JPS631289B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel anti-ulcer agent. It has been known that methylmethionine sulfonium chloride (hereinafter referred to as MMSC) is useful as an anti-ulcer agent. The present inventors synthesized various MMSC derivatives and searched for their pharmacological effects in order to develop better anti-ulcer agents. As a result, a new derivative with aromatic acylation at the amino group of MMSC was found to be particularly effective. The present invention was completed based on the discovery that it has an anti-ulcer effect. The present invention is based on the general formula This is an anti-ulcer agent containing an MMSC derivative represented by the formula (wherein R represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group) as an active ingredient. In the compound of the formula, the substituent R is a hydrogen atom, 1
an alkyl group having ~4 carbon atoms or 1-4
an alkoxy group having 5 carbon atoms, particularly a hydrogen atom, a methyl group or a methoxy group. The compound of formula is a new compound, for example
It can be produced by acylating MMSCs with an aromatic acylating agent under conventional acylation conditions, or by first acylating methionine with an aromatic acylating agent and then methylsulfonation (JP-A-Show). 53-149926). As the acylating agent, for example, benzoic anhydride, benzoic acid halide, p-methylbenzoyl halide, p-methoxybenzoyl halide, and acid anhydrides and halides corresponding to the acyl group can be used. As the solvent, in addition to acetic acid or an acid corresponding to an acyl group, an aqueous sodium hydroxide solution can also be used. The reaction takes place under mild conditions.
For example, it usually finishes in 10 to 24 hours at around room temperature. As is clear from the experimental examples below, the compound of the formula has anti-ulcer and anti-allergic effects as well as gastric wall blood flow increasing effects that are superior to MMSC, and are effective against gastric ulcers, duodenal ulcers, gastritis, skin ulcers, gastric hyperacidity, etc. It is effective in the treatment and prevention of. Although the compounds of the formula may be used as such to administer the anti-ulcer agents of the present invention, it is preferred to use them as formulations prepared in conventional manner using conventional carriers. For oral administration, dosage forms such as tablets, sugar-coated tablets, pills, capsules, granules, and powders are preferred. For parenteral administration, it is usually used in the form of a sterile solution or suspension. The active substances of the formula can each be in free form or in the form of a physiologically acceptable carboxylic acid salt or in a mixture thereof. Preferred salts include metal salts, such as sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. The formulations can be prepared in a conventional manner using conventional excipients and conventional auxiliaries. For example, excipients for producing preparations for oral administration include corn starch, wheat starch, potato starch, lactose, sucrose, glucose, mannitol, calcium sulfate, calcium phosphate, calcium carbonate,
Sodium chloride, boric acid, etc. can be used. Examples of the binder include the above-mentioned starches, dextrin, gum arabic, gum tragacanth, carrageenin, sodium alginate, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose,
Hydroxypropylcellulose, hydroxyethyl starch, polyvinylpyrrolidone, polyvinyl alcohol, etc. are used. As the lubricant, for example, magnesium stearate, talc, aluminum silicate, boric acid, magnesium oxide, etc. can be used. The dosage of the anti-ulcer agent of the present invention varies depending on the type and degree of ulcer, but is generally 100 to 1000 mg per day for oral administration and 10 to 500 mg per day for parenteral administration.
mg of active substance can be used. Experimental examples regarding the anti-ulcer effect and other properties of the compound of the formula are shown below. The following drugs were used as test drugs. Active substances of the formula according to the invention: Comparative drug: Methylmethionine sulfonium chloride (MMSC) Experimental Example 1 Inhibitory effect of aspirin on ulcers (non-pylorus ligation short-term method): Aspirin 70mg/Kg was orally administered to rats (10 animals per group), sacrificed 1 hour later, and the length of the ulcer that developed in the stomach was measured. The sum was used as the ulcer index. The drug was orally administered 1 hour before aspirin administration.
The results are shown in Table 1.

【table】

[Table] Experimental Example 2 Inhibitory effect on acetic acid ulcer: 0.05 ml of 10% acetic acid aqueous solution was injected into the serosa side of the glandular stomach of rats (10 animals per group) to create an ulcer, and the rats were sacrificed on the 8th day after creation. The area of ulcers that developed in the stomach was measured and used as an ulcer index. The drug was orally administered twice a day for 7 days from the day after the ulcer was created. The results are shown in Table 2.

[Table] Experimental Example 3 Inhibitory effect of Compound 48/80 on ulcers: 2 mg/Kg of Compound 48/80 was administered to rats (group 1).
The drug was subcutaneously administered to 10 mice (10 mice), sacrificed 3 hours later, the length of the ulcer that had developed on the gastric mucosa was measured, and the sum of the lengths was used as the ulcer index. The drug was orally administered 30 minutes before administration of compound 48/40. The results are shown in Table 3.

[Table] Experimental Example 4 Inhibitory effect on stress ulcers: Rats (10 rats per group) that had been fasted for 15 hours were subjected to water immersion stress (water temperature 23°C) for 7 hours and then sacrificed.
The length of the ulcer that developed in the stomach was measured, and the sum was used as the ulcer index. The drug was orally administered at the same time as the stress load. The results are shown in Table 4.

