Guanidine-containing compounds useful as muscarinic receptor antagonists

A compound and alkyl technology, applied in the field of treatment of lung diseases, can solve the problems of cardiovascular side effects, dry mouth, insufficient treatment, etc., and achieve the effects of large therapeutic window, long receptor half-life, and improved binding affinity

Inactive Publication Date: 2010-08-04
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even when administered by inhalation, large amounts of muscarinic receptor antagonists are often absorbed into the systemic circulation, leading to systemic side effects such as dry mouth, dilated pupils, and cardiovascular side effects
[0004] In addition, many inhaled muscarinic receptor antagonists have a relatively short duration of action, requiring multiple daily doses
Not only is this multiple daily dosing regimen inconvenient, but patient non-compliance with the required frequent dosing schedule poses a significant risk of inadequate treatment

Method used

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  • Guanidine-containing compounds useful as muscarinic receptor antagonists
  • Guanidine-containing compounds useful as muscarinic receptor antagonists
  • Guanidine-containing compounds useful as muscarinic receptor antagonists

Examples

Experimental program
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Effect test

example

[0199] 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.

[0200] Unless otherwise stated, the following abbreviations have the following meanings, and any other abbreviations not defined herein have their standard meanings:

[0201] AC adenylyl cyclase

[0202] BSA bovine serum albumin

[0203] cAMP 3′-5′ cyclic adenosine monophosphate

[0204] CHO Chinese Hamster Ovary

[0205] m 5 Cloned Chimpanzee M 5 receptor

[0206] DCM dichloromethane (i.e. methylene dichloride)

[0207] DIPEA N,N-Diisopropylethylamine

[0208] dPBS Dulbecco's phosphate buffered saline

[0209] DMF N,N-Dimethylformamide

[0210] EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide

[0211] EDTA ethylenediaminetetraacetic acid

[0212] EtOAc ethyl acetate

[0213] FBS fetal bovine serum

[0214] FLI...

example 1

[0241] 4-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetyl)-N-thiophen-2-ylmethylpiperazine-1-carboxamidine

[0242]

[0243] To a stirred solution of (R)-2-cyclopentyl-2-hydroxy-2-phenyl-1-piperazin-1-ylethanone (3.9 g 13.7 mmol) in DMF (200 mL) was added DIPEA (4.8 mL, 27.3 mmol), and then C-(bis-benzotriazol-1-yl)methyleneamine (3.6 g, 13.7 mmol) was added. It was stirred at room temperature for 30 minutes, then C-thiophen-2-yl-methylamine (2.8 mL, 27.3 mmol) was added. The mixture was heated at 60°C for about 14 hours. The reaction was cooled to room temperature, and the solvent was removed by reduced pressure. The crude material was purified by reverse phase-HPLC to obtain the title compound (0.7 g, 1.3 mmol) as TFA salt. MS m / z: [M+H] + The computed value is C 23 h 30 N 4 o 2 S, 427.21; experimental value 427.2.

[0244] alternative synthesis

[0245] Add DIPEA (7.3 mL, 41.6 mmol) to (R)-2-cyclopentyl-2-hydroxy-2-phenyl-1-piperazin-1-ylethanone dissolved in etha...

example 2

[0247] 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-hydroxybenzyl)piperazine-1-carboxamidine

[0248]

[0249] (R)-2-Cyclopentyl-2-hydroxy-2-phenyl-1-piperazin-1-ylethanone (5.00 g 17.3 mmol; prepared as described in Preparation 1) in DMF (200 mL ) was added DIPEA (10.6 mL, 60.7 mmol) followed by C-(bis-benzotriazol-1-yl)-methyleneamine (5.48 g, 20.8 mmol). It was stirred at room temperature for 30 minutes, then 4-hydroxybenzylamine (12.0 g mL, 97 mmol) was added. The mixture was heated at 60°C for about 14 hours. The reaction was cooled to room temperature, and the solvent was removed by reduced pressure. The crude material was purified by reverse phase-HPLC to obtain the title compound (1.7 g, 3.1 mmol) as TFA salt. MS m / z: [M+H] + The computed value is C 25 h 32 N 4 o 3 , 437.25; the experimental value is 437.2.

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Abstract

The invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-3, R5-7, a, X, Y, Y', Y'', and Z are as defined in the specification. These compounds are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes for preparing such compounds and methods of using such compounds to, for example, treat pulmonary disorders such as chronic obstructive pulmonary disease and asthma.

Description

technical field [0001] The present invention relates to guanidine-containing compounds having muscarinic receptor antagonist activity or anticholinergic activity. The invention also relates to pharmaceutical compositions comprising these compounds, processes for their preparation and methods for the treatment of pulmonary diseases. Background technique [0002] Lung diseases or respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma suffer from millions of people worldwide and are a leading cause of morbidity and mortality. [0003] Muscarinic receptor antagonists are known to have bronchoprotective effects, and such compounds are therefore useful in the treatment of respiratory disorders such as COPD and asthma. When used to treat such conditions, muscarinic receptor antagonists are typically administered by inhalation. However, even when administered by inhalation, large amounts of muscarinic receptor antagonists are often absorbed into the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14C07D213/38C07D231/12C07D277/28C07D307/52C07D307/81C07D317/58C07D333/20C07D333/58C07D295/13A61K31/496
CPCC07D333/20C07D213/38C07D307/81C07D231/12C07D317/58C07D209/14C07D333/58C07D307/52C07D277/28C07D333/24C07D295/13A61P1/04A61P1/12A61P11/00A61P11/02A61P11/06A61P11/08A61P13/10A61P15/00A61P25/16A61P25/28A61P29/00A61P37/08A61P43/00A61P9/06
Inventor 季玉华克雷格·胡斯费尔德穆永齐里克·李李莉
Owner THERAVANCE BIOPHARMA R&D IP LLC
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