardial infarction in rabbits or dogs, it exhibits remarkable preventive and therapeutic effects.
For example, when administering 200 mg/Kg to rabbits,
A clear infarction suppressing effect is seen compared to the case of no administration. (b) Toxicity The compound represented by the general formula () was found to be a highly safe substance for living organisms through acute toxicity tests on mice. Test Example 1 Effect on experimental myocardial infarction A white male rabbit weighing around 2 kg was anesthetized with pentobarbital sodium (35 mg/Kg, iv),
The chest was opened under artificial respiration, and the left anterior descending artery (approximately 7 mm below the origin) was ligated. After 24 hours, the heart was removed, and the myocardium from the apex of the heart to the ligated area was sliced into 2 mm thick slices, and the infarct focus was stained by phosphorylase reaction to calculate the area percentage of necrotic area. Drugs were administered 5 minutes before ligation (100mg/Kg, iv), immediately after ligation and up to 1 hour after ligation (50mg/Kg/hr, infusion),
It was administered 2 hours after ligation (25 mg/Kg, iv) and 3 hours after ligation (25 mg/Kg, iv). The administered drug was used as a physiological saline solution. In cases where it was poorly soluble, it was used as a sodium salt. The control group received only physiological saline. As a result, as shown in Table 1, the control group showed a necrosis rate of 14.9%, whereas the necrosis rate was 11.2-12.0% in the group administered with the drug of the present invention, and a remarkable necrosis suppressing effect was observed. Ta. Test Example 2 Acute Toxicity Test ddN male mice weighing 20 to 28 g were used. The drug was administered through the tail vein. As a result, as shown in Table 1, the drug of the present invention was 1
No change in symptoms was observed in the test animals even when administered up to g/Kg, confirming extremely high safety.

【table】

[Table] (c) Dosage The dosage of the compound of general formula () and its non-toxic salt in the present invention varies depending on the degree of symptoms of myocardial infarction, but is usually about 100 mg to 100 mg per day.
g can be administered to the patient. (d) Dosage Form When the compound represented by the general formula () 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 excipients such as lactose, sucrose, sodium chloride, glucose solution, starch, calcium carbonate, crystalline cellulose, and silicic acid, water, ethanol, propanol, glucose, starch solution, and gelatin. solutions, binders such as carboxymethylcellulose, methylcellulose, potassium phosphate,
Dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate,
Disintegrants such as stearic acid monoglyceride, starch, and lactose, and lubricants such as stearate, boric acid powder, and solid polyethylene glycol, which 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, examples of diluents include water, ethyl alcohol, propylene glycol, polyoxyethylene sorbitol, sorbitan ester, and the like. At this time, a sufficient amount of salt, glucose, or glycerin may be included to prepare an isotonic solution, and usual solubilizing agents, buffering agents, soothing agents, preservatives, etc. may be added as necessary. It may also be included. (Examples) Examples are described below to make the present invention easier to understand, but the following examples do not limit the present invention. Production example 1 tert-butoxycarbonyl-L-leucine 1
In a solution of hydrate (19.9 g) and N-hydroxysuccinimide (9.21 g) in ethyl acetate (320 ml),
A solution of N,N'-dicyclohexylcarbodiimide (16.51 g) in ethyl acetate (80 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. β- again under ice cooling
A solution of (3,4-dimethoxyphenyl)ethylamine (14.5 g) in ethyl acetate (100 ml) was added dropwise,
Stir overnight at room temperature. Separate the precipitate and drain the liquid.
Wash with 1N hydrochloric acid, sodium bicarbonate solution, and saturated saline in this order.
After drying with Glauber's salt, the solvent was distilled off under reduced pressure to obtain a crude reaction mixture as a brown solid. This product was purified by silica gel column chromatography (developing solvent: benzene: ethyl acetate = 2:1), and (s)-1-[2-
26.15 g of tert-butyl (3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamate as a light brown powder (yield 82.9%)
Obtained. NMR (CDCl ₃ ) δ; 0.87 (6H, m, (CH ₃ ) ₂ CH−) 1.38 (9H, s, ( CH ₃ ) ₃ C−) 1.51 (3H, m,

[Formula]) 2.67 (2H, m, -NHCH ₂ CH ₂ -) 3.38 (2H, m, -NHCH ₂ CH ₂ -) 3.76 (6H, s,

