JPS642086B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula () (wherein R represents a hydrogen atom, a hydroxycarbonylethyl group, a lower alkoxycarbonylethyl group, or a benzyloxycarbonylethyl group) The present invention relates to a novel therapeutic agent for peptic ulcers containing a cyclohexanecarboxylic acid derivative or a salt thereof represented by the following formula. Peptic ulcer is a general term that includes gastric ulcer and duodenal ulcer. Although its etiology is still not completely understood, it is thought to occur when the balance between aggressive and defensive factors is disrupted, and the aggressive factors become stronger than the defensive factors. Attack factors include gastric juice, that is, acid and pepsin, and defense factors include mucosal resistance and mucus defense power. In other words, peptic ulcers are thought to occur when the mucous membrane resistance and mucus defense power can no longer withstand attacks on the stomach and duodenum by gastric acid, pepsin, and the like. Furthermore, the number of patients tends to increase due to repeated recurrences. The present inventors conducted various studies in order to find an excellent drug that is effective not only in the acute phase of peptic ulcer disease but also in the chronic phase. The present invention was completed based on the discovery that the present invention is useful as a therapeutic agent for ulcers. Therefore, the present invention aims to provide a therapeutic agent for peptic ulcer. The compound of general formula () or a salt thereof, which is the active ingredient of the present invention, is produced as follows. (In the formula, R' represents a hydrogen atom, a lower alkoxycarbonylethyl group, or a benzyloxycarbonylethyl group, and R is the same as above.) That is, 4-guanidinomethylcyclohexanecarboxylic acid of the formula () or its reactive derivative and the formula A cyclohexanecarboxylic acid derivative of general formula () or a salt thereof is produced by reacting the compound represented by () and optionally hydrolyzing the product. Here, the reactive derivatives of 4-guanidinomethylcyclohexanecarboxylic acid of formula () include acid halides such as acid chlorides and acid bromides, acid anhydrides, and various active esters. Solvents used in the reaction include dimethylformamide, dimethylacetamide, pyridine,
Examples include acetonitrile and dichloroethane. When the 4-guanidinomethylcyclohexanecarboxylic acid of formula () is subjected to the reaction in a state in which the carboxyl group is free, it is preferable to use dicyclohexylcarbodiimide, N-alkyl-2-halopyridinium salt, etc. as the condensing agent. Among the substituents in the active ingredient of the present invention represented by the general formula (), when R has a free carboxyl group, after the completion of the esterification reaction, the carboxyl group is protected by a protecting group such as a benzyl group. It can be obtained by removing it by a method such as hydrolysis. The compound of the general formula () obtained as described above may be prepared using an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc. or an inorganic acid such as acetic acid, lactic acid, maleic acid, fumaric acid, citric acid, methanesulfonic acid, etc., if desired. Acid addition salts with organic acids can be formed, and these acid addition salts are also included as active ingredients in the present invention. Further, the compound of general formula () has cis-trans isomers, but the trans isomer is particularly preferred. The active ingredient of the present invention represented by the above general formula () exhibits excellent preventive and therapeutic effects on various experimental ulcer models. That is, the active ingredient of the present invention has extremely excellent preventive and therapeutic effects on acute ulcer models such as pylorus ligation ulcer, stress ulcer, aspirin ulcer, indomethacin ulcer, and phenylbutazone ulcer, and on chronic ulcer models such as acetic acid ulcer. are doing. In experiments using pylorus-ligated rats, the active ingredient of the present invention was administered at a concentration of 200 to 400 mg/day.
Intraperitoneal administration of Kg showed significant inhibition. In addition, in experiments using an acetic acid ulcer model, 100 to 500 mg/Kg
showed a significant therapeutic effect when administered orally. Furthermore, the active ingredient of the present invention is an excellent drug with high safety. That is, in acute toxicity tests in rats, the LD ₅₀ of the compound of general formula ()
