JP2501232B2 - Novel benzothiazole and benzimidazole derivatives and antiulcer agents containing them as active ingredients - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel benzothiazole derivative and benzimidazole derivative having an antiulcer action, and a gastric ulcer or duodenum containing at least one of them as an active ingredient. The present invention relates to an anti-ulcer drug which is effective in treating and preventing ulcers and the like.

(Prior Art) As an anti-ulcer agent, it is desired to have both functions of suppressing gastric acid secretion and protecting gastrointestinal mucosa. Histamine represented by cimetidine is a drug that suppresses gastric acid secretion.
There are H ₂ receptor blockers, but they do not protect the gastric mucosa. In addition, it has undesired side effects on the central system, and is therefore insufficient for use in the prevention and treatment of ulcers.

Further, recent benzimidazole derivatives represented by omeprazole have a strong H ⁺ , K ⁺ ATPase inhibitory action and strongly suppress the secretion of gastric acid, but it is also known to cause acidemia. In addition, these compounds have the drawback of being unstable to acid and susceptible to decomposition by gastric acid.

Therefore, it is desired to develop an anti-ulcer agent that has both a suppressive effect on gastric acid secretion and a protective effect on gastric mucosa, is effective against various ulcers, has low toxicity and is stable against gastric acid.

On the other hand, for benzothiazole compounds, H ⁺ , K ⁺ ATP
A compound having an ase inhibitory action and a gastric acid secretion inhibitory action has been reported (J. Med. Chem., 31 , 1778 (1988)), but its efficacy in various experimental ulcers has not been reported yet.

(Problems to be Solved by the Invention) The present invention has a good balance of gastric acid secretion inhibitory action and gastric mucosal protective action as described above, has low toxicity, is effective in the prevention or treatment of various ulcers, and The aim is to develop stable anti-ulcer drugs.

(Means for Solving Problems) As a result of repeated studies to solve the problems in the previous period, the present inventors have found that certain benzothiazole derivatives and benzimidazole derivatives have a strong gastric acid secretion inhibitory action and are excellent. The present invention was completed by discovering that it has a gastric mucosal protective effect and exhibits a remarkable effect on various experimental ulcers.

The present invention has the following general formula (I) (In the formula, X represents S or NH, R ¹ represents hydrogen, a lower alkoxy group, a chlorine atom, a bromine atom or an iodine atom, and R ² represents a hydrogen atom, an optionally substituted lower alkyl group, a vinyl group, an aryl group. Group or an acyl group, m represents an integer of 0, 1 or 2, and n represents an integer of 0 or 1, provided that when n is 0, R ² is not a hydrogen atom.) The present invention relates to a novel benzothiazole derivative and a benzimidazole derivative, and also relates to an antiulcer agent effective for treating and preventing gastric ulcer, duodenal ulcer, etc., containing at least one of them as an active ingredient. The optionally substituted lower alkyl group for R ² is, for example, a C _{1 to} C ₄ lower alkyl group optionally substituted with a halogen atom, a hydroxyl group, an alkoxy group, a hydroxyalkoxy group or an aryl group.

Among the compounds represented by the general formula (I) according to the present invention, the following general formula (Ia) (In the formula, X, R ¹ , R ² and m have the same definition as above)
The compound represented by can be obtained by the following method [A] or [B].

[A] method General formula (II) (Wherein X and R ¹ have the same definitions as described above) and a compound represented by the general formula (III) Y (CH ₂ ) _m OR ² (III) (wherein R ² and m have the same definitions as in the preceding term). Y represents a halogen atom, a tosyloxy group, a trifluoromethanesulfonyloxy group, or a mesyloxy group.) In a solvent that does not participate in the reaction, such as N, N-dimethylformamide, in which a metal hydride, preferably sodium hydride, or By reacting in the presence of sodium hydroxide,
The compound represented by a) can be obtained.

[B] method General formula (IV) (In the formula, R ¹ has the definition of the previous term, and Z represents a halogen atom.) And a compound represented by the general formula (V) HS (CH ₂ ) _m OR ² (V) (in the formula, R ² , m has the same definition as above.) in a solvent which does not participate in the reaction with a compound represented by the formula (3), such as a metal hydride in N, N-dimethylformamide, preferably sodium hydride, or a metal hydroxide, preferably hydroxide. By reacting in the presence of sodium, the compound represented by the general formula (Ia) can be obtained.

By reacting the compound (Ia) with an oxidant in an amount of 1 to 1.2 molar equivalents in a solvent that does not participate in the reaction, the following general formula (I
b) A sulfoxide compound represented by the formula (wherein X, R ¹ , R ² and m have the same definition as above) can be obtained as a main component. In addition, in this oxidation reaction, 1-
By increasing the amount by 1.5 molar equivalents, the general formula (Ic) as the main product (In the formula, X, R ¹ , R ² and m have the same definitions as described above.), Thereby obtaining a sulfone compound.
As the oxidizing agent used in this oxidation reaction, hydrogen peroxide, peracid derivatives such as metachloroperbenzoic acid and sodium periodate, manganese dioxide, tert-butyl hydroperoxide and N-bromosuccinine are used. Mid, etc. can be mentioned. Examples of the solvent to be used include water, acetic acid, alkyl halides such as methylene chloride, ketones such as acetone, and other commonly used solvents, but it is preferable to use peroxide in the presence of sodium tungstate in acetic acid. The oxidation reaction can be carried out with metachloroperbenzoic acid in hydrogen or methylene chloride.

