JPH075462B2 - Pharmaceutical composition containing a benzimidazole derivative - Google Patents

Description

The present invention relates to a novel benzimidazole derivative, more specifically the following general formula (I) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group or an aralkyl group, and R ₂ represents a hydrogen atom or a lower alkyl group, or R ₁ and R ₂ are adjacent to each other. It may form a ring together with a nitrogen atom, and R ₃ and R ₄ each represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an amino group.). The present invention relates to an anti-ulcer agent containing a benzimidazole derivative.

The applicant has already described the general formula (I ′) (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as above) and the anti-ulcer has an excellent gastric acid secretion inhibitory action based on the specific H ⁺ + K ⁺ ATPase inhibitory action. We found that it is useful as an agent and applied for a patent.

[Japanese Patent Application No. Sho 59-182400, 60-61194, 60-61195, 60-178951] As a result of further intensive research, as a result, a sulfide body of the general formula (I) which is a synthetic intermediate of the general formula (I ′) is obtained. Also has an excellent gastric acid secretion inhibitory effect and is useful as an anti-ulcer agent, and completed the present invention.

That is, the present invention provides an antiulcer agent containing a benzimidazole derivative (I) as an active ingredient.

The benzimidazole derivative (I) of the present invention is, for example,
It is produced by reacting 2-mercaptobenzimidazoles (II) with 2-aminobenzyl compound (III) according to the following reaction formula.

(In the formula, X represents a reactive group, and R _{1 to} R ₄ are the same as above.) The raw material (II) of the method of the present invention is a known compound,
For example, Organic Synthesis (Org.Synth.) No. 30
Vol., Page 56. Examples of the reactive group represented by X in the raw material (III) include halogen atoms such as chlorine and bromine, and sulfonyloxy groups such as methylsulfonyloxy and toluenesulfonyloxy groups. For example, X is a chlorine atom. Compounds are Journal of the Chemical Society (J.Chem.Soc.) 9
It is manufactured by the method described in 8-102 (1942). These may be subjected to the reaction in the form of salt.

The reaction between compound (II) and compound (III) or a salt thereof is
The reaction is carried out by stirring in an inert solvent such as toluene, benzene, ethanol or acetone at room temperature or under reflux for 30 minutes to 24 hours. At this time, NaOH, KOH, K ₂ C
It is preferable to allow the generated acid to be present in the presence of an alkaline agent such as O ₃ or NaHCO ₃ . The sulfoxide compound represented by the general formula (I ') can be derived by oxidizing the compound (I) of the present invention by a known method.

Next, the efficacy, toxicity and dose of the active ingredient of the present invention will be explained.

[Experimental Example 1] Gastric acid secretion inhibitory action Conventional method [Shei H et al, Gastroenterology (Sh
ay, H. et al., Gastroenterology), 5 , 43-61 (1945)]
According to the above, male Donryu rats weighing 200 to 250 g were fasted for 24 hours (water intake freely), the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was intraduodenally administered. After 4 hours, the animals were killed, the stomach was removed and the gastric juice was collected. Regarding the acidity (Acid output), the value obtained by titrating to pH 7.0 with 0.1 N NaOH using a free titrator was compared with the value of a subject animal which was not similarly treated with the test compound. The results are shown in Table 1.

[Experimental Example 2] Acute toxicity test 0.2% of the test compound was applied to ICR male mice weighing 28 to 34 g.
Suspended in CMC-Saline, orally administered at a rate of 0.1 ml / 10 g,
Mortality and general symptoms were observed for 3 days. The result is the second
Shown in the table.

As is clear from the above experimental examples, the benzimidazole derivative represented by the general formula (I), which is the active ingredient of the present invention, has an excellent gastric acid secretion inhibitory action and has a very high safety. It is useful as an agent.

The compound (I) of the present invention can be administered orally or parenterally. Examples of the dosage form of the orally administered drug include tablets,
Capsules, powders, granules, syrups and the like can be mentioned, and parenteral administration forms include injections and the like. Conventional excipients, disintegrants, binders, lubricants, pigments, diluents and the like are used for the preparation of these. As excipients, glucose, lactose, etc., as disintegrants, starch, carboxymethylcellulose calcium, etc., as lubricants, magnesium stearate, talc, etc., as binders, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, etc. Is used.

