JPS6237622B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel amidinophenyl ester derivatives, more specifically, the following general formula () (wherein R is 2-furyl, 2- or 3-thienyl, 2-(2-thienyl)vinyl, 3-pyridyl, 6-methyl-3-pyridyl, 5-methyl-
2-pyridyl, 3-indolylmethyl, 3-(5
-methoxy-2-methylindolyl)methyl, 1
The invention relates to an amidinophenyl ester derivative represented by -(2-methyl-1,2,3,4-tetrahydroisoquinolyl)methyl or 2-tenyl group) and its acid addition salt. The present inventor synthesized various amidinophenyl ester derivatives and searched for their pharmacological actions, and found that the amidinophenyl ester derivatives represented by the above general formula ( The present invention was completed based on the discovery that it has an inhibitory effect on thrombin and the like. Therefore, the present invention provides a novel amidinophenyl ester derivative represented by the formula (). The compound () of the present invention is produced by reacting a heterocyclic carboxylic acid () with an amidinophenol (), for example, according to the following reaction. (In the formula, R and A are the same as above.) Examples of the heterocyclic carboxylic acid represented by the general formula () include furancarboxylic acid, thiophenecarboxylic acid, pyrrolecarboxylic acid, pyridinecarboxylic acid, indoleacetic acid, Isoquinoline acetic acid, thiophene acetic acid, thiophene acrylic acid, etc. are used. In addition, the reaction between this heterocyclic carboxylic acid (2) and amidinophenol (2) can be carried out using a normal esterification reaction, for example, by directly reacting the heterocyclic carboxylic acid or its reactive derivative or in the presence of a condensing agent with amidinophenol or its reactive derivative. It is carried out by reacting with a derivative. The compound () obtained in this way can be further treated with inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid; or acetic acid, propionic acid, maleic acid, fumaric acid, It can lead to organic acid salts such as tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. The results of testing the enzyme inhibitory effect of the thus obtained compound of the present invention () are as follows. (1) Chymotrypsin inhibitory effect According to the method of Muramatsu et al. [see The Journal of Biochemistry 62 , 408 (1967)],
Dimethyl sulfoxide solution of test compound 0.1
ml, water 0.1 ml and chymotrypsin 10 μg/ml buffer solution (0.1 M Tris-HCl buffer; PH
8.0) Incubate the mixed solution of 0.1 ml for 10 minutes, mix it with 0.2 ml of acetyl-L-tyrosine ethyl ester 25mM buffer solution,
The reaction was carried out at 37°C for 30 minutes, and the amount of remaining substrate was determined by developing color using the hesterin method and measuring the absorbance at 530 nm. Note that tosylphenylalanine chloromethyl ketone (TPCK), which is known as a chymotrypsin inhibitor, was used as a comparison compound. The results are shown in Table 1. (2) Trypsin inhibitory effect According to the method of Muramatsu et al. [see The Journal of Biochemistry 58 , 214 (1967)],
Dimethyl sulfoxide solution of test compound 0.1
ml, buffer solution (0.1M Tris-HCl buffer: PH8.0
solution of 10mM calcium chloride in) 0.1
ml and trypsin 2.5 μg/ml buffer solution
Incubate the mixed solution of 0.1 ml for 10 minutes, and add tosyl arginine methyl ester to this solution.
Mix 0.2 ml of 25 mM buffer solution and incubate at 37 °C for 30
After reacting for a minute, the amount of remaining substrate was determined by color development using the hesterin method and absorbance at 530 nm was measured. The results are shown in Table 1. ( 3 ) Method for measuring thrombin inhibitory effect Test compound in dimethyl sulfoxide solution using the method of Tamura et al.
0.1ml, buffer (0.1M sodium phosphate buffer: PH7.4) 0.1ml and thrombin 37.5unit/
ml of buffer solution was incubated for 10 minutes, mixed with 0.2 ml of tosylarginine methyl ester 25mM buffer solution, reacted for 30 minutes at 37°C, and the amount of remaining substrate was determined using the hesterin method. The color was developed and the absorbance at 530 nm was measured. The results are shown in Table 1.

