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; R<3> = 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); R<5> = H, 1-10C alkyl, aryl, 7-20C alkyl, COOH, alkoxycarbonyl, CH2OH, alkoxymethyl, acyloxymethyl, CN, CH2NH2, CH2N(alkyl, acyl)1,2 (sic) or halomethyl; R<6>, R<7> = H or R<6> + R<7> = an additional bond or O; R<8> = halo or CN; X = O, (OR<23>)2, 2-10C alkylenedioxy, (H, OR<9>) or CR<10>R<11>; R<23> = 1-20C alkyl; R<9> = H or P'; R<10>, R<11> = H, 1-20C alkyl, aryl or 7-20C aralkyl or CR<10>R<11> = 5-7 membered carbocyclyl; T-Y = O-C(O), O-CH2, CH2-C(O), N(R<24>)-C(O) or N(R<24>)-SO2; R<24> = H or 1-10C alkyl; Z' = O or (H, OR<12>); R<12> = H or P' and P' = a protecting group. Independent claims are included for new intermediates of formulae (C), (BC) and (ABC). T' = OR<20>; R<20> = P', halo (preferably Br or I), N3 or protected amino; R<21> = 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; R<13> and R<14> are not defined.