【formula】) 3.96 (1H, m,

【formula】) 4.84 (1H, m,

[Formula]) 6.18 (1H, m, -N H CO -) 6.57 (3H, m, aromatic proton) Hydrogen chloride gas was introduced into ethyl acetate (400 ml) under ice cooling to saturate it, and the above obtained (s )-1-[2-
Tert-butyl (3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamate (16.2 g) was added and stirred for 1 hour. The solvent and excess hydrogen chloride were distilled off under reduced pressure, water (100 ml) was added to the residue, the mixture was made basic with saturated sodium bicarbonate solution, and after addition of common salt, the mixture was extracted three times with 80 ml each of ethyl acetate.
After drying with Glauber's salt, the solvent was distilled off under reduced pressure to give (s)-2-amino-N-[2-(3,4-dimethoxyphenyl)
6.48 g (yield: 55%) of ethyl]-4-methylpentanamide was obtained as a pale yellow powder. NMR (CDCl ₃ ) δ; 0.92 (6H, m, (CH ₃ ) ₂ CH−) 1.34 (2H, m, −NH ₂ −) 1.62 (3H, m,

[Formula]) 2.70 (2H, m, -NHCH ₂ CH ₂ -) 3.37 (3H, m, -NHCH ₂ CH ₂ -,

【formula】) 3.80 (6H, s,

[Formula]) 6.61 (3H, m, aromatic proton) 7.20 (1H, br, -NH CO-) trans-epoxymonoethyl succinate (3.53
g) and N-hydroxysuccinimide (2.53
g) in ethyl acetate (90 ml) under water cooling, add N,
N'-dicyclohexylcarbodiimide (4.54g)
A solution of ethyl acetate (20 ml) was added dropwise to the
Stir for hours. (s)-2 obtained above under ice cooling again
-Amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-methylpentanamide (6.45
g) was added and stirred overnight at room temperature. After separating the precipitate, the liquid was washed with 1N hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude reaction mixture as a brown solid. This product was purified by silica gel column chromatography (developing solvent: ethyl acetate), trans-3-[(s)-1
-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]
8.26 g (yield: 86%) of ethyl oxirane-2-carboxylate was obtained as a white powder. IR (KBr) cm ^-1 , 1745, 1640, 895 NMR (CDCl ₃ ) δ: 0.90 (6H, m, ( CH ₃ ) ₂ CH−) 1.26 (3H, t, J=7Hz, −CO ₂ CH ₂ C H ₃ ) 1.55 (3H, m,

[Formula]) 2.68 (2H, m, -NHCH ₂ CH ₂ -) 3.40 (2H, m, -NHCH ₂ CH ₂ -) 3.44~3.60 (2H, m,

【formula】) 3.78 (6H, s,

[Formula]) 4.15 (2H, q, J=7Hz, -CO ₂ CH ₂ CH ₃ ) 4.20 (1H, m,

[Formula]) 6.06 (1H, m, -NH CO-) 6.50 (1H, m, -NH CO-) 6.60 (3H, m, aromatic proton) MS (m/e): 436 (M ⁺ ) , 320, 228, 164 (100
%), 151 trans-3-[(s)-1-[2-
(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]oxirane-2-carboxylate (8.24 g) in ethanol (200 ml) under ice-cooling, 0.5N potassium hydroxide-ethanol solution (37.8 ml) was added and stirred for 2 hours. After distilling off the ethanol under reduced pressure, water (100 ml) was added to dissolve it, washed with chloroform, acidified with 1N hydrochloric acid, and the precipitated white crystals were collected and dried to give trans-3-[(s )-1-
[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid as white crystals,
7.26g (yield 94%) was obtained. IR (KBr) cm ^-1 : 1730, 1640, 895 NMR (CDCl ₃ ) δ; 0.87 (6H, m, ( CH ₃ ) ₂ CH−) 1.50 (3H, m,

[Formula]) 2.65 (2H, m, -NHCH ₂ CH ₂ -) 3.39 (2H, m, -NHCH ₂ CH ₂ -) 3.48 ~ 3.60 (2H, m,

【formula】) 3.78 (6H, s,

【formula】) 4.41 (1H, m,

[Formula]) 6.57 (3H, m, aromatic proton) 6.97 (1H, m, -NH CO-) 7.45 (1H, m, -NH CO-) 9.50 (1H, br, -CO ₂ H ) MS (m/e): 408 (M ⁺ ), 200, 164 (100%),
151 Trans-3-[(s)-1-[2-] obtained above
To a solution of (3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid (5.94 g) in ethyl acetate (25 ml) was added water (30 ml), and sodium hydrogen carbonate (1.18 g) ) and stirred for 30 minutes. The aqueous layer was separated, washed with ethyl acetate, concentrated to dryness under reduced pressure, and trans-3-[(s)-1-[2-
5.92 g (yield 94%) of sodium (3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]oxirane-2-carboxylate was obtained as a pale yellow powder. IR (KBr) cm ^-1 ; 1640, 895 NMR (DMSO-d ⁶ ) δ; 0.95 (6H, m, (CH ₃ ) ₂ CH-) 1.40 (3H, m,

[Formula]) 2.40 to 2.80 (2H, m, -NHCH ₂ CH ₂ -) 2.90 to 3.40 (4H, m, -NHCH ₂ CH ₂ -,

[Formula]) 3.63 (3H, s, -OC H ₃ ) 3.67 (3H, s, -OC H ₃ ) 4.20 (1H, m,

[Formula]) 6.40-6.80 (3H, m, aromatic proton) 8.00-8.60 (2H, m, -N H CO - x 2) Production example 2 tert-butoxycarbonyl-L-leucine 1
Hydrate (5.00g) and p-anisidine (2.46g)
and (s)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamate tert-butyl was condensed in the same manner as to obtain (s)-1- (4-methoxyphenylcarbamoyl)-3-methylbutylcarbamic acid
6.60 g of tert-butyl as a yellowish brown powder (yield: 98
%) was obtained. IR (KBr) cm ^-1 , 1660, 820 NMR (CDCl ₃ ) δ: 0.96 (6H, m, ( CH ₃ ) ₂ CH−) 1.44 (9H, s, ( CH ₃ ) ₃ C−) 1.71 ( 3H, m,

[Formula]) 3.74 (3H, s, -OC H ₃ ) 4.36 (1H, m,

[Formula]) 5.48 (1H, m, -O ₂ CN H -) 6.76 (2H, d, J = 8Hz, aromatic proton) 7.40 (2H, d, J = 8Hz, aromatic proton) 8.82 (1H, br , -NH CO-) (s)-1-(4-methoxyphenylcarbamoyl)-3-methylbutylcarbamic acid obtained above
tert-butyl (6.50g) in methylene chloride (5ml)
Trifluoroacetic acid (15 ml) was added to the solution under water cooling, and the mixture was stirred for 30 minutes. After distilling trifluoroacetic acid off under reduced pressure, ethyl acetate (50 ml) was added to dissolve it, and sodium bicarbonate was added to neutralize it. The organic layer was washed with saturated brine, dried over sodium sulfate, and then dissolved under reduced pressure. The residue was distilled off to obtain 3.17 g (yield: 69%) of (s)-2-amino-N-(4-methoxyphenyl)-4-methylpentanamide as a yellowish brown powder. IR (KBr) cm ^-1 ; 3410, 3260, 1660, 820 NMR (CDCl ₃ ) δ: 0.96 (6H, m, ( CH ₃ ) ₂ CH-) 1.64 (2H, m, -NH ₂ ) 1.74 ( 3H, m,

【formula】) 3.51 (1H, m,

[Formula]) 3.82 (3H, s, -OC H ₃ ) 6.92 (2H, d, J = 8Hz, aromatic proton) 7.57 (2H, d, J = 8Hz, aromatic proton) 9.47 (1H, br, - N H CO-) Trans-epoxy monoethyl succinate (480
mg) and (s)-2-amino-N-(4
-methoxyphenyl)-4methylpentanamide (709 mg) and trans-3-[(s)-1-[2-
(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid ethyl was condensed in the same manner as to obtain trans-3-[(s)-1-(4 1.01 g (yield: 88%) of ethyl oxirane-2-carboxylate (-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane was obtained as a pale yellow powder. IR (KBr) cm ^-1 ; 1745, 1650, 820 NMR (CDCl ₃ ) δ: 0.94 (6H, m, ( CH ₃ ) ₂ CH−) 1.24 (3H, t, J=7Hz, −CO ₂ CH ₂ C H ₃ ) 1.68 (3H, m,

【formula】) 3.36, 3.46 (2H, m,

[Formula]) 3.62 (3H, s, -OC H ₃ ) 4.09 (2H, q, J=7Hz, -CO ₂ C H ₂ CH ₃ ) 4.56 (1H, m,

[Formula]) 6.54 (2H, d, aromatic proton) 6.84 (1H, m, -NH CO-) 7.12 (2H, m, aromatic proton) 8.49 (1H, m, -NH CO-) MS ( m/e); 378 (M ⁺ ), 322, 262, 228,
149, 134, 123 (100%), 108, 96 Ethyl trans-3-[(s)-1-(4-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylate obtained above A 0.5N sodium hydroxide-ethanol solution was added dropwise to a solution of (1.00 g) in ethanol (10 ml) under ice cooling, and the mixture was stirred for 2 hours. After distilling off the ethanol under reduced pressure, water (20 ml) was added to the residue to make a solution.
After washing with chloroform, acidifying with 1N hydrochloric acid, extracting three times with ethyl acetate, drying with sodium sulfate, and evaporating the solvent under reduced pressure to obtain trans-3-[(s)-1-(4-
896 mg (yield 97%) of methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid was obtained as a pale yellow powder. IR (KBr) cm ^-1 ; 1720, 1645, 818 NMR (CDCl ₃ ) δ: 0.92 (6H, m, ( CH ₃ ) ₂ CH−) 1.66 (3H, m,

