Dual-acting benzoimidazole antihypertensive agents

A technology of alkyl and alkylene, applied in the field of novel compounds

Inactive Publication Date: 2010-03-17
THERAVANCE INC
View PDF6 Cites 6 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Despite advances in the art, there remains a need for highly effective monotherapies with multiple mechanisms of action to provide the degree of blood pressure control currently only achievable with combination therapies

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
  • Dual-acting benzoimidazole antihypertensive agents
  • Dual-acting benzoimidazole antihypertensive agents
  • Dual-acting benzoimidazole antihypertensive agents

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0365] Preparation of Aryl Compounds

[0366]

[0367] Compound (1d) can be prepared using synthetic methods reported in literature such as Duncia et al., (1991) J.Org.Chem. 56:2395-400 and among others References cited. Alternatively, the starting material (1e) is commercially available in protected form. Using commercially available unprotected starting material (1d), first protect R 1 group to form a protected intermediate (1e), followed by addition of a leaving group (L), such as by halogenation, to form compound (1f). For example, bromination of the methyl group of N-triphenylmethyl-5-[4'-methylbiphenyl-2-yl]tetrazole is described in Cao et al., (2005) Chinese Chemical Huihuizhi (J.Chinese Chem.Soc.) 52:539-544. In addition, when Ar * Having a -CN group can then be converted to the desired tetrazolyl, which can be protected. Nitrile groups are readily converted by reaction with suitable azides such as sodium azide, trialkyltin azide (especially tributyltin azide)...

example

[0514] The following Preparations and Examples are provided to illustrate specific embodiments of the invention. However, these specific examples are not intended to limit the scope of the invention in any way unless specifically indicated otherwise.

[0515] Unless otherwise indicated, the following abbreviations have the following meanings, and any other undefined abbreviations used herein have their standard meanings:

[0516] ACE angiotensin converting enzyme

[0517] APP aminopeptidase P

[0518] AT 1 Angiotensin II type 1 (receptor)

[0519] AT 2 Angiotensin II type 2 (receptor)

[0520] BSA bovine serum albumin

[0521] DCM dichloromethane

[0522] DIPEA N,N-Diisopropylethylamine

[0523] DMF N,N-Dimethylformamide

[0524] DMSO Dimethyl Sulfoxide

[0525] Dnp 2,4-Dinitrophenyl

[0526] DOCA deoxycorticosterone acetate

[0527] EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0528] EDTA ethylenediaminetetraacetic acid

...

example 1

[0566] 4'-[6-((R)-1-Benzyl-2-hydroxycarbamoylethylcarbamoyl)-4-methyl-2-propylbenzimidazol-1-yl Methyl]biphenyl-2-carboxylic acid tert-butyl ester (1a; R 1a = tert-butyl) and 4'-[6-((R)-1-benzyl-2-hydroxycarbamoyl ethylamine Formyl)-4-methyl-2-propylbenzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid (1b; R 1a ＝H)

[0567]

[0568] Dichloromethane (20 mL) and TFA (30 mL) were added to (R)-tert-butyl 1-benzyl-2-hydroxycarbamoylethyl)carbamate (2.8 g, 9.5 mmol; prepared as described in Preparation 4 prepared) solution. The mixture was stirred at room temperature for 30 minutes and concentrated to dryness under reduced pressure. The solid was dissolved in DMF (60 mL), followed by the addition of 3-(2'-tert-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzimidazole-5- Formic acid (2.6 g, 5.4 mmol; prepared as described in Preparation 3), HOBt (1.3 g, 10 mmol), EDC (1.8 g, 10 mmol) and DIPEA (3.9 mL, 22.4 mmol). The final mixture was stirred overnight ...

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 is directed to compounds having the formula: (I) wherein: Ar, r, n, X, R2-3 and R5-7 are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

Description

technical field [0001] The present invention relates to type 1 (AT) with angiotensin II 1 ) receptor antagonist activity and neprilysin (neprilysin) inhibitory activity of the novel compound. The invention also relates to pharmaceutical compositions comprising said compounds, processes and intermediates for preparing said compounds, and methods of using said compounds for the treatment of diseases such as hypertension. Background technique [0002] The aim of antihypertensive therapy is to lower blood pressure and prevent hypertension-related complications such as myocardial infarction, stroke and kidney disease. In patients with uncomplicated hypertension (i.e., no risk factors, target organ damage, or cardiovascular disease), lowering blood pressure would hopefully prevent cardiovascular and renal comorbidity (i.e., condition in the same patient) develops. For patients with existing risk factors or comorbidities, the goal of treatment is to slow the progression of the c...

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 Applications(China)
IPC IPC(8): C07D235/08C07D401/12C07D403/10C07D403/12C07D405/12A61P9/12A61K31/4184A61K31/4402A61K31/4406A61K31/4409A61K31/496A61K31/5377
CPCC07D401/12C07D403/10C07D403/12C07D405/12C07D235/08A61K31/4184A61K31/4439A61K31/5377A61P9/00A61P9/12A61P43/00A61K45/06C07D405/10
Inventor 保罗·阿莱格雷蒂崔锡基保罗·R·法特里罗兰·根德龙瑞安·赫德森基思·珍达罗伯特·默里·麦金内尔达伦·麦克默特里布鲁克·奥尔森
Owner THERAVANCE INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap