JPS63230633A - Protecting agent for gastroenteric cell - Google Patents

Abstract

PURPOSE:To obtain the titled protecting agent by using a benzimidazole derivative as an active component. CONSTITUTION:A protecting agent for gastroenteric cell can be produced by using a compound of formula I (R<1> and R<2> are H or lower alkyl; R<3> and R<4> are H, lower alkyl or lower alkoxy; when R<4> is H, R<1> and R<2> are different lower alkyls) [e.g. 2-(2-dimethylamino-5-methoxybenzylsulfinyl)-5-methoxyben zimidazole] as an active component. The compound of formula I can be pro duced by reacting a compound of formula II with a compound of formula III (X is reactive group) and reacting the resultant compound of formula IV. The agent is useful for the prevention or remedy of inflammatory diseases and lowers the incidence and degree of ulcer. It is administered in a dose of <=500mg, preferably 100mug-300mg daily per person.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel gastrointestinal cell protective agents.

[Background of the Invention] Prostaglandin derivatives (U.S. Pat. No. 408,399 (Roberts et al.)
No. 8, MM4081553, lq No. 4097603) are known. Additionally, pyridylmethylsulfinylbenzimidazoles such as 2-((3,5-dimethyl-4-methoxypyridin-2-yl)methylsulfinylgo-5-methoxybenzimidazole (omebrazole)) are effective as cytoprotective agents. This is also known (Japanese Patent Publication No. M5B57-53406, US Pat. No. 4,359,465).

As shown in the above-mentioned patents and publications, cytoprotective agents can be used for P1 therapy and prevention of gastrointestinal inflammatory diseases resulting from various causes. These inflammatory diseases are gastrointestinal inflammatory diseases that are not caused by gastric acid secretion, such as gastric inflammatory diseases such as gastritis, Crohn's disease, inflammatory bowel disease, infectious enteritis, colitis, ulcerative ulcerative inflammation, These include intestinal inflammatory diseases such as pseudomembranous colitis, diverticulitis, and allergic and radiation inflammatory diseases.

Such inflammatory diseases are known to be caused by a wide variety of substances present in the gastrointestinal tract, such as microorganisms B (viruses and fungi), bacterial toxins, and chemical agents. These attack the surface epithelium of the gastrointestinal tract and cause an inflammatory condition.

In addition, the above-mentioned prostaglandin derivatives and 2-((3,
5-dimethyl-4-methoxypyridin-2-yl)methylsulfinyl]-5-methoxybenzimidazole, etc., have both cytoprotective and gastric acid secretion suppressive effects. shows.

That is, both of them are known to exhibit a cell protective effect when used in small amounts, but also to suppress gastric acid secretion when used in large amounts.

However, the gastric juice secretion suppressing effect and the cytoprotective effect are independent pharmacological effects that are not related to each other [Roberts et al., ``Cytoprotective effect of prostaglandins in rats''.
, Gastroenterology, Vol. 77, pp. 433-443, 1979].

The present inventors previously prepared the following general formula (I): (wherein R and R represent a hydrogen atom or a lower alkyl group,
R'! and R4 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group.

However, when R' is a hydrogen atom, R1 and R2 represent different basic alkyl groups) The new benzimidazole derivative represented by the following shows excellent gastric acid secretion suppressing action, and therefore is effective as an anti-ulcer agent. I found out. Patent applications have already been filed regarding this compound, its synthesis method, and its potential (Japanese Patent Application No. 182400/1982, Japanese Patent Application No. 60-61194, Japanese Patent Application No.
Application No. 0-61195).

As a result of further intensive research, the present inventors found that the benzimidazole derivative of the above general formula (I) not only has an effect of suppressing gastric acid secretion but also has an excellent cytoprotective effect, and therefore it can be used as a gastrointestinal cell protectant. The present invention was completed based on the discovery that the present invention is also useful.

CObject of the Invention An object of the present invention is to provide a novel gastrointestinal cell protective agent.

[Structure of the Invention] The present invention relates to the following general formula (I) (wherein R and R represent a hydrogen atom or a lower alkyl group,
R' and R4 represent a hydrogen atom, a lower alkyl group or a lower alkoxy group. .

However, when R' is a hydrogen atom, R1 and R2 represent different lower alkyl groups. A certain benzimidazole derivative of general formula (I) can be obtained by the method shown in the following formula.

HRINR2 HRINR2 (In the formula, X represents a propagating group, and R1 to R4 are the same as above.) Representative compounds represented by general formula (I) include, for example, the following compounds.

Compound L: 2-<2-dimethylamino-5-methoxybenzylsulfinyl)-5-methoxybenzimidazole Compound 2: 2-C2-dimethylamino-5-methylbenzylsulfinyl)-5-methoxybenzimidazole Compound 3: 2- [2-(N-isobutyl-N-methylamino)benzylsulfinyl] Benzimidazole compound 4: 2-(2-dimethylamino-5-methoxybenzylsulfinyl)benzimidazole compound 5: 2-[2-(N-isobutyl- N-methylamino)-5-methoxybenzylsulfinyl]benzimidazole compound 6: 2- [2-(N-isobutyl-N-methylamino)-5-methoxybenzylsulfinyl]-5-methoxybenzimidazole compound 7: 2- [2-(N-isobutyl-N-methylamino)-5-methylbenzylsulfinyl]-5-methoxybenzimidazole Compound 8: 2-[2-(N-hexyl-N-methylamino)benzylsulfinyl]benzimidazole In the benzimidazole derivative used in the present invention, R1 in the general formula (I) is preferably an alkyl group having 1 to 8 carbon atoms, and R2 is preferably a lower alkyl group. Examples of the alkyl group Σ and lower alkoxy group include alkyl groups and alkoxy groups having 1 to 6 carbon atoms.

The benzimidazole derivative of the present invention was used in a test for gastrointestinal cell protection (effect on hydrochloric acid-ethanol gastric damage).
It showed a strong effect. Note that this gastric injury model test using hydrochloric acid-ethanol is a test in which high-concentration hydrochloric acid is introduced into the stomach from the outside, and therefore, when evaluating the effects of compounds introduced into the stomach, it is necessary to This is a test system in which the influence of secretion can be almost ignored.

That is, salt sensitivity using rats - 1 hour after ethanol administration, linear or band-like damage was observed in the glandular gastric mucosa;
It was confirmed that the benzimidazole derivative represented by: inhibits this damage in a dose-dependent manner.

Furthermore, an acute toxicity test was conducted on mice when 0 body weight was 23g or 26g of ICR-based zuimidazole was orally administered and observed for 3 days. As a result, the MLD was 10
00 mg/kg or more.

Therefore, the benzimidazole derivatives of the present invention are useful as gastrointestinal cytoprotective agents, and are effective against non-gastric S-induced, non-traumatic, non-neoplastic corrosion as shown in the patent specification of Roberts et al. It can be used for the treatment or prevention of inflammatory diseases in humans and mammals suffering from sexual gastrointestinal inflammatory diseases, or in humans and animals susceptible to the development of these diseases.

It is known in the industry that the onset of the disease is particularly likely in the following cases: those who consume large amounts of alcohol on a daily basis, those who are exposed to electromagnetic waves with cell-destroying doses, or those exposed to cell-destroying chemicals. This includes exposure to drugs such as acute or chronic ingestion of drugs, or exposure to pathogens that cause cell destruction. It is also known that patients with a history of multiple gastric or duodenal ulcers are more likely to develop inflammatory diseases and have recurrences.

Therefore, of course the prevention or treatment of these inflammatory diseases,
The cytoprotective agents of the present invention are useful in reducing the incidence and severity of ulcer formation commonly caused by these diseases, and in the complete treatment of ulcers and inflammatory reactions.

The gastrointestinal cell protective agent containing the benzimidazole derivative represented by the general formula (I) as an active ingredient is orally administered. Examples of dosage forms for oral administration include tablets, capsules, powders, granules, and syrups. These preparations include the usual excipients, disintegrants,
Binders, lubricants, dyes, diluents, etc. are used. Excipients include glucose, lactose, etc., disintegrants include starch, carboxymethyl cellulose calcium, etc., lubricants include stearin pus magnesium, talc, etc., and binders include hydroxypropyl cellulose,
Gelatin, polyvinylpyrrolidone, etc. are used.

The dosage for adults is usually 500 mg or less, preferably about 11,001 L to 300 mg per day, but it can be increased or decreased depending on age, symptoms, etc.

The dose for expressing the cytoprotective effect of the compound of the present invention is:
Approximately 1% compared to omeprazole, a known cytoprotective agent.
/3 is sufficient, and this is clear from the results of the cytoprotective effect test against hydrochloric acid-ethanol gastric damage described below. That is, it has been confirmed that 10 mg/kg of the above-mentioned compound of the present invention and 30 mg of omebrazole exhibit equivalent effects when administered 2 hours before the test procedure described below.

The fact that in the case of omeprazole, the cytoprotective effect is sufficiently expressed at a dose less than 1/1O of the dose required to suppress gastric acid secretion (Japanese Patent Application Laid-Open No. 57-53406, U.S. Patent No. 43
No. 59465), and the experimental results described below showing that the compound of the present invention and omeprazole are almost equivalent in the gastric juice secretion suppressing effect, S and the test results described above, it is found that the compound of the present invention suppresses gastric acid secretion. It is clear that the compound of the present invention exhibits a cell-protecting effect at a dose of 1/30 or less of the dose that produces an inhibitory effect, and thus the compound of the present invention is a highly distinctive cell-protecting agent.

