Unlock instant, AI-driven research and patent intelligence for your innovation.

Benzimidazole derivatives serving as calcium channel blocker

A use, technology of phenyl, applied in the field of benzimidazole derivatives used as calcium channel blockers

Active Publication Date: 2013-03-20
IDORSIA PHARM LTD
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007]Despite the great need for compounds of this profile, due to unacceptable CYP3A4 drug interactions, miberadil was launched in 1998 (one year after its market launch) qiut the market

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Benzimidazole derivatives serving as calcium channel blocker
  • Benzimidazole derivatives serving as calcium channel blocker
  • Benzimidazole derivatives serving as calcium channel blocker

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0204] Example 1: Racemic-(1R ＊ , 2R ＊ , 4R ＊ )-2-(2-{[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-benzene Base-bicyclo[2.2.2]oct-5-en-2-ol

[0205] 1.1 (Procedure P1.1): rac-(1R ＊ , 2R ＊ , 4R ＊ )-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid

[0206] To 4.0g rac-(1R * , 2R * , 4R * 2.1 g LiOH.H 2 O, 8mL H 2 O and 22 mL MeOH. The reaction mixture was stirred at room temperature for 3 days and then concentrated. Make the residue in water with Et 2 O distribution. The aqueous layer was separated and acidified with 1N HCl, resulting in the formation of a white solid. The solid was filtered, washed with 5 mL of dilute HCl and dried in vacuo to obtain 3.2 g of rac-(1R * , 2R * , 4R * )-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid.

[0207] LC-MS: t R =0.86min; [M-H 2 O+H] + : 241.28.

[0208] 1.2 (Procedure P 1.2): rac-(1R ＊ , 2R ＊ , 4R ＊ )-N-[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-2-(2-hydro...

example 1A

[0214] Example 1A: rac-isobutyric acid (1R ＊ , 2R ＊ , 4R ＊ )-2-(2-{[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-benzene yl-bicyclo[2.2.2]oct-5-en-2-yl ester

[0215] 1A.1 (Procedure P1.4): rac-isobutyric acid (1R ＊ , 2R ＊ , 4R ＊ )-2-(2-{[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-benzene yl-bicyclo[2.2.2]oct-5-en-2-yl ester

[0216] At 0°C to 199mg rac-(1R * , 2R * , 4R * )-2-(2-{[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-benzene A solution of 1-bicyclo[2.2.2]oct-5-en-2-ol in 4 mL of DCM was added with 0.2 mL of NEt 3 and 0.1 mL of isobutyryl chloride. The reaction mixture was stirred overnight to allow the temperature to slowly reach room temperature. Saturated with NaHCO 3 The reaction was quenched with aqueous solution, the phases were separated and the aqueous phase was re-extracted with DCM. The combined organic phases were washed with brine, washed over MgSO 4 Dry and concent...

example 2

[0221] Example 2: (1R, 2R, 4R)-2-(2-{[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino }-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol or (1S,2S,4S)-2-(2-{[3-(4,7-di Methoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol

[0222] 2.1: (1R,2R,4R)-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid or (1S,2S,4S)-(2- Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid

[0223] According to procedure P1.1 in Example 1, using rac-(1R * , 2R * , 4R * )-(2-Hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert-butyl ester enantiomer B (see K1A.6).

[0224] LC-MS: t R =0.91min; [M-H 2 O+H] + : 241.10.

[0225] 2.2: (1R, 2R, 4R)-2-(2-{[3-(4,7-dimethoxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino} -Ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol or (1S,2S,4S)-2-(2-{[3-(4,7-dimethyl Oxy-1H-benzimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol

[0226] Prepared according to Procedu...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to compounds of formula (I) wherein R1 represents aryl, which is unsubstituted, or mono-, di-, or tri-substituted wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and trifluoromethyl; R2 represents hydrogen, or —CO—R21; R21 represents (C1-5)alkyl, (C1-3)fluoroalkyl, or (C3-6)cycloalkyl; m represents the integer 2, or 3; p represents the integer 2 or 3; and R3 represents hydrogen, or (C1-5)alkyl; and pharmaceutically acceptable salts of such compounds. These compounds are useful as calcium channel blockers.

Description

technical field [0001] The present invention relates to novel benzimidazole derivatives and their use in the treatment or prevention of chronic stable angina, hypertension, ischemia (renal and cardiac), arrhythmias including atrial fibrillation, cardiac hypertrophy or congestive heart failure Use as potent calcium channel blockers; to pharmaceutical compositions containing these derivatives; and to processes for their preparation. The benzimidazole derivatives of the present invention can also be used alone or in the form of a pharmaceutical composition for the treatment of kidney disease, diabetes and its complications, hyperaldosteronism, epilepsy, neuralgia or cancer in humans and other mammals. [0002] Background technique [0003] Many cardiovascular disorders have been associated with "calcium overload" caused by abnormally elevated calcium influx across the plasma membrane of cardiac and vascular smooth muscle cells. There are three main pathways through which extra...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/14A61K31/4184A61P9/00
CPCC07D235/14A61P13/12A61P9/00A61P9/04A61P9/06A61P9/10A61P9/12
Inventor 弗朗西斯·于布莱库尔特·希尔珀特多尔特·伦内贝格
Owner IDORSIA PHARM LTD