JPS62212386A - 2-pyridylmethylbenzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is 1-10C alkyl which may be substituted by alkenyl, aryl, cyano, OH alkoxycarbonyl or aminocarbonyl) and salt thereof. EXAMPLE:2-Methylthio-1-(2-pyridylmethyl)benzimidazole. USE:A remedy for peptic ulcer having inhibitory effect on gastric acid secretion and protective action on gastric mucosae with low toxicity. PREPARATION:For example, an imidazole derivative expressed by formula II is reacted with 2-picolyl chloride expressed by formula III in the presence of a base, e.g. sodium hydride, etc., in an organic solvent, e.g. DMF, etc., at room temperature - 80 deg.C to give a sulfide compound in the compound expressed by formula I. the resultant compound is then reacted with one equivalent oxidizing agent, e.g. m-chloroperbenzoic acid, etc., in a solvent to afford the aimed sulfinyl compound. When the aobve-mentioned sulfide compound is reacted with 2 equivalents oxidizing agent, the aimed sulfonyl compound is obtained.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (1) (wherein R is an alkenyl group, an aryol group, a cyano group, a hydroxy group, an acoloxycarbonyl group, and an aminocarbonyl group). represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms which may have a substituent selected from the group; n represents 0.1 or 2) 2- The present invention relates to pyridylmethylbenzimidazole derivatives and pharmaceuticals containing the same. More specifically, the 2-pyridylmethylbenzimidazole derivative having the general formula (1) and its pharmacologically acceptable acid addition salt have the effect of suppressing the attack factor and the effect of enhancing the protective factor of peptic ulcer, and It is a new compound useful as a therapeutic agent for peptic ulcers due to its low toxicity.

[Conventional technology]

Although the pathogenesis of peptic ulcer disease has been discussed in terms of an imbalance between offensive and protective factors, the factors that increase mucosal resistance have not been determined.

Therefore, the saying "There is no ulcer where there is no acid" is
This adage still lives on, and the current goal of treatment for peptic ulcer disease is still to control gastric acid.

However, even anticholinergic drugs that can bring the stomach into a near acid-free state are not very effective in preventing the worsening and recurrence of ulcers. Drugs that suppress aggressive factors alone cannot be expected to be sufficiently effective in treating ulcers.

Therefore, at present, drugs to suppress the aggressive factor and tissue repair measures to prevent recurrence are different types and are selected depending on the symptoms.

Compounds that have traditionally been said to have both of the above effects also
Although several proposals have been made, these actually do not have a very strong effect of suppressing aggressive factors, and their main effect is repairing the m-woven fabric.

[Problem that the invention seeks to solve]

As mentioned above, there is a strong desire to develop a powerful anti-peptic ulcer drug that has a balanced effect of protecting against attacking factors and protecting the gastric mucosa. Furthermore, it is important that the agent has as little toxicity and side effects as possible as a peptic ulcer agent. Therefore, the present inventors planned and studied the development of a drug focusing on these active and toxic aspects, and as a result, the present inventors developed the 2-pyridyl compound of the present invention, which is a novel compound with well-balanced activities and weak toxicity. They succeeded in obtaining a methylbenzimidazole derivative and completed the present invention.

[Means for solving problems]

The novel compound 2-pyridylmethylbenzimidazole derivative represented by the general formula (1) and the pharmacologically acceptable acid addition salt according to the present invention have a gastric acid secretion suppressing effect, a gastric mucosal protective effect, and a weakly toxic compound. Therefore, it is a useful substance that can be used in the treatment of peptic ulcers.

Among the compounds represented by the above general formula of the present invention, sulfide compounds can be synthesized as follows.

That is, an imidazole derivative represented by the general formula (2) (wherein R is as defined above) is heated in an organic solvent in the presence of a base at room temperature to 80°C.
2- expressed by the following formula (3) or (3') at a temperature of °C.
A desired compound can be obtained by reacting with picolyl chloride or 2-picolyl chloride hydrochloride for about several hours.

However, there is also a method of synthesizing a sulfide compound having an aminocarbonyl group by reacting an amine with a compound having an alkoxycarbonyl group obtained by the above reaction at a temperature from room temperature to 100°C.

Examples of solvents that can be used in the reaction include dimethylformamide, dimethyl sulfoxide, dry tetrahydrofuran, benzene, and toluene.

On the other hand, as the base used in the reaction, sodium hydride, sodium amide, potassium t-butoxide sodium alcoholate, sodium metal, etc. are preferably used.

Furthermore, the compound thus obtained can be reacted in a solvent such as chloroform or methylene chloride at a temperature of about 1 equivalent below, preferably under cooling with water, to obtain the desired sulfinyl compound and about 2 equivalents of m-chloro. The desired sulfonyl compound can be obtained by reacting it with an oxidizing agent such as perbenzoic acid at a temperature of 100° C. or lower, preferably at room temperature.

After completion of the reaction, the desired compound can be purified by recrystallization, column chromatography, etc., or can be treated with a pharmacologically acceptable acid and purified as an acid addition salt by recrystallization or chromatography. .

