Patent FR-2955325-A1 (FR)
Title: New heterocyclic alkyl carbamate derivatives are fatty acid amide hydrolase inhibitors useful for preventing or treating e.g. vomiting, nausea, eating disorders, neurological and psychiatric diseases, epilepsy, sleep disorders, and cancers
Inventor: ABOUABDELLAH AHMED
IPC: A61K31/422
Filed: 2010-01-20
Abstract: Heterocyclic alkyl carbamate derivatives (I) and their base or acid addition salts are new. Heterocyclic alkyl carbamate derivatives of formula (I) and their base or acid addition salts are new. R2 : H, F, OH, CN, CF 3, 1-6C alkyl, 1-6C alkoxy or NR8R9; n, m : 1-3, provided that the sum of m and n is at most equal to 5; A : a covalent bond, O, 1-6C-alkylene or -O-1-6C-alkylene in which the end represented by an oxygen atom is related to the group R1; R1 : R5 group (optionally substituted by one or more R6 and/or R7 groups); R5 : phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, isobenzofuranyl, benzofuranyl, benzothiophenyl, benzothiadiazolyl, benzoxadiazolyl, indazolyl, indolizinyl, indolyl, isoindolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, fluoropyridinyl, fluoropyrimidinyl, fluoropyrazinyl, fluoropyridazinyl, fluorotriazinyl, oxazolopyridinyl, oxazolopyrimidinyl, oxazolopyrazinyl, oxazolopyridazinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, isoxazolopyrazinyl, isoxazolopyridazinyl, oxadiazolopyridinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, thienotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl, isothiazolopyridinyl, isothiazolopyrimidinyl, isothiazolopyrazinyl, isothiazolopyridazinyl or thiadiazolopyridinyl; R6 : halo, CN, -CH 2CN, nitro, OH, 1-8C alkyl, 1-6C alkoxy, 1-6C thioalkyl, 1-6C haloalkyl, 1-6C haloalkoxy, 1-6C halothioalkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 3-7C cycloalkyl-1-3C-alkylene-O-, - (CH 2) p-NR8R9, -NR8COR9, -NR8CO 2R9, -NR8SO 2R9, -NR8SO 2NR8R9, -COR8, -CO 2R8, -(CH 2) p-CONR8R9, -SO 2R8, -SO 2NR8R9 or -O-(1-3C-alkylene)-O-; R7 : phenyl, phenyl-1-4C-alkylene, phenyl-(CH 2) p-O-, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadazolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, fluoropyridinyl, thienopyridinyl, imidazopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl or thiazolopyridinyl (all optionally substituted by one or more R6); p : 0-3; R3 : F, H, 1-6C alkyl or CF 3; R4 : 5-membered heterocyclic ring (comprising furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrazolyl, oxadiazolyl, thiadiazolyl, imidazole, triazolyl or tetrazolyl), which is optionally substituted by one or more halo, 1-6C alkyl, 1-6C haloalkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkylene, 1-6C-haloalkoxy, CN, -NR8R9, -NR8C(O)R9, -NR8CO 2R9, NR8SO 2R9-, -NR8SO 2NR8R9, -C(O)R8, -CO 2R8, C(O)NR8R9, -C(O)N(R8) (1-3C-alkylene-NR10R11)-SO 2R8, SO 2NR8R9, or -O-(1-3C-alkylene)-O-; either R8, R9 : H or 1-6C-alkyl; or NR8R9 : azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine, or oxazepine (all optionally substituted by 1-6C-alkyl or benzyl); or NR8COR9 : lactam ring; or NR8CO 2R9 : oxazolidinone, oxazinone or oxazepinone ring; or NR8SO 2R9 : sultam; or NR8SO 2NRBR9 : thiazolidine dioxide or thiadiazinane dioxide; and R10, R11 : H or 1-6C alkyl. Provided that (I) excludes: 4-hydroxy-4-(4-chloro-phenyl)-piperidine-1-carboxylate of 5-methyl-isoxazol-3-ylmethyl. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Analgesic; Antiemetic; Eating-Disorders-Gen.; Neuroprotective; Neuroleptic; Anticonvulsant; Hypnotic; Cardiovascular-Gen.; Nephrotropic; Vasotropic; Cytostatic; Immunomodulator; Antiallergic; Virucide; Antiparasitic; Antibacterial; Antiinflammatory; Osteopathic; Ophthalmological; Respiratory-Gen.; Gastrointestinal-Gen.; Uropathic; Antiarthritic; Antirheumatic; Antigout; Muscular-Gen.; Muscle relaxant; Tranquilizer; Antiparkinsonian; Nootropic; Antipsoriatic; Immunosuppressant; Antianemic. MECHANISM OF ACTION : Fatty acid amide hydrolase (FAAH) inhibitor. The ability of (I) to inhibit FAAH was tested in mouse brains using radioenzymatic test. The result showed that (+)-(S)-3-(naphthalen-2-yloxymethyl)-pyrrolidine-1-carboxylate of 3-carbamoyl-isoxazol-5-ylmethyl exhibited an IC 5 0value of 8 nM.