Patent FR-2955323-A1 (FR)
Title: New substituted indazole compounds are heat shock protein 90 inhibitors useful for preventing or treating e.g. Huntington's disease, Alzheimer's disease, multiple sclerosis, malaria, thrombosis, retinopathy, and macular degeneration
Inventor: BERTIN LUC
IPC: A61K31/4184
Filed: 2010-01-19
Abstract: Substituted indazole compounds (I) and their tautomers and racemic isomers, enantiomers, diastereoisomers, addition salts with mineral and organic acids or bases, or prodrugs, are new. Substituted indazole compounds of formula (I) and their tautomers and racemic isomers, enantiomers, diastereoisomers, addition salts with mineral and organic acids or bases, or prodrugs, are new. R 4> : H, CH 3, CH 2CH 3, CF 3, Cl or Br; Het : dihydro or tetrahydro-mono or bicyclic 5-11 membered aromatic or partially unsaturated heterocycle containing 1-4 heteroatoms of N, O or S, optionally substituted by one or more R 1>or R1a groups; R : heterocycilc group of formula (A)-(D), or 2H-isoquinolin-1-one-6-yl; R 1>, R1a : H, halo, CF 3, nitro, CN, alkyl, hydroxy, mercapto, amino, alkylamino, dialkylamino, alkoxy, phenyl, alkylthio, free carboxy or esterified by alkyl, carboxamide, CO-NH(alkyl), CON(alkyl) 2, NH-CO-alkyl, sulfonamide, NH-SO 2-alkyl, S(O) 2-NHalkyl, S(O 2)-N(alkyl) 2, where the alkyl, alkoxy and alkylthio are optionally substituted by one or more halo, OH, alkoxy, amino, alkylamino or dialkylamino; W 1>-W 3> : CH or N; X : O, S, NR 2>, C(O), S(O) or S(O) 2; V 1> : H, halo, -O-R 2>or -NH-R 2>; and R 2> : 1-6C alkyl, 3-8C cycloalkyl, mono- or bicyclic 3-10C heterocycloalkyl (all optionally substituted by one or more O-PO 3H 2, PO 3Na 2, -O-SO 3H 2, -O-SO 3Na 2, -O-CH 2-PO 3H 2, -O-CH 2-PO 3Na 2, O-CO-alanine, O-CO-glycine, O-CO-serine, O-CO-lysine, O-CO-arginine, O-CO-glycine-lysine, -O-CO-alanine lysine, halo, hydroxy, mercapto, amino, carboxamide, carboxy, heterocycloalkyl, cycloalkyl, heteroaryl, carboxy esterified alkyl, CO-NH(alkyl), -CO-O-alkyl, -NH-CO-alkyl, alkyl, alkoxy, alkylthio, alkylamino, dialkylamino, where the alkyl, alkoxy and alkylthio are optionally substituted by one or more hydroxy, mercapto, amino, alkylamino, dialkylamino, CO 2alkyl, NHCO 2alkyl or heterocycloalkyl (where the cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted by one or more hydroxy, alkyl, alkoxy, CH 2OH, amino, alkylamino, dialkylamino, CO 2alkyl or NHCO 2alkyl)) or H. Independent claims are included for: (1) the preparation of (I); and (2) intermediates comprising substituted 1H-indazole compound of formula (IV), 1H-indazole compound of formula (V), and heterocyclic substituted 1H-indazole compound of formula (VI). T : Br, F or NHR 2>; and Z : O-triflate, I, Br, B(OH) 2, B(OR) 2, CO-OCH 3, COOH, COH, OH or O-CH 2-phenyl. [Image] [Image] [Image] ACTIVITY : Cytostatic; Neuroprotective; Anticonvulsant; Nootropic; Antiparkinsonian; Cerebroprotective; Vasotropic; Antimalarial; Nematocide; Protozoacide; Fungicide; Antiinflammatory; Hepatotropic; Virucide; Muscular-Gen.; Anticoagulant; Thrombolytic; Ophthalmological; Antipsoriatic. MECHANISM OF ACTION : Heat shock protein 90 (Hsp90) inhibitor; Hsp82 inhibitor. The ability of (I) to inhibit Hsp82 was tested using Hsp82/ATPase test. The result showed that 2-(trans-4-hydroxy-cyclohexylamino)-4-(3-methyl-4-quinolin-3-yl-indazol-1-yl)-benzamide exhibited an IC 5 0value of less than 1 mu M.