JPH0794445B2 - Benzimidazole derivative, method for producing the same, and antiulcer agent containing the same - Google Patents

Description

The present invention relates to a novel benzimidazole derivative, more specifically, the following general formula (I): (Wherein R ¹ represents a hydrogen atom and R ² represents a lower alkyl group), a method for producing the same, and an anti-ulcer agent containing the same.

[Prior Art] Conventionally, it is well known in the art that H ⁺ + K ⁺ ATPase is the final gastric acid secretory mechanism in gastric cells [Scandinavian Journal of Gastroenterology (Scand.J. Gastroenterol.) 14 , 131〜135 (197
9)], Norinium bromide is known as a substance having an H ⁺ + K ⁺ ATPase inhibitory action [Proceeding of the Society for Experimental Biology and Medesin (Proceeding of th
e Society for Experimentel Biology and Medicin
e), 172 , 308-315 (1983)].

On the other hand, 2- [2- (3,5-dimethyl-4-methoxy)-
Pyridylmethylsulfinyl]-(5-methoxy) -benzimidazole [omeprazole] is being developed as an anti-ulcer drug having an H ⁺ + K ⁺ ATPase inhibitory action [American Journal of Physiology (Am.Jo
f Physiol.) 245 , G64-G71 (1983)].

[Problems to be Solved by the Invention] Therefore, it is desired to provide a novel compound having an excellent H ⁺ + K ⁺ ATPase inhibitory action.

[Means for Solving the Problems] Under the circumstances, as a result of intensive studies by the present inventors, the novel benzimidazole derivative represented by the formula (I) has a specific H ⁺ + K ⁺ ATPase inhibitory action. Based on the finding that it has an excellent gastric acid secretion inhibitory action based on the above, the present invention has been completed.

Therefore, the present invention provides a benzimidazole derivative (I) useful as an anti-ulcer agent.

The present invention also provides a novel method for producing the benzimidazole derivative (I).

Furthermore, the present invention provides an anti-ulcer agent containing the benzimidazole derivative (I) as an active ingredient.

The benzimidazole derivative (I) of the present invention is, for example,
It is produced by reacting 2-mercaptobenzimidazole (II) with 2-aminobenzyl compound (III) to give compound (IV) according to the following reaction formula, and then oxidizing this.

(In the formula, X represents a reactive group, and R ¹ and R ² are the same as above.) In the above formula, the lower alkyl group represented by R ² is an alkyl group having 1 to 6 carbon atoms.

The raw material (II) of the production method of the present invention is a known compound, for example, organic synthesis (Org.Synth.)
It is produced by the method described in Volume 30, Page 56. The reactive group represented by X in the raw material (III) includes halogen atoms such as chlorine and bromine, methylsulfonyloxy,
Examples thereof include a sulfonyloxy group such as a toluenesulfonyloxy group. For example, a compound in which X is a chlorine atom is described in Journal of Chemical Society (J. Chem.
c.) manufactured by the method described in 98-102 (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
It 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, it is preferable to allow an alkaline agent such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium hydrogencarbonate to be present to receive the generated acid.

Oxidation of compound (IV) can be carried out by a conventional method. For example, hydrogen peroxide, an organic peracid such as m-chloroperbenzoic acid, or an oxidizing agent such as sodium metaperiodate can be used to synthesize compound (IV). ) Should be oxidized. The reaction is chloroform,
It is carried out in an inert solvent such as dichloromethane, methanol or ethyl acetate at a temperature of -30 ° C to 50 ° C, preferably -15 ° C to 5 ° C.

The results of testing the pharmacological effects of the representative compounds of the compound (I) of the present invention thus obtained are as follows.

(1) H ⁺ ＋ K ⁺ ATPase inhibitory action The method of Forte et al. [J. Applied Physiol.] 32,714
~ 717 (1972)], gastric acid secreting cells of rabbit gastric mucosa were isolated, and vesicles containing H ⁺ + K ⁺ ATPase were prepared by centrifugation in a discontinuous density gradient of Ficoll. 5 mM imidazole buffer (pH 6.0), test substance 2 x 10
After incubating the enzyme for 25 minutes at room temperature in 0.5 ml of a solution containing ^-4 M, the enzyme was transferred to 37 ° C and left for another 5 minutes. 4 mM
Magnesium chloride, 80 mM imidazole buffer (pH 7.
4), 0.5 ml of a solution containing 20 mM potassium chloride and 4 mM ATP was added, and the mixture was reacted at 37 ° C for 15 minutes. Then, 1 ml of 24% trichloroacetic acid was added to stop the reaction, and the released inorganic phosphorus was removed by using Taussky and Shawl. (Shorr) Method [Journal of Biological Chemistry (J.Biol.C
hem.) 202,675-685 (1953). The K ⁺ -dependent ATPase activity was calculated by subtracting the activity in the absence of potassium chloride. The results are shown in Table 1. In addition,
Compound 1 is a comparative compound and compound 2 is the compound of the present invention obtained in Example 1.

(2) Gastric acid secretion inhibitory action Conventional method (Shay Etch et al., Gastroenterology (Sh
ay, H. et al, .Gastroenterology) 5,43-61 (1945)), after fasting Donryu male rats weighing 200 to 250 g for 24 hours (however, water intake is free), 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 killed, the stomach was removed and the gastric juice was collected. Acid output
Using an automatic titrator, adjust the pH to 7.
Titration to 0 and the values obtained were compared to the values of control animals treated in the same way but without the test compound. The results are shown in Table 2.

