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FAAH inhibitors

A technology of inhibitors and pharmaceuticals, applied in the field of indole and azaindole compounds, which can solve problems such as the increase of prostaglandin

Inactive Publication Date: 2014-01-08
硬木药品公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, some prostamines may be increased in the presence of FAAH inhibitors

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0334] Embodiment 1 (see route 1, operation A, B, C and D)

[0335] 2-(1-((5-chloropyrazin-2-yl)methyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(2-methoxy Pyridin-4-yl)-2-oxoacetamide (12)

[0336]

[0337] To a solution of 5-methoxy-2-methyl-1H-indole (3.45 g, 21.4 mmol) in dichloromethane (100 mL) was added oxalyl chloride (2.06 mL, 23.5 mmol) at 0°C. After 30 minutes, the reaction was allowed to warm to room temperature, and LCMS analysis indicated the presence of ketoacid chloride (via methanolysis product analysis). The reaction mixture was concentrated to dryness, then reconstituted in dichloromethane (100 mL) and cooled to 0 °C. Methanol (8.00 mL, 198 mmol) was added, then the reaction mixture was warmed to room temperature, causing a solid precipitate to form, which was filtered and washed with hexanes, dried to give 2-(5-methoxy- Methyl 2-methyl-lH-indol-3-yl)-2-oxoacetate (4.08 g, 16.5 mmol, 77% yield). The material was used without further purification. 1 HNMR...

Embodiment 2

[0341] Example 2 (see general route 2, operation E, F, C and D)

[0342] 2-(1-(4-chlorobenzyl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-(2-methoxypyridin-4-yl) -2-oxoacetamide (3)

[0343]

[0344] To a solution of 2-methyl-1H-pyrrolo[3,2-b]pyridine (74.4 mg, 0.563 mmol) and 4-chlorobenzyl chloride (0.0780 mL, 0.619 mmol) in DMSO (8 mL) at room temperature Powdered potassium hydroxide (69.5mg, 1.24mmol) was added. The reaction was stirred at room temperature for 12 hours, then LCMS analysis indicated the reaction was complete. The reaction mixture was diluted in water and extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to a clear residue. Purification was achieved by silica gel chromatography using 30 to 90% ethyl acetate in hexane over 80 minutes to afford 1-(4-chlorobenzyl)-2-methyl-1H-pyrrolo[3 ,2-b]pyridine (64.2 mg, 0.250 mmol, 44% yield). 1 H NMR (400MHz, CDCl 3 )δ (ppm): 8.41 (dd, 1H), 7.41 (d, 1H), 7.24 (d, 2H),...

Embodiment 3

[0347] Embodiment 3 (referring to general scheme 3, operation E and operation G)

[0348] 2-(1-(4-chlorobenzyl)-5-cyano-2-methyl-1H-indol-3-yl)-N-(2-methoxypyridine -4-yl)-2-oxoacetamide (15)

[0349]

[0350] To 2-methyl-1H-indole-5-carbonitrile (1.89g, 12.1mmol) and 1-chloro-4-(chloromethyl)benzene (1.53mL, 12.1mmol) in DMSO (40.3mL) at room temperature Powdered potassium hydroxide (1.39 g, 24.2 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 12 hours, diluted in water, extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to a clear residue. Purification was achieved by silica gel chromatography using 10 to 60% ethyl acetate in hexane over 75 minutes to give 1-(4-chlorobenzyl)-2-methyl-1H-indole-5 as an off-white solid -Formonitrile (2.75 g, 9.80 mmol, 81% yield). 1 H NMR (400MHz, CDCl 3 )δ(ppm):7.88(d,1H),7.34(dd,1H),7.26(d,2H),7.20(d,1H),6.86(d,2H),6.41(s,1H),5.29( s,2H), 2.30(...

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Abstract

The present disclosure relates to compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment or prevention of various disorders. Compounds of the invention are described in Table 1.

Description

[0001] priority statement [0002] This application claims priority to US Provisional Application Serial Nos. 61 / 426,362, filed December 22, 2010 and 61 / 446,808, filed February 25, 2011. The entire content of the above application is incorporated herein by reference. technical field [0003] The present disclosure relates to indole and azaindole compounds useful as fatty acid amide hydrolase (FAAH) inhibitors. The present disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the present disclosure and methods of using such compositions in the treatment of various disorders. Background of the invention [0004] The endocannabinoid (eCB) system is involved in a variety of processes, including cell signaling, memory encoding, compensatory mechanisms, and immunosuppressive and anti-inflammatory responses. The eCB system comprises at least two receptors: the CB1 cannabinoid receptors, which are widely distributed in the brain and are pres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/12C07D403/14C07D471/04A61K31/404A61P25/04
CPCC07D401/12C07D471/04C07D403/12C07D403/14C07D401/14C07D209/22A61K31/4045A61K31/4439A61K31/444A61K31/497A61K31/501A61K31/506A61P1/00A61P1/04A61P1/08A61P1/16A61P1/18A61P3/04A61P3/06A61P3/10A61P5/14A61P5/38A61P7/06A61P7/10A61P9/00A61P9/10A61P9/12A61P11/00A61P11/02A61P11/06A61P13/00A61P17/00A61P17/02A61P17/06A61P17/14A61P19/00A61P19/02A61P19/10A61P23/00A61P25/00A61P25/04A61P25/06A61P25/14A61P25/16A61P25/20A61P25/24A61P25/28A61P25/30A61P25/32A61P25/34A61P25/36A61P27/02A61P27/06A61P27/16A61P29/00A61P31/00A61P31/18A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08C07D209/14A61K45/06
Inventor C.赫森T.C.巴登J.贾A.默梅里安B.彭J.杨X.Y.于K.斯普罗特A.弗雷岑
Owner 硬木药品公司
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