JPS642089B2 - - 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 lower alkyl group, a phenyl group, anisyl group, or a benzyl group) The present invention relates to a novel peptic ulcer therapeutic agent containing a cyclohexylcarboxylic acid derivative or a salt thereof, which is a novel compound 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 mucosal defense power. In other words, peptic ulcers are thought to occur when mucosal resistance and mucosal defenses can no longer withstand attacks on the stomach and duodenum by gastric acid, pepsin, and the like. Incidentally, it has recently been found that gastric juice has a greater influence than protective factors on the etiology of duodenal ulcers. Most of the drugs currently in use act on either attack or defense factors. The present inventors have conducted studies to find an excellent therapeutic agent for peptic ulcers, and found that the general formula ()
The cyclohexanecarboxylic acid derivative represented by has the property of being involved in both attack and defense factors.
Therefore, they discovered that the present invention is an excellent therapeutic agent for peptic ulcers, and completed the present invention. Therefore, an object of the present invention is to provide an excellent therapeutic agent for peptic ulcers. Examples of the salts of the cyclohexylcarboxylic acid derivatives represented by the general formula (), which are the active ingredients of the present invention, include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, lactic acid, maleic acid, fumaric acid,
Examples include acid addition salts with organic acids such as citric acid and methanesulfonic acid. Furthermore, although cis-trans isomers exist in the cyclohexylcarboxylic acid derivative of the general formula (), the trans isomer is particularly preferred. The cyclohexanecarboxylic acid derivative of general formula () and its salt are produced as follows. (In the formula, R' represents a lower alkyl group, a fer group, anisyl group, or a benzyl group, and R is the same as above.) That is, 4-guanidinomethylcyclohexanecarboxylic acid of the formula () or a reactive derivative thereof and the general formula ( ) are reacted,
By removing anisyl group, benzyl group, t-butyl group, etc. as desired, the general formula ()
A cyclohexanecarboxylic acid derivative or a salt thereof is produced. Examples of reactive derivatives of the compound of formula () include acid halides such as acid chlorides and acid bromides, mixed acid anhydrides such as alkyl carbonate ethers, and the like. The acid halide can be obtained by reacting a halogenating agent such as thionyl chloride or thionyl bromide with a compound of formula () at room temperature to the boiling point of the halogenating agent. The reaction between the thus obtained reactive derivative of the compound of formula () and the compound of formula () is carried out by stirring at room temperature to reflux temperature for 1 to 40 hours. Examples of the solvent include dimethylformamide, dimethylacetamide, pyridine, dichloroethane, dichloromethane, chloroform, and acetonitrile. A tertiary amine such as triethylamine or dimethylaniline is preferably present in order to inactivate hydrogen halide produced as the reaction progresses. Next, when 4-guanidinomethylcyclohexanecarboxylic acid is subjected to the reaction with its carboxyl group free, a carbodiimide such as dicyclohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, or an oxychloride is used. It is preferable to use phosphoric acid such as phosphorus, sulfuric acid-boric acid, carbodiimidazole, sulfodiimidazole, or the like. The reaction is carried out at room temperature to reflux temperature, and as the solvent used, in addition to those mentioned above, toluene, xylene, dimethyl sulfoxide, or a mixture thereof can be used. Next, when a compound in which R in the formula () is a hydrogen atom is desired, a compound represented by the formula () in which R' is a t-butyl group, a benzyl group, or an anisyl group is prepared, and then the compound is processed. Obtained by hydrogenolysis or hydrolysis.
Preferably, the hydrolysis is carried out using a catalyst such as palladium, and the hydrolysis is carried out using trifluoroacetic acid. The active ingredient of the present invention can also be produced as follows. (In the formula, R' is the same as above.) That is, the compound of formula () is produced by reacting the compound of formula () or a reactive derivative thereof with the compound of formula (). The reaction is carried out in substantially the same manner as the reaction between the compound of formula () and the compound of formula () above.
In addition, various salt forms of the compound represented by the formula () can be obtained from the desired acid addition salt of the compound () or the compound () used as a raw material (although it is not impossible to apply the commonly used salt preparation method). When used as a compound, a salt of the desired target compound can be suitably obtained. The compound of general formula () or a salt thereof, which is the active ingredient of the peptic ulcer therapeutic agent of the present invention obtained as described above, has excellent prophylactic and therapeutic effects on various experimental ulcer models. The effect is thought to be due to the attenuation of aggressive factors through strong suppression of gastric juice discontinuation and the enhancement of defensive factors through improved blood flow in the gastrointestinal wall. Various experimental ulcer models include acute ulcer models such as pylorus ligation ulcer, stress ulcer, aspirin ulcer, indomethacin ulcer, and serotonin ulcer; chronic ulcer models include acetic acid ulcer; and duodenal ulcer model includes cysteamine ulcer. and histamine ulcers in rats, the active ingredient of the present invention showed extremely excellent preventive and therapeutic effects. The active ingredient of the present invention, such as trans-4-
Guanidinomethylcyclohexanecarboxylic acid o-
Benzyloxycarbonyl phenyl ester hydrochloride (hereinafter referred to as active ingredient A) almost completely inhibited the development of ulcers at 75 mg/Kg. On the other hand, currently commercially available sucrose sulfate aluminum salt and cetraxate hydrochloride are 250 mg/Kg and 300 mg/Kg, respectively.
The effect was the same for Kg. In addition, in an experiment using rats with stress ulcers, that is, an experiment using water immersion restraint, 200
Oral administration of mg/Kg and 400 mg/Kg showed a significant suppressive effect. In experiments on cysteamine ulcers in rats as a duodenal ulcer model, doses of 250mg/Kg to 500mg/
A significant therapeutic effect of 70-85% was observed with Kg oral administration. Furthermore, for acetic acid ulcer in rats, which is a chronic ulcer model, an almost complete therapeutic effect was observed with oral administration of 100 to 500 mg/Kg/day. It also showed excellent suppressive or therapeutic effects in experiments in other ulcer models. Next, the effects of the active ingredient of the present invention on total gastric fluid volume, acidity, and pepsin concentration in pylorus-ligated rats were investigated. As a result, gastric juice volume was suppressed by administration of atropine sulfate (12.5mg/Kg) and administration of cimetidine (300mg/Kg).
The active ingredient A administration (150 mg/Kg) was superior to the active ingredient A administration (150 mg/Kg) at 3, 6, and 12 hours after pylorus ligation. Furthermore, the inhibitory effects on acidity and pepsin concentration were similar to those on gastric juice volume. Therefore, it can be said that the active ingredient of the present invention is an excellent drug that strongly suppresses the depletion of both gastric acid and pepsin, which are attack factors. Furthermore, the durability of the effect is superior to that of atropine sulfate and cimetidine, which were used as controls. Furthermore, when blood flow in the gastric wall and gastric mucosa was measured, the active ingredient of the present invention significantly increased compared to the control, and is thought to enhance mucosal resistance, which is a protective factor. Furthermore, the active ingredient of the present invention is a safe drug with low toxicity. That is, in acute toxicity tests using rats and mice, for example, active ingredient A:
When administered orally, the LD ₅₀ was 8000 mg/Kg or more in rats and 7600 mg/Kg or more in mice. In addition, in a 1-month subacute toxicity test in rats, 40~
Oral administration of 400 mg/Kg did not show any toxic symptoms.
No abnormalities were observed in the findings of each organ. Furthermore, as a result of testing for microbial mutagenicity in accordance with the Code of Practice of the Occupational Safety and Health Regulations,
No mutagenicity was observed. Although the peptic ulcer therapeutic agent of the present invention exhibits its effects when administered either orally or parenterally, oral administration is preferred because of the 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 hydroxypropyl cellulose, and other coloring agents, flavors, sweeteners, etc. The dosage can be increased or decreased depending on age, symptoms, etc., but is preferably about 50 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 2'-benzyloxycarbonyl phenyl ester hydrochloride: trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 10.6 g, benzyl salicylate
11.4g and dicyclohexylcarbodiimide
Suspend 11.3g in 100ml of pyridine and cool at 35-40℃.
After reacting for 15 hours and separating the precipitated crystals, the solvent was distilled off. 200 ml of 0.1N hydrochloric acid was added to the residue, and the mixture was stirred for 0.5 hour. Take the precipitated crystals and use this
Dissolved in 100ml methanol. After separating the insoluble matter,
The liquid part was concentrated and water was added to collect precipitated crystals. The obtained crystals were recrystallized from acetone-water,
Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-benzyloxycarbonylphenyl ester hydrochloride 17.9g (yield
89.2%). This product was further recrystallized from methanol-ether to give white crystals with a melting point of about 83°C. IR (Nujiol) νmax cm ^-1 : 1730 Elemental analysis Calculated value (%) as C ₂₃ H ₂₇ N ₃ O ₄・HCl C: 61.95, H: 6.33, N: 9.42 Measured value (%) C: 61.38, H: 6.38, N: 9.19 Example 2 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-hydroxycarbonylphenyl ester hydrochloride: Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-benzyloxycarbonylphenyl ester hydrochloride 8.9 g was dissolved in 30 ml of acetic acid and 10 ml of methanol, and hydrogenolyzed using palladium on carbon as a catalyst. After absorbing about 500ml of hydrogen,
The catalyst was separated and concentrated. The obtained crystals were washed with ethyl ether and dried to give trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-hydroxycarbonylphenyl ester hydrochloride 6.5
g (yield 91.3%). When this product was recrystallized from ethanol ether, crystals with a melting point of 166-168°C were obtained. IR (nujiol) νmax cm ^-1 : 1750, 1730 Elemental analysis Calculated value (%) as C ₁₆ H ₂₁ N ₃ O ₄・HCl C: 54.01, H: 6.23, N: 11.81 Measured value (%) C: 53.85, H: 6.05, N: 11.42 Example 3 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-ethoxycarbonylphenyl ester hydrochloride: trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 7.1g, ethyl salicylate 5.5
g and dicyclohexylcarbodiimide 7.2 g
was suspended in 100 ml of pyridine and reacted at room temperature for 15 hours. After the reaction was completed, insoluble materials were separated and the reaction solution was concentrated. 100 ml of 0.1N hydrochloric acid was added to the residue, and after stirring for 1 hour, insoluble materials were separated, the liquid was washed with ether, and the aqueous layer was concentrated. Add ether to the residue, stir, collect the precipitated crystals, and trans-4-
Guanidinomethylcyclohexanecarboxylic acid 2′-
8.4 g (yield 72.9%) of white crystals of ethoxycarbonyl phenyl ester hydrochloride was obtained. This product was recrystallized from methanol-ether and had a melting point of 110.