The acids used to prepare the acid addition salts of the 2-pyridylmethylbenzimidazole derivatives according to the invention include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, acetic acid, Oxalic acid, citric acid, lactic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, gluconic acid,
Examples include organic acids such as mandelic acid and methanesulfonic acid.

The novel 2 represented by the general formula (1) according to the present invention
- The pyridylmethylbenzimidazole derivative itself may be administered alone, but it can be made into various dosage forms using known formulation techniques. For example, when administered orally, it is usually formulated as a tablet, powder, granule, capsule, syrup, etc., and when administered parenterally, it is formulated as an injection, suppository, etc. In either case, it can be mixed with a known liquid or solid diluent or carrier commonly used in pharmaceutical preparations to form preparations in various shapes.

Examples of such diluents or carriers include, for example, polyvinylpyrrolidone, gum arabic, gelatin, sorbitol, tragacanth, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol,
Examples include silica, lactose, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethyl cellulose calcium, sodium lauryl sulfate, water, ethanol, glycerin, mannitol, syrup, and the like.

The peptic ulcer therapeutic agent of the present invention can contain an effective amount of the compound represented by general formula (1) or a pharmacologically acceptable acid addition salt thereof.

The effective dosage of the peptic ulcer therapeutic agent of the present invention can be changed as appropriate depending on various factors, such as the symptoms of the patient to be treated, age, route of administration, dosage form, number of administrations, etc. 50~2.000mg per day, preferably 100~
A range of 1.000++g can be exemplified.

Main Basis The present invention will be explained in more detail below with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Synthesis of 2-methylthio-1-(2-pyridylmethyl)benzimidazole 5.0 g (30
, 44 mmol) was dissolved in 50 ml of dimethylformamide, and 3.0 ml of 60% sodium hydride was added to this under water cooling.
4 g (76.11 mmol) was added, followed by pressing the teffl, and 5.49 g (33 mmol) of 2-picolyl chloride hydrochloride was added.
, 5 mmol) was added. After stirring at 80°C for 2 hours, the mixture was diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from methylene chloride; n-hexane to obtain 5.66 g (yield: 73%) of the title compound. .

Ōfunemasushi two rules The following compounds were synthesized in the same manner as in Example 1.

The physical properties of these obtained compounds are summarized in Table 1.

Dairanji - Mainly 2-methylthio-1-(2-pyridylmethyl)benzimidazole Carbonization - Mainly 2-isobutylthio-1-(2-pyridylmethyl)benzimidazole Example 4 2-isopropylthio-1-(2 -pyridylmethyl)benzimidazole Example 5 2-cyclohexylthio-1-(2-pyridylmethyl)
Benzimidazole 2-allylthio-1-(2-pyridylmethyl)benzimidazole IL-1 2-benzylthio-1-(2-pyridylmethyl)benzimidazole Example 8 2-cyanomethylthio-1-( 2-pyridylmethyl)benzimidazole disaster once 2-(2-hydroxyethyl)thio-1-(2-pyridylmethyl)benzimidazole the next step 2-ethoxycarbonylmethylthio-1-(2-pyridylmethyl) Benzimidazole Ohtabi Team A method for synthesizing 2-morpholinocarbonylmethylthio-1-(2-pyridylmethyl)benzimidazole.

0.32 g (3,0 mmol) of morpholine was added to 1.0 g (3,05 mmol) of 2-ethoxycarbonylmethylthio-1-(2-pyridylmethyl)benzimidazole, which was the compound synthesized in Example 10. The mixture was heated and stirred at 100°C for 18 hours. After cooling, the mixture was diluted with water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from chloroform and n-hexane to obtain 0.81 g (yield: 72%) of the title compound.

Example 12 2-(N-methylcarbamoylmethylthio)-1-(2
- Synthesis method of pyridylmethyl)benzimidazole 2.0 g (6.12 mmol) of 2-ethoxycarbonylmethylthio-1-(2-pyridylmethyl)benzimidazole, which is the compound synthesized in Example 10, was added to methylamine-tetrahydrofuran. Solution (5 mmol/mj
! )l was dissolved in 2 ml of water, and the mixture was stirred at room temperature for 20 hours. The residue obtained by distilling off the solvent was recrystallized from methylene chloride; ether to obtain 1.43 g of the title compound (yield: 7
5%).

2-Ethoxycarbonylmethylthio-1-, which is the compound synthesized in Example 10 of the synthesis method for 2-carbamoylmethylthio-1-(2-pyridylmethyl)benzimidazole.
(2-pyridylmethyl)benzimidazole 0.50g
(1,53 mmol) was added to a mixed solution of 2 ml of 28% ammonia water and 2 ml of isopropanol in a sealed tube for 10 min.
The mixture was stirred at 0°C for 15 hours. After cooling, isopropanol was distilled off, water was added, and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from chloroform and n-hexane to obtain 0.28 g (yield: 61%) of the title compound.

