New, chemically and metabolically stable 16-halo or cyano-epothilone derivatives are cell division regulators useful e.g. for treating malignant tumors or chronic inflammatory disease

摘要

16-(Halo or cyano)-epothilone derivatives (I) are new. Also new are partial fragment and non-cyclized intermediates (C), (BC) and (ABC). Epothilone derivatives of formula (I) are new. R1a, R1b, R2a, R2b, R4a, R4b = H, 1-10C alkyl, aryl or 7-20C aralkyl or R1a + R1b, R2a + R2b, R4a + R4b = (CH2)n; n = 2-5; R3 = H, 1-10C alkyl, aryl or 7-20C aralkyl; G = O or CH2; D-E = CH2CH2, CH=CH, CC, oxirane-2,3-diyl, CH(OH)CH(OH), CH(OH)CH2 or H2C-OHHO-CH2 (sic; this definition is not fully legible in the specification); R5 = H, 1-10C alkyl, aryl, 7-20C alkyl, COOH, alkoxycarbonyl, CH2OH, alkoxymethyl, acyloxymethyl, CN, CH2NH2, CH2N(alkyl, acyl)1,2 (sic) or halomethyl; R6, R7 = H or R6 + R7 = an additional bond or O; R8 = halo or CN; 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 carbocyclyl; T-Y = O-C(O), O-CH2, CH2-C(O), N(R24)-C(O) or N(R24)-SO2; R24 = H or 1-10C alkyl; Z' = O or (H, OR12); R12 = H or P' and P' = a protecting group. Independent claims are included for new intermediates of formulae (C), (BC) and (ABC). T' = OR20; R20 = P', halo (preferably Br or I), N3 or protected amino; R21 = OP'', halo, PPh3+.halide-, P(O)(OQ)2 or P(O)Ph2; P'' = hydroxy protecting group; Q = 1-10C alkyl or Ph; U = as for X; R13 and R14 are not defined.