White crystals were obtained at ~111°C. IR (nujiol) νmax cm ^-1 : 1740 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: 55.97, H: 6.72, N: 10.54 Example 4 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-benzyloxycarbonylphenyl ester hydrochloride monohydrate: Trans-4-guanidinomethylcyclohexanecarboxylic acid 2 obtained in Example 1 '-benzyloxycarbonyl phenyl ester hydrochloride was recrystallized from acetone-water (85:15) and dried at 40°C to give 2'-benzyloxy trans-4-guanidinomethylcyclohexanecarboxylate with a melting point of 96-105°C. Carbonylphenyl ester hydrochloride monohydrate was obtained. NMR: δPyridine-d ₅ 1.0~3.4 (m, 12H) 5.25 (s, 2H) 5.4 (s, 2H) 7.3~9.1 (m, 14H) Elemental analysis C ₂₃ H ₂₇ N ₃ O ₄ HCl・H ₂ O Measured value (%) C: 59.61, H: 6.57, N: 9.18, Cl: 7.67 Calculated value (%) C: 59.54, H: 6.52, N: ~9.06, Cl: 7.64 Moisture content (according to Karl Fischer) ) Measured value (%) 3.93 Calculated value (%) 3.88 Example 5 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenoxycarbonyl phenyl ester hydrochloride: Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 27.5 g, phenyl salicylate
25g, N,N'-dicyclohexylcarbodiimide 26.5g, N,N'-dimethylformamide 100ml
and react at room temperature for 21 hours. Add 150 ml of water and 120 ml of hydrochloric acid to collect the precipitated crystals, wash with water, and extract with methanol. After separating the insoluble matter, it is concentrated, and ether is added to the residue to obtain a crystalline product. This product is trans-4-guanidinomethylcyclohexanecarboxylic acid-2'-phenoxycarbonyl phenyl ester hydrochloride, yielding 34.1 g (67.5
%), melting point 157-162°C. IR νmax cm ^-1 : 1740, 1750 (C=0) NMR: δCD ₃ OD 0.7 to 3.1 (m, 12H) 6.8 to 8.1 (m, 9H) Elemental analysis Calculated value as C ₂₂ H ₂₅ N ₃ O ₄・HCl (%) C: 61.18, H: 6.07, N: 9.73 Measured value (%) C: 61.01, H: 5.95, N: 9.79 Example 6 2'-benzyloxycarbonylphenyl trans-4-guanidinomethylcyclohexanecarboxylate Ester p-toluenesulfonate: The reaction was carried out in the same manner as in Example 1, using 3.71 g of trans-4-guanidinomethylcyclohexanecarboxylic acid p-toluenesulfonate instead of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride. Trans-4 with a melting point of 110-114℃
-guanidinomethylcyclohexanecarboxylic acid
2'-benzyloxycarbonyl phenyl ester p-toluenesulfonate 4.3g (yield 73.9%)
I got it. IR νmax cm ^-1 : 1735, 1760 (C=0) NMR: δCD ₃ OD 0.7-3.0 (m, 15H) 5.3 (m, 2H) 7.0-8.1 (m, 13H) Example 7 Trans-4-guanidinomethyl Cyclohexanecarboxylic acid 2'-benzyloxycarbonyl phenyl ester hydrochloride: trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 5.89g, benzyl salicylate
5.71 g and 5.75 g of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were suspended in 25 ml of pyridine and stirred at room temperature for 24 hours. 50 ml of water was added to the reaction mixture, and hydrochloric acid was added to make it acidic, and the precipitated crystals were washed with water. The obtained crystals were recrystallized from methanol ether to obtain 9.27 g (yield: 83.2%) of trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-benzyloxycarbonylphenyl ester hydrochloride. Example 8 Effect on pyloric ligation ulcer Using SD male rats weighing 160 to 180 g,
After an hourly fast, the rat's abdomen was opened under ether anesthesia, and the pylorus-duodenal junction was ligated. 18 hours after surgery, the rat's abdomen was opened under ether anesthesia, and the cardia was ligated.
