JPH0139421B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the following general formula () (In the formula, R ₁ and R ₂ together with a nitrogen atom form a 4-alkylpiperazinyl group, or R ₁ is a hydrogen atom and R ₂ is a phenyl group optionally substituted with an alkyl group. , a cycloalkyl group or a carboxyalkyl group), an acid addition salt thereof, and a method for producing the same.

The present inventors synthesized a large number of cyclohexanecarboxylic acid derivatives and investigated their pharmacological effects, and found that a novel cyclohexanecarboxylic acid amide derivative represented by the above general formula () and its acid addition salt exhibited excellent antiulcer activity. The present invention has been completed based on this discovery.

Therefore, an object of the present invention is to provide a novel compound represented by the above general formula () that is useful as a medicine.

Another object is to provide a method for producing a compound represented by the general formula ().

The novel cyclohexanecarboxylic acid amide derivative represented by the general formula () includes cis-trans isomers, but the trans isomer is particularly preferred. Examples of the 4-alkylpiperazinyl group formed by R ₁ and R ₂ in general formula () include 4-methylpiperazinyl group, 4-ethylpiperazinyl group, and 4-isopropylpiperazinyl group. can give. When R ₁ is a hydrogen atom, R ₂ is a phenyl group, a cyclopentyl group, a cyclohexyl group, etc., which may be substituted with an alkyl group such as a phenyl group, a methylphenyl group, an ethyl phenyl group, a propylphenyl group, a butylphenyl group, etc. Examples include carboxyalkyl groups such as a cycloalkyl group, a carboxymethyl group, and a carboxyethyl group.

In addition, acid addition salts of the compound of general formula () include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid,
Examples include acid addition salts with p-toluenesulfonic acid, fumaric acid, maleic acid, etc.

The compound of the present invention of the general formula () can be obtained by adding 4-guanidinomethylcyclohexanecarboxylic acid or a reactive derivative thereof to the following formula (). (In the formula, R ₁ ′ and R ₂ ′ together with the nitrogen atom form a 4-alkylpiperazinyl group, or R ₁ ′ is a hydrogen atom and R ₂ ′ is substituted with an alkyl group. phenyl group, cycloalkyl group or protected carboxyalkyl group)
It is produced by reacting amines represented by:

Reactive derivatives of 4-guanidinomethylcyclohexanecarboxylic acid include acid halides such as acid chloride and acid bromide, mixed acid anhydrides, p-
Examples include active esters such as nitrophenyl ester and 2,4-dinitrophenyl ester. Further, when 4-guanidinomethylcyclohexanecarboxylic acid is used as it is, it is preferable to coexist with a condensing agent such as diphenyl sulfite or methanesulfonyl chloride. The reaction is carried out in an organic solvent such as pyridine, dimethylformamide, or dimethylacetamide at a temperature between room temperature and 120°. When isolating the target product in the form of an acid addition salt, the target product can be directly isolated as an acid addition salt by reacting the raw material 4-guanidinomethylcyclohexanecarboxylic acid in the form of the desired acid addition salt. It is preferable to do so.

The novel cyclohexanecarboxylic acid amide derivatives of general formula () and acid addition salts thereof obtained as described above have excellent anti-ulcer effects. That is, when the anti-ulcer effect of the compound of the present invention was investigated using experimental ulcer models such as pylorus ligation ulcer, stress (water immersion restraint) ulcer, and indomethacin ulcer in rats, it was found that oral administration of 100 to 300 mg/Kg resulted in a
It showed 100% inhibition of ulcer formation. In addition, as a result of examining the effect on gastric juice secretion using pylorus-ligated rats, the compound of the present invention inhibited gastric juice secretion by about 50% when administered 100 to 300 mg/Kg of duodenal fat into the intestine.

EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 1-(trans-4-guanidinomethylcyclohexanecarbonyl)-4-methylpiperazine hydrochloride: 8.4 g of N-methylpiperazine was dissolved in 200 ml of anhydrous dimethylformamide, and the solution was stirred at 0°.
Trans-4-guanidinomethylcyclohexanecarboxylic acid p-nitrophenyl ester hydrochloride 20
The resulting yellow mixture was stirred at room temperature under a nitrogen stream for 16 hours. The solvent was distilled off under reduced pressure, and the residue was washed with anhydrous ether and then dissolved in a small amount of methanol. Add excess ethyl acetate, stir at room temperature, collect precipitated crystals, and obtain 16 g of 1-(trans-4-guanidinomethylcyclohexanecarbonyl)-4-methylpiperazine hydrochloride ( A yield of 90% was obtained.

IR ν ^KBr _nax cm ^-1 : 1650 NMR (CD ₃ OD) δ: 0.8-2.0 (10H, m, cyclohexane hydrogen) 2.37 (3H, S, N-C H ₃ ) 2.50, 3.70 (each 4H, s, piperazine Hydrogen) 3.13 (2H, d, J = 6.4Hz, NHC H ₂ ) Example 2 N-(trans-4-guanidinomethylcyclohexanecarbonyl)-β-alanine hydrochloride: β-alanine benzyl ester p-toluenesulfonate 26.5 g was dissolved in a saturated aqueous sodium bicarbonate solution at room temperature, and extracted with methylene chloride under salting out. After washing with a small amount of saturated sodium chloride aqueous solution,
Dry over anhydrous sodium sulfate, evaporate the solvent, and dry under reduced pressure to obtain β-alanine benzyl ester 13.5
g was obtained as a pale yellow oil.

This β-alanine benzyl ester 13.5g, trans-4-guanidinomethylcyclohexanecarboxylic acid p-nitrophenyl ester hydrochloride 24.5g
A mixture of g and 250 ml of anhydrous dimethylformamide was stirred at room temperature under a nitrogen stream for 18 hours. The yellow oil obtained after evaporation of the solvent was washed with ethyl acetate and ether to obtain N-(trans-4
-guanidinomethylcyclohexanecarbonyl)
-β-alanine benzyl ester hydrochloride was obtained.
This was dissolved in 200 ml of water, and after washing with ethyl acetate, the aqueous layer was separated. Add 300 ml of t-butyl alcohol and 6 g of 5% palladium carbon to this aqueous solution,
The mixture was stirred at room temperature for 18 hours under hydrogen gas. After removing the palladium on carbon using Celite, the solvent was distilled off under reduced pressure in a 30-35° water bath. Isopropyl alcohol was added to the resulting pale orange oil and stirred under ice cooling.
The precipitated crystals were collected and washed with cold isopropanol. Dissolve this in methanol, separate the insoluble matter, add ether and remove the precipitated crystals.
9.5 g of N-(trans-4-guanidinomethylcyclohexanecarbonyl)-β-alanine hydrochloride was obtained as a pale orange powder with a melting point of 213-215°C. Also,
The isopropanol layer was concentrated, the residue was dissolved in methanol, decolorized with activated carbon, concentrated, and ether was added to obtain 2.8 g of N-(trans-4-guanidinomethylcyclohexanecarbonyl)-β-alanine hydrochloride as above.

IR ν ^KBr _nax cm ^-1 : 1710 NMR (CD ₃ OD) δ: 0.80 to 2.20 (10H, m, cyclohexane hydrogen) 2.40 (2H, t, J = 7Hz, NHC H ₂ CH ₂ ) 2.94 (2H, d, J = 7 Hz, NHC H ₂ ) 3.30 (2H, t, J = 7 Hz, CH ₂ CO) Example 3 N-cyclohexyl-trans-4- guanidinomethylcyclohexanecarboxamide hydrochloride: 8.3 g of cyclohexylamine was added to 500 ml of anhydrous dimethylformamide. Dissolve in the trans-
30.0 g of 4-guanidinomethylcyclohexanecarboxylic acid p-nitrophenyl ester hydrochloride was added, and the mixture was stirred at room temperature under a nitrogen stream for 42 hours. The solvent was distilled off under reduced pressure, and the resulting yellow residue was diluted with ethyl acetate,
It was thoroughly washed with ether and then recrystallized from methanol-ether to obtain 15.2 g (yield 57%) of N-cyclohexyl-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride as colorless crystals with a melting point of 213-216°C. .