[Table] Experimental Example 5: Effect on local blood flow in the gastric mucosa: A plate-shaped electrode was attached to the serosa muscle layer in the center of the anterior stomach wall of a dog under anesthesia and laparotomy, and gastric mucosal blood flow was measured using the thermocouple method. The drug was administered intravenously 1 hour after electrode attachment. Regarding this experimental method, reference is made to "Angiology" Vol. 17, No. 6, pp. 587-591. The results obtained are shown in Table 5.

[Table] Experimental Example 6 Effect on left gastric artery blood flow: An electromagnetic flowmeter probe was attached to the left gastric artery of a dog under anesthesia and laparotomy, and blood flow was measured non-invasively. The drug was administered intravenously 1 hour after the probe was attached. The results are as shown in the drawings, and it was found that the active substances a, b, and c of the present invention significantly increased the left gastric artery blood flow compared to MMSC. The numbers in the diagram indicate the dose of the drug, and the blood flow rate is known by the height of the peak. Experimental Example 7 Wound Healing Promotion Effect: Male Wistar rats (10 rats per group) were anesthetized with ether, and a longitudinal incision wound 5 cm in length was created along the dorsal midline. The wound was closed with four metal clips spaced 1 cm apart. After 5 days, the rats were killed with ether, skin strips with three wounds in the center were cut out from each rat, one of the skin strips was fixed and a load was applied to the other, and the load required for the wound site of the skin strip to rupture was measured. was measured. The drug was orally administered at a dose of 300 mg/Kg twice a day from the day after the incision was made. The results are shown in Table 6. Table 6 Drug Wound tension (g/cm) Control 158.9±12.1 Compound a 233.3±7.9 Compound c 211.8±5.9 MMSC 139.7±8.3 Experimental example 8 Antiallergic effect: In male Wistar rats (10 rats per group) , 5 ml of a 50-fold dilution of anti-ovalbumin mouse serum was administered intraperitoneally, and 2 hours later, 5 ml of Tyrode's solution containing 2 mg of ovalbumin and 25 units of heparin was administered intraperitoneally. After 5 minutes, the animals were decapitated and killed by exsanguination. and ascites fluid was collected. Ascites was centrifuged at 200×g for 5 minutes, histamine present in the supernatant and precipitate was quantified by fluorescence photometry, and the histamine release rate was calculated using the following formula. Histamine release rate (%) = amount of histamine in supernatant / [amount of histamine in precipitate] + [amount of histamine in supernatant] × 100 The drug was administered intraperitoneally at 30 mg/Kg 1 minute before antigen administration. . The results obtained are shown in Table 7.

[Table] As is clear from the above experimental results, the effective substance according to the present invention has anti-ulcer effects, gastric wall blood flow increasing effects, and anti-allergic effects that are superior to MMSCs. Furthermore, this effective substance has a gastric acid secretion suppressing effect equivalent to or superior to that of MMSC. That is, when gastrin 1γ/Kg/hour is continuously injected intravenously into dogs to stimulate gastric acid secretion, and the drug is intravenously administered 90 minutes after gastrin injection, this compound a in particular is 30mg/Kg.
30 minutes after administration, the amount of gastric acid secretion was reduced by approximately 60%.
, and 60 minutes later, it decreased to about 50% (assuming the required amount of stomach acid before drug administration is 100%). In contrast to this
MMSCs at a dose of 100 mg/Kg reduced gastric acid secretion to about 50% 40 minutes after administration, but then increased it to more than about 70% 60 minutes later. Compound c is 100mg/
At a dose of Kg, the secretion amount decreased to less than 50% within 30 to 40 minutes of administration, but increased to approximately 60% after 60 minutes.
It showed a somewhat similar effect to MMSC. As a result of examining the acute toxicity of the active substance of the present invention using SD rats (4 weeks old, female and male),
For compounds a, b and c, the LD ₅₀ by oral administration in both females and males was
5000mg/Kg or more, LD ₅₀ by intravenous administration is 3000
It was more than mg/Kg. Furthermore, no abnormal findings were observed when 3000 mg/Kg was orally administered for 14 consecutive days, indicating that this compound is extremely safe. Some examples of formulations containing compounds of formula as active ingredients are given below. These preparations can be manufactured from each component by conventional methods. Example 1 Tablet, compound formula per tablet 25 mg Sodium bicarbonate 250 mg Neusilin 100 mg Example 2 Powder, compound formula per gram 50 mg Neusilin 400 mg Calcium carbonate 200 mg Magnesium carbonate 150 mg Example 3 Granule, formula per gram Compound of formula 250mg Example 4 Injection, compound of formula per ampoule 150mg Distilled water for injection (solubilizing agent) 2ml Example 5 Injection for intravenous injection 500mg of compound of formula per ampoule, 20%
Dissolve in 20ml of glucose injection (dissolving agent) before use.

[Brief explanation of the drawing]

The figure is a graph showing the results of measuring the effect of the drug of the present invention on left gastric artery blood flow.

Claims (1)

[Claims] 1. General formula An anti-ulcer agent containing a methylmethionine sulfonium chloride derivative represented by the formula (wherein R represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group) as an active ingredient.