The stomach was removed, incised along the greater curvature, and visually observed. The drug was administered intraperitoneally immediately after surgery. (however,
Oral administration of sucrose sulfate aluminum salt only)
The degree of gastric disorder was graded and evaluated by the method of Adami et al. The results are shown in Table 1. 0 = no damage. 1 = Bleeding spots present. 2 = 1-5 small ulcers (<3 mm in diameter). 3 = small ulcer (>5) or large ulcer (1). 4 = Many large ulcers. 5 = Perforated ulcer present.

[Table] Example 9 Effect on acetic acid ulcer Using male SD rats weighing around 200 g, the abdomen was opened under ether anesthesia, and 0.05 ml of a 10% aqueous acetic acid solution was injected between the serosa and the muscle at a site near the pylorus of the stomach. death,
The incision was brought together. Starting from the next day, a sample suspended in a 0.5% carboxymethyl cellulose solution was orally administered once a day at a volume 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. Evaluation criteria 1... Ulcer area 0-10mm ² 2... 〃 11-20mm ² 3... 〃 21-30mm ² 4... 〃 31-40mm ² 5... 〃 40mm ² or more

[Table] Example 10 Effect on duodenal ulcer Cysteamine (400 mg/Kg) was administered subcutaneously to SD female rats weighing approximately 200 g and fasted for 24 hours. Food was allowed to be consumed ad libitum from 7 hours after administration. The drug was orally administered as an aqueous suspension 4 times in total, the first time 7 hours after administration of cysteamine, and the second and subsequent times a day. The next morning after the final administration, laparotomy was performed.
The ulcer area was measured and expressed as an ulcer index. The results are shown in Table 3.

[Table] Example 11 Effects on gastric fluid secretion in rats Healthy SD male rats weighing 160-180 g were fasted for 20 hours (however, they were given free access to drinking water) and then placed under ether anesthesia. Open the abdomen and remove the pylorus.
The duodenal junction was ligated. Immediately after ligation surgery,
Drugs were administered intraperitoneally. Surgery 3, 6 and 12
After an hour, the rat's abdomen was opened under ether anesthesia, the cardia was ligated, and the stomach was removed. Gastric juice was collected from the excised stomach, the amount of gastric juice was measured, and the mixture was centrifuged at 1300 g for 10 minutes at room temperature to collect the supernatant. The acidity and pepsin activity of the separated supernatant were measured. Acidity was determined by titration with 0.01N sodium hydroxide solution, and pepsin activity was determined by the method of Anson et al. (J.Gen.
Physiol., 22, 79-89 (1938)).
The results are shown in Tables 4-6. Note that the acidity was expressed by titration, and the pepsin activity was expressed in terms of the amount equivalent to crystalline pepsin.

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[Table] Example 12 Acute toxicity test The above active ingredient A was tested in dd mice and
Table 7 shows the acute toxicity test results for oral administration using SD rats.

[Table] Example 13 Formulation Example 1 (Tablet) One tablet (220 mg) is a film-coated tablet containing the following ingredients. Active ingredient A 50mg Corn starch 100mg Crystalline cellulose 50mg Magnesium stearate 1mg Hydroxypropyl methylcellulose 15mg Hydroxypropyl cellulose 4mg Formulation example 2 (granules) 1g of granules contains the following ingredients. Active ingredient A 100mg Avicel 470mg Corn starch 400mg Hydroxypropyl cellulose 30mg In both Formulation Examples 1 and 2, active ingredient A is the same as above.

Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrogen atom, a lower alkyl group, a phenyl group, anisyl group, or a benzyl group)
1. A novel therapeutic agent for peptic ulcers, comprising a cyclohexanecarboxylic acid derivative or a salt thereof. 2. The novel peptic ulcer therapeutic agent according to claim 1, wherein the active ingredient is trans-4-guanidinomethylcyclohexanecarboxylic acid o-benzyloxycarbonylphenyl ester hydrochloride. 3. The novel peptic ulcer therapeutic agent according to claim 1, wherein the active ingredient is trans-4-guanidinomethylcyclohexanecarboxylic acid o-benzyloxycarbonylphenyl ester hydrochloride monohydrate.