(Action and Effect) The compound of the general formula (I) of the present invention has an inhibitory action on various experimental ulcers, and is useful as a therapeutic drug for peptic ulcer.
The effects of the compound of the present invention will be specifically described below by pharmacological experiments.

1. Water immersion restraint stress ulcer test Male Wistar rats (11 weeks old) fasted for 18 hours were housed in a restraint gauge, and the chest was soaked in water at a water temperature of 20-22 ° C and left for 6 hours to apply stress. did.
The rat pulled up from the water was sacrificed by cervical dislocation, the stomach was removed, 5 ml of a 5% formalin aqueous solution was injected into the stomach, and the whole stomach was immersed in the same solution for 30 minutes and fixed. The fixed specimen was incised along the greater radius, the major axis (mm) of the formed ulcer was measured using a caliper, and the sum was used as the ulcer index. The test compound was 0.5% carboxymethylcellulose (C
MC) and was orally administered once in a volume of 5 ml / kg body weight 1 hour before stress loading.

2. Histamine ulcer test In male DonRyu rats that had been fasted for 24 hours, histamine dihydrochloride was dissolved in physiological saline to obtain 200 m
It was administered intravaginally in a volume of g / 5 ml / kg body weight. Five hours later, the ulcer index was determined by slaughtering the stomach and removing the stomach in the same manner as in the case of stress ulcer and treating it with an aqueous formalin solution. The test compound is
Suspended in 0.5% carboxymethylcellulose (CMC), 5m
It was orally administered in a volume of l / kg body weight 1 hour before administration of histamine.

 The ulceration inhibition rate was calculated by the following formula.

3. Aspirin ulcer 0.5% aspirin carboxymethylcellulose (C
MC) and was orally administered at a dose of 300 mg / 5 ml / kg body weight. After 4 hours, as in the case of stress ulcer, the ulcer index was calculated after slaughtering, removing the stomach and treating with a formalin aqueous solution. The test compound was suspended in 0.5% carboxymethylcellulose and orally administered at a volume of 5 ml / kg body weight.

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

4. Ethanol ulcer Donryu fasted for 48 hours and water for 24 hours
100% ethanol was orally administered to male rats at 5 ml / kg. One hour later, the animals were sacrificed in the same manner as above, and the stomach was excised and treated. The test compound was suspended in 0.5% carboxymethylcellulose and orally administered at a volume of 5 ml / kg body weight. While the negative control administered with 0.5% carboxymethylcellulose alone showed almost 100% erosion, the compound of Example 2 had 5
Administration of 0 mg / kg suppressed erosion almost 100%.

Next, the acute toxicity of the compound of the present invention will be explained. The compound obtained in Example 2 described below was added to 0.5% CMC solvent at
Suspended at 10 ml / kg body weight and given a single oral gavage to three 5-week-old ICR male mice, and observed for 7 days.
No deaths were observed after the administration of 00 mg / kg.

The compound represented by the above general formula (I) of the present invention may be administered alone, but if necessary or desired, it may be combined with other conventional pharmacologically acceptable carriers, excipients and diluents. They can be mixed to give the desired dosage form and administered orally.
In that case, 50-500 mg of the compound represented by the general formula (I) is usually administered to an adult daily. Solutions for parenteral administration by injection are aqueous solutions of a pharmaceutically acceptable water-soluble salt of the active compound, preferably in a concentration of 0.5-10% by weight. In this case, the daily active ingredient for adults is 0.
Administer 5-10 mg.

Hereinafter, the present invention will be described more specifically with reference to Examples, but the technical scope of the present invention is not limited to these Examples.

Example 1 5-chloro-2-[(2-ethoxyethyl) thio] benzothiazole 5-chloro-2-mercaptobenzothiazole 5.00 g
(24.8 mmol) was added to N, N-dimethylformamide (25 m
l), and 710 mg (29.6 mmol) of sodium hydride was added to this solution and stirred at room temperature. After 1 hour, 5.44 ml (49.6 ml) of 2-chloroethyl ethyl ether was added to this suspension.
Was added and the mixture was stirred for 2 hours while heating to 50 ° C.
The reaction solution was diluted with 500 ml of chloroform, 20% sodium chloride (500 ml) was added thereto, and the mixture was shaken and washed. The chloroform layer was separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography to give the title compound as a colorless oil.
Obtained 5.40 g. Yield 80%.

Example 2 5-chloro-2-[(2-ethoxyethyl) sulfinyl] benzothiazole 2.00 g (7.3 mmol) of the compound obtained in Example 1 was added to acetic acid 10
Dissolve in 30 ml of 30% hydrogen peroxide solution (0.99 ml (8.74
(Mmol) and a catalytic amount of sodium tungstate were sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 200 ml of 20% sodium chloride, and sodium hydrogencarbonate was added thereto for neutralization, followed by extraction with 200 ml of chloroform. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography, recrystallized from ethanol, and the melting point is
1.47 g of crystals of the title compound showing 96-97 ° C. were obtained. Yield 69
%.

