Patent DE-102005014628-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: C07D401/04
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 : (hetero)aromatic or partially-(hetero)aromatic 2-10C mono- or bicyclic ring comprising 0-4 N atoms or 0-2 of O-atoms and 0-2 of S-atoms and substituted with R a 1> and with 1-3 residues of R a 1> 1>, R a 1> 2> or R a 1> 3>; R a 1> 1>, R a 1> 2>, R a 1> 3>H, Cl, Br, I, F, CN, CF 3, OCF 3, OCNF 2, CO-NH 2, CO-NH (1-4C alkyl), CO-N-(1-4C alkyl) (1-4C alkyl), NH 2, NH (1-4C alkyl), N(1-4C alkyl)(1-4C alkyl), NHCHO, NH-CO-NH 2, NH-CO (1-4C alkyl), NO 2, OH, O-1-4C alkyl, O-(0-4C alkylene)-phenyl, phenyl, 1-6C alkyl, 1-6C haloalkyl, 2-6C alkenyl or 2-6C alkynyl; R a 1>R a 2>-(1-4C alkylene)-R a 4>; R a 2>(0-4C-alkylene)-O, (0-4C alkylene)-NR a 5>, (0-4C alkylene)-S, (0-4C-alkylene)-SO, (0-4C-alkylene)-SO 2, (0-4C-alkylene)-CO, (0-4C-alkylene)-NR a 5>-CO, (0-4C-alkylene)-CO-NR a 5>, (0-4C-alkylene)-CO-O, (0-4C-alkylene)-NR a 5>-SO 2, (0-4C alkylene)-SO 2-NR a 5>, (0-4C-alkylene)-NR a 5>-CO-NR a 6>, (0-4C-alkylene)-O-CO-NR a 5>, (0-4C-alkylene)-NR a 5>-CO-O or single bond; R a 4>NH 2, NH(1-4C-alkyl), N(1-4C-alkyl)(1-4C-alkyl), NH(1-4C-alkylene-O-1-4C-alkyl), N(1-4C-alkyl) (1-4C-alkylene-O-1-4C-alkyl), NH-CHO, N(1-4C-alkyl)-CHO, NH-CO-NH 2, N(1-4C alkyl)-CO-NH 2, NH-CO-1-4C-alkyl, N(1-4C-alkyl)-CO-1-4C-alkyl, NH-SO 2-1-4C-alkyl, N(1-4C-alkyl)-SO 2-1-4C-alkyl or ring R a 8>; R a 5>, R a 6>, R a 9>H, 1-4C-alkyl or 1-4C-haloalkyl; R a 8>e.g. -azetidine, -pyrrolidine, -piperidine, -morpholine or -thiomorpholine; B 1>2-10C (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 b 1>, R b 2> or R b 3>; R b 1>-R b 3>F, CN, CF 3, OCF 3, OCHF 2, CO-NH 2, CO-NH (1-4C-alkyl), CO-N(1-4C-alkyl), H, Cl, Br, I, (1-4C-alkyl), NH 2, NH (1-4C-alkyl), N(1-4C-alkyl) (1-4C-alkyl), NH-CHO, NH-CO-NH 2, NN-CO-1-4C-alkyl, NO 2, OH, O-1-4C-alkyl, O-CO-4C-alkylene-phenyl, phenyl, 1-6C-alkyl, 1-6C-haloalkyl, 2-6C-alkenyl or 2-6C-alkynyl; R 1>H, Cl, Br, I, F, CN, CF 3, OCF 3, OCHF 2, CO-NH 2, CO-NH (1-4C-alkyl), CO-N(1-4C-alkyl) (1-4C-alkyl), NH 2, NH(1-4C-alkyl), N(1-4C-alkyl) (1-4C-alkyl), NH-CHO, NH-CO-NH 2, NH-CO-(1-4C-alkyl), NO 2, OH, O-(1-4C-alkyl), O-(0-4C-alkylene)-phenyl, phenyl, 1-6C-alkyl, 1-6C-haloalkyl, 2-6C-alkenyl or 2-6C-alkynyl; R 2>H, 1-4C-alkyl, O-1-4C-alkyl, Cl or F; Y 1>-N(R y 1>)(C(R y 2>)(R y 3>)(R y 4>)); either R y 1>H, 1-4C-alkyl or 1-4C-haloalkyl; and R y 2>H or phenyl (optionally substituted with 1-5 residues of R ph 1>-R ph 5>); or R y 1>+R y 2>4-7 membered optionally saturated carbocyclic ring (where the C atom in the ring is substituted with heteroatoms of O, S or NR y 5>) substituted with R y 6> and R y 7>; R ph 1>-R ph 5>H, halo, 1-6C-alkyl or 1-6C-alkoxy, 1-6C-alkyl, 3-7C-cycloalkyl or 1-6C-haloalkyl; R y 5>H, 1-4C-alkyl or CO-1-4C-alkyl; either R y 6>, R y 7>F, CN, H, Cl, Br, I, CF 3, OCF 3, OCHF 2, CO-NH 2, CO-NH (1-4C-alkyl), CO-N(1-4C-alkyl) (1-4C-alkyl), NH 2, NH(1-4C-alkyl), N(1-4C-alkyl)(1-4C-alkyl), NH-CHO, NH-CO-NH 2, NH-CO-(1-4C-alkyl), OH, O-1-4C-alkyl, O-CO-1-4C-alkyl, O(CH 2) 0 - 2-phenyl, phenyl or 1-6C-alkyl; or CR y 6>, CR y 7>condensed phenyl ring or 5-6 membered aromatic heterocyclic group comprising 1-4 heteroatoms of N, O or S; R y 3>H, 1-4C-alkyl or 1-4C-haloalkyl; R y 4>CO-NR y 2> 1>R y 2> 2>, H, CO-1-4C-alkyl, COOH or CO-O-1-4C-alkyl; and either R y 2> 1>, R y 2> 2>H, 1-4C-alkyl or 1-4C-haloalkyl; or R y 2> 1>+R y 2> 2>4-6 membered optionally saturated carbocyclic ring. An independent claim is 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 (S)-1-[5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-pyrrolidin-2-carboxylic acid dimethylamide was less than 1 nM.