Patent EP-2025675-A1 (EP)
IPC: C07D401/02
Filed: 2008-02-26
Abstract: Amide compounds (I) and their enantiomers, diastereomers, mixtures and salts, preferably with organic or inorganic acids or bases, are new. Amide compounds of formula (R 5>-A-R 4>-B1-R 3>-A-D1-Y1-N(R 2>)-SO 2-R 1>) (I) and their enantiomers, diastereomers, mixtures or salts, preferably with organic or inorganic acids or bases, are new. A : a bond, 1-4C-alkyl or-CH 2-C(O)-; B1 : a bond, 1-3C-alkyl, -O- or -C(O)-; D1 : -N(R 2>)-C(=O)- or -C(=O)-N(R 2>)-; Y1 : 1-6C alkyl (optionally substituted by R 2>, where methylene group is additionally substituted by Y2); Y2 : -O-, -S-, -S(O)-, -N(R 2>)-, -N(R 2>)-C(O)-, -C(O)-N(R 2>)-, -C(O)-, -CH(aryl)-, 3-6C-cycloalkylene or-S(O) 2-; R 1>3-7C-cycloalkyl- or aryl-, heteroaryl- or aryl-1-3C-alkyl- (substituted by 1-3 residues of R1a); R1a : H, F, Cl, Br, I, 1-3C-alkyl-, F 3C-, HO-, 1-3C-alkyl-O- or 1-3C-alkyl-O-2-4C-alkylene-O-; R 2>H or 1-3C-alkyl- (where each methylene group is substituted with up to 2 F and each methyl group is substituted with up to 3 F), or (H 3C-C(O)-); R 3>1-6C-alkyl, mono-, di- or tri-substituted 3-6C-cycloalkyl, mono- or di-substituted 5-7C-cycloalkenyl (which is condensed over the unsaturated bond with a phenyl ring), N(R 2>), mono- or di-substituted hetero(aryl), mono- or di-substituted saturated 4-7-membered heterocyclic ring, mono- or di-substituted unsaturated 5-7-membered heterocyclic ring (which is condensed over the unsaturated bond with one or two phenyl rings), or mono- or di-substituted saturated 8-10-membered aza-heterobicycle (all optionally substituted by R3a), or -O-; R 4>mono- or di-substituted hetero(aryl), mono- or di-substituted 4-7-membered saturated heterocyclic ring, mono- or di-substituted saturated 8-10-membered diaza-heterobicyclic ring, mono- or d- substituted 5-7-membered unsaturated heterocyclic ring, which is condensed over the unsaturated bond with one or two phenyl rings, a saturated 9-11-membered diaza-spirocycle (all optionally substituted by R4a), -O-, -C(O)O-, -C(O)NR 2>-, -NR 2>-, -NR 2>-NR 2>-, 3-7C-cycloalkylene or 1-6C-alkylene; R3a, R4a : H, F, Cl, Br, I, 1-3C-alkyl-, HO-, 1-3C-alkyl-O- or 1-3C-alkyl-O-2-4C-alkylene-O-; R 5>mono- or -di-substituted phenyl, mono- or di-substituted heteroaryl, mono- or -di-substituted 4-7-membered saturated heterocyclic ring (all optionally substituted by R5a), H, HO-, 1-3C-alkyl-, 3-7C-cycloalkyl (optionally substituted by 1-3C-alkyl-), H 2N-, 1-4C-alkyl-NH-, (3-6C-cycloalkyl)-NH-, (1-4C-alkyl) 2N-, (1-4C-alkyl)(3-6C-cycloalkyl)N- or (cyclopropylmethyl)(methyl)N-, H 2N-C(O)-; and R5a : H, F, Cl, Br, I, 1-3-alkyl-, HO-, 1-3C-alkyl-O-, (1-3C-alkyl) 2N- or 1-3C-alkyl-O-2-4C-alkylene-O-. Provided that: R 3>is -O- when B1 is not -O-. ACTIVITY : Analgesic; Vulnerary; Neuroprotective; Antiarthritic; Osteopathic; Antirheumatic; Antipyretic; Cytostatic; Antimigraine; Antiinflammatory; Antiasthmatic; Antiallergic; Respiratory-Gen; Dermatological; Vasotropic; Gastrointestinal-Gen; Antiulcer; Nephrotropic; Ophthalmological; Antipsoriatic; Immunosuppressive; Antidiabetic; Antidiuretic; Antiparkinsonian; Nootropic; Antipruritic; Anticonvulsant; Uropathic. MECHANISM OF ACTION : Bradykinin B1-receptor antagonist. The bradykinin B1-receptor antagonistic activity of (I) was tested in Chinese hamster ovary cells. The results showed that N-[3-(4-cyclobutyl-piperazin-1-yl)-cyclopentyl]-2-{2-[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}-N-methyl-acetamide exhibited an inhibition constant value of 0.34 nM.