New dolastatin conjugates useful as anticancer agents, especially against carcinomas with high levels of steroid hormone receptor expression, e.g. ovarian and breast cancer

摘要

Estradiol-dolastatin conjugates (I) are new. Estradiol-dolastatin conjugates of formula (I) are new: A = an estradiol group of formula (i): R1 = H, 1-6C alkyl, 2-6C alkenyl, 1-6C acyl, arylcarbonyl or aryl(1-6C)alkylcarbonyl; aryl = phenyl or naphthyl optionally substituted by halogen, 1-6C alkyl, 1-6C alkoxy, 1-6C acyl, CN, NO2, NH2, 1-6C alkylamino or di(1-6C alkyl)amino; R2 = H, 1-6C alkyl, 1-6C acyl, arylcarbonyl, aryl(1-6C)alkylcarbonyl or a bond to D; R3 = H when R2 is a bond to D, or a bond to D when R2 is H, 1-6C alkyl, 1-6C acyl, arylcarbonyl or aryl(1-6C)alkylcarbonyl; D = -X-Y-Z-, with X bonded to E and Z bonded to A; X = 1-6C alkylene, -CO-Ra- or -P(O)(Rb)-O-Ra-; Ra = 1-6C alkylene; Rb = 1-6C alkyl; Y = CO or NHCO with the carbonyl group bonded to Z; Z = a single bond, -NH-Ra- or -Ra-CO-; E = a dolastatin-15 group of formula (ii) or a dolastatin-10 group of formula (iii): R4 = isopropyl or CH(Me)O with the O atom bonded to X: R5 = a group of formula E1 or E2 when R4 is isopropyl or a group of formula E1' or E2' when R4 is CH(Me)O: R6 = H, 1-6C alkoxy or an O atom bonded to X; R7 = an O atom bonded to X when R6 is H or alkoxy, or 1-6C alkoxy when R6 is an O atom bonded to X: R8 = an O atom bonded to X; n = 1-4; R'6 = H or 1-6C alkoxy; R'7 = 1-6C alkoxy; R'8 = H or 1-6C alkoxy; R9 = a group of formula E3 or E4 when R4 is isopropyl, or a group of formula E3' or E4' when R4 is CH(Me)O: R10 = -CO-O- with the O atom bonded to X, or -CO-NH- with the N atom bonded to X; R11 = an O atom bonded to X; R'10 = H; R'11 = H or 1-6C alkoxy. An Independent claim is included for methods of preparing (I).