(3) Acute toxicity test The compound 2 of the present invention was orally administered to ICR male mice weighing 23 to 26 g and observed for 3 days. As a result, MLD was 1000 mg / kg or more.

(4) Bladder disorder action test Compound 2 according to the present invention (a compound in which -NR ₁ R ₂ is -NHCH _{3 in} the general formula (I)), and -NR ₁ R ₂ is -N (CH ₃ ) ₂ dimethyl. The comparative compound, which is an amino group, was orally administered to beagle dogs at a dose of 135 mg / kg (body weight) continuously for 14 days to examine the possibility of developing bladder disorders. As a result, no occurrence of bladder disorder was observed in the continuous administration of the compound 2 according to the present invention, but occurrence of bladder disorder (occurrence of erosion) was observed in the continuous administration of the dimethylamino compound for comparison. .

The compound (I) of the present invention can be administered orally or parenterally. Examples of the dosage form of the orally administered agent include tablets, capsules, powders, granules, syrups, and the like, and examples of the dosage form of the parenteral administration agent 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.
Magnesium stearate, talc, etc. are used as lubricants, and hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, etc. are used as binders.

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 (i) 2-benzylthiobenzimidazole: 2-mercaptobenzimidazole 5 g, benzyl chloride 4.2 g, sodium hydroxide 1.47 g water 5 ml-ethanol
It was added to 50 ml of solution and heated under reflux for 1 hour. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration to give 7.7 g (96%) of coarse crystals. Recrystallization from ethanol gave 5.9 g of colorless needle crystals. mp184 ° C (ii) 2-benzylsulfinylbenzimidazole: 4.5 g of 2-benzylthiobenzimidazole was dissolved in 30 ml of chloroform, and m-chloroperbenzoic acid (purity 70%) 4.
6g was added little by little below 0 ° C. After stirring for further 20 minutes, the precipitated crystals were separated by filtration, the filtrate was washed with saturated sodium hydrogen carbonate solution, sodium thiosulfate and saturated saline, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.3 g of crude crystals. Recrystallization from 43 ml of ethanol gave 2.0 g of 2-benzylsulfinylbenzimidazole as colorless crystals. mp169-170 ° C. [Example 1] (i) 2- (2-Methylaminobenzylthio) benzimidazole: 2-mercaptobenzimidazole 1.8 g, 2-methylaminobenzyl chloride / hydrochloride 2.5 g, ethanol 10 ml
It was stirred for 30 minutes at room temperature. 10 ml of ether was added, and the precipitated crystals were collected by filtration, washed with ether, and 2- (2-methylamino-benzylthio) benzimidazole hydrochloride 3.5 g
(85%) was obtained.

Further, the crystals were suspended in ethyl acetate, neutralized by adding a saturated sodium hydrogen carbonate solution, and the organic layer was washed with brine and dried with sodium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from acetonitrile to give 2- (2-methylaminobenzylthio) benzimidazole as colorless crystals, 1.87 g (6
8%) obtained. mp: 107-108 ° C (ii) 2- (2-methylaminobenzylsulfinyl)
Benzimidazole: 2- (2-Methylaminobenzylthio) benzimidazole (1.0 g) was dissolved in chloroform (20 ml), cooled to -10 ° C, and m-chloroperbenzoic acid (purity 70%) (0.87 g) was added little by little. The mixture was further stirred at the same temperature for 10 minutes, washed with a saturated sodium hydrogen carbonate solution and saturated saline, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetonitrile to obtain 0.43 g of 2- (2-methylaminobenzylsulfinyl) benzimidazole as a white crystalline powder. mp: 122.5-124 ° C 1Rν (KBr): cm ^-1 3220,1600,1500,1435, 1400,1305,1265,1045 ¹ H-NMR (CDCl ₃ ): δ 2.52 (s, 3H, NCH ₃ ) 6.30 to 7.80 (m, 8H, aromatic protons) [Example 2] Formulation example (tablet) One tablet (220 mg) contains the following components.

Active ingredient 50 mg Lactose 103 Starch 50 Magnesium stearate 2 Hydroxypropyl cellulose 15 [Example 3] Formulation example (capsule) A hard gelatin capsule contains the following ingredient (350 mg).

 Active ingredient 40 mg Lactose 200 Starch 70 Polyvinylpyrrolidone 5 Crystalline cellulose 35 [Example 4] Formulation example (granules) 1 g of granules contains the following ingredients.

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

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Tomio Yamakawa 1-12-4 Shinmei Soka-shi, Saitama Prefecture Abe Corp. No. 202 (72) Inventor Yutaka Nomura 899 Hachiman-cho, Soka-shi, Saitama Prefecture (72) Masatoshi Hayashi Tokyo 6, Tanidaicho, Shinjuku-ku, Tokyo (56) References Japanese Patent Laid-Open No. 61-56168 (JP, A)

Claims (3)

[Claims] 1. The following general formula (I): (In the formula, R ¹ represents a hydrogen atom and R ² represents a lower alkyl group.) A benzimidazole derivative. 2. General formula (II): 2-mercaptobenzimidazole represented by the general formula (III): (Wherein R ₁ represents a hydrogen atom, R ₂ represents a lower alkyl group, and X represents a reactive group), and a 2-aminobenzyl compound represented by the formula: (Wherein R ₁ and R ₂ are the same as above), and the compound is then oxidized to give a compound of the general formula (I): (In the formula, R ₁ and R ₂ are the same as described above.) A method for producing a benzimidazole derivative. 3. The following general formula (I): (In the formula, R ₁ represents a hydrogen atom and R ₂ represents a lower alkyl group) An anti-ulcer agent containing as an active ingredient a benzimidazole derivative.