| 摘要 |
<p>Substituted pyrido[3',2':4,5](thieno or furo)[3,2-d]pyrimidine-2,4(1H,3H)-dione and -4(3H)-one derivatives (I) and their solvates, salts, prodrugs, metabolites and tautomers are new. Substituted pyrido[3',2':4,5](thieno or furo)[3,2-d]pyrimidine-2,4(1H,3H)-dione and -4(3H)-one derivatives of formula (I) and their solvates, salts, prodrugs, metabolites and tautomers are new. Y : O or S; R1>, R3>1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl, benzyl, 1-12C alkylacyl, naphthyl, 3-14C cycloalk(en)yl, benzoyl, naphthoyl, heterocyclic acyl, 1-6C alkylamino, di-(1-5C alkyl)amino, cycloalkylamino, 3-14C arylamino, heteroarylamino (all optionally substituted by R); H, phenyl-(2-6C) alkyl, phenyl (optionally substituted by R in 2-, 3-, 4-, 3,4- or 3,4,5-position(s)), CHF2, CF3, mono- or bicyclic saturated or mono- or polyunsaturated heterocyclyl containing 5-14 ring atoms including 1-4 heteroatoms, specifically N, O or S, OH, SH, 1-10C alkoxy, 1-6C alkylthio, 1-6C alkylsulfinyl, 1-6C alkylsulfonyl, CHO, COOH, 1-4C alkoxycarbonyl, CONH2, mono- or di-(1-6C alkyl)carbamoyl, CN, SCN, NO2, SO3H, 1-5C alkoxysulfonyl, Cl, Br, I, F, NH2, morpholino, thiomorpholino, thiomorpholino S,S-dioxide, pyrrolidino, piperidino, piperazino or 4-(methyl, hydroxyethyl or phenyl)-piperazino; R2>H, 1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl, phenyl-1-6C alkyl or phenacyl (both optionally substituted by R), COOH, 1-4C alkoxycarbonyl, CONH2, mono- or di(1-6C alkyl)carbamoyl, CHO, 1-12C alkylcarbonyl (optionally substituted by R), CN, NO2, NH2, mono- or di(1-6C alkyl)amino, -N=N-Ph (optionally substituted by R), 1,3-diphenyl-pyrazol-4-yl, thiazolin-2-yl, imidazolin-2-yl or 3,4,5,6-tetrahydropyrimidinyl; R4>2-14C alkyl, 2-14C alkenyl, 2-14C alkynyl, 3-14C cycloalk(en)yl, naphthyl or mono-, bi- or tricyclic, saturated or mono- or polyunsaturated heterocyclyl containing 4-14 ring atoms including 1-5 heteroatoms, specifically N, O, S or Se (all optionally substituted by R); phenyl (optionally substituted by R in the 2-, 3-, 4-, 1,5- (sic), 3,5,5- (sic), 3,4-, 3,4,5- or 1,3,4- (sic) position(s)); 1-6C alkoxymethyl, CH2OCOR', COOH, 1-5C alkoxycarbonyl, NH2, 1-6C alkylamino, NHNH2, NHNHCOR', SO3H or phenacylthio; or 1-8C alkylthio, 1-8C alkylsulfinyl, 1-8C alkylsulfonyl, 2-8C alkenylthio, 2-8C alkenylsulfinyl, 2-8C alkenylsulfonyl, 2-6C alkynylthio, 2-6C alkynylsulfinyl or 2-6C alkynylsulfonyl (all optionally substituted by OH, CN, SCN, NO2, Ph or 3-7C cycloalkyl); R' : 1-6C alkyl, 2-6C alkenyl or phenyl (all optionally substituted by 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, SO3H, 1-8C alkylsulfonyloxy, 6-14C arylsulfonyloxy, COOH, 1-8C alkoxycarbonyl, 1-8C alkylcarbonyl, CONH2, mono- or di(1-6C alkyl)carbamoyl, NH2, mono- or di(1-6C alkyl)amino, mono- or di(6-14C aryl)amino, heteroarylamino, N-1-6C alkyl-N-6-14C arylamino, methyl, CHF2, CF3, ethyl, isopropyl, n-propyl, n-butyl, 2-hydroxyethyl, 2-thioethyl, 2-methylthioethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-6C cycloalkyl, 3-6C cycloalkylmethyl, fluoro, chloro, bromo, iodo, CN, NO2 or SCN; Provided that the following compounds are excluded: (IA; R1> = Me; R2> = H; R3> = Me); (IA; R1> = Me; R2> = acetyl; R3> = 4-dimethylaminophenyl or 4-nitrophenyl); (IB; R1> = ethoxy; R2> = CN; R3> = Ph; R4> = benzyl, phenyl (in part polysubstituted with Me, OMe, NO2 and Cl) or 3,4-methylenedioxy-phenyl); (IB; R1>, R3> = Ph; R2> = H; R4> = Ph, p-(chloro or methoxy)-phenyl, 2,3,4-trimethoxyphenyl or 2-thienyl); (IB; R1>, R3> = Me; R2> = H; R4> = methoxymethyl, ethoxymethyl, acetyloxymethyl, CH2COOPh, SCH2COPh, NH2, NHNH2, COOH or Ph); (IB; R1> = Me; R2> = H; R3> = Ph or p-bromophenyl; R4> = COOEt); (IB; R1> = p-bromophenyl; R2> = H; R3> = Me; R4> = COOMe); (IB; R1> = Me; R2> = CH2Ph; R3> = Me; R4> = COOMe); and (IB; R1> - R3> = Me; R4> = COOMe). Independent claims are included for: (A) pharmaceutical compositions (C1) containing (I) without the above exclusions, optionally together with auxiliaries and/or carriers; and (B) the use of (I) without the above exclusions for the production of TNF-alpha inhibiting medicaments. ACTIVITY : Antirheumatic; Antiarthritic; Osteopathic; Antiasthmatic; Antiinflammatory; Immunosuppressive; Dermatological; Neuroprotective; Antiulcer; Antipsoriatic; Nootropic; Antidiabetic; Antibacterial; Cerebroprotective; Protozoacide; Nephrotropic; Analgesic; Antiarteriosclerotic; Cardiant; Antialopecia; Vasotropic; Ophthalmological; Virucide; Anti-HIV; Cytostatic; Antiparkinsonian; Antiallergic. MECHANISM OF ACTION : Tumor necrosis factor-alpha (TNF-alpha ) release inhibitor. 7-(3,4-Dimethoxyphenyl)-9-methyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (Ia) inhibited lipopolysaccharide-stimulated release of TNF-alpha in human whole blood by more than 20% at a concentration of 10 nM.</p> |