【table】

[Table] As is clear from the results shown in Table 1, the compound () of the present invention has an excellent protease inhibitory effect and is useful as a chymotrypsin, trypsin and thrombin inhibitor. Examples will be further described below. Example 1 4'-amidinophenyl furan-2-carboxylate: 2.61 g of furan-2-carbonyl chloride was added dropwise to a 20 ml solution of pyridine containing 1.73 g of p-amidinophenol monohydrochloride under ice cooling, and the mixture was reacted at room temperature for 4 hours. I let it happen. After the reaction was completed, the resulting insoluble matter was removed, and ether was added to the mother liquor, resulting in crystallization. Recrystallization once each from water and methanol-ether gave 1.45 g (yield 54.3%) of 4'-amidinophenylfuran-2-carboxylate monohydrochloride as colorless crystals. Melting point: 216-9℃ Elemental analysis value: C _H N Cl _Calculated value (%) 54.05 4.16 10.50 _13.29 Experimental value (%) 54.06 4.23 10.63 13.23 Example 2 4' _- amidinophenyl Thiophene-2-carboxylate: If 1.73 g of p-amidinophenol monohydrochloride and 2.93 g of thiophene-2-carbonyl chloride are used and treated in the same manner as in Example 1, 4'-amidinophenol thiophene-2 is obtained as colorless crystals. -Carboxylate monohydrochloride 1.50 g (yield 53%) was obtained. Melting point: 215-8℃ Elemental analysis value: C ₁₂ H ₁₀ N ₂ O ₂ As S・HCl C H N Cl Calculated value (%) 50.98 3.92 9.91 12.54 Experimental value (%) 51.07 3.92 10.12 12.40 Example 3 4'- Amidinophenyl thiophene-3-carboxylate: 0.86 g of p-amidinophenol and thiophene-3-carboxylate
When 1.47 g of 3-carbonyl chloride was used and treated in the same manner as in Example 1, 0.47 g (yield: 33.3%) of 4'-amidinophenyl thiophene-3-carboxylate monohydrochloride was obtained as colorless crystals. Melting point: 227.5-9.5℃ Elemental analysis value: C ₁₂ H ₁₀ N ₂ O ₂ S・HCl Calculated value (%) 50.98 3.92 9.91 12.54 Experimental value (%) 51.03 4.14 9.76 12.62 Example 4 4'- Amidinophenyl thiophene-2-acrylate: 1.73 g of p-amidinophenol and thiophene-2-acrylate
If 3.45 g of 2-acroyl chloride is used and treated in the same manner as in Example 1, 1.30 g of 4'-amidinophenyl thiophene-2-acrylate will be obtained as colorless crystals.
g (yield 42.0%). Melting point: 221.5-2.5℃ Elemental analysis value: C ₁₄ H ₁₂ N ₂ O ₂ S・HCl Calculated value (%) 54.46 4.24 9.07 11.48 Experimental value (%) 54.53 4.27 9.24 11.32 Example 5 4'- Amidinophenylpyridine-3-carboxylate: Nicotinic acid chloride monohydrochloride in 25ml pyridine solution of 3.6g p-amidinophenol monohydrochloride.
7.5 g was quickly added under ice-cooling, and the mixture was stirred at room temperature overnight. The precipitate was collected, washed with chloroform, and recrystallized from water to obtain 2.6 g (yield: 39.6%) of 4'-amidinophenylpyridine-3-carboxylate dihydrochloride as colorless crystals. Melting point: 240-4℃ (decomposition) Elemental analysis value: C ₁₃ H ₁₁ N _{3 O} 2.2HCl Calculated value (%) 49.70 4.17 13.37 22.57 Experimental value (%) 49.78 4.18 13.19 22.71 Example 6 4 '-amidinophenyl 6-methylpyridine-
3-Carboxylate: To a solution of 1.4 g of 6-methylpyridine-3-carboxylic acid and 0.9 g of 4-amidinophenol monohydrochloride in 12 ml of pyridine, 2.1 g of dicyclohexylcarbodiimide was added with stirring under ice cooling. Stir overnight at room temperature, collect the precipitate, extract with methanol, concentrate, and recrystallize from water to obtain 0.7 g of colorless crystals of 4'-amidinophenyl 6-methylpyridine-3-carboxylate monohydrochloride (yield 45.8). %)was gotten. Melting point: 218-20℃ Elemental analysis value: C ₁₄ H ₁₃ N ₃ O ₂・HCl Calculated value (%) 57.64 4.84 14.40 12.15 Experimental value (%) 57.59 4.82 14.29 12.31 Example 7 4′-amidinophenyl 5-methylpyridine-
2-Carboxylate: To a pyridine solution of 1.4 g of 5-methylpyridine-2-carboxylic acid and 0.9 g of 4-amidinophenol monohydrochloride was added 2.1 g of dicyclohexylcarbodiimide under ice cooling and stirring. Stir overnight at room temperature, collect the precipitate, extract with methanol, add hydrochloric acid-methanol under ice cooling, concentrate, and recrystallize from ethanol-ethyl acetate to obtain colorless crystals.
