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Fluoroindole derivatives as muscarinic m1 receptor positive allosteric modulators

An indole compound, indole technology, applied in the direction of drug combination, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of poor brain permeability and free fraction availability, etc.

Active Publication Date: 2018-05-11
SUVEN LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the prior art discloses M1 PAM compounds useful in the treatment of CNS-related diseases, there are problems of poor brain penetration and availability of free fractions

Method used

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  • Fluoroindole derivatives as muscarinic m1 receptor positive allosteric modulators
  • Fluoroindole derivatives as muscarinic m1 receptor positive allosteric modulators
  • Fluoroindole derivatives as muscarinic m1 receptor positive allosteric modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0330] N-[(1S,2S)-2-Hydroxycyclohexyl]-1-(1-methyl-1H-pyrazol-4-ylmethyl)-4-fluoro-1H-indole-3-carboxamide

[0331]

[0332] Step 1: 1-[1-(1-Methyl-1H-pyrazol-4-ylmethyl)-4-fluoro-1H-indol-3-yl]-2,2,2-trifluoroethanone

[0333]

[0334] in N 2 To a cooled solution of 2,2,2-trifluoro-1-(4-fluoro-1H-indol-3-yl)-ethanone (1-10, 13.30 g, 0.057 mol) in DMF (100 mL) was added K 2 CO 3 (47.06 g, 0.34 mol), 4-chloromethyl-1-methyl-1 H-pyrazole hydrochloride (13.07 g, 0.078 mol) and the contents were stirred overnight at RT. The reaction mixture was quenched in ice-cold water (1000 mL) and extracted with ethyl acetate (250 mL×3). The combined organic layers were washed with water (200 mL×3), brine solution (100 mL) and washed under Na 2 SO 4 Dry on top. The organic phase was concentrated under vacuum to obtain the crude compound, which was further purified by flash chromatography using (ethyl acetate:n-hexane (80:20)) to provide 1-[1-(1-methyl-1H-pyrazole -4-ylmethyl)-4-f...

Embodiment 2

[0344] N-[(1S,2S)-2-Hydroxycyclohexyl]-1-(2-chloropyridin-4-ylmethyl)-4-fluoro-1H-indole-3-carboxamide

[0345]

[0346] Step 1: 4-Fluoro-1H-indole-3-carboxylic acid

[0347]

[0348] To 2,2,2-trifluoro-1-(4-fluoro-1H-indol-3-yl)-ethanone (1-10, 18.49 g, 0.080 mol) was added 4N aqueous NaOH (200 mL, 0.80 mol), and heated to 100°C for 3 hours. The reaction mixture was cooled to RT and diluted with ice-cold water (200 mL). The aqueous layer was washed with ethyl acetate (100 mL×2) and acidified to pH about 4 with dilute HCl. The obtained solid was filtered and washed with 100 mL of water and n-hexane, respectively. These solids were dried under vacuum.

[0349] Yield: 5.43g (38%); 1 H-NMR (DMSO-d 6 , 400MHz) δppm: 6.84-6.89(m, 1H), 7.12-7.17(m, 1H), 7.26-7.28(m, 1H), 8.02(s, 1H), 11.87(s, 1H), 12.05(m, 1H);

[0350] Mass (m / z): 180.2 (M+H) + .

[0351] Step 2: N-[(1S,2S)-2-Hydroxycyclohexyl]-4-fluoro-1H-indole-3-carboxamide

[0352]

[0353] in N 2 To a solu...

Embodiment 3 to 19

[0360] Examples 3 to 19: The compounds of Examples 3 to 19 were prepared by following the experimental procedures described in Examples 1 and 2 with some minor changes.

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

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Abstract

The present invention relates to compound of formula (I), or stereoisomers and pharmaceutically acceptable salts as muscarinic M1 receptor positive allosteric modulators. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to muscarinic M1 receptor.(Formula I) (I)

Description

technical field [0001] The present invention relates to a compound of formula (I) as a muscarinic M1 receptor positive allosteric modulator (muscarinic M1 receptor positive allosteric modulator, M1 PAM), or its isotope form, stereoisomer or pharmaceutically acceptable salt. The invention also describes methods of preparing such compounds, pharmaceutical compositions comprising such compounds and uses thereof. Background technique [0002] The muscarinic acetylcholine receptor (mAChR) belongs to the class A G protein-coupled receptor (GPCR) family and is widely expressed throughout the body. Five isoforms, termed M1 to M5, that respond to the endogenous neurotransmitter acetylcholine (ACh) have been identified so far. They play a key role in regulating the activity of many important functions of the central and peripheral nervous systems, including cognitive functions. M1, M3 and M5 are coupled to Gq, while M2 and M4 are coupled to downstream signaling pathways and related ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D417/06C07D417/14C07D401/06C07D401/12C07D403/06C07D403/14A61K31/4439A61K31/416A61K31/427A61K31/4155A61K31/428A61K31/4545A61P25/00
CPCA61K31/4155A61K31/4439A61P25/00A61P25/28C07D401/06C07D401/12C07D401/14C07D403/06C07D403/14C07D417/06C07D417/14
Inventor 罗摩克里希纳·尼罗吉阿尼尔·卡巴里·欣德阿卜杜勒·拉希德·穆罕默德拉姆库马·苏布拉马尼安维贾伊·西德拉姆·贝纳德戈皮纳德·比拉普涅尼文卡特斯瓦卢·贾斯蒂
Owner SUVEN LIFE SCI LTD
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