Patent DE-102005014936-A1 (DE)
Title: New substituted oxindole derivatives are vasopressin receptor binders useful to treat e.g. diabetes insipidus, enuresis nocturna, incontinence, hypertonia, heart failure, myocardial infarction, coronary spasm and renal disorders
Inventor: OOST THORSTEN
IPC: C07D401/12
Filed: 2005-03-26
Abstract: Substituted oxindole derivatives (I) and their tautomers, enantiomers, diastereomers, prodrugs and salts, are new. Substituted oxindole derivatives of formula (I) and their tautomers, enantiomers, diastereomers, prodrugs and salts, are new. A : phenyl or naphthalene (optionally substituted with 1-4 of R 4>); R 4>H, Cl, Br, I, F, (CH 2) 0-2-CN, CF 3, OCF 3, CO-NH 2, CO-NH(1-4C-alkyl), CO-N(1-4C-alkyl)(1-4C-alkyl), NHCHO, NHCONH 2, NH(0-4C-alkylene)CONH 2, NH(0-4C-alkylene)CONH(1-4C-alkyl), NHCOCH 3, NO 2, (CH 2) 0-2-OH, O-(1-6C)-alkyl, (CH 2) 1-2-O-(1-4C)-alkyl, O-(0-4C)-alkylene-phenyl, phenyl, 1-6C-alkyl, 2-6C-alkenyl or 2-6C-alkynyl; B 1>6-10C (hetero)aromatic or partially-(hetero)aromatic mono- or bicyclic ring comprising 0-4 N atoms, 0-2 O atoms and/or 0-2 S atoms and 1-3 residues of R 6>-R 9>; R 6>-R 9>H, Cl, Br, I, F, (CH 2) 0-2-CN, CF 3, OCF 3, CO-NH 2, CO-NH(1-4C-alkyl), CO-N(1-4C-alkyl)(1-4C-alkyl), NHCHO, NH(0-4C-alkylene)CONH(1-4C-alkyl), NHCOCH 3, NO 2, OH, O-1-4C-alkyl, (CH 2) 0-2-O-(CH 2) 0-3-CH 3, O-(0-4C)-alkylene-phenyl, phenyl, 1-6C-alkyl, 2-6C-alkenyl or 2-6C-alkynyl; R 1>CN; R 2>H, 1-4C-alkyl, O-(1-4C-alkyl), Cl or F; R 3>a group (W 1>)-(X)-(Y 1>)-Z; W 1>1-4C-alkylene, (0-4C-alkylene)-O-(0-4C-alkylene) or (0-4C-alkylene)-NR 5>-(0-4C-alkylene); R 5>H or 1-4C alkyl; X : CO, SO 2, (C=NH) or (C=N-CN); Y 1>10 nitrogen containing cyclic compounds e.g. pyrrolidine, piperidine, azepane and [1,4]diazepane (optionally substituted with R 10>or R 11>); R 10>, R 11>H, 1-6C-alkyl, 2-6C-alkenyl, 2-6C-alkynyl, OH, O-(1-4C)-alkyl, O-(0-4C)-alkylene-phenyl, NH 2, NH(1-4C-alkyl) or N(1-4C-alkyl)(1-4C-alkyl); Z : 5-15C mono-, bi- or tricyclic heteroaromatic ring system (optionally substituted with R 12>-R 14>), where the ring members next to C-atoms contains 1-7 heteroatoms of O, N or S, where the heteroatoms are distributed in one or two of the cycle, and the ring system contain maximum one S-atom, two O-atoms and 4 N-atoms; R 12>H, Cl, Br, I, F, (CH 2) 0-2-CN, CF 3, OCF 3, CO-NH 2, CO-NH(1-4C-alkyl), CO-N(1-4C-alkyl)(1-4C-alkyl), NHCHO, NHCONH 2, N(0-4C-alkylene)CONH 2, NH(0-4C-alkylene)CONH(1-4C-alkyl), NHCOCH 3, NO 2, (CH 2) 0-2-OH, O-(1-6C)-alkyl, (CH 2) 1-2-O-(1-4C)-alkyl, O-(0-4C)-alkylene-phenyl, phenyl, 1-6C-alkyl, 2-6C-alkenyl, 2-6C-alkynyl, NH 2, NH(1-4C alkyl) or N(1-4C-alkyl)(1-4C-alkyl); R 13>H, Cl, Br, I, F, (CH 2) 0-2-CN, CF 3, OCF 3, CO-NH 2, COOH, CO-NH(1-4C-alkyl), CO-N(1-4C-alkyl)(1-4C-alkyl), NHCHO, NHCONH 2, N(0-4C-alkylene)CONH 2, NH(0-4C-alkylene)CONH(1-4C-alkyl), NHCOCH 3, NO 2, (CH 2) 0-2-OH, O-(1-6C)-alkyl, (CH 2) 1-2-O-(1-4C)-alkyl, O-(0-4C)-alkylene-phenyl, phenyl, 1-6C-alkyl, 2-6C-alkenyl, 2-6C-alkynyl, NH 2, NH(1-4C alkyl) or N(1-4C-alkyl)(1-4C-alkyl); and R 14>H, Cl, F, 1-6C-alkyl, 2-6C-alkenyl, 2-6C alkynyl or (0-4C)-alkylene-phenyl. An independent claim is also included for the preparation of (I). [Image] ACTIVITY : Antidiabetic; Uropathic; Cardiant; Vasotropic; Antianginal; Nephrotropic; Antiinflammatory; Antidiuretic; Cardiovascular-Gen; Gastrointestinal-Gen; Hepatotropic; Antiulcer; Antiemetic; Antidepressant; Tranquilizer; Nootropic; Neuroprotective; Neuroleptic; Endocrine-Gen; Hypnotic; Antiaddictive. MECHANISM OF ACTION : Vasopressin receptor binder; Oxytoxin receptor binder. The affinity of (I) to bind human vasopressin subtype VIb was tested using biological assays. The results showed that binding affinity constant (Ki) of 4-(pyridin-4-yl)-piperazin-1-carboxylic acid-(5-cyano-1-(2,4-dimethoxy-benzol-sulfonyl)-3-(2-ethoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-ester was less than 10 nM.