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Piperidin-4-yl-zetidine diamides as monoacylglycerol lipase inhibitors

A pyridyl and phenyl technology, applied in the directions of anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as difficulty in separating side effects

Inactive Publication Date: 2013-08-21
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] While the use of synthetic cannabinoid agonists has indeed demonstrated that enhanced cannabinoid signaling produces analgesia and anti-inflammatory effects, it remains difficult to separate these beneficial effects from the undesired side effects of these compounds

Method used

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  • Piperidin-4-yl-zetidine diamides as monoacylglycerol lipase inhibitors
  • Piperidin-4-yl-zetidine diamides as monoacylglycerol lipase inhibitors
  • Piperidin-4-yl-zetidine diamides as monoacylglycerol lipase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0324]

[0325] A. tert-Butyl 3-(pyridin-4-yl)azetidine-1-carboxylate, 1c. equipped with thermocouple, magnetic stirrer, condenser, heating mantle and N 2A 1-liter 3-neck round bottom flask with an inlet adapter was charged with anhydrous dimethylacetamide (DMA, 100 mL) and zinc (42.94 g, 650.2 mmol). The mixture was stirred at 20 °C while 1,2-dibromoethane (DBE, 5.38 mL, 62.34 mmol) and trimethylchlorosilane (TMS-Cl, 7.54 mL, 59.28 mmol). The resulting slurry was aged for 15 min. A solution of tert-butyl 3-iodoazetidine-1-carboxylate 1a (122.78 g, 420.69 mmol) in DMA (201 mL) was added dropwise at a rate to keep the temperature below 65 °C over 1 h, and the milky The suspension was stirred for 30 min while cooling slowly to 20 °C.

[0326] in N 2 Under the conditions equipped with thermocouple, mechanical stirrer, condenser, heating mantle and N 2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (4.73 g, 5.74 mmol), cuprous iodide ...

example 2

[0337]

[0338] A. 3-Chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride, 2b. Thionyl chloride (73.7 mmol, 5.36 mL) was added to a mixture of 4-fluorocinnamic acid 2a (21.1 mmol, 3.5 g) and pyridine (2.53 mmol, 0.2 mL). The mixture was heated at 135 °C for 30 min, then cooled to room temperature. The crude mixture was triturated with hot hexanes to remove the solid pyridine hydrochloride by-product. Compound 2b was isolated from the combined hexane solutions.

[0339]B. 4-{1-[(3-chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-1-(1,3-thiazole-2 -ylcarbonyl)piperidine, Cpd8. Compound 2b (0.45mmol, 112mg) was dissolved in 4mL CH at 0°C 2 Cl 2 The solution in was added compound 1j mono-TFA salt (0.41mmol, 150mg) in Et 3 N (2.46mmol, 0.34mL) in solution. The resulting reaction mixture was stirred at 0 °C for 3 h. The crude product was purified by preparative reverse phase chromatography to provide 18 mg (9% yield) of Cpd8. 1 H NMR (CD 3 OD, 400MHz): δ=7.8...

example 3

[0343]

[0344] A. 3-Methyl-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 3c. Methyl thioglycolate 3b (30.3 mmol, 2.76 mL) was added dropwise to a suspension of NaH (60% oil dispersion, 75.8 mmol, 3.03 g) in 10 mL THF and 50 mL DMSO at 20 °C. The mixture was stirred for 15 min, and a solution of 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanone 3a (24.3 mmol, 5.0 g) in 10 mL DMSO was added. The reaction mixture was stirred at 20 °C for 4 h, and water was added. The mixture was extracted with EtOAc. MgSO for organic layer 4 Drying and concentration afforded compound 3c as a white solid.

[0345] B.4-(1-{[3-methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azetidin-3-yl)-1-(1 , 3-thiazol-2-ylcarbonyl)piperidine, Cpd20. To compound 1j mono-TFA salt (0.27mmol, 100mg) and compound 3c (0.30mmol, 78mg) in 4mL CH 2 Cl 2 Et was added to the stirred solution in 3 N (1.09 mmol, 0.15 mL). After 20 min at 20 °C, HATU (0.33 mmol, 125 mg) was added and the mixture was s...

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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 (I) as follows: Formula (I), wherein Y, Z, and R are 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 sativa 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, 1990, 346, 561-4) and type 2 cannabinoid receptors (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 expressed i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P29/00A61K31/4523C07D205/04C07D211/16C07D417/12C07D417/14
CPCC07D401/04C07D401/14C07D409/14C07D413/14C07D417/14A61P1/00A61P1/02A61P1/18A61P11/00A61P13/02A61P13/10A61P15/00A61P17/00A61P17/02A61P17/04A61P19/02A61P21/00A61P25/00A61P25/04A61P25/06A61P29/00A61P43/00A61K31/4523
Inventor P.J.康诺利H.卞X.李L.刘M.J.马切拉M.E.麦克唐奈
Owner JANSSEN PHARMA NV
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