Next 1” Rainbow-■ 2-Methylsulfinyl-1-(2-pyridylmethyl)
Synthesis of benzimidazole 1.50 g of 2-methylthio-1-(2-pyridylmethyl)benzimidazole, which is the compound of Example 1 (5,
87 mmol) to 50 mj of methylene chloride! Dissolved in
Under water cooling, 80% m-chloroperbenzoic acid 1.27 g (5
, 87 mmol) was added little by little. After stirring at room temperature for 1 hour, the mixture was washed with an aqueous sodium bicarbonate solution, and the organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent was crystallized from methylene chloride; ether to obtain 1.36 g (yield: 85%) of the title compound.
I got it.

The following compound was synthesized in the same manner as in Example 14. However, in Example 15, the compound of Example 2, the compound of Example 1
In Example 6, the compounds of Example 3 were used as starting materials, respectively. The physical properties of the obtained compounds are summarized in Table 1.

Example 17 Synthesis of 2-methylsulfonyl-1-(2-pyridylmethyl)benzimidazole 1.50 g of 2-methylthio-1-(2-pyridylmethyl)benzimidazole, the compound of Example 1 (5,
87 mmol) was dissolved in 50 ml of methylene chloride, and 2.53 g of 80% m-chloroperbenzoic acid (11,
75 mmol) was added in small portions. After stirring at room temperature for 6 hours, the organic layer was washed with an aqueous sodium hydrogen carbonate solution, separated, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was recrystallized from chloroform/ether to obtain 1.69 g (yield: 100%) of the title compound.

The physical properties of each compound synthesized in Examples 1 to 17 are shown in Table 1 below. In addition, in the table below, R and n indicate the type of substituent R and the number of the substituent R in the general formula (1).

The following tests were conducted on the pharmacological effects of the compounds of the present invention.
W has the effect of suppressing gastric acid secretion and protecting the gastric mucosa.
I recognized it.

Trial J fake friend 1, effect on gastric acid secretion (Shay rat) weight 20
0-240 g of Sprague
- Dawley male rats were used after being fasted for 24 hours (water was provided ad libitum). Laparotomy was performed under ether anesthesia,
After ligating the pyloric region, the abdomen was closed and the animals were left under fasting conditions for 4 hours. The stomach was removed under ether anesthesia and gastric juice was collected. The collected gastric juice was centrifuged at 3000 rpm for 10 minutes, and the volume of the supernatant was 11 (after measuring mj, 1 nl of gastric juice; fr-0
The acidity (μEB/ml) was determined by titration to pH 7.0 with a 1N sodium hydroxide solution.

Furthermore, the amount of acid excreted (μEg/4h) is calculated from the product of gastric juice volume and acidity.
was calculated; the inhibition rate was calculated from the following formula. All test drugs were suspended in physiological saline at a concentration of 0.2 mJ! / 100g
It was administered into the duodenum immediately after pyloric ligation at a proportion of body weight.

Sprague-Dourii (Sp) weighing 200-240 g
(Rague-Dawley) male rats were used after being fasted for 24 hours. A 60% ethanol solution containing 150 mmol hydrochloric acid was orally administered to the rat in a volume of 0.5 mL and 100 g body weight, and one hour later, the stomach was removed under ether anesthesia. Inject 1 Qmg of 2% formalin solution into the stomach, and further soak in the 2% formalin solution for about 15 minutes.
The inner and outer walls of the stomach were fixed. An incision was made along the tenryu, and the length of damage occurring on the dorsal part of the gland was measured under a stereomicroscope with a magnification of 10 times.
The inhibition rate was calculated using the following formula, and the inhibition rate was then plotted on a semi-logarithmic graph against the dose (■/kg). I found the value.

All test drugs were suspended in physiological saline, 0.5 ml
/100 g body weight was orally administered 30 minutes before administration of the hydrochloric acid ethanol solution.

Results of the above Test 2 - ED of the compound of Example 1. value is 0
．． It was 8 mg/kg.

The inhibition rate data obtained from Tests 1 and 2 are shown in Table 2.

Margin below Table 2 2 42.1 (30) 70.4 (30) 8
34.5 (30) 9 37.3 (30)

Claims (1)

[Claims] 1. General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R is an alkenyl group, an aryl group, a cyano group,
Represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, which may have a substituent selected from a hydroxy group, an alkoxycarbonyl group and an aminocarbonyl group; n is 0, 1 2-pyridylmethyl)benzimidazole derivatives and pharmacologically acceptable acid addition salts thereof. 2. The compound according to claim 1, wherein R is a linear or branched alkyl group having 1 to 10 carbon atoms. 3. R is an alkenyl group having 2 to 5 carbon atoms, 6 to 10 carbon atoms
Aryl group, cyano group, hydroxy group, carbon number 1-4
1 carbon number having a substituent selected from an alkoxycarbonyl group having an alkyl group and an aminocarbonyl group
The compound according to claim 1, which is a linear or branched alkyl group of -5. 4. General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R is a substituent selected from an alkenyl group, an aryl group, a cyano group, a hydroxy group, an alkoxycarbonyl group, and an aminocarbonyl group) 1 to 1 carbon atoms, which may have
2-pyridylmethylbenzimidazole derivatives (10 linear, branched or cyclic alkyl groups; n represents 0, 1 or 2) and/or pharmacologically acceptable acid addition salts thereof A peptic ulcer treatment containing as an active ingredient.