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Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors

A technology of alkyl group and substituent is applied in the field of oxopiperazine-azetidine amide and oxodiazepine*-azetidine amide as monoacylglycerol lipase inhibitor, and can solve the problem of Difficulty separating side effects

Inactive Publication Date: 2013-05-01
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] While enhanced cannabinoid signaling has indeed been shown to produce analgesia and anti-inflammatory effects using synthetic cannabinoid agonists, it remains difficult to separate these beneficial effects from the undesired side effects of these compounds

Method used

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  • Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors
  • Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors
  • Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0315] 4-pyrimidin-2-yl-1-(1-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl) Piperazin-2-one, compound 23

[0316]

[0317] Step A. 1-(6-Trifluoromethyl-benzo[b]thiophene-2-carbonyl)-azetidin-3-one 1e. N-Boc-azetidin-3-one 1a (171 mg, 1.0 mmol) and TFA (1 mL) were dissolved in CH 2 Cl 2 (4 mL) was stirred at room temperature for 2 h. The solution was concentrated to obtain intermediate 1b, which was used in the next step without further purification. To 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 1c (246 mg, 1.0 mmol) in CH 2 Cl 2 To the suspension in (10 mL) was added oxalyl chloride (0.105 mL, 1.2 mmol) followed by DMF (2 drops). The reaction mixture was stirred at room temperature for 4 h and concentrated to obtain the acid chloride 1d which was used in the next step without further purification. To 1b (1.0mmol) and Et at 0°C 3 N (0.835 mL, 6.0 mmol) in CH 2 Cl 2 (7 mL) was added 1d (1.0 mmol) in CH 2 Cl 2 (5 mL). The reactio...

example 2

[0323] 4-pyrimidin-2-yl-1-[1-({1-[4-(trifluoromethyl)phenyl]-1H-indol-5-yl}carbonyl)azetidinine- 3-yl]piperazin-2-one, compound 24

[0324]

[0325] Step A. [2-(Pyrimidin-2-ylamino)-ethyl]-carbamic acid tert-butyl ester 2a.

[0326] Within 9h, 2-bromopyrimidine 1i (600mg, 3.77mmol), N-Boc-ethylenediamine 1f (1000mg, 6.24mmol) and K 2 CO 3 (781mg, 5.66mmol) in dioxane (20mL) and H 2 The mixture in O (10 mL) was heated to reflux. The mixture was concentrated to remove most of the dioxane, and the resulting mixture was extracted with EtOAc. The organic solution was washed with NaCl aqueous solution, with Na 2 SO 4 Dried and concentrated. Purification by column chromatography (silica gel, 50% EtOAc / heptane) afforded Intermediate 2a (770 mg) as a white solid.

[0327] Step B. 3-[2-(Pyrimidin-2-ylamino)-ethylamino]-azetidine-1-carboxylic acid tert-butyl ester 2b .

[0328] Intermediate 2a (610 mg, 2.56 mmol) was dissolved in TFA (2 mL) and CH 2 Cl 2 (8 mL) wa...

example 3

[0334] 1-pyrimidin-2-yl-4-[1-({1-[4-(trifluoromethyl)phenyl]-1H-indol-5-yl}carbonyl)azetidinine- 3-yl]piperazin-2-one, compound 3

[0335]

[0336] Step A. tert-butyl 3-oxo-4-pyrimidin-2-yl-piperazine-1-carboxylate 3b .

[0337] To 1-Boc-3-oxopiperazine 3a (390 mg, 1.95 mmol) in DMF (5 mL) was added NaH (60% in oil, 97 mg, 2.44 mmol) at 0°C. The reaction was stirred at 0° C. for 25 min before adding a solution of 2-bromopyrimidine 1i (465 mg, 2.92 mmol) in DMF (2 mL). The reaction was slowly warmed to room temperature overnight. Add H to the reaction mixture 2 0, and the resulting mixture was extracted with EtOAc. The organic solution was washed with NaCl aqueous solution, with Na 2 SO 4 Dried and concentrated. By column chromatography (silica gel, 3% MeOH / CH 2 Cl 2 ) to obtain 3b (120 mg) as a yellow oil.

[0338] Step B. 3-(3-Oxo-4-pyrimidin-2-yl-piperazin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester 3c .

[0339] Intermediate 3b (120 mg, 0.43 m...

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PUM

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Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds, and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, are represented by Formula (la) and Formula (lb) as follows: wherein Y, Z, and n are defined herein; and wherein Yb and Zb are as defined herein.

Description

[0001] Cross references to related patent applications [0002] Not applicable. [0003] Statement Regarding Federally Sponsored Research or Development [0004] The research or development of the invention described below was not federally funded. Background technique [0005] Cannabis sattva has been used for many years to treat pain. Δ 9 - THC is the main active ingredient from cannabis and is a cannabinoid receptor agonist (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two cannabinoid G protein-coupled receptors, type 1 cannabinoid receptors (CB 1 Matsuda et al., Nature "Nature" 1990, 346, 561-4) and type 2 cannabinoid receptor (CB 2 Munro et al., Nature, 1993, 365, 61-5). CB 1 Expressed centrally in brain regions such as the hypothalamus and nucleus accumbens, and peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, New Insights in Lipidology, 2007, 18, 129-140). CB 2 Mainly expre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D403/14C07D409/14C07D417/14A61K31/506A61P29/00
CPCC07D417/14C07D403/14C07D403/04C07D409/14A61P1/02A61P1/04A61P1/16A61P1/18A61P13/02A61P13/10A61P15/00A61P17/00A61P17/04A61P19/02A61P25/00A61P25/06A61P29/00A61P37/00A61P43/00A61K31/506
Inventor P.J.康诺利M.J.麦切拉格M.E.麦唐奈尔B.朱
Owner JANSSEN PHARMA NV
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