The value was 5-8 g/Kg by oral administration. Although the therapeutic agent for peptic ulcers of the present invention exhibits its effects when administered either orally or parenterally, oral administration is preferred because of ease of administration. Dosage forms for oral administration include tablets, capsules, powders, granules, syrups, etc. When making these forms, excipients such as lactose, cornstarch, crystalline cellulose, magnesium stearate, etc. There is no problem in adding a lubricant, a binder such as hydroxypropylcellulose, and other coloring agents, flavors, sweeteners, etc. The dosage can be increased or decreased depending on age, symptoms, etc., but is preferably about 55 to 1500 mg/day for adults. EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Example 1 Trans-4-guanidinomethylcyclohexanecarboxylic acid phenyl ester hydrochloride: 11.8 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 5.6 g of phenol and 12.4 g of dicyclohexylcarbodiimide were dissolved in 75 ml of pyridine and 75 ml of dimethylformamide. The reaction was allowed to proceed overnight at room temperature. The solvent was distilled off under reduced pressure, 200 ml of 0.1N hydrochloric acid was added to the residue to separate insoluble matter, and the aqueous layer was washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure to a total volume of 100 ml, cooled, and the precipitated crystals were collected and washed with isopropyl alcohol-isopropyl ether to obtain trans-4-guanidinomethylcyclohexanecarboxylic acid with a melting point of 150-153°C. Phenyl ester hydrochloride
12.5g (yield 80.2%) was obtained. IR (nujiol) νmax cm ^-1 : 1755 (C=0), 1620~
1680 (C=N) Elemental analysis C ₁₅ H ₂₁ N ₃ O ₂ Calculated value as HCl (%) C: 57.78, H: 7.11, N: 13.48 Measured value (%) C: 57.49, H: 7.25, N: 13.27 Example 2 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4′-(2″-benzyloxycarbonylethyl)phenyl ester hydrochloride: 7.1 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 4-hydroxyphenylpropion 8.5 g of acid benzyl ester and 7.2 g of dicyclohexylcarbodiimide were suspended in 75 ml of pyridine and reacted at 25°C for 15 hours. After the reaction, insoluble matter was separated and the reaction solution was concentrated under reduced pressure. 0.1N hydrochloric acid was added to the residue. After adding 100 ml and 50 ml of ethyl acetate and stirring for 1 hour, insoluble materials were separated, the liquid was separated, and the organic layer was concentrated. Ethyl ether was added to the resulting gummy substance and stirred thoroughly to precipitate crystals. Recrystallized from methanol-ether, melting point 77
13.1 g (yield 92.1%) of trans-4-guanidinomethylcyclohexanecarboxylic acid 4′-(2″-benzyloxycarbonylethyl) phenyl ester hydrochloride was obtained as white crystals at ~80°C. IR (Nudiyol) νmax cm ^-1 : 1745, 1725 Elemental analysis C ₂₅ H ₃₁ N ₃ O ₄ Calculated value (%) as HCl C: 63.35, H: 6.80, N: 8.86 Measured value (%) C: 62.98, H: 6.65, N :9.04 Example 3 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2''-ethoxycarbonylethyl) phenyl ester hydrochloride: Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 11.8g, 4-hydroxyphenyl 10.7 g of ethyl propionate and 11.4 g of dicyclohexylcarbodiimide were suspended in 150 ml of pyridine and reacted at 25° C. for 15 hours. After separating the precipitated crystals, the solvent was distilled off, 100 ml of 1N hydrochloric acid was added to the residue, and the mixture was stirred for 1 hour. After separating the precipitated crystals, the solution was washed with ether, and the aqueous layer was concentrated. Add ether to the residue, stir well, and recrystallize the precipitated crystals from ethanol-ether to obtain 4'-(2''-ethoxycarbonylethyl trans-4-guanidinomethylcyclohexanecarboxylate) as white crystals with a melting point of 90-91°C. Phenyl ester hydrochloride 17.9g (yield
86.9%). IR (nujiol) νmax cm ^-1 : 1740, 1725 Elemental analysis Calculated value (%) as C ₂₀ H ₂₉ N ₃ O ₄・HCL C: 58.32, H: 7.34, N: 10.24 Measured value (%) C: 57.98, H: 7.10, N: 10.13 Example 4 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2''-carboxyethyl 5-phenyl ester hydrochloride: trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 11.8g, 4 -15.4 g of benzyl hydroxyphenyl propionate and 14.4 g of dicyclohexylcarbodiimide were dissolved in 80 ml of pyridine and 80 ml of dimethylformamide and reacted overnight at room temperature.The solvent was distilled off under reduced pressure,
200 ml of 0.1N hydrochloric acid and 100 ml of ethyl acetate were added to the residue to separate insoluble matter. The solution portion was separated, the aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined and concentrated to obtain a gummy substance. Methanol, acetic acid and water were added to the mixture to make it homogeneous, and the mixture was hydrolyzed using 10% palladium on carbon as a catalyst. After absorbing a sufficient amount of hydrogen, the catalyst was separated and the liquid was concentrated.
The obtained crystals were recrystallized from methanol-acetic acid to give trans-4-guanidinomethylcyclohexanecarboxylic acid 4′-(2″-
Carboxyethyl) phenyl ester hydrochloride 14.3
g (yield 74.5%). IR (nujiol) νmax cm ^-1 :: 1750 (C=0), 1706
(C=0), 1630-1680 (C=N) Elemental analysis Calculated value (%) as C ₁₈ H ₂₅ N ₃ O ₄ HCl C: 56.32, H: 6.83, N: 10.95 Measured value (%) C: 55.98 , H: 6.51, N: 10.72 Example 5 Pyloric ligation ulcer A group of 10 SD male rats weighing approximately 200 g were subjected to laparotomy under ether anesthesia, and the pylorus was ligated.
Sutured. Immediately before suturing, administer the drug 0.5ml/100 intraperitoneally.
g of body weight. After 18 hours, the abdomen was opened, the cardia was ligated and removed, and an incision was made at the greater curvature of the stomach for evaluation. The results are shown in Table 1. Evaluation method 0... No damage 1... Bleeding spots 2... 1 to 5 small ulcers (diameter <3 mm) 3... 5 or more small ulcers or 1 large ulcer 4... Many large ulcers 5... Perforated ulcers present

