JPS6141340B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula ()

The present invention relates to an aminophenylpropionic acid derivative represented by the formula: an acid addition salt thereof, and a method for producing the same. In the formula, R ₁ is hydrogen or a lower alkyl group,
R ₂ represents a lower alkyl group, a carboxyalkyl group, or a halogen-substituted phenyl group; a naphthyl group; or a halogen-substituted naphthyl group. An object of the present invention is to obtain a substance useful as a pharmaceutical. The compound () of the present invention is a nitrocinnamic acid ester derivative represented by the formula () produced by a conventional dehydration condensation reaction between the nitrocinnamic acid represented by the formula () and the phenol derivative or naphthol derivative represented by the formula (). It can then be produced by reducing this. Examples of the reduction means include catalytic reduction using catalysts commonly used for catalytic reduction such as palladium on carbon, platinum, and Raney nickel. This reaction formula is shown below. In the formula, R ₁ is hydrogen or a lower alkyl group, R ₂
is a lower alkyl group, a carboxyalkyl group, or a phenyl group substituted with a halogen; a naphthyl group; or a naphthyl group substituted with a halogen. can be synthesized under the conditions used in well-known reactions such as Perkin reaction and Claisen reaction. In carrying out the present invention, the compound () can be obtained by a conventional dehydration condensation reaction between the above-mentioned raw material () and the phenol derivative (). That is, the compound () can be obtained by a conventional and well-known dehydration condensation reaction such as the DCC (dicyclohexylcarbodiimide) method, the DPPA (diphenylphosphoryl azide) method, the mixed acid anhydride method, or the acid chloride method. . However, in these reactions, the acid chloride method is preferred from the viewpoints of operational difficulty, economic efficiency, product purity, and the like. The acid chloride method is a reaction that produces hydrogen halide as a by-product, and is best carried out in the presence of a dehydrohalogenating agent, such as an organic base such as triethylamine, tributylamine, or pyridine, or an inorganic base such as potassium carbonate or soda carbonate. It's advantageous. Usable solvents include benzene, ethyl acetate, ether, tetrahydrofuran, pyridine, etc., but ethyl acetate is preferred from the viewpoint of product purity. The reaction proceeds relatively easily over a wide temperature range. The reaction may be carried out at room temperature or with slight cooling, and the reaction is generally completed in 30 minutes to 1 hour at a temperature of 0 to 30°C. When producing aminophenyl propionate ester (), which is the target compound of the present invention, from compound (), compound () is dissolved or suspended in an organic solvent, and the compound () is dissolved or suspended in an organic solvent in the presence of a catalyst such as palladium on carbon, Raney nickel, or platinum oxide. Compound () can be easily synthesized by passing hydrogen gas. Examples of solvents that can be used include ethanol, methanol, dimethylformamide, tetrahydrofuran, and ether, with ethanol and methanol being preferred.
The reaction proceeds relatively easily over a wide temperature range. The reaction may be carried out at room temperature or with slight cooling; generally, the reaction is carried out at a temperature of 20 to 40°C for 1 to 2 hours.
Finish in time. When taking out compound () from the reaction solution, compound () can be obtained by a usual treatment method, that is, by removing the catalyst from the reaction solution and concentrating the mother liquor under reduced pressure. Furthermore, acid addition salts can be obtained if desired. The compounds of the present invention have enzyme inhibitory activity against proteolytic enzymes (trypsin, thrombin, C1 esterase, kallikrein, plasmin, etc.) and are therefore useful for treating diseases caused by these enzymes. Next, the present invention will be explained with reference to Examples. Example 1 19.3 g of p-nitrocinnamic acid was suspended in 300 ml of ethyl acetate, 22 g of phosphorus pentachloride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure to precipitate p-nitrocinnamic acid chloride.
Dissolve this in 300 ml of ethyl acetate and add 10.8 g of p-cresol. Gradually add 12 g of triethylamine while stirring at room temperature. After reacting for 1 hour at room temperature, the reaction solution was washed with 10% HCl, 10% NaOH and water, dried over anhydrous magnesium sulfate,
The solvent is distilled off to obtain p-nitrocinnamic acid p-methylphenyl ester. Yield 26.8g, yield 95%. Melting point 168-170℃. IR (cm
^-1 ) 1720, 1510, 1345. Obtained 26.8 g of para-nitrocinnamic acid p-methylphenyl ester and 2.0 g of 10% palladium on carbon.
When 200ml of ethanol is dissolved in 200ml of ethanol and hydrogen is passed under stirring, approximately 8.5g of hydrogen gas is produced in 2 hours.
Absorb. After the reaction is complete, the palladium is removed and the solvent is distilled off under reduced pressure. Pour the residue into 200ml of ethyl ether.
When hydrochloric acid gas is passed through the solution, p-aminophenylpropionic acid p-methylphenyl ester hydrochloride is precipitated as colorless crystals. Yield 24.2g, yield
87.7%, melting point 203-205℃ (decomposition) IR. (cm ^-1 )
3250-2500, 1745, 1506 MS.M ⁺ = m/e255 (MW-HCl) Elemental analysis C ₁₆ H ₁₈ NO ₂ Cl = 291.77, theoretical value C: 65.86%, H: 6.22%, N: 4.80% Actual measurement Values C: 65.96%, H: 6.33%, N: 4.76% This substance inhibits the action of thrombin to hydrolyze tosylarginine methyl ester in vitro. The concentration of this substance that inhibited this hydrolysis reaction by 50% was 8.8×10 ⁻⁴ M. Example 2 20.7 g of p-nitro-α-methylcinnamic acid was suspended in 300 ml of ethyl acetate, 22 g of phosphorus pentachloride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is complete,
When the solvent is distilled off under reduced pressure, p-nitro-α-methyl cinnamic acid loride is precipitated. Add this to ethyl acetate
Dissolve in 300ml and add 12.5g of p-chlorophenol. After reacting for 1 hour at room temperature, the reaction solution was reduced to 10%.
Washed with HCl, 10% NaOH, water, dried over anhydrous magnesium sulfate, evaporated the solvent, p-nitro-α
-Methylcinnamic acid p-chlorophenyl ester is obtained. Yield 29.8g, yield 93.9%. Melting point 111-112℃.
IR (cm ^-1 ) 1721, 1512, 1342. 29.8 g of the obtained p-nitro-α-methylcinnamic acid p-chlorophenyl ester and 3.0 g of 10% palladium on carbon were suspended in 250 ml of ethanol, and hydrogen gas was passed through the mixture while stirring, resulting in approximately 8.5 g of hydrogen gas in 2 hours. Absorb. After the reaction is complete, the palladium is removed and the solvent is distilled off under reduced pressure. The residue was dissolved in 200 ml of ethyl ether and hydrochloric acid gas was passed through the solution to precipitate p-amino-α-methyl-phenylpropionic acid p-chlorophenyl ester hydrochloride as colorless crystals. Yield 24.8g, yield 81.0%, melting point 216-218
℃. IR (cm ^-1 ) 3250-2500, 1741, 1510, 1198 MS.M ⁺ = m/e 289, 291 (MW-HCl). Elemental analysis C ₁₆ H ₁₇ NO ₂ Cl ₂ = 326.23 Theoretical value C: 58.90%, H: 5.25%, N: 4.29% Actual value C: 58.62%, H: 5.10%, N: 4.21% This substance is in Inhibits trypsin's hydrolysis of tosylarginine methyl ester in vitro. The concentration of this substance that inhibited this hydrolysis reaction by 50% was 3.3×10 ⁻⁴ M. Next, Table 1 shows other representative compounds of the aminophenylpropionic acid derivatives of the present invention and their physical constants.

