Patent DE-102004063223-A1 (DE)
Title: New quinoline derivatives are ephrin receptor kinase inhibitors useful for the treatment of e.g. blood vessels diseases, hyperproliferations, chronic or acute neurodegenerative diseases, psoriasis, eczema and scleroderma
Inventor: SCHWEDE WOLFGANG
IPC: C07D495/04
Filed: 2004-12-22
Abstract: Quinoline derivatives (A) and their N-oxides, solvate, hydrate, stereoisomers, diastereomers, enantiomers and salts are new. Quinoline derivatives of formula (A) and their N-oxides, solvate, hydrate, stereoisomers, diastereomers, enantiomers and salts are new. A : -6-12C aryl, -5-18C heteroaryl, -3-12C cycloalkyl or 3-12C heterocycloalkyl; either R 1>, R 2>H, OH, halo, NO 2, CN, -1-6C alkyl, -1-4C hydroxyalkyl, -2-6C alkenyl, -2-6C alkynyl, -3-10C cycloalkyl, 3-12C heterocycloalkyl, -6-12C aryl, -5-18C heteroaryl, -1-6C alkoxy, -1-6C alkoxy-1-6C alkoxy, -1-6C alkoxy-1-6C alkyl, -1-6C alkoxy-1-6C alkoxy-1-6C alkyl, -(CH 2) n-6-12C aryl, -(CH 2) n-5-18C-heteroaryl, -(CH 2) n-3-10C cycloalkyl, -(CH 2) n-3-12C heterocycloalkyl, -phenylene-(CH 2) p-R 6>, -(CH 2) pPO 3(R 6>) 2, -(CH 2) p-NR 5>R 6>, -(CH 2) p-NR 4>COR 5>, -(CH 2) p-NR 4>CSR 5>, -(CH 2) pNR 4>S(O)R 5>, -(CH 2) p-NR 4>S(O) 2R 5>, -(CH 2) p-NR 4>CONR 5>R 6>, -(CH 2) p-NR 4>COOR 5>,-(CH 2) p-NR 4>C(NH)NR 5>R 6>, -(CH 2) p-NR 4>CSNR 5>R 6>, -(CH 2) p-NR 4>S(O)NR 5>R 6>, -(CH 2) pNR 4>S(O) 2NR 5>R 6>, -(CH 2) p-COR 5>, -(CH 2) p-CSR 5>, -(CH 2) p-S(O)R 5>, -(CH 2) p-S(O)(NH)R 5>, -(CH 2) p-S(O) 2R 5>, -(CH 2) p-S(O) 2NR 5>R 6>, -(CH 2) p-SO 2OR 5>, -(CH 2) p-CO 2R 5>, -(CH 2) p-CONR 5>R 6>, -(CH 2) pCSNR 5>R 6>, -OR 5>, -(CH 2) p-SR 5> or -CR 5>(OH)-R 6>, where 1-6C alkyl, -2-6C alkenyl, -2-6C alkynyl, -3-10C cycloalkyl, -3-12C heterocycloalkyl, -6-12C aryl, -5-18C heteroaryl and/or -1-6C alkoxy are optionally substituted with OH, halo, NO 2, CN, phenyl, -NR 5>R 6>, alkyl and/or -OR 5>, where the carbon system of -3-10C cycloalkyl and -1-10C alkyl is replaced with N, O, S and/or C=O groups and contains one or more double bonds; or R 1>R 2>bridge of 3-10 methylene units, where up to two methyl units are optionally replaced with O, S and/or -NR 4>; X, Y 1>, Z : -CR 3>, -CR 3>R 4>-, -C(O)-, -N=, -S-, -O-, -NR 3>-, -S(O) 2-, -S(O)- or -S(O)NH- (single or double bond lies between X, Y 1> and Z); R 3>H, -1-10C alkyl or -1-10C alkanoyl; R 4>H or 1-10C alkyl; either R 5>, R 6>1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, 1-6C alkoxy, 3-10C cycloalkyl, 3-12C heterocycloalkyl, 6-12C aryl, 5-18C heteroaryl (all optionally substituted with OH, halo, CN, NO 2, -OR 7>, -NR 7>R 8>, -C(O)NR 7>R 8>, -C(O)OR 7> and/or -1-6C alkyl (optionally substituted with halo, OH, CN, -NR 7>R 8>, -OR 7> and/or phenyl)) or H; or R 5>R 6>a bridge of 3-10 methylene units, where up to two methyl units are optionally replaced with O, S and/or -NR 4>; either R 7>, R 8>1-4C alkyl, 6-12C aryl, 5-18C heteroaryl (optionally substituted with halo and/or alkoxy) or H; or R 7>R 8>a bridge of 3-10 methylene units, where up to two methyl units are optionally replaced with O, S and/or -NR 4>; l, m : 0-4; n : 1-6; and p : 0-6. Provided that when X, Y 1>, Z is 1-3 of N, then the skeleton in the part grouping X-Y 1>-Z is not N-CH-N, CH-N-N or N-N-N; and X is not NH when Y 1> and Z are simultaneously CH. Independent claims are also included for: (1) the preparation of (I); and (2) a medicament comprising (I), suitable formulation material and carrier materials. [Image] ACTIVITY : Vasotropic; Cytostatic; Neuroprotective; Antipsoriatic; Dermatological; Anticonvulsant; Nootropic; Antiparkinsonian; Anti-HIV. MECHANISM OF ACTION : Ephrin (Eph) receptor kinase inhibitor; EphB4 receptor kinase inhibitor. The ability of (I) to inhibit EphB4 kinase was tested using biological assays. The results showed that the median inhibitory concentration of 4-methyl-3-(2-methyl-thiazoIo[4,5-f]quinolin-9-ylamino)-phenol was 270 nM.