【formula】) 3.48, 3.60 (2H, m,

[Formula]) 3.62 (3H, s, -OC H ₃ ) 4.66 (1H, m,

[Formula]) 6.58 (2H, d, aromatic proton) 7.16 (2H, m, aromatic proton) 7.40-7.90 (1H, br, -NH CO-) 8.16 (1H, br, -CO ₂ H ) 8.92 (1H, m, -N H CO -) Trans-3-[(s)-1-(4-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid (857 mg) obtained above Water (4.9 ml) in ethyl acetate (8 ml) solution of
and potassium bicarbonate (244 mg).
Stir for 30 minutes. The aqueous layer was separated, washed with ethyl acetate, concentrated to dryness under reduced pressure, and trans-3
-[(s)-1-(4-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]potassium oxirane-2-carboxylate as pale yellow powder
870 mg (yield 92%) was obtained. IR (KBr) cm ^-1 ; 1660, 1600, 895, 820 NMR (DMSO-d ⁶ ) δ; 0.90 (6H, m, ( CH ₃ ) ₂ CH-) 1.60 (3H, m,

【formula】) 3.12, 3.38 (2H, m,

[Formula]) 3.68 (3H, s, -OC H ₃ ) 4.40 (1H, m,

[Formula]) 6.80 (2H, m, aromatic proton) 7.54 (2H, m, aromatic proton) 8.88, 9.40 (1H, m, -NH CO-) 10.36 (1H, m, -NH CR-) Production example 3 tert-butoxycarbonyl-L-leucine 1
Hydrate (5.00 g) and 3,4-dimethoxyaniline (3.60 g) were combined into (s)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-
Condensation was carried out in the same manner as to obtain tert-butyl methylbutylcarbamate to obtain tert-butyl (s)-1-(3,4-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamate as a pale yellow powder6.23 g (yield 85%) was obtained. IR (KBr) cm ^-1 ; 1738, 1660, 1608, 842, 760 NMR (CDCl ₃ ) δ; 0.96 (6H, m, ( CH ₃ ) ₂ CH−) 1.48 (9H, s, (CH ₃ ) ₃ C-) 1.65 (3H, m,

[Formula]) 3.81 (3H, s, -OC H ₃ ) 3.83 (3H, s, -OC H ₃ ) 4.35 (1H, m,

[Formula]) 5.36 (1H, d, J = 8Hz,

[Formula]) 6.67-7.22 (3H, m, aromatic proton) 8.82 (1H, br, -NH CO-) (s)-1-(3,4-dimethoxyphenylcarbamoyl)-3 obtained above - From tert-butyl methylbutylcarbamate (2.75 g), (s)-2-
In the same manner as to obtain amino-N-(4-methoxyphenyl)-4-methylpentanamide, (s)-
2-amino-N-(3,4-dimethoxyphenyl)
-4-Methylpentanamide as yellowish brown powder
1.98g (yield 99%) was obtained. IR (KBr) cm ^-1 ; 1670, 830, 720 NMR (CDCl ₃ ) δ; 0.87 (6H, m, ( CH ₃ ) ₂ CH−) 1.68 (3H, m,

[Formula]) 3.74 (3H, s, -OC H ₃ ) 3.75 (3H, s, -OC H ₃ ) 3.98 (1H, m,

[Formula]) 6.04 (2H, m, -N H ₂ ) 6.60-7.10 (3H, m, aromatic proton) 9.59 (1H, br, -NH CO-) Trans-epoxymonoethyl succinate (480
mg) and (s)-2-amino-N- obtained above.
(3,4-dimethoxyphenyl)-4-methylpentanamide (799 mg) and trans-3-[(s)
-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-methylbutylcarbamoyl]oxirane-2-carboxylate ethyl was condensed in the same manner as to obtain trans-3-[(s )−
1-(3,4-dimethoxyphenylcarbamoyl)
-3-Methylbutylcarbamoyl]oxirane-
787mg of ethyl 2-carboxylate as pale yellow crystals
(yield 64%). IR (KBr) cm ^-1 ; 1735, 1660~1640, 1220,
890, 835, 760 NMR (CDCl ₃ ) δ; 0.94 (6H, m, ( CH ₃ ) ₂ CH−) 1.26 (3H, t, J=7Hz, −CO ₂ CH ₂ CH ₃ ) 1.66 (3H, m,

