JPS6141510B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has a general formula useful as a medicine. (In the formula, Z represents a carbon-carbon covalent bond, a methylene group, an ethylene group, and a vinylene group, and R ¹ ,
R ² represents hydrogen or a lower alkyl group. ) The present invention relates to a guanidinobenzoic acid derivative or an acid addition salt thereof, and a method for producing the same. According to the present invention, the guanidinobenzoic acid derivative represented by the general formula [] has the general formula [] (In the formula, X represents a halogen atom.) Compounds represented by and general formula [] (In the formula, Z, R ¹ and R ² represent the same meanings as above.) A compound represented by the above is heated in an inert solvent in the presence of a dehydrohalogenating agent at -20°C to room temperature for 1 to 5 hours. It can be produced by reaction. Examples of the dehydrohalogenation agent that can be used in the above reaction include tertiary amines such as triethylamine, tri-n-butylamine, N,N-dimethylaniline, N-methylpiperidine, and pyridine. Examples of the solvent include benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, pyridine, etc., or a mixed solvent of two or more of these. Among them, pyridine is used both as a solvent and as a dehydrohalogenating agent. This is preferable in that it also acts as a catalyst. Since the reaction product is produced in the form of an acid addition salt, it may be isolated as it is, or it may be prepared by adding a solvent insoluble to the reaction solution, a residue obtained by distilling off the reaction solvent under reduced pressure, or a reaction product to the reaction solution. The precipitated crystals may be collected by adding an aqueous solution of sodium bicarbonate to the residue from which most of the solvent has been removed. The compound represented by the general formula [] can be easily converted into an acid addition salt of a pharmacologically acceptable acid, if necessary. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, acetic acid, lactic acid, succinic acid, tartaric acid, malic acid, citric acid, benzenesulfonic acid, toluenesulfonic acid, and methane. Examples include organic acids such as sulfonic acid. The compound represented by the general formula [] can be produced from p-guanidinobenzoic acid by a conventional method. For example, by heating with thionyl chloride, p
- Guanidinobenzoic acid chloride hydrochloride is obtained, which is used as it is in the next reaction. The compound represented by the general formula [] is the general formula [] (Z represents the above meaning.) Esters of compounds represented by, for example, methyl,
Ethyl, propyl, phenyl, p-nitrophenyl, cyanomethyl ester and a primary or secondary amine are combined with ether, tetrahydrofuran, methanol, benzene, toluene, or
It can be obtained by reacting at a temperature of room temperature to 150°C in a solvent such as acetonitrile or without a solvent. Examples of amines include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, dimethylamine, diethylamine,
Di-n-propylamine, di-n-butylamine, di-iso-propylamine, N-ethyl-n
- Examples include butylamine, ammonia, etc. The compound obtained according to the present invention has the effect of inhibiting trypsin and plasmin, and these inhibitory effects were strongly manifested at extremely low concentrations. Furthermore, the compounds of the present invention have excellent solubility in water and are suitable for administration as drugs in aqueous solutions, physiological saline, glucose solutions, and other solutions. The inhibitory effects of trypsin and plasmin in vitro were determined by the method of Muramatsu et al. [For trypsin, see The Journal of Biochemistry, 58 ;
214 (1965); about plasmin, see the same magazine, 57 ,
402 (1964)] and obtained the results shown in Table 1.