【table】

[Table] Example 6 Acetic acid ulcer A group of 10 SD male rats weighing around 200 g were subjected to laparotomy under ether anesthesia, and treated with a 10% acetic acid aqueous solution.
0.05 ml was injected between the serosa and the muscle at a site close to the pylorus of the stomach, and the incision was sutured. From the next day, the drug dissolved in 0.5% carboxymethyl cellulose was administered once a day at a rate of 1 ml/100 g for 10 consecutive days. During this time, the animals were allowed to drink food and water ad libitum. After 10 days, the rat's abdomen was opened, and the ulcer at the acetic acid injection site was evaluated according to the following criteria. The results are shown in Table 2. 1... Ulcer area 0-10mm ² 2... 〃 11-20mm ² 3... 〃 21-30mm ² 4... 〃 31-40mm ² 5... 〃 41mm ² or more

[Table] Example 7 Formulation Example 1 (Tablet) One tablet (270 mg) is a film-coated tablet containing the following ingredients. Active ingredient A 100mg Lactose 100mg Crystalline cellulose 50mg Magnesium stearate 1mg Hydroxypropylmethylcellulose 15mg Hydroxypropylcellulose 4mg Formulation example 2 (granules) 1g of granules contains the following ingredients. Active ingredient A 100mg Lactose 573mg Coarse starch 300mg Hydroxybropylcellulose 27mg

Claims (1)

[Claims] 1. General formula (wherein R represents a hydrogen atom, a hydroxycarbonylethyl group, a lower alkoxycarbonylethyl group, or a benzyloxycarbonylethyl group) A novel digestibility characterized by containing a cyclohexanecarboxylic acid derivative or a salt thereof represented by Ulcer treatment.