【formula】) 3.46, 3.46 (2H, m,

[Formula]) 3.65 (3H, s, -OC H ₃ ) 3.66 (3H, s, -OC H ₃ ) 4.18 (2H, q, J=7Hz, -CO ₂ C H ₂ CH ₃ ) 4.58 (1H, m ,

[Formula]) 6.60-7.15 (4H, m, aromatic proton, -NH
CO−) 8.44 (1H, br, -NH CO−) MS (m/e); 408 (M ⁺ ), 352, 292, 228,
179, 164, 153 (100%), 138 trans-3-[(s)-1-(3,4
-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylate (672 mg), trans-3-[(s)
-1-(4-methoxyphenylcarbamoyl)-3
-Methylbutylcarbamoyl]oxirane-2-
In the same manner as the carboxylic acid was obtained, trans-3
-[(s)-1-(3,4-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid as white crystals 545
mg (yield 87%) was obtained. IR (KBr) cm ^-1 ; 1730, 1660, 895, 850, 800,
763 NMR (CDCl ₃ ) δ; 0.94 (6H, m, ( CH ₃ ) ₂ CH−) 1.66 (3H, m,

【formula】) 3.40~3.70 (2H, m,

[Formula]) 3.68 (3H, s, -OC H ₃ ) 3.75 (3H, s, -OC H ₃ ) 4.67 (1H, m,

[Formula]) 6.60-7.02 (3H, m, aromatic proton) 7.30-7.90 (1H, br, -NH CO-) 7.47 (1H, br, -CO ₂ H ) 8.80 (1H, br, -NH CO−) MS (m/e); 380 (M ⁺ ), 362, 324, 200,
179, 164, 153 (100%) 138 Trans-3-[(s)-1-(3,4
-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylic acid (395 mg), trans-3-[(s)-1-
Trans-
3-[(s)-1-(3,4-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]
372 mg (yield: 86%) of potassium oxirane-2-carboxylate was obtained as a pale yellow powder. IR (KBr) cm ^-1 ; 1660-1600, 897, 840, 762 NMR (DMSO-d ⁶ ) δ; 0.92 (6H, m, (CH ₃ ) ₂ CH-) 1.58 (3H, m,

【formula】) 3.08, 334 (2H, m,

[Formula]) 3.70 (6H, m, -OC H ₃ ×2) 4.40 (1H, m,

[Formula]) 6.75-7.40 (3H, m, aromatic proton) 8.80-9.40 (1H, br, -NH CO-) 10.32 - (1H, br, -NH CO-) Formulation example 1 tablet 1 tablet (220 mg) Film-coated tablets containing the following ingredients: trans-3-[(s)-1-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-3-
Sodium methylbutylcarbamoyloxirane-2-carboxylate 50mg Lactose 100mg Crystalline cellulose 50mg Magnesium stearate 1mg Hydroxypropylmethylcellulose 15mg Hydroxypropylcellulose 4mg Other compounds used as active ingredients in the present invention can also be made into film-coated tablets using the same formulation. is possible. Formulation Example 2 Granules 1 g of granules contains the following ingredients. Sodium trans-3-[(s)-1-(4-methoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylate
200g Lactose 500mg Corn starch 500 Other compounds used as active ingredients in the present invention can also be made into granules using the same formulation. Formulation Example 3 Injection One ampoule contains the following ingredients. Sodium trans-3-[(s)-1-(3,4-dimethoxyphenylcarbamoyl)-3-methylbutylcarbamoyl]oxirane-2-carboxylate 100mg Potassium phosphate buffer (0.4M solution)
1ml Add sterile distilled water to the above ingredients to make 10ml. Other compounds used as active ingredients in the present invention can also be made into injections using the same formulation.

Claims (1)

[Claims] 1. General formula An acid amide derivative represented by However, in the formula, ^R1 means a hydrogen atom, an alkali metal atom, or a linear or branched alkyl group having 4 or less carbon atoms, n means an integer from 0 to 2, and m is 1. means an integer between 3 and 3. 2 General formula A prophylactic and therapeutic agent for myocardial infarction, which contains an acid amide derivative represented by the following as an active ingredient. However, in the formula, ^R1 means a hydrogen atom, an alkali metal atom, or a linear or branched alkyl group having 4 or less carbon atoms, n means an integer from 0 to 2, and m is 1. means an integer between 3 and 3.