IR ν ^KBr _nax cm ^-1 : 1540, 1632 NMR (CD ₃ OD) δ: 0.76 to 2.38 (21H, m, cyclohexane hydrogen) 3.09 (2H, d, J = 7Hz, NHC H ₂ ) Example 4 N-phenyl -Trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride: 500 ml of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride and 197 mg of aniline are dissolved in a mixture of 5 ml of anhydrous dimethylformamide and 1 ml of anhydrous pyridine, and diphenyl sulfite is added to this.
Add 497mg and incubate for 28 hours at room temperature in a nitrogen stream for 40
The mixture was stirred at 70°C for 18 hours and then at 70°C for 5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with anhydrous ether and powdered with isopropanol-ether to obtain N-phenyl-trans-4-guanidinomethylcyclohexane as a colorless powder with a melting point of 307-308°C (decomposition point). Carboxamide hydrochloride 150mg
I got it.

IR ν ^KBr _nax cm ^-1 : 1660 NMR (CF ₃ COOH) δ: 1.0 to 3.2 (12H, m, aliphatic hydrogen) 7.52 (5H, s, aromatic hydrogen) Example 5 N-p-n-butylphenyl- Trans-4-
Guanidinomethylcyclohexanecarboxamide hydrochloride: Trans-4-guanidinomethylcyclohexanecarboxylic acid p-nitrophenyl ester hydrochloride and 42mg of p-n-butylaniline were dissolved in 1ml of anhydrous dimethylformamide, and the solution was heated to 18% at room temperature in a nitrogen stream. After stirring for an hour, add 0.2 ml of anhydrous pyridine.
Furthermore, add 100 mg of p-n-butylaniline,
The mixture was stirred for 4.25 days under the same conditions. The solvent was distilled off under reduced pressure, and the residue was washed with anhydrous ether and then dissolved in water. Furthermore, after washing the aqueous layer with ether, water was distilled off. Dissolve the residue in isopropanol and
Add ethyl acetate to this and let it stand, melting point 145-151
26.7 mg of N-p-n-butylphenyl-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride was obtained as a colorless powder at .degree.

IR ν ^KBr _nax cm ^-1 : 1660 NMR (CD ₃ OD) δ: 0.8 to 3.1 (21H, m, aliphatic hydrogen) 7.03, 7.37 (each 2H, d, J = 7.2Hz, aromatic hydrogen)

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₂ together with a nitrogen atom form a 4-alkylpiperazinyl group, or R ₁ is a hydrogen atom and R ₂ is a phenyl group optionally substituted with an alkyl group. A novel cyclohexanecarboxylic acid amide derivative and its acid addition salt represented by: 2 4-guanidinomethylcyclohexanecarboxylic acid or its reactive derivative has the following general formula: (In the formula, R ₁ ′ and R ₂ ′ together with the nitrogen atom form a 4-alkylpiperazinyl group, or R ₁ ′ is a hydrogen atom and R ₂ ′ is substituted with an alkyl group. (representing a phenyl group, a cycloalkyl group or a protected carboxyalkyl group) is reacted with the amines represented by the following, and if there is a protecting group, the protecting group is removed. (In the formula, R ₁ and R ₂ together with a nitrogen atom form a 4-alkylpiperazinyl group, or R ₁ is a hydrogen atom and R ₂ is a phenyl group optionally substituted with an alkyl group. , cycloalkyl group or carboxyalkyl group) or an acid addition salt thereof.