Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation

A diene and diazepine technology, applied in the field of cannabinoid receptor modulators, can solve problems such as poor compliance and liver toxicity

Inactive Publication Date: 2009-11-04
GLENMARK PHARMACEUTICALS LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Current treatments for alcohol abuse or dependence often suffer from poor adherence or potential hepatotoxicity

Method used

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  • Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation
  • Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation
  • Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0751] Example 1: 5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0 2，6 .]dec-2(6),3-dien-3-yl- Preparation of phenyl phenone:

[0752] The Grignard reagent was generated from bromobenzene (187 μl, 1.80 mmol) and magnesium turnings (50 mg, 2.10 mgatoms) in ether (15 ml) and was added dropwise with intermediate 6 ( 500 mg, 1.50 mmol), and the mixture was stirred at room temperature for 2 hours. Add saturated NH 4 Cl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, Na 2 SO 4 , and evaporate the solvent. Purification by chromatography followed by preparative HPLC provided the title compound as a waxy solid (269 mg, 51%). 1 H-NMR (δppm, CDCl 3 , 300MHz): 8.30(d, J=7.2, 2H); 7.79-7.68(m, 1H); 7.62-7.44(m, 3H); 7.02(t, J=9.0, 2H); 3.70(br.s, 1H); 3.51(br.s, 1H); 2.14(d, J=8.4, 1H); 1.99(d, J=7.5, 2H); 1.72(d, J=8.4, 1H), 1.28(d, J =9.3, 2H). MS (m / z): 351.41 ([M+H] + ).

Embodiment 2

[0753] Example 2: 1-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0 2，6 ]dec-2(6),3-diene-3- The preparation of base]-1-hexanone:

[0754] The title compound was synthesized by a method similar to that described for Example 1. Intermediate 6 (500 mg, 1.50 mmol), Mg turnings (50 mg, 2.10 mmol), diethyl ether (15 mL), 1-bromo-n-pentane (223 μl, 1.80 mmol) provided the title compound as pale yellow Oil (125 mg, 24%). 1 H-NMR (δppm, CDCl 3 , 300MHz): 7.74-7.68(m, 1H), 7.07-7.00(m, 2H); 3.71(br.s, 1H); 3.46(br.s, 1H); 3.05-2.95(m, 2H); 2.07 (d, J = 9.0, 1H); 1.96 (d, J = 9.0, 2H); 1.80-1.60 (m, 3H); 1.42-1.30 (m, 4H); 1.22 (d, J = 10.2, 2H); 0.95-0.86 (m, 3H). IR (cm -1 , KBr): 3091(m), 2956(s), 2932(s), 2872(s), 1683(s), 1610(m), 1521(s), 1428(m), 1404(m), 1367 (m), 1325(w), 1270(m), 1189(w), 1145(m), 1092(m), 965(m). MS (m / z): 345.38 ([M+H] + ).

Embodiment 3

[0755] Example 3: 5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0 2，6 .]dec-2(6),3-dien-3-yl - Preparation of 1-naphthyl ketone:

[0756] The title compound was synthesized by a method similar to that described for Example 1. Intermediate 6 (500 mg, 1.50 mmol), Mg turnings (50 mg, 2.10 mmol), diethyl ether (15 mL), 1-bromonaphthalene (250 μl, 1.80 mmol) provided the title compound after purification by preparative HPLC As an off-white solid (66 mg, 11%). M.P.: 81-84°C. 1 H-NMR (δppm, CDCl 3 , 300MHz): 8.37(d, J=5.7, 1H); 8.02-7.98(m, 2H); 7.90(d, J=5.7, 1H); 7.74-7.66(m, 1H); 7.60-7.50(m, 3H); 7.09-6.90 (m, 2H); 3.50 (br.s, 1H); 3.39 (br.s, 1H); 2.10 (d, J=9.0, 1H); 2.02-1.89 (m, 2H); 1.66 (d, J=9.0, 1H); 1.30-1.19 (m, 2H). MS (m / z): 401.38 ([M+H] + ).

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Abstract

The present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and / or disorders modulated by a cannabinoid receptor (such as pain, neurodegenative disorders, eating disorders, weight loss or control, and obesity).

Description

[0001] This application claims the benefit of Indian Patent Application No. 1838 / MUM / 2006, filed November 3, 2006. field of invention [0002] The present invention relates to novel cannabinoid receptor modulators, particularly cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptor modulators, and their treatment of diseases, conditions and / or disorders modulated by cannabinoid receptors ( Uses such as pain, neurodegenerative disorders, eating disorders, weight loss or management, and obesity). Background of the invention [0003] The endocannabinoid system comprises two major receptors, CB1 and CB2, and several ligands, including anandamide and virodhamine, which demonstrate maximal activity at cannabinoid receptors (Jonathan A W & Louis J A, Obes Man., 5-19, 2005). Anandamide, produced postsynaptically, is the main fatty acid involved in this system. It gains access to the extra cellular space and activates the CB1 cannabinoid receptors located on presynaptic nerve terminal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/54C07D401/06C07D403/04C07D413/04C07D413/12C07D417/04A61K31/416A61K31/422A61P3/00A61P25/00
CPCC07D413/04C07D417/04C07D231/54C07D403/04C07D401/06A61P1/04A61P1/14A61P1/16A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P19/06A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/02A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/24A61P25/28A61P25/32A61P25/34A61P25/36A61P27/02A61P27/06A61P29/00A61P3/00A61P31/18A61P35/00A61P3/04A61P3/06A61P37/06A61P37/08A61P43/00A61P7/06A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10
Inventor M·穆苏帕兰塔潘K·苏克尔塞G·巴拉苏布拉马尼安S·古拉帕利N·K·乔希S·纳拉亚南P·V·卡尔尼克
Owner GLENMARK PHARMACEUTICALS LIMITED
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