Benzimidazole derivative containing alkoxy substituted pyridine

Abstract

The invention belongs to the technical field of medicines, and in particular relates to a benzimidazole derivative containing pyridine substituted by alkoxy as well as pharmaceutically acceptable salts or isomers thereof shown in a general formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5> and n are defined as the specification. The invention also relates to a method for preparing the compounds and a pharmaceutical composition containing the compounds, and application of the compounds to preparing the medicines for treating and / or preventing peptic ulcer.

Description

1. Technical field

[0001] The invention belongs to the technical field of medicine, and in particular relates to benzimidazole derivatives containing pyridine substituted by alkoxy groups, pharmaceutically acceptable salts and isomers thereof, methods for preparing these compounds, and pharmaceutical compositions containing these compounds , and the application of these compounds in the preparation of medicines for treating and / or preventing peptic ulcer. 2. Background technology

[0002] Digestive system disease is one of common and frequently-occurring diseases, wherein the ulcer disease sickness rate accounts for about 10%~12% of the total population. The initial treatment is mainly to use antacids (such as sodium bicarbonate, aluminum hydroxide, etc.) to neutralize gastric acid to relieve symptoms. After the 1970s, with the H 2 The discovery of gastric acid secretion inhibitors such as receptor blockers and proton pump inhibitors has created a new era of peptic ulcer t...

Examples

Embodiment 1

[0102] Example 1 Preparation of 2-mercapto-4-methoxycarbonyl-benzimidazole

[0103] Put 10g (60mmol) of 2,3-diamino-benzoic acid methyl ester into the reaction flask, add 200ml of ethyl acetate, then add 12.8g (80mmol) of potassium ethoxysulfonate, and heat to reflux at 80°C for 4h. After the reaction was completed, cool to room temperature, pour the reaction solution into 200ml of ice water, stir evenly, adjust the pH to 3-4 with 4N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, and vacuum-dry the filter cake to obtain 9.1g of the product. Rate: 73.2%.

Embodiment 2

[0104] Example 2 Preparation of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide

[0105] Add 16.8g (100mmol) of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide, 100ml of 1,3-propylene glycol monomethyl ether, powder Potassium carbonate 20g, heated and stirred under reflux for 12h, stopped the reaction, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to recover excess 1,3-propanediol monomethyl ether, and the oily substance 4-(3-methoxypropoxy) - 11.2 g of 2,3-dimethyl-N-pyridine oxide, yield: 53.2%, directly put into the next step for reaction.

Embodiment 3

[0106] Example 3 Preparation of 4-(3-methoxypropoxy)-2-hydroxymethyl-3-methyl-pyridine

[0107] Add 21.1g (100mol) of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide and 200ml acetic anhydride to a dry reaction flask, heat up to 60°C and stir for reaction 1 After 2 hours, the acetic anhydride was distilled off under reduced pressure, 150ml of 2N sodium hydroxide solution was added to the residue, stirred and reacted at 40°C for 4 hours, extracted with chloroform (100ml×3), dried and concentrated to obtain 14.8g of oil, yield 70.2%.

1. Technical field

[0001] The invention belongs to the technical field of medicine, and in particular relates to benzimidazole derivatives containing pyridine substituted by alkoxy groups, pharmaceutically acceptable salts and isomers thereof, methods for preparing these compounds, and pharmaceutical compositions containing these compounds , and the application of these compounds in the preparation of medicines for treating and / or preventing peptic ulcer. 2. Background technology

[0002] Digestive system disease is one of common and frequently-occurring diseases, wherein the ulcer disease sickness rate accounts for about 10%~12% of the total population. The initial treatment is mainly to use antacids (such as sodium bicarbonate, aluminum hydroxide, etc.) to neutralize gastric acid to relieve symptoms. After the 1970s, with the H 2 The discovery of gastric acid secretion inhibitors such as receptor blockers and proton pump inhibitors has created a new era of peptic ulcer t...

Examples

Embodiment 1

[0102] Example 1 Preparation of 2-mercapto-4-methoxycarbonyl-benzimidazole

[0103] Put 10g (60mmol) of 2,3-diamino-benzoic acid methyl ester into the reaction flask, add 200ml of ethyl acetate, then add 12.8g (80mmol) of potassium ethoxysulfonate, and heat to reflux at 80°C for 4h. After the reaction was completed, cool to room temperature, pour the reaction solution into 200ml of ice water, stir evenly, adjust the pH to 3-4 with 4N hydrochloric acid, precipitate a solid, filter, wash with water until neutral, and vacuum-dry the filter cake to obtain 9.1g of the product. Rate: 73.2%.

Embodiment 2

[0104] Example 2 Preparation of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide

[0105] Add 16.8g (100mmol) of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide, 100ml of 1,3-propylene glycol monomethyl ether, powder Potassium carbonate 20g, heated and stirred under reflux for 12h, stopped the reaction, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to recover excess 1,3-propanediol monomethyl ether, and the oily substance 4-(3-methoxypropoxy) - 11.2 g of 2,3-dimethyl-N-pyridine oxide, yield: 53.2%, directly put into the next step for reaction.

Embodiment 3

[0106] Example 3 Preparation of 4-(3-methoxypropoxy)-2-hydroxymethyl-3-methyl-pyridine

[0107] Add 21.1g (100mol) of 4-(3-methoxypropoxy)-2,3-dimethyl-N-pyridine oxide and 200ml acetic anhydride to a dry reaction flask, heat up to 60°C and stir for reaction 1 After 2 hours, the acetic anhydride was distilled off under reduced pressure, 150ml of 2N sodium hydroxide solution was added to the residue, stirred and reacted at 40°C for 4 hours, extracted with chloroform (100ml×3), dried and concentrated to obtain 14.8g of oil, yield 70.2%.

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