JPS6141508B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel aminophenylpropionic acid derivatives represented by formula () and acid addition salts thereof. and a novel guanidinophenylpropionic acid derivative represented by the formula () and an acid addition salt thereof. In the formula, R ₁ is hydrogen or a lower alkyl group, R ₂ is a lower alkoxy group,

[Formula], R ₃ and R ₄ represent hydrogen or a lower alkyl group, and n represents 0, 1, 2. An object of the present invention is to obtain a substance useful as a pharmaceutical. The compound () of the present invention is obtained by producing a nitrocinnamic acid ester derivative represented by the formula () by a conventional dehydration condensation reaction between a nitrocinnamic acid represented by the formula () and a phenol derivative represented by the formula (), and then , can 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 oxide, and Raney nickel. Moreover, the compound () of the present invention can be produced by reacting the above-mentioned invention substance (2) with cyanamide. This reaction formula is shown below. In the above formula, R ₁ is hydrogen, lower alkyl, R ₂ is lower alkoxy,

[Formula], R ₃ and R ₄ represent hydrogen or lower alkyl, and n represents 0, 1, 2. The raw material () used in the present invention can be synthesized by combining nitrobenzaldehyde and a lower fatty acid anhydride or a lower fatty acid ester under conditions used in a reaction well known as a Perkin reaction or a 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 (dicyclohexyl carbodiimide) method, the DPPA (diphenylphosphoryl azide) method, the mixed acid anhydride method, or the acid chloride method. can. However, in these reactions, the acid chloride method is preferred from the viewpoints of operational difficulty, economic efficiency, product purity, etc. The acid chloride method is a reaction that produces hydrogen halide as a by-product, and is advantageously carried out in the presence of a dehydrohalogenating agent, for example, an organic base such as triethylamine or tributylamine pyridine, or an inorganic base such as potassium carbonate or soda carbonate. It is. 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 aminophenylpropionate ester () from compound (), compound () is dissolved or suspended in an organic solvent and then palladium on carbon,
Compound () can be easily synthesized by passing hydrogen gas in the presence of a catalyst such as Raney nickel or platinum oxide. Examples of solvents that can be used include ethanol, methanol, dimethylformamide, tetrahydrofuran, and ether.
Ethanol and methanol are preferred. 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 1 to 2 hours at a temperature of 20 to 40°. When the compound () is taken out from the reaction solution, the 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. When producing guanidinophenylpropionate (), which is the target compound of the present invention, from aminophenylpropionate (), the compound () can be dissolved or suspended in an organic solvent, or it can be mixed with cyanamide without a solvent. Compound () can be obtained by reaction. Examples of solvents that can be used include ethanol, methanol, dimethylformamide, tetrahydrofuran, and ether, with ethanol-methanol being preferred. The reaction proceeds easily by heating from room temperature to the boiling point of the solvent. When removing the compound () from the reaction solution, the usual processing method,
That is, it can be easily obtained by concentrating the reaction solution under reduced pressure and recrystallizing the residue from an appropriate solvent. Moreover, its acid addition salt can be obtained if desired. The compound () of the present invention has low toxicity and has specific enzyme inhibitory activity against proteolytic enzymes (trypsin, thrombin, C/esterase, kallikrein, plasmin, etc.), and therefore can be used to treat diseases caused by these enzymes. It is useful for Furthermore, the compound () of the present invention not only has enzyme inhibitory activity by itself, but is also useful as a synthetic intermediate for (). Next, the present invention will be explained with reference to Examples. Example 1 Synthesis of p-aminocarbamoylmethoxycarbonylphenyl p-amino-α-ethylphenylpropionate Suspend 22.1 g of paranitro-α-ethylcinnamic acid in 300 ml of ethyl acetate, add 25 g of phosphorus pentachloride, and stir at room temperature for 1 hour. After the reaction is complete,
