Patent DE-102004061288-A1 (DE)
Title: New 3-amino-pyrazolo(3,4b)pyridine derivatives are protein tyrosine kinases inhibitors useful e.g. for treating hyperproliferation of body cells, neurodegenerative disease, blood vessel disease and angiogenic disease
Inventor: SCHWEDE WOLFGANG
IPC: A61P17/00
Filed: 2004-12-14
Abstract: 3-Amino-pyrazolo[3,4b]pyridine derivatives (I) and their solvate, hydrate, stereoisomere, diastereomere, enantiomere and salts, are new. 3-Amino-pyrazolo[3,4b]pyridine derivatives of formula (I) and their solvate, hydrate, stereoisomere, diastereomere, enantiomere and salts, are new. R 1>3-10C heterocycloalkyl, heteroaryl, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-10C cycloalkyl or aryl (all optionally substituted with one or more K 1>) (where 3-10C heterocycloalkyl and/or heteroaryl are interrupted by N, O and/or S; 3-10C heterocycloalkyl and/or heteroaryl are connected over a carbon ring atom with the pyrazolopyridine; and 3-10C cycloalky and/or 3-10C heterocycloalkyl are optionally interrupted through -(CO)-, -SO or -SO 2- group and contains one/more double bond in the ring or -O-(CH 2) n-O and substituents 3-10C cycloalkyl, aryl, 3-10C heterocycloalkyl or heteroaryl, where the end terminal oxygen atom of -O(CH 2) n-O- group is connected with 3-10C cycloalkyl ring-, aryl ring-, 3-10C heterocycloalky ring- or heteroaryl ring-carbon atom); K 1>3-10C cycloalkyl, 3-10C heterocycloalkyl, aryl or heteroaryl (all optionally substituted with L) (where 3-10C heterocycloalkyl and/or heteroaryl are interrupted by N, O and/or S; and 3-10C cycloalky and/or 3-10C heterocycloalkyl are optionally interrupted through -(CO)-, -SO or -SO 2- group and optionally contains one/more double bond), halo, OH, or -OR 3>, COR 4> or -NR 5>R 6>; L : 1-6C alkyl, -COR 4>, -OR 3> or -NR 5>R 6>; R 2>1-6C alkyl, 3-10C cycloalkyl, aryl or heteroaryl (all optionally substituted with M); R 3>1-6C alkyl, aryl or -(CH 2) n-aryl (all optionally substituted with one or more -NR 5>R 6>); R 4>H, OH, 1-6C alkyl or 1-6C alkoxy; M : 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, (optionally substituted with amino, CN, halo, OH, NO 2 or 1-6C alkoxy), -O-R 3>, -CO RHO  4>, -CO-N-R 7> amino, CN, halo, OH or NO 2; R 5>, R 6>H, 1-6C alkyl or -COR 4>; R 7>H or NH 2; and n : 1-4. Provided that: (A) if R 1> is methyl then R 2> is not methyl, -CH 2-O-CH 3, phenyl, chlorophenyl, or OH and/or methoxy replaced benzofuranyl, -CF 3 or furanyl; (B) if R 1> is -CH 2-O-CH 3 then R 2> is not methyl; (C) if R 1> is -CH=CH-phenyl then R 2> is not phenyl; (D) if R 1> is -CH=CH-chlorophenyl then R 2> is not phenyl or chlorophenyl; (E) if R 1> is -CH=CH-methoxyphenyl then R 2> is not phenyl or methoxyphenyl; (F) if R 1> is (methyl)phenyl then R 2> is not -CF 3, methyl, methoxyphenyl or phenyl; (G) if R 1> is methoxyphenyl then R 2> is not -CF 3; (H) if R 1> is chlorophenyl then R 2> is not chlorophenyl or -CF 3; (I) if R 1> is dichlorophenyl or bromophenyl then R 2> is not trimethoxyphenyl; (J) if R 1> is alkyl (substituted by phenyl or p-methoxyphenyl), alkenyl, aryl, aralkyl or cycloalkyl then R 2> is not alkyl, alkenyl, aryl, aralkyl, CN, heterocyclic or cycloalkyl; (K) if R 1> is lower alkyl, alkoxy or aryloxy then R 2> is not lower alkyl; or (L) if R 1> is hydroxyphenyl or benzyloxyphenyl then R 2> is not heterocycyl or -COO-tert-butyl replaced heterocycloalkyl. Independent claims are also included for: (1) a pyridin-2-one compound of formula (II) or a pyridine compound of formula (III) useful as intermediates in the preparation of (I); and (2) a medicament containing (I). X : halo or -O-SO 2-C mF 2m+1; R 1a>, R 2a>R 1> and R 2> respectively; K : -COR 4>; R 4>trimethylsilyl, tert-butyl-dimethylsilyl, tert-butyl-diphenylsilyl, triethylsilyl, 1-2C alkyl, 3-6C allyl, benzyl or -COR-4a; and m : 1-4. [Image] [Image] ACTIVITY : Cytostatic; Neuroprotective; Vasotropic; Antiangiogenic; Antiarteriosclerotic; Antiinflammatory; Antiarthritic; Antirheumatic; Anticonvulsant; Nootropic; Antiparkinsonian. MECHANISM OF ACTION : Protein tyrosine kinases inhibitor. The ability of (I) to inhibit protein tyrosine kinases was tested using biological assays. The results showed that 6-tert-butyl-4-(3-methoxyphenyl)-1H-pyrazolo[3,4b]pyridin-3-yl-amine exhibited a median inhibitory concentration value of 6.1 mu M.