The dosage is usually about 1 mg to 50 m per day by injection in adults.
Oral administration is about 10 mg to 500 mg per day, but it can be increased or decreased depending on the age, symptoms, etc.

Next, the present invention will be described with reference to Reference Examples and Examples.

Reference Example 1 2- (2-aminobenzylthio) benzimidazole: 2-aminobenzyl chloride / hydrochloride 1.8 g, 2-mercaptobenzimidazole 1.5 g were dissolved in ethanol 40 ml,
The mixture was stirred at room temperature for 23 hours under ordinary light. The precipitated powder was taken, washed with ethanol and ether, and recrystallized from methanol-ether to obtain 2- (2-aminobenzylthio) benzimidazole hydrochloride (18 g) as colorless granular crystals. mp:
207 ℃ (decomposition).

H-NMR (DMSO-d ₆ ) δ: 4.98 (s, 2H, -S CH ₂ ‐) 7.00-7.80
(M, 8H, aromatic protons), 10.66 (br, 5H, N H , N H ₂ , HC
l) Reference Example 2 2- (2-Methylaminobenzylthio) benzimidazole: 2-mercaptobenzimidazole 1.8 g, 2-methylaminobenzyl chloride / hydrochloride 2.5 g in ethanol 10 ml 30
Minutes stirred at room temperature. 10 ml of ether was added, and the precipitated crystals were collected and washed with ether to obtain 3.5 g (85%) of 2- (2-methylaminobenzylthio) benzimidazole hydrochloride. mp: 1: 88-190 ℃ (decomposition) ′ H NMR (CD ₃ OD-CDCl ₃ ) δ: 3.22 (s, 3H, N CH ₃ ), 5.10
(S, 2H, -S CH _2- ), 7.32-7.88 (m, 8H, aromatic proton
s) Reference Example 3 2- (2-Dimethylaminobenzylthio) benzimidazole: 2-mercaptobenzimidazole 4.73 g in ethanol
After dissolving in 150 ml, 2-dimethylaminobenzyl chloride / hydrochloride (6.18 g) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected, saturated NaHCO ₃ solution was added to the crystals, and extracted with chloroform. The chloroform layer was washed with saturated saline and dried with mirabilite. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-acetonitrile to obtain 2.39 g of 2- (2-dimethylaminobenzylthio) benzimidazole as colorless crystals. mp: 164 ° C.

′ H NMR (CDCl ₃ ) δ: 2.88 (s, 6H, -N CH ₃ ), 4.37 (s, 2
H, -S CH _2- ), 6.88-7.80 (m, 8H, aromatic protons) Reference Example 4 2- (2-diethylaminobenzylthio) benzimidazole: 2-mercaptobenzimidazole 500 g ethanol 500 m
2-diethylaminobenzyl chloride.
77.9 g of hydrochloride was added and stirred at room temperature for 30 minutes. The precipitated crystals were collected, saturated NaHCO ₃ solution was added to the crystals, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over sodium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in ethanol and treated with activated carbon. Activated carbon was separated, ethanol was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain 88.7 g of 2- (2-diethylaminobenzylthio) benzimidazole as a light brown crystalline powder. mp: 134-135 ° C.

