New, chemically and metabolically stable epothilon derivatives having modified macrocyclic ring, useful e.g. for treating malignant tumors or chronic inflammatory disease, are cell division regulators

摘要

Epothilon derivatives (I), having a modified carbon chain in the 7-10 positions of the macrocyclic ring, are new. Epothilon derivatives of formula (I), including all stereoisomers and their mixtures, are new. R1a, R1b, R2a, R2b = H, 1-10C alkyl, aryl or 7-20C alkyl; or R1a + R1b, R2a + R2b = (CH2)n; or R1a + R1b = (CH2)2O(CH2)2; n = 2-5; G-G'-E-E' = C(R3a)(R3b)-T'-CH2, C(R3a)=C(R4)CH=CH or a group of formula (a); T' = C(R4)=CH, C(2H)(R4)CH(2H), C(3H)(R4)CH(3H), C(R4)(OH)-CH(OH), C(R4)(OH)CH2 or CHR4CH(OH); R3a, R4 = H, 1-10C alkyl, aryl or 7-20C alkyl; R14 = H, OR14a, halo or OSO2R14b; R3b = OP'; or R3b + R14a = bond; R5 = (CH2)sA or as R4; s = 1-4; A = OR22 or halo; R22 = H or P'; R6, R7 = H; or R6 + R7 = additional bond or O; R8 = H; or 1-10C alkyl, aryl or 7-20C alkyl (all optionally substituted); X = O, (OR23)2, 2-10C alkylenedioxy, (H, OR9) or CR10R11; R23 = 1-20C alkyl; R9 = H or P'; R10, R11 = H, 1-20C alkyl, aryl or 7-20C aralkyl; or CR10R11 = 5-7 membered carbocycle; Y' = O or H2; Z' = O or (H, OR12); R12 = H or P'; and P' = protecting group. Independent claims are included for: (i) the preparation of (I); and (ii) new intermediate partial fragments of formulae (B), (AB) and (ABC). R13 = CH2OR13a, CH2-Hal, C(O)H, COOR13b or C(O)-Hal; R'14 = H, R'14a, halo or OSO2R'14b; R13a, R'14a = H, alkylsulfonyl, arylsulfonyl or aralkylsulfonyl; or R13a + R'14a = (CH2)o or CR15aR15b; R13b, R'14b = H, 1-10C alkyl, aryl or 7-20C aralkyl; R15a, R15b = H, 1-20C alkyl, aryl or 7-20C aralkyl; or R15a + R15b = (CH2)q; o = 2-4; q = 3-6; V', W' = as X but not CR10R11; R20 = H or P'; R21 = OP'', halo, PPh3+.Hal-, P(O)(OQ)2 or P(O)Ph2; Q = 1-10C alkyl or Ph; Ph = phenyl; Hal = halo; and P'' = H or P'.