| 摘要 |
New hydroxamic acid and carboxylic acid derivatives (I) are new. - Hydroxamic acids and carboxylic acids of formula (I) and their salts and stereoisomers are new: R1 = CO2H, C(O)NHOH, C(O)NHOR7, SH, CH2CO2R7, COR7, N(OH)COR7, SN2H2R7, SONHR7, CH2CO2H, PO(OH)2, PO(OH)NHR7, CH2SH, C(O)NHOR7, CO2R7 or their common prodrug derivatives; R2, R3, R5, R6 = U-X-Y-Z-Ua-Xa-Ya-Za; U = absent or O, NRa, CO, COO, OCO, CONRa, NRaCO, OCOO, OCONRa, NRaCOO, NRaCONRa, S(O)p, S(O)pNRa, NRaS(O)p or NRaSO2NRa; X, Xa = absent or H, 1-10C alkylene, 2-10C alkenylene or 2-10C alkynylene; Y, Ya = absent or H, O, NRa, S(O)p or CO; Z, Za = absent, H or 3-13C carbocyclic residue or 5-14-membered heterocyclic containing 1-4 O, N and/or S heteroatoms (both optionally substituted by 1-5 Rc); Ua = H, O, NRa, CO, COO, OCO, CONRa, NRaCO, OCOO, OCONRa, NRaCOO, NRaCONRa, S(O)p, S(O)pNRa, NRaS(O)p or NRaSO2NRa; Ra, Ra' = H, 1-4C alkyl, phenyl or benzyl or Ra + Ra' form a 5-6-membered ring containing 0-1 additional O, N or S atoms; Rb = 1-6C alkyl, ORa, Cl, F, Br, I, O, CN, NO2, NRaRa', CORa, COORa, CONRaRa', S(O)2NRaRa', S(O)pRa, CF3 or CF2CF3; Rc = a group Rb, NRaSO2Ra' or 5-14-membered heterocyclyl containing 1-4 N, O and/or S atoms; R4 = H, 1-5C alkyl or 1-5C alkyl-aryl; R7 = 1-10C alkyl, alkylaryl or their common prodrug derivatives; A = SO2, SO or CHOH; E = (CR8R9)m-W-(CR8R9)n; W = absent or CH2, COH, O, S(O)m or NR10; m, n = 0-2, provided that when W = O, S or NR10, then m is not 0; R8, R9 = H, 1-8C alkyl or 1-8C alkenylaryl (substituted by 0-5 Rb), 1-8C alkenyl, 3-13C carbocyclic residue or 5-14-membered heterocyclyl containing 1-4 O, N and/or S atoms (both optionally substituted by 1-5 Rc), amino, 1-8C alkyl-NR10 or OH or R8 + R9 form a ring interrupted by O, S(O)m or NR10; R10 = H, 1-8C alkyl or 1-8C alkylaryl; J1-J4 = CH or N with no more than two N in the cycle. MECHANISM OF ACTION - Inhibitors of matrix metalloproteinase, including aggrecanase; production of tumor necrosis factor (TNF), particularly secretion of active TNF-alpha from cells. ACTIVITY - Antiinflammatory. |