′ H NMR (CDCl ₃ ) δ: 1.10 (t, 6H, J = 8Hz, -CH ₃ ) 3.5
4 (q, 4H, J = 8Hz, -N CH _2- ), 4.48 (s, 2H, -S CH _2- ), 6.92
-7.60 (m, 8H, aromatic protons) Reference Example 5 2- (2-Dimethylaminobenzylthio) -5-methoxybenzimidazole: 2.70 g of 2-mercapto-5-methoxybenzimidazole is dissolved in 60 ml of ethanol to give 2- Dimethylaminobenzyl chloride / hydrochloride (3.09 g) was added, and the mixture was stirred at room temperature for 30 minutes.
The precipitated crystals were collected to obtain 5.27 g of 2- (2-dimethylaminobenzylthio) -5-methoxybenzimidazole hydrochloride as a light brown crystalline powder. mp: 210 ℃ (decomposition) ′ H NMR (CD ₃ OD-CDCl ₃ ) δ: 3.46 (s, 6H, N CH ₃ ), 3.90
_{(S, 3H, -O CH 3} ), 5.22 (s, 2H, -SC H 2 -) 7.0~8.0 (m, 7
H, aromantic protons) Reference example 6 2- (2-piperidinobenzylthio) benzimidazole: 2-mercaptobenzimidazole 0.87 g in a solution of 2-piperidinobenzyl chloride hydrochloride 1.42 g in ethanol 35 ml
And NaOH 0.5 g were added, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with 10% NaOH and saturated saline, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was washed with ether,
1.0 g of 2- (2-piperidinobenzylthio) benzimidazole was obtained as a yellow powder. mp165 ° C ′ H NMR (CDCl ₃ ) δ: 1.4-2.1 (m, 6H), 2.8-3.1 (m, 4
H), 4.34 (s, 2H), 6.9-7.6 (m, 8H) Reference Example 7 2- (2-Dimethylaminobenzylthio) -4-methylbenzimidazole: 2-mercapto-4-methylbenzimidazole 1.0 g 1.26 g of 2-dimethylaminobenzyl chloride hydrochloride was added to a suspension of 10 ml of ethanol, and the mixture was stirred for 2 hours at room temperature. The precipitated crystals were collected, washed with ethanol and ether, dissolved in chloroform, and neutralized with a saturated NaHCO ₃ solution. The chloroform solution was washed with saturated brine, dried over sodium sulfate, the solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected and 2- (2-dimethylaminobenzylthio) -4-methylbenzimidazole was added. Was obtained as a white crystalline powder to give 1.38 g.

mp136-137.5 ℃ ′ H NMR (CDCl ₃ ) δ: 2.52 (s, 3H), 2.84 (s, 6H), 4.3
6 (s, 2H), 6.8-7.6 (m, 7H) Reference Example 8 2- (2-Dimethylamino-6-methylbenzylthio) benzimidazole: 2-Dimethylamino-6-methylbenzyl chloride hydrochloride
4.41 g was dissolved in 40 ml of acetone, 3.64 g of 2-mercaptobenzimidazole, 10 g of K ₂ CO ₃ and 4 ml of water were added, and the mixture was stirred at room temperature for 1 hour. Chloroform and water were added, the chloroform layer was separated, washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol and hexane and the crystals were collected to give 4.68 g of 2- (2-dimethylamino-6-methylbenzylthio) benzimidazole as a light brown powder. mp146-147.5 ℃ ′ H NMR (CDCl ₃ ) δ: 2.42 (s, 3H), 2.84 (s, 6H), 4.4
2 (s, 2H), 6.8-7.6 (m, 7H) Reference Examples 9 to 27 The following compounds were produced in the same manner as in Reference Examples 1 to 8.

Example 1. Formulation example (tablet) One tablet (180 mg) contains the following ingredients.

Active ingredient 50 mg Lactose 65 Crystalline cellulose 30 Carboxymethyl cellulose calcium 25 Hydroxypropyl cellulose 8 Magnesium stearate 2 Example 2. Formulation example (capsule) One hard gelatin capsule contains the following ingredient (250 mg).

Active ingredient 4 mg Lactose 110 Starch 70 Talc 5 Crystalline cellulose 23 Magnesium stearate 2 Example 3. Formulation example (granules) 1 g of granules contains the following ingredients.

Active ingredient 200 mg Lactose 450 Corn starch 300 Hydroxypropyl cellulose 50

Claims (1)

[Claims] 1. A general formula (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group or an aralkyl group, and R ₂ represents a hydrogen atom or a lower alkyl group, or R ₁ and R ₂ are adjacent to each other. It may form a ring together with a nitrogen atom, and R ₃ and R ₄ each represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or an amino group.). An anti-ulcer agent containing a benzimidazole derivative as an active ingredient.