Example 3 5-chloro-2-[(2-ethoxyethyl) sulfonyl] benzothiazole 89 mg (0.33 mmol) of the compound obtained in Example 1 was added to 1 m of acetic acid.
Dissolve in l, 30% hydrogen peroxide water 0.094 ml (0.83 mmol)
And a catalytic amount of sodium tungstate are added sequentially,
Allowed to react for hours. Thereafter, the same treatment as in Example 2 was carried out to obtain 80 mg of the title compound. Yield 80.5%.

Example 4 is processed in the same manner as in any one of Examples 1 to 3.
~ 22 compounds were synthesized. The physicochemical properties of the obtained compound are shown in Table 2.

Example 4 2-[(2-Ethoxyethyl) sulfinyl] benzothiazole Example 5 2-[(2-Ethoxyethyl) thio] -6-ethoxybenzothiazole Example 6 2-[(2-Ethoxyethyl) sulfinyl] -6-Ethoxybenzothiazole Example 7 2-[(2-Ethoxyethyl) sulfonyl] -6-ethoxybenzothiazole Example 8 5-Chloro-2-[(2-hydroxyethyl) thio] benzothiazole Example 9 5 -Chloro-2-[(2-hydroxyethyl) sulfinyl] benzothiazole Example 10 5-chloro-2- [2- {2- (2-hydroxyethoxy) ethoxy} ethylthio] benzothiazole Example 11 5-chloro- 2- [2- {2- (2-hydroxyethoxy) ethoxy} ethylsulfinyl] benzothiazole施例 12 5-Chloro-2 - [(2-vinyloxyethyl) thio]
Benzothiazole Example 13 5-Chloro-2-[(2-vinyloxyethyl) sulfinyl] benzothiazole Example 14 2-[(2-Benzyloxyethyl) sulfinyl]-
5-Chlorobenzothiazole Example 15 5-Chloro-2-[(2-phenylacetoxyethyl)
Sulfinyl] benzothiazole Example 16 2-[(2-Ethoxyethyl) thio] benzimidazole Example 17 2-[(2-Ethoxyethyl) sulfinyl] benzimidazole Example 18 2-[(2-Ethoxyethyl) sulfonyl] Benzimidazole Example 19 5-chloro-2-[(3-ethoxypropyl) thio] benzothiazole Example 20 5-chloro-2-[(3-ethoxypropyl) sulfinyl] benzothiazole Example 21 5-chloro-2 -[(3-Methoxypropyl) thio] benzothiazole Example 22 5-Chloro-2-[(3-methoxypropyl) sulfinyl] benzothiazole

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical display location C07D 277/76 C07D 277/76 (72) Inventor Yasukatsu Yuda 760 Meiji, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Confectionery Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Motohiro Nishio 760 Meiji, Shimooka-cho, Kohoku-ku, Yokohama, Kanagawa Confectionery Co., Ltd. (72) Inventor, Yuji Matsubashi 760, Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Pharmaceutical Research Institute Co., Ltd. (72) Inventor Takashi Tsuruoka 760 Meiji Confectionery, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd. (72) Inventor Kiyoaki Katano 760 Meiji Confectionery, Shimooka-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture (72) Inventor Shigeharu Inoue 760 Meiji Confectionery Co., Ltd. 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Masato Ikeda, Examiner, General Research Institute for Pharmaceutical Sciences (56) Reference JP-A-58-201864 (JP, A) Zh. Org. Khim. , 2 (10) (1966) (Russia) P. 1883 ~ 1891

Claims (4)

(57) [Claims] 1. The following general formula (I): (In the formula, X represents S or NH, R ¹ represents hydrogen, a lower alkoxy group, a chlorine atom, a bromine atom or an iodine atom, and R ² represents a hydrogen atom, an optionally substituted lower alkyl group, a vinyl group, an aryl group. Group or an acyl group, m represents an integer of 0, 1 or 2, and n represents an integer of 0 or 1, provided that when n is 0, R ² is not a hydrogen atom). Benzothiazole and benzimidazole derivatives. 2. The benzothiazole derivative and the benzimidazole derivative according to claim 1, wherein n is an integer of 1. 3. An anti-ulcer agent containing the compound according to claim 1 or 2 as an active ingredient. 4. Chloro-2-[(2-ethoxyethyl) sulfinyl] benzothiazole, 2-[(2-ethoxyethyl) sulfinyl] benzothiazole, 5-
Chloro-2- [2-hydroxyethyl) sulfinyl]
Benzothiazole, 5-chloro-2- [2- {2- (2
-Hydroxyethoxy) ethoxy} ethylsulfinyl] benzothiazole, 2-[(2-ethoxyethyl)
An anti-ulcer agent containing a compound selected from sulfinyl] benzimidazole as an active ingredient.