When the solvent is distilled off, paranitro-α-ethylcinnamic acid chloride is precipitated. Add this to chloroform
Dissolve in 300 ml, add 100 ml of a chloroform solution of 19.5 g of para-aminocarbamoylmethoxycarbonylphenol, and add 13 g of triethylamine while stirring. After reacting at room temperature for 3 hours,
The reaction solution is washed with 10% HCl, 5% NaOH, and water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain para-aminocarbamoylmethoxycarbonylphenyl para-nitrocinnamate. Yield 33.6
g. Yield 84.4%. Melting point 193-195℃. IR (cm ^-1 )
3480 ( _NH2 ), 1727, 1717, 1692 (CO). Obtained para-aminocarbamoylmethoxycarbonylphenyl paranitrosinnamate 31.8g
and 10% palladium carbon 3.0g in ethanol 300
ml and pass hydrogen gas under stirring to absorb approximately 7.2 mL of hydrogen gas in 2 hours. After the reaction is completed, the palladium on carbon is removed and the solvent is distilled off under reduced pressure to obtain para-aminocarbamoylmethoxycarbonylphenyl para-amino-α-ethylphenyl propionate. Dissolve this in 300 ml of ethyl ether and pass hydrochloric acid gas through it to obtain the hydrochloride. Yield: 25.1g. yield
77.2%. Melting point 184-185℃. IR (cm ^-1 ) 3450~
2500, 1725, 1675. This substance inhibits the action of thrombin to hydrolyze tosylarginine methyl ester in vitro. The concentration (ID ₅₀ ) that inhibited this hydrolysis reaction by 50% was 8.8×10 ⁻⁴ M. Example 2 Synthesis of para-aminocarbamoylmethoxycarbonylphenyl paraguanidino-α-ethylphenylpropionate 20.3 g of para-aminocarbamoylmethoxycarbonylphenyl paraguanidino-α-ethylphenylpropionate hydrochloride obtained in Example 1 and 4.2 g of cyanamide were added to 100 ml of ethanol and stirred at 50°C overnight. After the reaction is completed, the solvent is distilled off to obtain para-aminocarbamoylmethoxycarbonylphenyl paraguanidino-α-ethylphenylpropionate hydrochloride as an oil. When this is dissolved in 30 ml of ethanol and added to a saturated NaHCO ₃ aqueous solution, colorless crystals are precipitated. This is taken and washed with water and acetone to obtain carbonate. This was further suspended in 50 ml of ethanol, 7 g of methanesulfonic acid was added, heated to dissolve, and 300 ml of ethyl ether was added to precipitate colorless crystals. If you take this, you will get methanesulfonate. Yield 15.2
g. Yield 59.8%. Melting point 112-115℃. IR (cm ^-1 )
3375, 3175, 1740, 1720, 1670. This substance inhibits the hydrolysis of tosylarginine methyl ester by trypsin in vitro. The ID ₅₀ was 5.5×10 ⁻⁵ M; similarly, the ID ₅₀ for plasmin was 4.8×10 ⁻⁴ M. Example 3 The physical constants of an aminophenylpropionic acid derivative synthesized according to a method similar to Example 1 are shown below. Melting point 161-163℃. IR (cm ^-1 ) 3250-2500, 1743, 1664. Melting point 125-128℃. IR (cm ^-1 ) 3300-2500, 1750, 1628. Example 4 The physical constants and enzyme inhibitory activity (ID ₅₀ ) of a guanidinophenylpropionic acid derivative synthesized according to the method of Example 2 are shown below. Melting point 110-112℃. IR (cm ^-1 ) 3380, 3190, 1750, 1725. Trypsin 8.0×10 ^-4 M. Melting point 120-122℃ (carbonate 86-88℃). IR (cm ^-1 ) 3370, 3180, 1730. Trypsin: 9.15×10 ⁻⁵ Plasmin: 1×10 ⁻⁶ C/esterase: 2.4×10 ⁻⁴ .

Claims (1)

[Claims] 1 (In the formula, A is amino or guanidino, R ₁ is hydrogen or a lower alkyl group, R ₂ is a lower alkoxy group, [formula], R ₃ and R ₄ are hydrogen or a lower alkyl group, n is 0, 1 , 2) and their acid addition salts. 2. The compound of claim 1, wherein A is amino. 3. The compound of claim 1, wherein A is guanidino.