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Di-azetidinyl diamide as monoacylglycerol lipase inhibitors

a technology of diazetidinyl diamide and monoacylglycerol, which is applied in the direction of biocide, drug composition, animal repellent, etc., can solve the problem of difficult to separate the beneficial effects of these compounds from the unwanted side effects

Inactive Publication Date: 2012-03-08
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new compound (Formula I) and its pharmaceutical composition. The compound has various structures and can be used to treat different disorders such as pain, inflammation, and CNS disorders. The invention also provides methods for making the compound and its pharmaceutical composition. The technical effects of the invention are the discovery of a new compound with various structures that can be used to treat different disorders and the methods for making the compound and its pharmaceutical composition.

Problems solved by technology

Although the use of synthetic cannabinoid agonists have conclusively demonstrated that increased cannabinoid signaling produces analgesic and anti-inflammatory effects, it has been difficult to separate these beneficial effects from the unwanted side effects of these compounds.

Method used

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  • Di-azetidinyl diamide as monoacylglycerol lipase inhibitors
  • Di-azetidinyl diamide as monoacylglycerol lipase inhibitors
  • Di-azetidinyl diamide as monoacylglycerol lipase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 5

[0227]

[0228]2-{1′-[(6-Phenylnaphthalen-2-yl)carbonyl]-1,3′-biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one, Cpd 69. A mixture of compound 90 (40 mg, 0.08 mmol), phenylboronic acid (21 mg, 0.17 mmol), K2CO3 (23 mg, 0.17 mmol), and Pd(dppf)Cl2.CH2Cl2 (4 mg, 0.005 mmol) in EtOH (0.75 mL) and H2O (0.15 mL) was heated in a microwave reactor at 130° C. for 30 min. The mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH / CH2Cl2) gave compound 69 (34 mg). MS 474 (M+H+).

[0229]Following the procedure described above for Example 5 and substituting the appropriate reagents, starting materials and purification methods known to those skilled in the art, the following compounds of the present invention were prepared:

CpdName and data2N-(1′-{[3′-(Trifluoromethyl)biphenyl-4-yl]carbonyl}-1,3′-biazetidin-3-yl)-1,3-thiazole-4-carboxamide.1H NMR (CHLOROFORM-d, 400 MHz): δ = 8.77 (s, 1H), 8.18 (d, J = 2.4 Hz, ...

example 6

[0230]

[0231]A. tert-Butyl 3-(benzyl(methyl)amino)azetidine-1-carboxylate, 6b. To a solution of 1-Boc-azetidin-3-one 1d (1.0 g, 5.85 mmol) and N-methyl-benzylamine 6a (1.02 g, 8.43 mmol) in 1,2-dichloroethane (12 mL) and acetic acid (1 mL) was added Na(OAc)3BH (1.30 g, 6.13 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc / heptane) gave compound 6b (1.40 g).

[0232]B. tert-Butyl 3-(benzyl(methyl)amino)-[1,3′-biazetidine]-1′-carboxylate, 6d. Intermediate 6d was prepared following the procedure described in Step B of Example 1.

[0233]C. (3-(Benzylmethyl)amino)-[1,3′-biazetidin]-1′-yl)(6-(trifluoromethyl)benzo[b]thiophen-2-yl)methanone, 6f. Intermediate 6f was prepared following the procedure described in Example 4.

[0234]D. N-Methyl-N-(1′-{...

example 7

[0237]

[0238]A. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 7d. A mixture of methyl indole-5-carboxylate 7a (0.5 g, 2.85 mmol), 1-bromo-4-fluoro-benzene 7b (2 mL, 18.21 mmol), CuI (0.544 g, 2.85 mmol), and K2CO3 (0.591 g, 4.28 mmol) was heated under microwave at 220° C. for 2.5 hours. The reaction mixture was diluted with CH2Cl2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 15% EtOAc / heptane) to give 7c (0.58 g).

[0239]B. 1-(4-fluorophenyl)-indole-5-carboxylic acid, 7d. A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 7c (0.58 g, 2.15 mmol) and LiOH.H2O (0.36 g, 8.6 mmol) in THF (15 mL) and H2O (10 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 7d (0.5 g).

[0240]Following the procedur...

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Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows:wherein Q and Z are defined herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]Not applicable.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The research and development of the invention described below was not federally sponsored.BACKGROUND OF THE INVENTION[0003]Cannabis sativa has been used for the treatment of pain for many years. Δ9-tetrahydrocannabinol is a major active ingredient from Cannabis sativa and an agonist of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two cannabinoid G protein-coupled receptors have been cloned, cannabinoid receptor type 1 (CB1 Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB2 Munro et al., Nature, 1993, 365, 61-5). CB1 is expressed centrally in brain areas, such as the hypothalamus and nucleus accumbens as well as peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB2 is predominantly expressed in immune ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/427A61K31/428C07D403/04A61K31/397C07D409/14C07D413/14A61K31/423C07D403/14A61K31/4035C07D401/14A61K31/454C07D513/04A61K31/429A61P29/00A61P1/00A61P25/06A61P19/02A61P21/00A61P17/00A61P1/02A61P17/02A61P13/10A61P31/00A61P11/02A61P17/04A61P11/00A61P1/18C07D417/14
CPCC07D205/04C07D403/14C07D409/14C07D413/14C07D417/12C07D417/14A61K31/454A61K31/397A61K31/4035A61K31/423A61K31/427A61K31/428A61K31/429C07D513/04A61P1/00A61P1/02A61P1/04A61P1/06A61P1/16A61P1/18A61P11/00A61P11/02A61P13/02A61P13/10A61P15/00A61P17/00A61P17/02A61P17/04A61P19/02A61P21/00A61P25/04A61P25/06A61P29/00A61P31/00A61P43/00
Inventor CONNOLLY, PETER J.MACIELAG, MARK J.ZHU, BIN
Owner JANSSEN PHARMA NV
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