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Dual-acting benzoimidazole derivative and their use as antihypertensive agents

A compound, alkyl technology, applied in the field of disease

Inactive Publication Date: 2010-11-24
THERAVANCE INC
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  • 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 that can achieve levels of blood pressure control currently only achievable through combination therapies

Method used

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  • Dual-acting benzoimidazole derivative and their use as antihypertensive agents
  • Dual-acting benzoimidazole derivative and their use as antihypertensive agents
  • Dual-acting benzoimidazole derivative and their use as antihypertensive agents

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0327] Preparation of compound (2)

[0328] Compound (2) can be readily synthesized by the following techniques described in the literature, for example, Neustadt et al. (1994) J. Med. Chem. 37: 2461-2476 and Moree et al. (1995) J. Org. Chem. 60:5157-69, and synthesized by using the exemplary procedures set forth below. Examples of depicted achiral compounds (2) include:

[0329]

[0330] Since compound (2) has a chiral center, it is desirable to synthesize specific stereoisomers and examples are provided below.

[0331] Chiral amino hydroxamate compound (2 i ) preparation

[0332]

[0333] To a solution of compound (2a) in DMF containing HOBt and hydroxylamine hydrochloride is added a base such as DIPEA and a coupling agent such as EDC. The mixture was stirred at room temperature until the reaction was complete, then concentrated in vacuo. The resulting material was partitioned between 5% THF in EtOAc and 1M phosphoric acid. The organic layer is collected and wash...

example

[0452] The following Preparations and Examples are provided to illustrate specific embodiments of the invention. However, unless expressly stated otherwise, these specific examples are not intended to limit the scope of the invention in any way.

[0453] Unless otherwise stated, the following abbreviations have the following meanings, and any other abbreviations used herein and not defined have their standard meanings:

[0454] ACE angiotensin converting enzyme

[0455] APP aminopeptidase P

[0456] AT 1 Angiotensin II type 1 (receptor)

[0457] AT 2 Angiotensin II type 2 (receptor)

[0458] BCA bisquinolinecarboxylic acid

[0459] BSA bovine serum albumin

[0460] DCM dichloromethane

[0461] DMF N,N-Dimethylformamide

[0462] DMSO Dimethyl Sulfoxide

[0463] Dnp 2,4-Dinitrophenyl

[0464] DOCA deoxycorticosterone acetate

[0465] EDC N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide

[0466] EDTA ethylenediaminetetraacetic acid

[0467] EGT...

example 1

[0498] 4-[6-((R)-1-Benzyl-2-hydroxycarbamoylethylcarbamoyl)-4-methyl-2-propylbenzene imidazol-1-ylmethyl]benzoylase (1-a) and 4-[5-((R)-benzyl-2-hydroxycarbamoyl ethyl Carbamoyl)-7-methyl-2-propylbenzimidazol-1-ylmethyl]benzoic acid (1-b)

[0499]

[0500] To 4-[6-((R)-1-benzyl-2-benzyloxycarbamoylethylcarbamoyl)-4-methyl-2-propylbenzimidazol-1-ylmethyl ]benzoic acid and 4-[5-((R)-1-benzyl-2-benzyloxycarbamoylethylcarbamoyl)-7-methyl-2-propylbenzimidazole-1- 10% Pd / C (200 mg) was added to a nitrogen-saturated solution of methyl]benzoic acid. The mixture was degassed and stirred overnight at room temperature under hydrogen (1 atm). mixture through diatomaceous earth It was filtered, concentrated to dryness, and purified by preparative reverse phase HPLC. The desired product, compound 1-b (TFA salt; 30 mg) was obtained as a colorless solid.

[0501] Compound 1-a: C30 h 32 N 4 o 5 ESMS[M+H] + Calculated value, 529.25; Experimental value, 529.2. Hold time (analy...

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Abstract

The invention relates to compounds having the formula: (I) wherein Ar, r, n, X, R2, R2', R3, and R5-7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and aprocess and intermediates for preparing such compounds.

Description

technical field [0001] The present invention relates to angiotensin II type 1 (AT 1 ) receptor antagonist activity and renal insulin residue lysozyme inhibitory activity of novel compounds. The invention also relates to pharmaceutical compositions comprising said compounds, processes and intermediates for preparing said compounds, and methods of using said compounds to treat diseases such as hypertension. Background technique [0002] The goals of antihypertensive therapy are to lower blood pressure and prevent hypertension-related complications such as myocardial infarction, stroke, and kidney disease. In patients with uncomplicated hypertension (that is, without risk factors, target organ damage, or cardiovascular disease), it is hoped that lowering blood pressure will prevent cardiovascular and renal comorbidities (concurrent existing pathology). For those patients with risk factors or comorbidities, the goal of treatment is to slow the progression of comorbidities and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08C07D235/26C07D403/10A61K31/4184A61P9/00
CPCC07D235/26C07D403/10C07D235/08A61P29/00A61P3/06A61P43/00A61P7/02A61P7/10A61P9/00A61P9/04A61P9/12A61P3/10
Inventor 崔锡基保罗·R·法特里罗伯特·默里·麦金内尔布鲁克·奥尔森
Owner THERAVANCE INC
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