[Table] Compound No. 1: Compound No. 2: Compound No. 3: 1. The concentration of the compound represented by the general formula [ ] that inhibits the hydrolysis of p-tosylarginine methyl ester by 50% by 0.5 μg of trypsin in a reaction at 37°C for 30 minutes. 2 Human euglobulin (10 times diluted solution) 0.1ml,
Streptokinase (2000 units/ml) 0.1ml,
Fibrinogen (40% solution) 0.4ml, buffer
The concentration of the compound represented by the general formula [] that inhibits plasmin by 50% when reacted at 37°C for 30 minutes in a system consisting of 0.3 ml and 0.1 ml of a solution of the compound of the general formula []. As described above, the guanidinobenzoic acid derivative represented by the general formula [ ] or its acid addition salt has the effect of strongly inhibiting the proteolytic enzymes trypsin and plasmin, and is used as a drug for the treatment of acute pancreatitis, etc., or as an anti-plasmin agent. It is useful as a drug for treating bleeding disorders and the like. The guanizidinobenzoic acid derivatives represented by the general formula [ ] included in the present invention include p-(p-guanidinobenzoyloxy)benzamide, p-(p-guanidinobenzoyloxy)-N
-Methylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Ethylbenzamide, p-(p-guanidinobenzoyloxy)-N
-n-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-iso-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-n-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-sec-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-tert-butylbenzamide, p-(p-guanidinobenzoyloxy)-
N,N-dimethylbenzamide, p-(p-guanidinobenzoyloxy)-
N,N-diethylbenzamide, p-(p-guanidinobenzoyloxy)-
N,N-di-n-propylbenzamide, p-(p-guanidinobenzoyloxy)-
N,N-di-iso-propylbenzamide, p-(p-guanidinobenzoyloxy)-
N,N-di-n-butylbenzamide, p-(p-guanidinobenzoyloxy)-
N,N-di-iso-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-ethylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-n-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-iso-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-n-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-sec-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Ethyl-N-n-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-ethyl-N-iso-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-Ethyl-N-n-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-ethyl-sec-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-n-pyropyl-N-iso-propylbenzamide, p-(p-guanidinobenzoyloxy)-N
-n-propyl-N-n-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-n-propyl-N-sec-butylbenzamide, p-(p-guanidinobenzoyloxy)-N
-n-butyl-N-sec-butylbenzamide, p-(p-guanidinobenzoyloxy)phenylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-methylacetamide, p-(p-guanidinobenzoyloxy) ) Phenyl-N-ethylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-n-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-iso-propylamitamide, p-(p- guanidinobenzoyloxy)phenyl-Nn-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-sec-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-tert-butylamitamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-dimethylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-diethylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N,N -di-n-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-di-iso-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-di-n-butyl Acetamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-di-iso-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-methyl-N-ethylacetamide, p-(p-guanidino benzoyloxy)phenyl-N-methyl-N-n-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-methyl-N-iso-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N -Methyl-Nn-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-methyl-N-sec-butylamitamide, p-(p-guanidinobenzoyloxy)phenyl-N-ethyl-N- n-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-ethyl-N-iso-propylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-ethyl-Nn-butylacetamide, p -(p-guanidinobenzoyloxy)phenyl-N-ethyl-N-sec-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-n-propyl-N-iso-propyl-
Acetamide, p-(p-guanidinobenzoyloxy)phenyl-N-n-propyl-N-n-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-n-propyl-N-sec-butylacetamide, p-(p-guanidinobenzoyloxy)phenyl-N-n-butyl-N-sec-butylacetamide, p-(p-guanidinobenzoyloxy)cinnamamide, p-(p-guanidinobenzoyloxy)-N
-Methylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-Ethylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-n-propylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-iso-propylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-n-butylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-sec-butylcinnamamide, p-(p-guanidinobenzoyloxy)-
N,N-dimethylcinnamamide, p-(p-guanidinobenzoyloxy)-
N,N-diethylcinnamamide, p-(p-guanidinobenzoyloxy)-
N,N-di-n-propylcinnamamide, p-(p-guanidinobenzoyloxy)-
N,N-di-iso-propylcinnamamide, p-(p-guanidinobenzoyloxy)-
N,N-di-n-butylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-ethylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-Nn-propylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-Methyl-N-n-butylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-Ethyl-N-n-propylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-N-n-butylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-ethyl-N-sec-butylcinnamamide, p-(p-guanidinobenzoyloxy)-N
-n-propyl-N-n-butylcinnamamide, p-(p-guanidinobenzoyloxy)phenylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N-methylpropionamide, p-(p- guanidinobenzoyloxy)phenyl-N-ethylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N-n-propylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N-iso-propylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-Nn-butylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N-sec-butylpropionamide, p-(p-guanidicibenzoyloxy)phenyl -N,N-dimethylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-diethylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-di-n-propylpropionamide , p-(p-guanidinobenzoyloxy)phenyl-N,N-di-iso-propylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N,N-di-n-butylpropionamide, p-( p-guanidinobenzoyloxy) phenyl-N-methyl-N-ethylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N-methyl-N-n-propylpropionamide, p-(p-guanidinobenzoyloxy) Phenyl-N-methyl-Nn-butylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N-ethyl-Nn-propylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-N- Examples include ethyl-Nn-butylpropionamide, p-(p-guanidinobenzoyloxy)phenyl-Nn-propyl-Nn-butylpropionamide, and the like. Next, the present invention will be explained with reference to Examples. Example 1 Production of p-(p-guanidinobenzoyloxy)phenyl-N,N-dimethylacetamide methanesulfonate 50 ml of thionyl chloride was added to 5.37 g of p-guanidinobenzoic acid, and the mixture was heated at a bath temperature of 70 to 75°C for 30 minutes. The mixture was heated and stirred for a minute, and petroleum ether was added thereto to collect crystals of p-guanidinobenzoic acid chloride hydrochloride, which were further washed with petroleum ether. 5.37 g of N,N-dimethyl-p-hydroxyphenylacetamide was dissolved in 20 ml of pyridine, and the previously obtained crystals of p-guanidinobenzoic acid chloride were added at 0°C, followed by stirring for 2 hours. 100 ml of ether was added to the reaction solution, the supernatant liquid was decanted, and saturated aqueous sodium bicarbonate solution was added to the residue. The precipitated crystals were collected, washed with water and acetone, and then dried. The obtained crystals were suspended in methanol, methanesulfonic acid was added (PH3) to dissolve and filter, and ether was added to the liquid. The precipitated crystals were collected and recrystallized from methanol to give the title compound.
7.71g was obtained. Melting _point : 204-207°C Elemental analysis _value : C _H N S Calculated value (%) 49.53 4.62 _{12.84 7.35} Actual value ₍ %) 49.71 4.43 12.98 7.13. Example 2 Production of p-(p-guanidinobenzoyloxy)phenyl-N-methylacetamide methanesulfonate p-guanidinobenzoic acid chloride hydrochloride was produced from 7.16 g of p-guanidinobenzoic acid in the same manner as in Example 1. did. Dissolve 6.93 g of N-methyl-p-hydroxyphenylacetamide in 26 ml of pyridine to dissolve the previously obtained p
-Crystals of guanidinobenzoic acid chloride were added at 5°C, and the mixture was stirred for 2 hours. After this, post-treatment and recrystallization were performed as in Example 1. Title compound
8.92g was obtained. Melting point: 166-168℃. Elemental analysis value: C _{H N} S Calculated value (%) 48.33 4.29 _{13.27 7.59} Actual value ( _% ) 48.57 4.42 13.03 _7.45 . Example 3 p-(p-guanidinobenzoyloxy)-
Production of N,N-dimethyl-benzamide methanesulfonate p-guanidinobenzoic acid in the same manner as in Example 1
Prepare p-guanidinobenzoic acid chloride hydrochloride from 4.48g, and add this salt to 17ml of pyridine with N,N-
The solution containing 4.95 g of dimethyl-p-hydroxybenzamide was added at 0°C, and then stirred at 5 to 10°C for 2 hours. Work-up was carried out as in Example 1 and recrystallization from dimethylformamide gave 5.31 g of the title compound. Melting point: 180-181℃. Elemental analysis value: C _{H N} S Calculated value (%) 48.33 4.29 _{13.27 7.59} Actual value ( _% ) 48.65 4.03 13.44 _7.73 .

Claims (1)

[Claims] 1. General formula [] (In the formula, Z represents a carbon-carbon covalent bond, a methylene group, an ethylene group, or a vinylene group, and R ¹ and R ² represent hydrogen or a lower alkyl group.) A guanidinobenzoic acid derivative or an acid addition salt thereof represented by . 2. The compound according to claim 1, which is p-(p-guanidinobenzoyloxy)phenyl-N,N-dimethylacetamide. 3. The compound according to claim 1, which is p-(p-guanidinobenzoyloxy)phenyl-N-methylacetamide. 4 p-(p-guanidinobenzoyloxy)-
The compound according to claim 1, which is N,N-dimethylbenzamide. 5 General formula [] (In the formula, X represents a halogen atom.) Acid addition salt of the compound represented by the general formula [] (In the formula, Z, R ¹ and R ² are
It has the same meaning as in the paragraph. ) A general formula characterized by reacting a compound represented by [] (In the formula, Z, R ¹ and R ² have the same meanings as above.) A method for producing a guanidinobenzoic acid derivative or an acid addition salt thereof.