4-Azaindole Derivatives

a technology of azaindole and derivatives, applied in the field of 4azaindole derivatives, can solve the problems of difficult to obtain selective machr m1 orthosteric ligands, side effects of dose-limiting peripheral cholinergics,

Inactive Publication Date: 2015-04-02
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]An object of the present invention is to provide compounds that are modulators of mAChR M1 which may be useful as prophylactic or therapeutic agents for a neurological disorder such as

Problems solved by technology

As a result, muscarinic activation by non-selective agonists has resulted in dose-limiting peripheral cholinergic side-effects which may be attributed to their relative lack of se

Method used

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Examples

Experimental program
Comparison scheme
Effect test

examples 1-105

Compound Examples 1-105

Example 1

N-((1S,2S)-2-hydroxycyclohexyl)-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

[0577]To a mixture of N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 4), (100 mg), 1-(chloromethyl)-4-methylbenzene (60 mg) and cesium carbonate (289 mg) was added DMF (4 mL) and left to stir at rt for 90 min. The crude product was purified by prep. LC-MS to give the desired compound (88 mg).

[0578]LCMS: m / z 364.65 [M+H]+.

[0579]1H NMR (400 MHz, CDCl3) ppm 1.20-1.88 (m, 6H) 2.10-2.21 (m, 2H) 2.34 (s, 3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.80-4.02 (m, 1H) 4.54 (br. s., 1H) 5.30 (s, 2H) 6.99-7.10 (m, 2H) 7.10-7.22 (m, 3H) 7.50-7.72 (m, 1H) 8.09 (s, 1H) 8.39-8.59 (m, 1H) 9.05 (d, J=6.1 Hz, 1H)

example 2

1-(3,5-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

[0580]To a mixture of N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 4), (80 mg), 1-(bromomethyl)-3,5-difluorobenzene (77 mg) and cesium carbonate (231 mg) was added DMF (3 mL) and left to stir at rt over the weekend. The crude product was diluted with MeOH and purified using an SCX-2 cartridge (washed sequentially with MeOH, H2O, MeOH and product eluted using 2 M methanolic ammonia). The solution was evaporated under vacuum to give a solid which was dissolved in DCM and purified using column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL / min, gradient 0-100% EtOAc in n-hexane) to give the desired compound (70 mg)

[0581]LCMS: m / z 386.59 [M+H]+.

[0582]1H NMR (400 MHz, CDCl3) ppm 1.15-1.67 (m, 4H) 1.72-1.91 (m, 2H) 2.07-2.23 (m, 2H) 3.59 (td, J=9.9, 4.5 Hz, 1H) 3.92 (dddd, J=11.5, 9.4, 7.0, 4.4 Hz, 1H) 5.34 (s, 2H) 6.57-6.69 (m, 2...

example 3

1-(2,5-Difluorobenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide

[0583]To a mixture of N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 4), (80 mg), 2-(bromomethyl)-1,4-difluorobenzene (77 mg) and cesium carbonate (231 mg) was added DMF (3 mL) and left to stir at rt over the weekend. The crude product was purified by prep. LC-MS to give the desired compound (68 mg).

[0584]LCMS: m / z 386.59 [M+H]+.

[0585]1H NMR (400 MHz, CDCl3) ppm 1.10-1.64 (m, 4H) 1.67-1.90 (m, 2H) 2.14 (d, J=11.6 Hz, 2H) 3.57 (td, J=9.8, 4.5 Hz, 1H) 3.81-4.00 (m, 1H) 5.36 (s, 2H) 6.57-6.77 (m, 1H) 6.88-7.05 (m, 1H) 7.05-7.14 (m, 1H) 7.22 (dd, J=8.3, 4.7 Hz, 1H) 7.69 (d, J=8.3 Hz, 1H) 8.11 (s, 1H) 8.53 (d, J=4.4 Hz, 1H) 9.04 (d, J=6.2 Hz, 1H)

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Abstract

4-Azaindole derivatives which are modulators of muscarinic acetylcholine receptor (mAChR) M1 and which may be effective for the prevention or disease modifying or symptomatic treatment of cognitive deficits associated with neurological disorders such as Alzheimer-type dementia (AD) or dementia with Lewy bodies (DLB), and a pharmaceutical composition comprising a 4-azaindole derivative as an active ingredient.

Description

FIELD OF THE INVENTION[0001]The present invention relates to 4-azaindole derivatives and the pharmaceutical use thereof. More particularly, the present invention relates to 4-azaindole derivatives which are modulators of muscarinic acetylcholine receptor (mAChR) M1 (mAChR M1) and may be effective for the prevention or disease modifying or symptomatic treatment of cognitive deficits associated with neurological disorders such as Alzheimer-type dementia (AD) or dementia with Lewy bodies (DLB), and to a pharmaceutical composition comprising a 4-azaindole derivative as an active ingredient.BACKGROUND[0002]It is believed that cholinergic hypofunction contributes to the cognitive deficits associated with Alzheimer's disease (Science, 1982, 215, 1237-1239) and acetylcholinesterase inhibitors, which inhibit acetylcholine hydrolysis, are used clinically for the treatment of cognitive impairment in Alzheimer's disease. Cholinergic deficits are also prominent in dementia with Lewy bodies (DLB)...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04C07D471/04A61P25/00A61K31/437A61P25/28
Inventor PAYNE, ANDREWCASTRO PINEIRO, JOSE LUISBIRCH, LOUISE MICHELLEKHAN, AFZALBRAUNTON, ALAN JAMESKITULAGODA, JAMES EDWARDSOEJIMA, MOTOHIRO
Owner EISIA R&D MANAGEMENT CO LTD
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