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Proton pump inhibitors

a proton pump inhibitor and pyrrole compound technology, applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems that the proton pump inhibitor can not meet the requirements of proton pump inhibitors sufficiently, and the effect and side effects of proton pump inhibitors are associated with problems

Inactive Publication Date: 2011-02-03
KAJINO MASAHIRO +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0201]While the compounds obtained in respective steps can be used for the next reaction in the form of a reaction mixture or a crude product, they can also be easily isolated and purified from the reaction mixture by a known separation and purification means, such as recrystallization, distillation, chromatography and the like.
[0228]In addition, the compound obtained in each step can be used for the next reaction in the form of a reaction mixture as it is or as a crude product. However, it can also be isolated from the reaction mixture according to a conventional method, and easily purified by a separation means such as recrystallization, distillation, chromatography and the like.
[0291]Compound (I) (or compound (II)) and a prodrug thereof of the present invention (hereinafter sometimes to be abbreviated as the compound of the present invention) have a proton pump inhibitory effect and effectively suppress gastric acid secretion. In addition, since they show low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like) and high water-solubility, and are superior in the stability, in vivo kinetics (absorbability, distribution, metabolism, excretion and the like), and efficacy expression, they are useful as pharmaceutical agents.
[0295]The compound of the present invention shows low toxicity and can be safely administered orally or parenterally (e.g., topical, rectal, intravenous administrations and the like) as it is or as a preparation containing a pharmaceutical composition containing a pharmacologically acceptable carrier admixed according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets), powder, granule, capsule (including soft capsule), orally disintegrating tablet, liquid, injection, suppository, sustained-release preparation, plaster and the like. Particularly, the compound of the present invention is preferably administered as an oral preparation in the form of tablet, granule, capsule and the like.
[0326]For eradication of Helicobacter pylori, a compound (I) or a salt thereof of the present invention with antibiotic penicillin (e.g., amoxicillin and the like) and antibiotic erythromycin (e.g., clarithromycin and the like) is preferably used. When the compound of the present invention is used for the purpose of eradication of Helicobacter pylori, while the compound of the present invention has an antibacterial activity against H. pylori, when co-used with other active ingredient, it can enhance the antibacterial action of other antibiotics based on the pH controlling action in the stomach and the like, in addition to the antibacterial activity of the compound per se of the present invention, and also provides an assistant effect such as an eradication effect based on the action of the antibiotics to be used in combination.

Problems solved by technology

However, the existing proton pump inhibitors are associated with problems in terms of effect and side effects.
As the situation stands, however, a proton pump inhibitor capable of sufficiently satisfying these requirements has not been found.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Ethyl 2-cyano-4-oxo-4-phenylbutanoate

[0330]Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL), and the mixture was stirred at 40-45° C. for 45 min. A solution (100 mL) of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→1:1) to give the title compound as a pale-yellow oil (yield 10.41 g, 90%).

[0331]1H-NMR (CDCl3) δ: 1.35 (3H, t, J=7.2 Hz), 3.55 (1H, dd, J=16.0 H...

reference example 2

Ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate

[0332]To a solution (60 mL) of ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g) in tetrahydrofuran was blown in hydrogen chloride (28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, nitrogen was blown in to remove hydrogen chloride. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1) to give the title compound as a pale-yellow solid (yield 4.24 g, 79%).

[0333]1H-NMR (CDCl3) δ: 1.37 (3H, t, J=6.8 Hz), 4.33 (2H, q, J=6.8 Hz), 6.87 (1H, d, J=3.2 Hz), 7.20-7.60 (5H, m), 8.79 (1H, br).

reference example 3

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate

[0334]To a solution (50 mL) of ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (8.5 g) in ethanol was added 10% palladium carbon (50% water containing product, 0.5 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a colorless solid (yield 4.50 g, 62%).

[0335]1H-NMR (CDCl3) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.91 (1H, m), 7.20-7.70 (6H, m), 8.77 (1H, br).

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Abstract

A proton pump inhibitor containing a compound represented by the formula (I)wherein X and Y are the same or different and each is a bond or a spacer having 1 to 20 carbon atoms in the main chain, R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R2, R3 and R4 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted thienyl group, an optionally substituted benzo[b]thienyl group, an optionally substituted furyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrimidinyl group, an acyl group, a halogen atom, a cyano group or a nitro group, R5 and R6 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, which has a superior proton pump action and shows an antiulcer activity and the like after conversion to a proton pump inhibitor in the body, or a salt thereof. or a prodrug thereof is provided.

Description

TECHNICAL FIELD[0001]The present invention relates to pyrrole compounds having a proton pump inhibitory activity.BACKGROUND ART[0002]Proton pump inhibitors represented by omeprazole, which suppress secretion of gastric acid for the treatment of peptic ulcer, reflux esophagitis and the like, have been widely used in clinical situations. However, the existing proton pump inhibitors are associated with problems in terms of effect and side effects. To be specific, since the existing proton pump inhibitors are unstable under acidic conditions, they are often formulated as enteric preparations, in which case several hours are required before expression of the effect. In addition, since the existing proton pump inhibitors show inconsistent treatment effects due to metabolic enzyme polymorphism and drug interaction with pharmaceutical agents such as diazepam and the like, an improvement has been desired.[0003]As pyrrole compounds having a proton pump inhibitory action, EP-A-0259085 describe...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377C07D207/48A61K31/40C07D409/12A61K31/4025C07D403/12A61K31/506C07D401/12A61K31/4439C07D405/12C07D417/12A61K31/428A61K31/4178C07D403/04A61K31/4155C07D487/04A61K31/519A61K31/501C07D413/12A61P1/00
CPCA61K31/4025A61K31/41A61K31/4439A61K31/501A61K31/506A61P1/00A61P1/04A61P35/00A61P43/00C07D207/335C07D207/48C07D401/04C07D401/12C07D403/04C07D403/12C07D405/04C07D405/12C07D409/04C07D409/12C07D417/12C07D487/04
Inventor KAJINO, MASAHIROHASUOKA, ATSUSHITARUI, NAOKITAKAGI, TERUFUMI
Owner KAJINO MASAHIRO
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