Patent EP-1683799-A1 (EP)
Inventor: REICHELT CLAUDIA
IPC: A61K31/4365
Filed: 2005-01-12
Abstract: 3-Amino-6-(hetero)aryl-thieno[2,3-b]pyridin-2-carboxylic acid amide derivatives (I) and their solvates, salts, prodrugs formulations, active metabolites or optionally tautomers are new. 3-Amino-6-(hetero)aryl-thieno[2,3-b]pyridin-2-carboxylic acid amide derivatives of formula (I) and their solvates, salts, prodrugs formulations, active metabolites or optionally tautomers are new. R 1>1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl (all optionally substituted with R 3>), phenyl, 4-R 3>-phenyl, 3-R 3>-phenyl, 2-R 3>-phenyl, 2-R 3>,3-R 3>-phenyl, 2-R 3>,4-R 3>-phenyl, 2-R 3>,5-R 3>-phenyl, 2-R 3>,6-R 3>-phenyl, 3-R 3>,4-R 3>-phenyl or 3-R 3>,4-R 3>, 5-R 3>-phenyl; R 2>H, OH, 1-3C alkyl, 1-3C alkoxy, 1-3C alkylthio, 1-3C hydroxyalkyl, 1-3C mercaptoalkyl, cyclopropyl, 2-hydroxycyclopropyl, CH 2F, CHF 2, CF 3, CH 2Br, CHBr 2, CBr 3, CH 2Cl, CHCl 2, CCl 3, CHFCH 3, CF 2CH 3, CH 2OAlk, CH 2SAlk, CH 2S(O)Alk, CH 2S(O) 2Alk, CH(OAlk) 2or CH(SAlk) 2(where Alk is 1-3C atoms); either R 3>1-4C alkyl, 1-4C alkoxy, benzyl, benzyloxy (optionally substituted with R 4>), trifluoromethoxy, difluoromethoxy, fluoromethoxy, 3-7C cycloalkyl, 3-7-cycloalkenyl, 3-7-cycloalkoxy, alkylthio, alkylsulfinyl, alkyl sulfonyl (where the alkyl is 1-4C), phenyl, 4-R 4>-phenyl, 3-R 4>-phenyl, 2-R 4>-phenyl, 2-R 4>,3-R 4>-phenyl, 2-R 4>, 4-R 4>-phenyl, 2-R 4>,5-R 4>-phenyl, 2-R 4>, 6-R 4>-phenyl, 3-R 4>, 4-R 4>-phenyl, 3-R 4>, 4-R 4>, 5-R-4-phenyl, phenoxy, 4-R 4>-phenoxy, 3-R 4>-phenoxy, 2-R 4>-phenoxy, 2-R 4>, 3-R 4>-phenoxy, 2-R 4>, 4-R 4>-phenoxy, 2-R 4>, 5-R 4>-phenoxy, 2-R 4>, 6-R 4>-phenoxy, 3-R 4>, 4-R 4>-phenoxy, 3-R 4>, 4-R 4>, 5-R 4>-phenoxy, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, fur-2-yl, imidazol-2-yl, oxazol-2-yl, isoxazol-2-yl, pyrrazol-4-yl, 1-7C alkacyl (optionally substituted with R 4>), formyl, benzoyl, 1- or 2-naphthoyl (optionally substituted with R 4>), F, Cl, Br, I, NO 2, OH, sulfhydryl, CN, rhodano, carboxyl, 1-4C alkoxycarbonyl, CONH 2, CONHAlk, CONAlk 2(where Alk is 1-6C), SO 3H, SO 2OAlk, SO 2NHAlk, SO 2NAlk 2(where Alk is 1-5C), NH 2, 1-6C alkylamino, di(1-5C)alkylamino, (thio)morpholino, thiomorpholino-S,S-dioxide, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-hydroxyethyl-1-piperazin-1-yl, 4-phenyl-piperazin-1-yl, cycloalkylamino, 3-14C arylamino, heteroarylamino (e.g. phenyl, 1 or 2-naphthyl, 2, 3 or 4-pyridyl, chinolinyl, isochinolinyl, acridinyl, phenothiazinyl, 2-thienyl or 2-furylamino) (optionally substituted with carbo- and/or hetero-cyclic rings with R 4>); or R 3>+4-R 3>OCH 2O, OCH 2CH 2O, SCH 2S or SCH 2CH 2S; and R 4>1-4C alkyl, 1-4C alkoxy, trifluormethoxy, difluormethoxy, fluoromethoxy, alkylthio, alkylsulfinyl, alkyl sulfonyl (where alkyl is 1-4C), F, Cl, Br, I, NO 2, OH, sulfhydryl, CN, rhodano, carboxyl, 1-4C alkoxycarbonyl, CONH 2, CONHAlk, CONAlk 2(where Alk is 1-6C), SO 3H, SO 2OAlk, SO 2NHAlk, SO 2NAlk 2(where Alk is 1-5C), amino, 1-6C alkylamino or di(1-5C) alkylamino. Provided that (I) is not: when R 1>is phenyl then R 2>is CH 3, CF 3or H; when R 1>is 4-bromo-phenyl then R 2>is CH 3, CF 3or H; when R 1>is 4-choro-phenyl then R 2>is H; when R 1>is 4-methyl-phenyl then R 2>is CF 3; when R 1>is 3- or 4-methoxy-phenyl then R 2>is CH 3or CF 3; when R 1>is 3,4-dimethoxy-phenyl then R 2>is CH 3or CF 3; when R 1>is 2,3-dihydro-1,4-benzodioxine then R 2>is CF 3; and when R 1>is 3,4-dichloro-phenyl then R 2>is CF 3. An independent claim is also included for a composition (A) comprising (I), auxiliary materials and/or carriers. [Image] ACTIVITY : Antiarthritic; Antirheumatic; Osteopathic; Antiasthmatic; Respiratory-Gen.; Immunosuppressive; Dermatological; Antiinflammatory; Antiulcer; Gastrointestinal-Gen.; Neuroprotective; Antipsoriatic; Nootropic; Antidiabetic; Antibacterial; Antimalarial; Cerebroprotective; CNS-Gen.; Nephrotropic; Antimicrobial; Analgesic; Antiarteriosclerotic; Cardiant; Vasotropic; Endocrine-Gen.; Vasotropic, Antiinflammatory; Ophthalmological; Cardiovascular-Gen.; Virucide; Cytostatic; Antiallergic; Muscular-Gen. MECHANISM OF ACTION : Tumor necrosis factor (TNF) alpha inhibitor. The ability of (I) to inhibit TNF-alpha was tested using biological assays. The results showed that the median effective concentration value of (I) was less than 5 nM.