Patent FR-2909668-A1 (FR)
Title: New 5-alkyloxy-indolin-2-one derivatives are vasopressin antagonist useful to treat/prevent e.g. cardiovascular disease, hypertension, pulmonary hypertension, heart failure, circulatory failure, myocardial infarction and atherosclerosis
Inventor: FOULON LOIC
IPC: A61K31/404
Filed: 2006-12-12
Abstract: 5-Alkyloxy-indolin-2-one derivatives (I) in the form of base, hydrates, solvates and/or cis/trans isomers are new. 5-Alkyloxy-indolin-2-one derivatives of formula (I) in the form of base, hydrates, solvates and/or cis/trans isomers are new. R 01-4C alkyl, mono- or polyfluoro 1-4C alkyl, -(CH 2) n-cyclopropyl, 2-4C alkenyl or 2-4C alkynyl, preferably methyl; R 1H, 1-4C alkyl, mono or polyfluoro-1-5C alkyl, hydroxy-1-5C alkyl or -(CH 2) m-3-5C cycloalkyl, 1-2C alkyl; Z 1H or halo, 1-4C alkyl, mono or polyfluoro-1-4C alkyl, 1-4C alkoxy, mono or polyfluoro-1-4C alkoxy or -(CH 2) n-cyclopropyl (optionally substituted by F), preferably halo and is present in position 2; Z 2T 1W 1, present in position 5; T 1-(CH 2) n-; W 1H, 1-4C alkyl, mono- or polyfluoro 1-4C alkyl or cyclopropyl (optionally substituted by F), -C(O)OR, -C(O)-NR 6R 7, -NR 8C(O)R 9, -NR 1 0R 1 1 or -OR 1 2, preferably -C(O)OR or -C(O)NR 6R 7; either R 6, R 7H, 1-6C alkyl or mono- or polyfluoro 1-6C alkyl, -(CH 2) m-3-6C cycloalkyl, -(CH 2) p-pyrrolidinyl, -(CH 2) p-piperidinyl, -(CH 2) p-pyridinyl (the pyrrolidinyl, piperidinyl and pyridinyl groups optionally substituted by halo, 1-4C alkyl, mono or polyfluoro 1-4C alkyl, benzyl or -OR), -(CH 2) q-NR 0 aR 0 b or -(CH 2) q-OR; or NR 6R 7monocyclic heterocycle (optionally substituted by F, 1-4C alkyl, mono- or polyfluoro 1-4C alkyl, -NR 0 1R or -OR), bicyclo heterocycle (optionally substituted by F, 1-4C alkyl, mono- or polyfluoro 1-4C alkyl, -OR or -N 0 1R); R 8H, 1-4C alkyl or mono or polyfluoro-1-4C alkyl; R 9H, 1-4C alkyl, mono or polyfluoro 1-4C alkyl, -(CH 2) rNR 0 cR 0 d, -(CH 2) m-pyrrolidinyl, -(CH 2) m-piperidinyl, -(CH 2) m-pyridinyl (the pyrrolidinyl, piperidinyl or pyridinyl optionally substituted by 1-4C alkyl, halo, mono or polyfluoro-1-4C alkyl or benzyl); R 1 0, R 1 1H, OH, 1-4C alkyl or mono or polyfluoro-1-4C alkyl; NR 1 0R 1 1monocyclic heterocycle (optionally substituted by 1-4C alkyl, mono or polyfluoro-1-4C alkyl or oxo); R 1 21-4C alkyl or mono or polyfluoro-1-4C alkyl, -(CH 2) q-NR 0 1R; R 41-4C alkyl, 1-4C mono or polyfluoro alkyl, -OR, 2-4C alkenyl, nitro, COOR 0 c, benzyloxy, -C(O)NR 1 3R 1 4, -NR 1 5R 1 6 or -NR 1 7C(O)R 1 8, preferably -C(O)NR 1 3R 1 4; R 1 3, R 1 4H, 1-6C alkyl, mono or polyfluoro 1-6C alkyl or -(CH 2) n-3-6C cycloalkyl (optionally substituted by F); either R 1 5, R 1 6H, OH, 1-4C alkyl or mono or polyfluoro-1-4C alkyl, -(CH 2) n-3-5C cycloalkyl (optionally substituted by F); or NR 1 5R 1 6monocyclic hetero cycle; R 1 7H or 1-4C alkyl or mono or polyfluoro 1-4C alkyl; R 1 81-4C alkyl, mono-or polyfluoro 1-6C alkyl, -(CH 2) n-3-6C cycloalkyl, NR 0 dR 0 e, phenyl (optionally substituted by 1-4C alkyl or mono or polyfluoro-1-4C alkyl); R 3, R 5H, halo, 1-4C alkyl, mono or polyfluoro-1-6C alkyl, 1-4C alkoxy or mono-or polyfluoro 1-4C alkoxy; either R 0 a, R 0 bH, 1-4C alkyl, 1-4C mono or polyfluoro alkyl, -(CH 2) n-cyclopropyl (optionally substituted by F); or NR 0 aR 0 bmonocyclic heterocycle (optionally substituted by OH, 1-4C alkyl, mono or polyfluoro-1-4C alkyl, 1-4C alkoxy, mono or polyfluoro 1-4C alkoxy or -NRR 0 1); R 0 1, R : H, 1-4C alkyl or 1-4C mono- or polyfluoro alkyl; R 0 cH, 1-4C alkyl, mono- or polyfluoro 1-4C alkyl or benzyl; either R 0 d, R 0 eH, halo, 1-6C alkyl or mono- or polyhalo 1-6C alkyl; R 0 dR 0 emonocyclic heterocycle (optionally substituted by F, 1-4C alkyl or mono-or polyfluoro 1-4C alkyl or -OR); m : 0-2; n : 0-1, preferably 0; p : 0-3; q : 2-5; and r : 0-4. [Image] ACTIVITY : CNS-Gen; Cardiovascular-Gen; Endocrine-Gen; Hepatotropic; Nephrotropic; Gastrointestinal-Gen.; Ophthalmological; Hypotensive; Cardiant; Vasotropic; Antiarteriosclerotic; Antianginal; Hemostatic; Analgesic; Antimigraine; Cerebroprotective; Antiinflammatory; Antidepressant; Tranquilizer; Eating-Disorders-Gen; Nootropic; Neuroleptic; Metabolic; Antidiabetic; Uropathic; Antimicrobial; Antiulcer; Antiemetic; Anorectic; Gynecological; Cytostatic; Auditory. MECHANISM OF ACTION : Vasopressin (V 2) antagonist. The ability of (I) as vasopressin antagonist was tested. The results showed that N-tert-butyl-4-(3-(4-chloro-N-(S)-pyrrolidin-3-yl-benzamid-3yl)-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-indole-1-sulfonyl)-3-methoxy-benzamide exhibited an IC 5 0 value of 1.3 nM.