Patent FR-2930941-A1 (FR)
Title: New azetidine compounds are cannabinoid receptor type 1 antagonists useful for treating/preventing e.g. psychiatric disorders, smoking cessation, cognitive disorders, acute and chronic neurodegenerative disorders and metabolic disorders
Inventor: SABUCO JEAN FRANCOIS
IPC: A61K31/397
Filed: 2008-05-06
Abstract: Azetidine compounds (I) and their acid or base addition salts are new. Azetidine compounds of formula (I) and their acid or base addition salts are new. R : 1-6C alkyl or halo-1-6C alkyl; R 1 aNR 4R 5or OR 8; either A, B 11C or 2C, where the carbon atoms are substituted by at least one H, 1-6C alkyl optionally substituted by OH, 1-6C alkoxy, halo(1-6C) alkyl, 1-6C-alkylS(O) p, NR 4R 5or CONR 4R 5; or A+B 12C; R 1H or 1-6C alkyl; R 2, R 3H, 1-6C alkyl optionally substituted by at least one OH, 1-6C alkoxy, halo(1-6C) alkyl, 1-6C-alkylS(O) p, NR 4R 5or CONR 4R 5; either R 4, R 5H or 1-6C alkyl; or NR 4R 5azetidine, pyrrolidine, piperidine, azepane, piperazine, homopiperazine, morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide or heterocycle optionally substituted by 1-6C alkyl; R 6, R 7phenyl (optionally substituted by H, halo, 1-6C alkyl, halo-1-6C alkyl, 1-6C alkoxy, halo-1-6C alkoxy or CN); Y 1H, halo, 1-6C alkyl, halo-1-6C alkyl, 1-6C alkoxy, halo-1-6C alkoxy, 1-6C alkylS(O) por CN; R 8H, 1-6C alkyl, halo-1-6C alkyl, allyl or phenyl-1-6C alkyl, where the phenyl is optionally substituted by 1 or 2 O-methyl groups; and p : 0-2. Independent claims are included for: (1) the preparations of (I); (2) intermediate compounds comprising 33 benzoic acid ester compounds e.g. 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid methyl ester, 3-({1-[bis-(4-fluoro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid methyl ester, 3-({1-[bis-(4-fluoro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-bromo-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid ethyl ester, 3-({1-[bis-(4-bromo-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-trifluoromethyl-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid ethyl ester, 3-({1-[bis-(4-trifluoromethyl-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-methoxy-phenyl) -methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid ethyl ester, 3-({1-[bis-(4-methoxy-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-methyl-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid methyl ester, 3-({1-[bis-(4-methyl-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-cyano-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid ethyl ester, 3-({1-[bis-(4-cyano-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-trifluoromethoxy-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid methyl ester, 3-({1-[bis-(4-trifluoromethoxy-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-fluoro-benzoic acid, 3-({1-[bis-(4-chloro-phenyl) -methyl]-azetidin-3-yl}-methanesulfonyl-amino)-2-fluoro-benzoic acid methyl ester, 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-2-fluoro-benzoic acid, 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-4-fluoro-benzoic acid ethyl ester, 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-4-fluoro-benzoic acid, 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-6-fluoro-benzoic acid methyl ester, 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-6-fluoro-benzoic acid and 3-({1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl}-methanesulfonyl-amino)-5-methoxy-benzoic acid methyl ester; and (3) a process for the preparation of an acid derivative of formula (5) comprising hydrolyzing ester compound of formula (4). R 2 a1-6C alkyl, halo-1-6C alkyl, allyl, phenyl-1-6C alkyl, where the phenyl is optionally substituted by 1 or 2 O-methyl groups. [Image] [Image] ACTIVITY : Neuroleptic; Antismoking; Nootropic; Neuroprotective; Metabolic; Anorectic; Antidiabetic; Analgesic; Antianginal; Antilipemic; CNS-Gen.; Gastrointestinal-Gen.; Antiemetic; Antidiarrheic; Antiulcer; Hepatotropic; Immunomodulator; Antiarthritic; Antirheumatic; Antiinflammatory; Antiparkinsonian; Uropathic; Endocrine-Gen.; Cardiovascular-Gen.; Hypertensive; Vasotropic; Antibacterial; Immunosuppressive; Antialcoholic; Antiaddictive; Antiasthmatic; Respiratory-Gen.; Ophthalmological; Antiinfertility; Antimicrobial; Cerebroprotective; Osteopathic; Cytostatic; Anticonvulsant. MECHANISM OF ACTION : Cannabinoid receptor type 1 antagonist. The ability of (I) to inhibit cannabinoid receptor type 1 antagonist was tested using U373MG cell lines exhibiting intracellular cyclic adenosine monophosphate. The results showed that 3-((1-[bis-(4-chloro-phenyl)-methyl]-azetidin-3-yl)-methanesulfonyl-amino)-N((S)-1-carbamoyl-ethyl)-5-fluoro-benzamide exhibited an IC 5 0value of 0.009 mu M.