Next, the present invention will be explained with reference to Examples.

Example 1 Gastrointestinal cell protection effect
After fasting for an hour, a hydrochloric acid/ethanol solution (1 m of hydrochloric acid containing 150 mM salt in 60% ethanol!L7200
g body weight was administered orally for 9 days. One hour later, the rats were sacrificed with ether, the stomach was removed, and the length of the damage (mm) generated in the glandular stomach area was measured. The sum of the lengths in (1) was taken as the damage factor.The test drug was suspended in a 1% carboxymethyl cellulose solution immediately before use, and administered orally at a dose of 0.5 ml and 17,100 g body weight 30 minutes before administration of hydrochloric acid and ethanol. The same dose of solvent alone was administered to the control group.The inhibition rate was calculated using the following formula, and the results are shown in Table 1.

Inhibition M''*(X) - [1 - Damage coefficient when administering drug (
mm)/damage coefficient when no drug is administered (mm)]
x 100゛Table 1 Toxybenzimidazolexybenzimidazole Midazole Reference Example 1 Synthesis method of 2-[2-(N-isobutyl-N-methylamino)pendylsulfinylcopenzimidazole 2-[2-(N-isobutyl -N-methylamino)benzylthio]benzimidazole 76°1 g (23
4 mmol) in 1.14 ml of chloroform and cooled on ice. 80% to prevent the internal temperature from rising above 5℃
m-chloroperbenzoic acid 50.2g (234mmo
Add l) little by little over 1 hour. 30 below 5℃
After stirring for several minutes, saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was stirred and separated.

The chloroform layer was roughly washed with a saturated aqueous sodium bicarbonate solution, a 10% aqueous sodium thiosulfate solution, and a saturated saline solution in this order, dried over cold nitrogen, and then the solvent was distilled off under reduced pressure. Add 100 ml of acetonitrile to suspend the precipitated crystals, and filter and separate. Is the target product washed with acetonitrile? Obtain 0.5° (88,4%). This product was dissolved in 500 ml of methylene chloride, and after concentration, 400 ml of acetonitrile was added, and the precipitated crystals were filtered off to obtain a yellow powder. mp 126-126.5℃
Bureau, Relaxed Ztsui 6, Tomono Otsu, Karisaki Rikistop] Koyo υ? Each plum
l.

Reference N2 Gastric secretion suppressing action conventional method (Shay H, et al, +Gastro
enterology.

5.43-61 (I945)), body weight 200-2
After administering 50 g of Donryu male rats for 24 hours (with free access to water), the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was administered into the duodenum. After 4 hours, the animals were sacrificed, the stomachs were removed, and gastric fluid was collected. Acidity (acidoutput) was determined by titrating to pH 7-0 with 0.1N sodium hydroxide using an automatic titration device, and the obtained value was compared with the value of the target animal treated in the same manner but not given the test compound. compared. The results are shown in Table 2.

Table 2 Reference Example 3 Effect on stress ulcers Donryu rats weighing 240 to 260 g were fed a 24-hour diet by Gotakagi et al.
.

18 (9) 9-18, 1968) and was placed in a restrained stress cage and immersed in water up to the xiphoid process of the thorax in a 21°C water tank to apply stress. After the TFtP period, the animals were removed from the tank, immediately killed, and their stomachs were removed. 1% formalin solution 10
At the same time as injecting m1 into the stomach.

1 Heng Roku 1b Marine Arrest 10 Kai Jinggang 1 Kasa Tin - An incision was made along the line, and the length (mm) of the stuffing ulcer that was likely to develop in the glandular stomach was measured, and no drug was administered. The inhibition rate was determined by comparison. The drug was orally administered 10 minutes before stress loading.

The results are shown in Table 3.

Table 3 (However, the compound person is the same as in Table 1) Example 2 Otori m Tachiji JL1 One tablet (220mg) contains the following ingredients.

Active Ingredients 50 mg lactose 103 mg starch
50mg magnesium stearate
2mg hydroxypropylcellulose 15m
Example 3 (Capsule) One hard gelatin capsule contains the following ingredients (350 mg).

Active Ingredients 40 mg lactose
200 mg starch
70 mg polyvinylpyrrolidone 5 m
gCrystalline cellulose 35 mggExample 4 Otori 11g 1g of granules contains the following components.

Claims (1)

[Claims] 1 The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 and R^2 are hydrogen atoms or lower alkyl groups, R^ 3 and R^4 represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group.However, when R^4 is a hydrogen atom, R^1 and R^2 represent different lower alkyl groups). A gastrointestinal cell protective agent containing as an active ingredient.