Patent DE-102005013622-A1 (DE)
Title: New tricyclic thiophene or furan derivatives useful as tumor necrosis factor alpha inhibitors, e.g. for treating asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, multiple sclerosis
Inventor: DAGHISH MOHAMMED
IPC: C07D495/14
Filed: 2005-03-24
Abstract: Tricyclic thiophene or furan derivatives (I) are new. Tricyclic thiophene or furan derivatives (I) of formula 1a or 1b and their solvates, salts, prodrugs and metabolites are new: X : CR 2>or N; Y : S or O; R 1>, R 3>H; 1-12C alkyl, 2-12C alkenyl or 2-12C alkynyl, each optionally substituted with R; phenyl(1-6C)alkyl or phenyl, each optionally substituted with 1-5 of R; mono-, di- or trifluoromethyl; 1- or 2-naphthyl, 3-14C cycloalkyl or 3-14C cycloalkenyl, each optionally substituted with R; 5- to 14-membered mono- or bicyclic heterocyclyl with 1-4 heteroatoms, optionally substituted with R; 1-12C alkyl acyl, benzoyl, 1- or 2-naphthoyl or heterocyclic acyl, each optionally substituted with R; OH, SH, 1-10C alkoxy, 1-6C alkylthio, 1-6C alkylsulfinyl, 1-6C alkylsulfonyl, CHO, COOH, 1-4C alkoxycarbonyl, CONH 2, mono- or di(1-6C alkyl)carbamoyl, CN, SCN, NO 2, SO 3H, 1-5C alkoxysulfonyl, halo, NH 2; 1-6C alkylamino or di(1-5C alkyl)amino, each optionally substituted with R; morpholino, thiomorpholino, thiomorpholino S,S-dioxide, pyrrolidino, piperidino, 1-piperazino, 4-methyl-1-piperazino, 4-hydroxyethyl-1-piperazino, 4-phenyl-1-piperazino, cycloalkylamino, 3-14C arylamino or heteroarylamino, each optionally substituted with R; R 2>H, 1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl; phenyl(1-6C)alkyl or phenacyl, each optionally substituted with R; COOH, 1-4C alkoxycarbonyl, CONH 2, mono- or di(1-6C alkyl)carbamoyl; 1-13C alkanoyl optionally substituted with R; CN, NO 2, NH 2, mono- or di(1-6C alkyl)amino, N=N-Ph, N=N-C 6H 4-R; 1,3-diphenyl-4-pyrazolyl, 2-thiazolinyl, 2-imidazolinyl, 3,4,5,6-tetrahydropyrimidinyl; R 4>2-14C alkyl, 3-14C cycloalkyl, 2-14C alkenyl, 3-14C cycloalkenyl, 2-14C alkynyl, each optionally substituted with R; phenyl, 4-R-phenyl, 3-R-phenyl, 2-R-phenyl, 2,5-di-R-phenyl, 3,5-di-R-phenyl, 3,4-di-R-phenyl, 3,4,5-tri-R-phenyl, 2,3,4-tri-R-phenyl; 1- or 2-naphthyl optionally substituted with R; 4- to 14-membered mono- or bicyclic heterocyclyl with 1-5 heteroatoms, optionally substituted with R; (1-6C alkoxy)methyl; CH 2OCOR'; COOH, 1-5C alkoxycarbonyl; NH 2, 1-6C alkylamino; NHNH 2, NHNHCOR'; SO 3H, S-phenacyl, 1-8C alkylthio, 1-8C alkylsulfinyl, 1-8C alkylsulfonyl; 2-8C alkenylthio, 2-8C alkenylsulfinyl, 2-8C alkenylsulfonyl, 2-6C alkynylthio, 2-6C alkynylsulfinyl, 2-6C alkynylsulfonyl, each optionally substituted with OH, CN, SCN, NO 2, phenyl or 3-7C cycloalkyl; R' : 1-6C alkyl, 2-6C alkenyl or phenyl optionally substituted with R; R : OH, SH, 1-8C alkoxy, 6-14C aryloxy, 1-4C alkylthio, 6-14C arylthio, 1-4C alkylsulfinyl, 6-14C arylsulfinyl, 1-4C alkylsulfonyl, 6-14C arylsulfonyl, SO 3H, 1-8C alkylsulfonyloxy, 6-14C arylsulfonyloxy, COOH, 1-8C alkoxycarbonyl, 1-8C alkylcarbonyl, CONH 2, mono- or di(1-6C alkyl)carbamoyl, NH 2, mono- or di(1-6C alkyl)amino, 6-14C arylamino, heteroarylamino, di(6-14C aryl)amino, N-(1-6C alkyl)-N-(6-14C aryl)amino, 1-4C n-alkyl, t-Bu, CH 2CH 2OH, CH 2CH 2SH, CH 2CH 2SMe, CH 2CF 3, CH 2CCl 3, CH 2CBr 3, CH 2CHF 2, CH 2CHCl 2, CH 2CHBr 2, CH 2CH 2F, CH 2CH 2Cl, CH 2CH 2Br, 3-6C cycloalkyl, (3-6C cycloalkyl)methyl, halo, CN, NO 2, SCN; the following compounds are excluded: 1a where R 1>/X/R 3>Me/CH/Me, Me/CAc/4-NMe 2Ph, Me/CAc/4-NO 2Ph; 1b where R 1>= OEt, X = CCN, R 3>= Ph, R 4>= benzyl, phenyl (in part polysubstituted with OMe, NO 2and Cl) or 3,4-methylenedioxyphenyl; R 1>= Ph, X = CH, R 3>= Ph, R 4>= Ph, p-OMe-Ph, p-Cl-Ph, 2,3,4-tri-OMe-Ph or 2-thienyl; R 1>= Me, X = CH, R 3>= Me, R 4>= CH 2OMe, CH 2OEt, CH 2OCOMe, CH 2COOPh, SCH 2COPh, NH 2, NHNH 2, COOH, Ph; R 1>= Me, X = CH, R 3>= Ph, R 4>= COOEt; R 1>= Me, X = CH, R 3>= p-Br-Ph, R 4>= COOEt; R 1>= p-Br-Ph, X = CH, R 3>= Me, R 4>= COOMe; R 1>Me, X = C-benzyl, R 3>= Me, R 4>= COOMe; R 1>R 3>= Me, X = C-Me, R 4>= COOMe; R 1>= Ph, X = N, R 3>= Me, R 4>= SEt. An independent claim is also included for a pharmaceutical composition comprising one or more compounds (I), including those excluded above. [Image] ACTIVITY : Antiasthmatic; Antiinflammatory; Antirheumatic; Antiarthritic; Osteopathic; Neuroprotective; Antiulcer; Antipsoriatic; Dermatological; Antiallergic; Ophthalmological; Immunosuppressive; Antidiabetic; Nootropic; Antiparkinsonian; Nephrotropic; Analgesic; Antiarteriosclerotic; Cardiant; Cerebroprotective; Cytostatic; Virucide; Anti-HIV. MECHANISM OF ACTION : Tumor necrosis factor alpha (TNFalpha ) inhibitor. 7-(4-Aminophenyl)-9-methyl-thieno[2,3-d:4,5-d']dipyrimidine-2,4(1H,3H)-dione had an IC50 of less than 10 nM in a TNFalpha inhibition assay.