4'-amidinophenyl 5-methylpyridine-2
-Carboxylate dihydrochloride 1.0g (yield 46.4
%)was gotten. Melting point: 198-9℃ (decomposition) Elemental analysis value: C ₁₄ H ₁₃ N ₃ O ₂・2HCl C H N Cl Calculated value (%) 51.24 4.61 12.80 21.60 Experimental value (%) 51.13 4.62 12.69 21.81 Example 8 4' -Amidinophenyl indole-3-acetate: 2.32 g of p-amidinophenol monomethanesulfonate, 3.84 g of β-indoleacetic acid and 150 mg of 4-pyrrolidinopyridine in dimethylformamide.
4.54 g of dicyclohexylcarbodiimide was added to the 20 ml solution under ice cooling and stirring. After one hour, the mixture was returned to room temperature and stirred overnight. Insoluble matters were removed and ether was added to the mother liquor to obtain a powder. When recrystallized from methanol-ether, the melting point is 223-226℃.
As crystals of 4'-amidinophenyl indole-3-acetate monomethanesulfonate 1.20
g (yield 30.8%) was obtained. Elemental analysis value: _C H N _Calculated value (%) 55.52 4.92 _10.79 Experimental _value (%) 55.51 4.98 10.80 Example 9 4' _- amidinophenyl 5 _- methoxy-2 -Methylindole-3-acetate: 3.35 g of 5-methoxy-2-methylindole-3-acetic acid and p-amidinophenol hydrochloride
3.72 g of dicyclohexylcarbodiimide was added to a 20 ml solution of 1.72 g of pyridine, and the mixture was stirred at room temperature overnight. Insoluble materials were removed and ether was added to the mother liquor to precipitate an oil. When this was purified by silica gel column chromatography (elution solvent: chloroform-methanol-acetic acid; 85:20:5), crystals were obtained. When this was recrystallized from methanol-ether, 4'-amidinophenyl 5-methoxy-2-
Methylindole-3-acetate hydrochloride 1.35
g (yield 36.2%) was obtained. Elemental analysis value: C _H N _Calculated value (%) 61.04 _5.39 11.24 Experimental value (%) 61.00 5.36 11.19 Example 10 4'-amidinophenyl 2 _- methyl-1,2,
3,4-Tetrahydroisoquinoline-1-acetate: 2.32 g of p-amidinophenol monomethanesulfonate and 2.46 g of 2-methyl-1,2,3,4-tetrahydroisoquinoline-1-acetic acid hydrochloride.
2.48 g of dicyclohexylcarbodiimide was added to a 30 ml solution of pyridine, and the mixture was stirred at room temperature overnight. After removing insoluble materials, ethyl acetate was added to obtain a powder. After adding water to this and removing insoluble matter,
Concentrate under reduced pressure, dry over phosphorus pentoxide, and add ethyl acetate to obtain 4′-
Amidinophenyl 2-methyl-1,2,3,4
-Tetrahydroisoquinoline-1-acetate・
Monomethanesulfonic acid monohydrochloride 1.60g (yield 35.1
%)was gotten. Elemental analysis value: C ₁₉ H ₂₁ N ₃ O ₂・CH ₃ SO ₃ H・HCl C H N Calculated value (%) 52.68 5.75 9.22 Experimental value (%) 52.39 5.49 9.15

Claims (1)

[Claims] 1. General formula (wherein R is 2-furyl, 2- or 3-thienyl, 2-(2-thienyl)vinyl, 3-pyridyl, 6-methyl-3-pyridyl, 5-methyl-
2-pyridyl, 3-indolylmethyl, 3-(5
-methoxy-2-methylindolyl)methyl, 1
An amidinophenyl ester derivative represented by -(2-methyl-1,2,3,4-tetrahydroisoquinolyl)methyl or 2-tenyl group) and its acid addition salt.