Patent FR-2866886-A1 (FR)
Title: New carbamoylalkyl alkylcarbamate ester derivatives, are fatty acid amidohydrolase inhibitors useful e.g. for treating pain, cancer or neurodegenerative, cardiovascular, inflammatory or allergic disease
Inventor: ABOUABDELLAH AHMED
IPC: C07D413/04
Filed: 2004-02-26
Abstract: Carbamoylalkyl N-((hetero)aryl-substituted alkyl)-carbamates (I) are new. Carbamates of formula (I) and their acid addition salts, hydrates and solvates are new. A : one or more of X, Y and/or Z; X : CH 2 (optionally substituted (os) by 1 or 2 of alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl); Y : 2C alkenylene (os by 1 or 2 of alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl) or 2C alkynylene; Z : 3-7C cycloalkylidene or 3-7C cycloalkylene; n : 1-7; R 1R 2 (os by one or more groups R 2 and/or R 3); R 2mono- or fused heteroaryl or naphthalenyl; R 3halo, CN, NO 2, alkyl, alkoxy, OH, alkylthio, fluoroalkyl, fluoroalkoxy, fluoroalkylthio, NR 5R 6, NR 5COR 6, NR 5COOR 6, NR 5SO 2R 6, COR 5, COOR 5, CONR 5R 6, SO 2R 5, SO 2NR 5R 6 or 1-3C alkylenedioxy; R 4phenyl, phenoxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl (all os by one or more groups R 3); R 5, R 6H or alkyl; or NR 5R 6azetidino, pyrrolidino, piperidino, morpholino, thiomorpholino, azepino or piperazino (all os by alkyl or benzyl); R 7H or alkyl; R 8H, alkyl, cycloalkyl or cycloalkyl-(1-3C) alkyl; alkyl moieties have 1-6C and cycloalkylene moieties 3-7C unless specified otherwise. Full definitions are given in the "Definitions" section. Independent claims are included for: (A) the preparation of (I); and (B) carbamate ester and oxazolidinedione derivative intermediates of formulae (IV) and (VII) as new compounds, provided that (i) ethyl 2-((((2-(5-hydroxy-1H-indol-3-yl)-ethyl)-amino)-carbonyl)-oxy)-propanoate and ethyl 2-((((2-(5-(phenylmethoxy)-1H-indol-3-yl)-ethyl)-amino)-carbonyl)-oxy)-propanoate are excluded as (IV) and (ii) 2-(2-(DOOD')-ethyl)-1-methyl-pyridinium iodide, 2-(2-(DOOD')-ethyl)-5-ethyl-1-methyl-pyridinium iodide, 5-methyl-3-(2-(2-(2- or 4-pyridinyl)-ethyl)-DOOD hydrochloride, 3-(5-imidazo-(1,2-a)-pyridin-5-ylpentyl)-DOOD, 3-(2-5-methyl-4-thiazolyl)-ethyl)-DOOD, 3-(2-(1H-pyrrol-2-yl)-ethyl)-DOOD, 3-(2-(2-thienyl)-ethyl)-DOOD, 3-(3-(2-thienyl)-propyl)-DOOD, 3-(4-(2-thienyl)-butyl)-DOOD, 5-(methyl or ethyl)-3-(2-(2-thienyl)-ethyl)-DOOD, 3-(2-(3-thienyl)-ethyl)-DOOD, 3-(2-(5-(methyl, acetyl or bromo)-2-thienyl)-ethyl)-DOOD, 5-(2-(DOOD')-ethyl) -2-thiophene-carboxaldehyde, 3-(3-(1-indolinyl)-propyl)-DOOD, 3-(3-(1-indolinyl)-propyl)-5-methyl-DOOD, 3-(2-(2- or 4-pyridinyl)-ethyl)-DOOD, 3-(2-(5-ethyl-2-pyridinyl)-ethyl)-5-(methyl, ethyl or isopropyl)-DOOD, 5-(ethyl or isopropyl)-3-(2-(2- or 4-pyridinyl)-ethyl)-DOOD and 3-(2-(5-ethyl-2-pyridinyl)-ethyl-DOOD are excluded as (VII). R : Me or Et; DOOD' : 2,4-dioxo-3-oxazolidinyl; DOOD : 2,4-oxazolidinedione. [Image] ACTIVITY : Analgesic; antimigraine; auditory; antiemetic; anorectic; immunomodulator; neuroleptic; relaxant; tranquilizer; antidepressant; neuroprotective; antiparkinsonian; nootropic; anticonvulsant; cerebroprotective; nephrotropic; cardiant; hypotensive; antiarrythmic; antiarteriosclerotic; vasotropic; cytostatic; immunosuppressive; antipsoriatic; dermatological; antianemic; antiallergic; antiparasitic; virucide; antibacterial; anti-HIV; antiinflammatory; antiarthritic; antirheumatic; osteopathic; antigout; ophthalmological; antitussive; antiasthmatic; antiulcer; antidiarrheic; uropathic. In phenylbenzoquinone-induced writhing tests for analgesic activity in mice, the most active compounds (I) (not specified) inhibited writhing by 35-70% at doses of 1-30 mg/kg p.o. or i.p. MECHANISM OF ACTION : Fatty acid amidohydrolase (FAAH) inhibitor. 2-Amino-2-oxoethyl (5-(isoquinolin-4-yl)-pentyl)-carbamate (Ia) had IC 5 0 267 nM for inhibition of FAAH.