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Claims (1)

[Claims] 1 Formula () (In the formula, R ₁ is hydrogen or a lower alkyl group, R ₂ is a lower alkyl group, a carboxyalkyl group, or a phenyl group substituted with a halogen; a naphthyl group;
or halogen-substituted naphthyl group)
Aminophenylpropionic acid derivatives and acid addition salts thereof. 2 formula () The formula () is obtained by a conventional dehydration condensation reaction between the nitrocinnamic acid derivative represented by the formula () and the phenol derivative or naphthol derivative represented by the formula () HO−R ₂ (). Formula () characterized in that a nitrocinnamic acid ester derivative represented by is produced, and then this compound is reduced and optionally converted into a salt. (In each of the above formulas, R ₁ represents hydrogen or a lower alkyl group, and R ₂ represents a lower alkyl group, a carboxyalkyl group, or a phenyl group substituted with a halogen; a naphthyl group; or a naphthyl group substituted with a halogen). A method for producing the aminophenylpropionic acid derivative and its acid addition salt. 3 formula () Formula () characterized in that the nitrocinnamic acid ester derivative represented by is reduced and optionally converted into a salt. (In each of the above formulas, R ₁ represents hydrogen or a lower alkyl group, and R ₂ represents a lower alkyl group, a carboxyalkyl group, or a phenyl group substituted with a halogen; a naphthyl group; or a naphthyl group substituted with a halogen). A method for producing the aminophenylpropionic acid derivative and its acid addition salt.