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1- alkyl-1-azoniabicyclo (2.2.2) octane carbamate derivatives and their use as muscarinic receptor antagonists

A technology of alkyl and alkoxy, applied in the field of 1-alkyl-1-azonium bicyclo[2.2.2]octane carbamate derivatives and their use as muscarinic receptor antagonists , can solve the problem of decreased M2 receptor affinity

Inactive Publication Date: 2006-09-13
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, darfenacin (Pfizer) and solifenacin (Yamanouchi) in the clinical stage showed M 3 antagonistic activity, and to M 2 Reduced affinity for the receptor

Method used

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  • 1- alkyl-1-azoniabicyclo (2.2.2) octane carbamate derivatives and their use as muscarinic receptor antagonists
  • 1- alkyl-1-azoniabicyclo (2.2.2) octane carbamate derivatives and their use as muscarinic receptor antagonists
  • 1- alkyl-1-azoniabicyclo (2.2.2) octane carbamate derivatives and their use as muscarinic receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Example 1: (R)-3-(benzylphenylcarbamoyloxy)-1-cyclopropyl-1-azonium bicyclo[2.2.2]octane bromide

[0149] 200 mg (0.59 mmol) of intermediate 3 and 0.47 mL of bromocyclopropane (0.59 mmol) were mixed in 5 mL of acetonitrile / chloroform (2:3). The resulting solution was refluxed for 12 hours. The solvent was evaporated and the residue was subjected to column chromatography [SiO 2 , eluent: dichloromethane-methanol (20:1)] to give 130 mg (47%) of the title compound as a hygroscopic white solid. 1 H-NMR (CDCl 3 ): 7.27(m, 10H), 4.87(m, 2H), 4.80(m, 1H), 3.18(ddd, 1H), 3.01(m, 1H), 2.80-2.50(m, 5H), 2.23(m, 1H), 1.98(m, 2H), 1.65-1.18(m, 6H).

[0150] Synthesize the following compounds according to Example 1:

Embodiment 2

[0151] Example 2: Chloride (R)-3-(benzylphenylcarbamoyloxy)-1-(2-chlorobenzyl)-1-azoniumbicyclo[2.2.2]octane

[0152] Obtained 131 mg (45%) of a yellow oil. IR (film, cm -1 ): 1694. 1 H-NMR (CDCl 3): 7.60-7.16(m, 14H), 5.03(m, 1H), 4.92(dd, 2H), 4.80(s, 2H), 4.10(m, 1H), 3.77(m, 3H), 3.35(m, 1H), 2.78(m, 1H), 2.28(m, 1H), 1.98(m, 2H), 1.78(m, 1H), 1.60(m, 1H).

Embodiment 3

[0153] Example 3: (R)-3-(Benzylphenylcarbamoyloxy)-1-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfur chloride Alkylmethyl)-1-azoniumbicyclo[2.2.2]octane

[0154] Obtained 77 mg (53%) of a white solid. 1 H-NMR (CDCl 3 ): 7.27-7.18(m, 10H), 6.97(t, 2H), 6.82(dd, 2H), 5.12(dd, 1H), 4.82(m, 2H), 4.34(s, 2H), 4.30-4.05( m, 3H), 4.05-3.70 (m, 4H), 3.05 (dd, 1H), 2.33 (m, 1H), 2.10-1.50 (m, 4H).

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Abstract

Carbamate of general formula (I), wherein R1, R2 and R3 are H, OH, NO2, SH, CN, F, Cl, Br, I, COOH, CONH2, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylsulfanyl, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxyl optionally substituted with one or several F, and (C1-C4)-alkyl optionally substituted with one or several F or OH; R4 is cycloalkyl, phenyl, heteroaryl or a bicyclic ring system; R5 is cycloalkyl, (C5-C10)-alkyl, a substituted (C1-C10)-alkyl; and X<-> is a physiologically acceptable anion. Carbamate (I) is selective M3 receptor antagonists versus M2 receptor and may be used for the treatment of urinary incontinence (particularly, the one caused by overactive bladder), irritable bowel syndrome, and respiratory disorders (particulary, chronic obstructive pulmonary disease, chronic bronchitis, asthma, emphysema, and rhinitis), as well as in ophthalmic interventions.

Description

[0001] The present invention relates to a novel 3-alkylphenylcarbamoyloxy-1-alkyl-1-azonium bicyclo[2.2.2]octane compound used as a muscarinic receptor antagonist, and a method for preparing the compound And the use of said compound in the prevention and treatment of diseases related to respiratory tract, digestive tract and urinary system. Background technique [0002] Compounds with muscarinic receptor antagonism are known to induce bronchodilation, inhibition of gastrointestinal motility, decreased gastric acid secretion, dry mouth, dilated pupils, tachycardia, and inhibition of urinary bladder contractions. [0003] During the period 1983-1993, there were successive advances in the understanding of the pharmacology of muscarinic receptors. During this period, a total of five human genes encoding muscarinic receptor types (m1, m2, m3, m4, and m5) encoding five functional receptors (M 1 , M 2 , M 3 , M 4 and M 5 ). [0004] m 1 The receptors are postsynaptic neuronal ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/06A61K31/435A61P43/00A61K31/439A61K31/444A61K31/506A61K45/00A61K45/06A61P1/00A61P7/12A61P11/00A61P11/02A61P11/06A61P13/10A61P27/02C07D453/02
CPCC07D453/02A61K45/06A61P1/00A61P11/00A61P11/02A61P11/06A61P13/00A61P13/10A61P27/02A61P43/00A61P7/12C07D453/04C07D405/12
Inventor J·L·卡泰纳鲁伊斯C·法雷伦斯加列米A·费尔南德斯赛拉特I·J·米克尔博诺D·巴尔萨罗佩斯C·拉古纳斯阿纳尔C·萨尔切多罗卡N·托勒多梅萨A·费尔南德斯加西亚
Owner CHIESI FARM SPA
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