JPH02223562A - Novel benzothiazole and benzimidazole derivatives and anti-ulcer drug containing the same derivatives as active ingredients - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X is S or NH; R<1> is H, lower alkoxy, Cl, Br or I; R<2> is H, (substituted) lower alkyl, vinyl, aryl or acyl; m and n are 0-2]. EXAMPLE:5-Chloro-2-[(2-ethoxyethyl)sulfinyl]benzothiazole. USE:A drug. An active ingredient for anti-ulcer agents. The compound has a strong gastric acid-secreting action and an excellent gastric mucosa-protecting action and is effective for treating and preventing gastric ulcer and duodenal ulcer. PREPARATION:For example, a compound of formula II is reacted with a compound of formula III (Y is halogen, tosyloxy, mesyloxy, etc.) in a solvent such as N,N-dimethylamide in the presence of NaH, etc., to provide the compound of formula I wherein n is 0. The compound of formula I is reacted with 1-1.2mol equivalent of an oxidizing agent such as H<2>O2 in the presence of a catalyst such as sodium tungstate to provide the compound of formula I wherein n is 1.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to novel benzothiazole derivatives and benzimidazole derivatives having anti-ulcer effects, and also relates to novel benzothiazole derivatives and benzimidazole derivatives having anti-ulcer effects, and also to anti-ulcer and duodenal ulcers containing at least one of them as an active ingredient. The present invention relates to an anti-ulcer agent that is effective in treating and preventing ulcers and the like.

(Prior Art) It is desired that an anti-ulcer agent have the dual functions of suppressing gastric acid secretion and protecting the gastrointestinal mucosa.

Drugs that suppress gastric acid secretion include histamine H2 receptor blockers, such as cimetidine.

These do not have a protective effect on the gastric mucosa. Furthermore, it has undesirable side effects on the central system, so it is not sufficient for use in the prevention or treatment of ulcers.

Furthermore, recent benzimidazole derivatives such as omeprazole have a strong H", K" ATPase inhibitory effect and strongly suppress gastric acid secretion, but are also known to cause achlorhydria. Additionally, these compounds have the disadvantage of being unstable to acids and susceptible to decomposition by gastric acid.

Therefore, it is desired to develop an anti-ulcer agent that has a well-balanced effect of suppressing gastric acid secretion and protecting the gastric mucosa, is effective against various types of ulcers, is low in toxicity, and is stable against gastric acid.

On the other hand, for penzothiazole compounds, H+K”AT
Compounds that have Pase inhibitory activity and gastric acid secretion suppressing activity have been reported (J, Mecl.

Chem, 31.1778 (1988)), and its effectiveness on various experimental ulcers has not yet been reported.

(Problems to be Solved by the Invention) As described above, the present invention has a well-balanced effect of suppressing gastric acid secretion and protecting the gastric mucosa, has low toxicity, is effective in preventing or treating various ulcers, and The aim is to develop a stable anti-ulcer drug.

(Means for Solving the Problems) As a result of repeated research to solve the problems in the previous stage, the present inventors found that certain benzothiazole derivatives and benzimidazole derivatives have strong gastric acid secretion suppressing effects and excellent The present invention was completed based on the discovery that it has a protective effect on the gastric mucosa and has a remarkable effect on various experimental ulcers.

The present invention represents a lower alkyl group of 01 to C4 which may be substituted with a group of the following general formula (I), a hydroxyalkoxy group or an aryl group.

Among the compounds represented by the above-mentioned formula (I) according to the present invention, those having the primary general formula (I a) (wherein X represents S or NH, and R1 is hydrogen, a lower alkoxy group, a chlorine atom, a bromine atom) or represents an iodine atom, R2
represents a hydrogen atom, an optionally substituted lower alkyl group, a vinyl group, an aryl group, or an acyl group, and m is 0.1 or 2
n represents an integer of 0°1 or 2. The present invention relates to novel benzothiazole derivatives and benzimidazole derivatives represented by the following formulas, and to anti-ulcer agents effective for the treatment and prevention of gastric ulcers, duodenal ulcers, etc., containing at least one of them as an active ingredient. The optionally substituted lower alkyl group of R2 is, for example,
Halogen atom, hydroxyl group, alkoxy (in the formula X, R', R
2 and m have the same definitions as above) can be obtained by the following method [A] or [B].

[A] Method A compound represented by the general formula (I[) (wherein X and R1 have the same definitions as above) and the general formula (III) Y(CH2),OR'' (I[[) (in the formula R2 and m have the same definitions as in the previous term, Y is /1 rogen atom, tosyloxy group, trifluoromethanesulfonyloxy group,
Represents mesyloxy group. ) and a solvent that does not participate in the reaction,
For example, by reacting in N,N-dimethylformamide in the presence of a metal hydride, preferably sodium hydride or sodium hydroxide, the compound represented by the above-formation (Ia) can be obtained.

[B] Process formation (IV) (wherein R1 has the above definition and Z represents a halogen atom) and general formula (V) R3 (CH2
), 0R2(V) (wherein R'' and m have the same definitions as above) with a solvent 1 that does not participate in the reaction, such as N, N-
The pre-formation (
A compound represented by Ia) can be obtained.

By reacting 1 to 1.2 molar equivalents of an oxidizing agent on this compound (Ia) in a solvent that does not participate in the reaction, the following general formula (Ib) (wherein, X, R', R2 and m are the same as above) is obtained. A sulfoxide compound represented by (having a definition) can be obtained as a main component. In addition, in this oxidation reaction, 1.
- obtaining a sulfone compound represented by the general formula (Ic) (wherein X, R', R2 and m have the same definitions as above) as the main product by increasing the amount by 1.5 molar equivalents; Can be done.

The oxidizing agents used in this oxidation reaction include hydrogen peroxide, metachloroperbenzoic acid, peracid derivatives such as sodium periodate, manganese dioxide,
Further examples include tert-butyl hydroperoxide and N-promosuccinimide.

Examples of the solvent used include water, acetic acid, alkyl halides such as methylene chloride, and ketones such as acetone, and other commonly used solvents.

Suitably, the oxidation reaction can be carried out using hydrogen peroxide in the presence of sodium tungstate in acetic acid or metachloroperbenzoic acid in methylene chloride.

(Action and Effect) The compound of general formula (I) of the present invention has an inhibitory effect on various experimental ulcers and is useful as a therapeutic agent for peptic ulcers. The effects of the compounds of the present invention will be explained in more detail in pharmacological experiments below.

1. Water immersion restraint stress ulcer test Wistar fasted for 18 hours
Male rats (11 weeks old) were housed in a restraint cage and the water temperature was 2.
The animals were immersed up to their chests in water at 0-22°C and left for 6 hours to apply stress. After raising the rat from the water and sacrificing it by cervical dislocation, the stomach was removed and treated with 5% formalin aqueous solution.
ml was injected into the stomach, and the entire stomach was fixed by immersing the limbs for 30 minutes.

The fixed specimen was incised along the greater curvature, and the long axis (mm) of the formed ulcer was measured using calipers.

The sum total was taken as the ulcer coefficient. Test compounds were suspended in 0.5% carboxymethylcellulose (CMC).

The same dose was administered orally at a volume of 5 ml/kg body weight 1 hour before stress loading.

The first sample was suspended in 0.5% carboxymethyl cellulose (CMC) in a volume of 5 ml/kg body weight, and histamine was administered for 1 day.
Administered orally before 1 hour.

The ulcer formation inhibition rate was calculated using the following formula.

Ulcer formation inhibition rate (%) * p < 0.05 ** p < 0.01 2. Histamine ulcer test The histamine ulcer test was dissolved in physiological saline on male Donryu rats that had been fasted for 24 hours.
It was administered intraperitoneally in a volume of 200 mg/5 ml/kg body weight. After 5 hours, the stomach was layered and removed as in the case of stress ulcers, treated with formalin aqueous solution, and the ulcer index was determined. Test Compound 3, Aspirin Ulcer Aspirin was suspended in 0.5% carboxymethyl cellulose (CMC) and administered to Donryu male rats fasted for 24 hours at 300 mg/5 m.
It was administered orally in a volume of Q/kg body weight.

After 4 hours, as in the case of stress ulcers, the stomachs were removed by layer killing and treated with an aqueous formalin solution, and then the ulcer index was determined. The test compound was suspended in 0.5% carboxymethyl cellulose and orally administered at a volume of 5 m+2/kg body weight.

The ulcer inhibition rate was calculated using the same formula as in the histamine ulcer test.

4. Donryu who fasted for 48 hours and water for 24 hours due to ethanol ulcer.
ryu) strain male rats were given 100% ethanol at 5 mQ/
kg was administered orally. One hour later, the animals were sacrificed in layers in the same manner as above, and the stomachs were removed and processed. The test compound was suspended in 0.5% carboxymethylcellulose and administered orally at a volume of 5 ml/kg body weight.

While the negative control administered with only 0.5% carboxymethyl cellulose showed almost 100% abrasion, the compound of Example 2 inhibited the abrasion by almost 100% when administered at 50 mg/kg.

