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Oxazole derivatives useful as modulators of FAAH

A compound and alkyl technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as weight, calorie intake, and liver triglyceride levels

Inactive Publication Date: 2013-02-06
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, inhibition of FAAH activity in vivo results in reductions in body fat, body weight, caloric intake, and hepatic triglyceride levels

Method used

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  • Oxazole derivatives useful as modulators of FAAH
  • Oxazole derivatives useful as modulators of FAAH
  • Oxazole derivatives useful as modulators of FAAH

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0409] Preparation of lysates and microsomes

[0410] CHO cells expressing FAAH were used to prepare crude cell lysates or microsomal fractions. To harvest the cells, decant the tissue culture medium slowly and replace the monolayer with Ca-free ++ Mg ++ The cells were washed three times with PBS and recovered after 15 min in enzyme-free dissociation medium (Millipore Corp, Billerica, MA). Cells were harvested by centrifugation at 2000 rpm for 15 min, and the cell pellet was washed with 50 mM HEPES (pH 7.4) containing 1 mM EDTA and the protease inhibitors aprotinin (1 mg / ml) and leupeptin (100 μM). )Resuspended. Distill the suspension at 4 0 C sonication and at 4 0 C with 12,000xg (14,600rpm, SS34 rotor) centrifugation 20min after recovering cell lysate to form the crude flake precipitate of cell debris, nucleus, peroxisome, lysosome and mitochondria; Supernatants or cell lysates were used for FAAH enzyme assays. In some cases, by subjecting cell lysates to 4 0 C was...

Embodiment A71

[0533] 2-(5-{5-[(5-Chloropyridin-2-yl)thio]-2-(tetrahydro-2 H -pyran-4-yl)-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol

[0534]

[0535] Oxazole 5-bromide A6.1 (172 mg, 0.467 mmol), 5-chloropyridine-2-thiol (136 mg, 0.934 mmol), K 3 PO 4 (297 mmol, 1.40 mmol), N,N- A mixture of dimethylglycine (9.6 mg, 0.093 mmol) and CuI (18 mg, 0.093 mmol) in DMF (4.67 mL) was heated at 145 °C for 5 h. Using reverse phase HPLC (C-18, 35-95% MeCN in H 2 O, containing 0.05% TFA) to give the product. 1 H NMR (CDCl 3 , 400 MHz)δ9.15 (bs, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 3.0, 8.4 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.84 (bs, 1H), 4.06 (td, J = 3.6, 8.4 Hz, 2H), 3.57 (dt, J = 3.2, 11.6 Hz, 2H), 3.17 (m, 1H), 2.10-1.97 (m, 4H), 1.55 (s, 6H). C 21 h 23 ClN 3 o 3 S HRMS (ES) [M+1] + Calculated: 432.1143, Found: 432.1141.

[0536] Intermediate A6.2

[0537]

[0538] tert-butyl 4-{5-bromo-4-[4-(methylsulfinyl...

Embodiment A713

[0549] 4-{5-[(5-chloropyridin-2-yl)thio]-4-[4-(methylsulfinyl)phenyl]-1,3-oxazol-2-yl}piperidine- tert-Butyl 1-formate

[0550]

[0551] Intermediate 6.2 (685 mg, 1.46 mmol), 5-chloropyridine-2-thiol (531 mg, 3.65 mmol) and potassium carbonate (605 mg, 4.38 mmol) were dissolved in NMP (14.6 mL) and the resulting solution Heat to 85 oC for 16 hours in a closed tube. The solution was then cooled to 25 °C, diluted with ethyl acetate, washed with aqueous lithium chloride (x3), dried over sodium sulfate and concentrated in vacuo. The crude oil was purified by silica gel chromatography (100 g using a gradient of 25-100% ethyl acetate in hexanes) to afford 658 mg of the desired product as a clear oil. LCMS (M+1) = 534.5. 1 H NMR (CDCl 3 ): δ8.38 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 6.8 Hz, 2H), 7.7 (d, J = 6.8 Hz, 2H), 7.54 (dd, J = 8.5 Hz, 2.1 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.15 (m, 2H), 3.1 (m, 3H), 2.73 (s, 3H), 2.15 (m, 2H), 1.95 (m, 2H), 1.51 (s, 9H).

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PUM

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Abstract

The present invention is directed to certain Oxazole derivatives which are useful as modulators of Fatty Acid Amide Hydrolase (FAAH) and as FAAH imaging agents. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer Disease, and Parkinson's Disease.

Description

Background of the invention [0001] The present application discloses compounds that inhibit the activity of fatty amide hydrolase (FAAH), compositions comprising the compounds, and methods of using the same. Compounds disclosed herein that are inhibitors of fatty amidohydrolase (FAAH) are useful in the treatment of diseases, conditions or disorders that would benefit from inhibition of fatty amidohydrolase and an increase in endogenous fatty amides. [0002] Fatty amide hydrolase (FAAH) is abundantly expressed throughout the CNS (Freund et al., Physiol. Rev. 2003; 83:1017-1066) and in surrounding tissues such as pancreas, brain, kidney, skeletal muscle, placenta and liver (Giang, D. K. et al., Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2238-2242; Cravatt et al., Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 29, 10821-10826). FAAH hydrolyzes the fatty amide (FAA) family of endogenous signaling lipids. General classes of fatty acid amides include N-acylethanolamides (NAE) and fatty ac...

Claims

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Application Information

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IPC IPC(8): A61K31/42A61K31/535
CPCC07D263/46C07D413/04C07D413/14A61P19/02A61P21/00A61P25/00A61P25/02A61P25/04A61P25/06A61P25/16A61P25/20A61P25/28A61P29/00A61P43/00
Inventor 杨志强P.G.南特梅特C.克里特索拉斯K.P.穆尔E.F.沙伦
Owner MERCK & CO INC
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