Patent EP-2298305-A1 (EP)
Inventor: HIMMELSBACH FRANK
IPC: A61K31/517
Filed: 2003-03-25
Abstract: 6-(Hetero)cycloalkoxy-4-(N-(phenyl or 1-phenylethyl)-amino)-quinazoline or quinoline derivatives (I) are new. Bicyclic heterocycles of formula (I) and their tautomers, stereoisomers, isomer mixtures and salts are new. [Image] R 1>H or T; T : 1-4C alkyl; R bPh' or CHMePh'; Ph' : phenyl substituted by R 1> - R 3>; R 1>, R 2>H, halo, T, OH, OT, 2-3C alkenyl, 2-3C alkynyl, Ar, OAr, CH 2Ar, OCH 2Ar, Het, OHet, CH 2Het, OCH 2Het, CH 2F, CHF 2, CF 3, OCH 2F, OCHF 2, OCF 3, CN, NO 2 or NH 2; R 3H, F, Cl, Br, Me or CF 3; R c(i) 4-6C cycloalkyl, substituted by NR 4>R 5> or by R 6>, (ii) azetidinyl-3-yl, pyrrolidin-3-yl or piperidin-(3 or 4)-yl, all substituted in the 1-position by R 5>; or (iii) tetrahydrofuran-3-yl or tetrahydropyran-(3 or 4)-yl; R 4>H or alkyl; R 5>H or alkyl (optionally monosubstituted by -CO-Q 1>); 2-4C alkyl monosubstituted by Q 2>; SO 2T (optionally monosubstituted by Q 3>); COOT; COQ 4>; CN; or SO 2Q 1>; Q 1>NH 2, mono- or dialkylamino, pyrrolidino, piperidino, homopiperidino, morpholino, homomorpholino, piperazino, N-alkyl-piperazino, homopiperazino or N-alkyl-homopiperazino; Q 2>OH, alkoxy, NHCOOT, NH 2, mono- or dialkylamino, NHCONH 2, mono- or dialkylaminocarbonylamino, pyrrolidinocarbonylamino, piperidinocarbonylamino, morpholinocarbonylamino, alkylsulfonyl, alkylsulfonylamino or R 6>; Q 3>Cl, Br or as for Q 1>; Q 4>H, T, alkoxy-(1-4C) alkyl, tetrahydrofuranyl, tetrahydropyranyl, -T-Q 1>, alkylsulfonyl-(1-4C) alkyl, Q 1>, (alkoxy-(2-4C) alkyl)-amino, N-alkyl-N-(alkoxy-(2-4C) alkyl)-amino, -NH-Ar, 2-oxa-5-aza-bicyclo (2.2.1) hept-5-yl, 3-oxa-8-aza-bicyclo (3.2.1) oct-8-yl or 8-oxa-3-aza-bicyclo (3.2.1) oct-3-yl; R 6>2-oxo-pyrrolidino, 2-oxo-piperidino, 3-oxo-morpholino, 2-oxo-imidazolidino, 3-alkyl-2-oxo-imidazolidino, 2-oxo-hexahydropyrimidino or 3-alkyl-2-oxo-hexahydropyrimidino; R dH, F, Cl, Br, OH, OT, OCH 2F, OCHF 2, OCF 3 or mono- to pentafluoroethoxy; 2-4C alkoxy substituted by R 6> or R 7>; tetrahydrofuran-3-yl, tetrahydropyran-(3 or 4)-yl, tetrahydrofuranyl-(1-4C) akyl or tetrahydropyranyl-(1-4C) alkyl; or OT, substituted by pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl (all optionally N-substituted by alkyl); R 7>OH, alkoxy, N(CH 2CH 2OMe) 2, Q 1>, 2-oxa-5-aza-bicyclo (2.2.1) hept-5-yl, 3-oxa-8-aza-bicyclo (3.2.1) oct-8-yl or 8-oxa-3-aza-bicyclo (3.2.1) oct-3-yl, NHCHO, NHCOT, alkoxyalkylcarbonylamino, NHCOOT, NHCONH 2, mono- or dialkylaminocarbonylamino, pyrrolidinocarbonylamino, piperidinocarbonylamino, morpholinocarbonylamino or alkylsulfonylamino; X : C-CN or N; Ar : phenyl (optionally substituted by 1 or 2 groups R 9>); R 9>H, halo, alkyl, OH, alkoxy, CHF 2, CF 3, OCHF 2, OCF 3 or CN; Het : pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl (all optionally substituted by 1 or 2 groups R 9>); pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl moieties are optionally substituted by 1 or 2 alkyl; unless specified otherwise alkyl moieties have 1-3C; the compound 4-((3-chloro-4-fluorophenyl)-amino)-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline is excluded. An independent claim is included for the preparation of (I). ACTIVITY : Cytostatic; Antiinflammatory; Antiasthmatic; Antiallergic; Antitussive; Antiulcer; Immunosuppressive; Antipsoriatic. MECHANISM OF ACTION : Tyrosine kinase-mediated signal transduction inhibitor. In particular (I) inhibit epidermal growth factor (EGF) receptor-mediated signal transduction, e.g. by inhibiting ligand biding, receptor dimerization or the tyrosine kinase itself. 4-((3-Chloro-4-fluorophenyl)-amino)-6-(1-((morpholin-4-yl)-sulfonyl)-piperidin-4-yloxy)-7-methoxy-quinazoline (Ia) had IC 5 0 0.1 nM for inhibition of EGF receptor kinase.