Next, the acute toxicity of the compounds of the present invention will be explained. The compound obtained in Example 2 below was suspended in a 0.5% CMC solvent so that the dose was 10 mO/kg body weight, and a single gavage injection was given to three 5-week-old ICR male mice. As a result of observation for 7 days after administration, no deaths were observed in the administration of 1000 mg/kg.

The compound represented by form (I) of the present invention may be administered alone, but if necessary or desired, it may be administered with other conventional pharmacologically acceptable carriers, excipients, and diluents. They can be mixed into a desired dosage form and administered orally. In that case, for adults, 50-500 mg of the compound represented by formula (I) is usually administered per day. Solutions for parenteral administration by injection are aqueous solutions of a pharmaceutically acceptable water-soluble salt of the active compound, preferably at a concentration of 0.5-10% by weight. In this case, 0.5 to 10 mg of the active ingredient is administered per day for adults.

The present invention will be explained in more detail with examples below.
The technical scope of the present invention is not limited to these examples.

Example 2 Example 1 5-chloro-2-mercaptobenzothiazole 5.00
g (24.8 mmol) was dissolved in N,N-dimethylformamide (25 ml) and sodium hydride 710
mg (29.6 mmol) was added to this solution and stirred at room temperature. After 1 hour, 5.44 rrl (49-6 mmol) of 2-chloroethyl ethyl ether was added to this suspension, and the mixture was stirred for 2 hours while heating to 50°C. The reaction solution was diluted with 500 mff of chloroform, 20% sodium chloride (500 m(2)) was added thereto, and washed by shaking.

The chloroform layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residual liquid was separated and purified by silica gel chromatography to obtain 5.40 g of the title compound as a colorless oil. Yield 80%.

Compound 2-00g (7.3 mmol) obtained in Example 1
was dissolved in 10 mQ of acetic acid, and 0.99 mQ (8.74 mmol) of 30% hydrogen peroxide solution and a catalytic amount of sodium tungstate were sequentially added to this solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 200 ml of 20% sodium chloride, neutralized by adding sodium bicarbonate, and extracted with 200 ml of chloroform. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.

The residue was separated and purified by silica gel column chromatography and recrystallized from ethanol to obtain 1.47 g of crystals of the title compound having a melting point of 96-97°C. Yield 69%.

Example 3 5-chloro-2-[(2-ethoxyethyl)sulfonyl]benzothiazole 89 mg (0.33 mmol) of the compound obtained in Example 1
Dissolved in 1 mα of acetic acid, 30% hydrogen peroxide solution 0.094
mg (0-83 mmol) and a catalytic amount of sodium tungstate were added sequentially and allowed to react for 12 hours. The mixture was treated in the same manner as in Example 2 to obtain 80 mg of the title compound. Yield 80.5%.

Example 8 Example 9 Examples 4 to 3 were prepared in the same manner as in Examples 1 to 3.
22 compounds were synthesized. The physicochemical properties of the obtained compound are shown in Table 2.

Example 4 Example 5 Example 10 one ru Example 11 Example 6 dithiazole Example I2 Example 7 Example 13 5-chloro [ (2-vinyloxyethyl) Example 20 Example 1 Example 2 Example 1 Example 22 Example 1 one [ (2-ethoxyethyl) Thio benzimi Dazol Example 1 Example 1 Example 1

Claims (1)

[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents S or NH, and R^1 represents hydrogen, a lower alkoxy group, or chlorine. atom, bromine atom or iodine atom, R
^2 represents a hydrogen atom, an optionally substituted lower alkyl group, a vinyl group, an aryl group, or an acyl group, and m is 0, 1
or represents an integer of 2, and n represents an integer of 0, 1 or 2. ) benzothiazole derivatives and benzimidazole derivatives represented by 2. The benzothiazole derivative and benzimidazole derivative according to claim 1, wherein n is an integer of 1. 3,5-chloro-2-[(2-ethoxyethyl)sulfinyl]benzothiazole. 4,2-[(2-ethoxyethyl)sulfinyl]benzothiazole. 5,5-chloro-2-[(2-hydroxyethyl)sulfinyl]benzothiazole. 6,5-chloro-2-[2-(2-(2-hydroxyethoxy)ethoxy)ethylsulfinyl]benzothiazole. 7,2-[(2-ethoxyethyl)sulfinyl]benzimidazole. 8. An anti-ulcer agent containing the compound according to claim 1 as an active ingredient. 9. An anti-ulcer agent containing the compound according to claim 2 as an active ingredient. 10. An anti-ulcer agent containing a compound selected from the compounds according to claims 3 to 7 as an active ingredient.