| 摘要 |
<p>2,4-Disubstituted pyrido-(3',2':4,5)-(thieno or furo)-(3,2-d)-pyrimidine compounds (I) are new. Pyrido-thieno-pyrimidine or pyrido-furo-pyrimidine derivatives of formula (I) (including their solvates, salts, prodrug formulations, active metabolites and tautomers) are new. Y : O or S; R1> and R3>H; 1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl, benzyl, (1-12C) alkylacyl, 1- or 2-naphthyl, cycloalkyl, cycloalkenyl, benzoyl, 1- or 2-naphthoyl, heterocyclylacyl (e.g. nicotinoyl, isonicotinoyl, 2-picolinoyl, 2-thienoyl or 2-furoyl), alkylamino, di-(1-5C) alkylamino, cycloalkylamino (no C-number specified) or (hetero)arylamino (where (hetero)aryl is e.g. Ph, naphthyl, pyridyl, quinolyl, isoquinolyl, acridinyl, phenothiazinyl, 2-thienyl or 2-furyl) (all optionally substituted (os) by R); or phenyl-(2-6C) alkyl, phenyl (os by R in the 2-, 3-, 4-, 3,4- or 3,4,5-position(s)), 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, alkylthio, alkylsulfinyl, alkylsulfonyl, CHO, COOH, (1-4C) alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, CN, SCN, NO2, SO3H, (1-5C) alkoxysulfonyl, halo, NH2, morpholino, thiomorpholino (optionally as the S,S-dioxide), pyrrolidino, piperidin, piperazino or 4-(methyl, hydroxyethyl or phenyl)-piperazino; R2>H, 1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl, phenylalkyl or phenacyl (both os by one or more R), COOH, (1-4C) alkoxycarbonyl, CONH2, mono- or dialkylcarbamoyl, CHO, (1-12C) alkylcarbonyl (os by R), CN, NH2, mono- or dialkylamino, -N=N-Ph (os 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, cycloalkyl, cycloalkenyl, 1- or 2-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 os by R); phenyl (os by R in the 2-, 3-, 4-, 3,4- or 3,4,5-position(s), 2-nitrophenyl being excluded); 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 os by OH, CN, SCN, NO2, Ph or 3-7C cycloalkyl); OR6>; or NR7>R8>; R6>1-4C n-alkyl, tert.-butyl, CH2CH2OH, CH2CH2SH, CH2CH2SMe, CH2CF3, CH2CCl3, CH2CHF2, CH2CHCl2, CH2CH2F, CH2CH2Cl, CH2CH2Br, 3-7C cycloalkyl (including (3-6C) cycloalkylmethyl and os by R), 2-5C alkenyl, 2-5C alkynyl, 3-7C cycloalkenyl, 6-14 membered, mon-, di- or tricyclic (hetero)aryl (e.g. phenyl, os by R in the 2-, 3-, 4-, 3,4- or 3,4,5-position(s)), 1- or 2-naphthyl (os by R), pyridyl, isoquinolyl, quinolyl or acridinyl; R7>, R8>H (but only both H if R5> = OR6>) or alkyl, benzyl, phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, 2-thienyl or 2-furyl (all os by R); or NR7>R8>morpholino, thiomorpholino (optionally as the S,S-dioxide), pyrrolidino, piperidin, piperazino or 4-(alkyl, 2-hydroxyethyl, benzyl or phenyl)-piperazino (all os by R in the heterocyclic ring); or the residue of another 5-14 membered, mono- or polycyclic, secondary heterocycloaliphatic amine (os by R); R5>OR6>, NR7>R8> (provided that R4> and R5> are not both NR7>R8>), N3, NHOH, O-(1-3C) alkylhydroxylamino, N-(1-3C) alkyl-hydroxylamino, N,N-di-(1-3C) alkyl-hydroxylamino, NHNH2, mono- or di-(1-4C) alkylhydrazino, benzylhydrazino, acylhydrazino, N,N-diacylhydrazino or NHCONH2; or 1-imidazolyl, 1,2,4-triazol-1-yl, 1-pyridinium, 1-pyrazinium or 1-pyridazinium (all os by alkyl); and R : OH, SH, 1-8C alkoxy, aryloxy, 1-4C alkylthio, arylthio, 1-4C alkylsulfinyl, arylsulfinyl, 1-4C alkylsulfonyl, arylsulfonyl, SO3H, (1-8C) alkylsulfonyloxy, arylsulfonyloxy, COOH, (1-8C) alkoxycarbonyl, (1-8C) alkylcarbonyl, CONH2, mono- or dialkylcarbamoyl, NH2, mono- or dialkylamino, mono- or diarylamino, heteroarylamino, N-alkyl-N-arylamino, Me, CHF2, CF3, Et, C(CH3)2, n-propyl, n-butyl, CH2CH2OH, CH2CH2SH, CH2CH2SMe, CH2CF3, CH2CCl3, CH2CHF2, CH2CHCl2, CH2CH2F, CH2CH2Cl, CH2CH2Br, 3-6C cycloalkyl, (3-6C) cycloalkylmethyl, halo, CN, NO2 or SCN. Provided that: (i) alkyl moieties have 1-6C, cycloalkyl or cycloalkenyl moieties 3-14C and aryl moieties 6-14C unless specified otherwise; and (ii) the compound (I; Y = S; R1>, R5> = OEt; R2> = CN; R3> = Ph; R4> = NEt2) is excluded. [Image] ACTIVITY : Antiasthmatic; antiinflammatory; antirheumatic; antiarthritic; osteopathic; neuroprotective; antiulcer; antipsoriatic; dermatological; antiallergic; ophthalmological; immunosuppressive; antidiabetic; nootropic; antiparkinsonian; antibacterial; nephrotropic; analgesic; antiarteriosclerotic; cardiant; cerebroprotective; virucide; cytostatic. MECHANISM OF ACTION : Tumor necrosis factor-alpha (TNF-alpha ) release inhibitor; phosphodiesterase 4 (PDE 4) inhibitor. 4-Ethoxy-(3,4-dimethoxyphenyl)-9-methyl-2-(piperazin-1-yl)-pyrido-(3',2':4,5)-thieno-(3,2-d)-pyrimidine (Ia) had IC50 in the range 20-2000 nM for inhibition of lipopolysaccharide-stimulated release of TNF-alpha in human whole blood by more than 20% at a concentration of 10 nM.</p> |
