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

摘要

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.