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New dolastatin conjugates useful as anticancer agents, especially against carcinomas with high levels of steroid hormone receptor expression, e.g. ovarian and breast cancer
New dolastatin conjugates useful as anticancer agents, especially against carcinomas with high levels of steroid hormone receptor expression, e.g. ovarian and breast cancer
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).
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机译：雌二醇-道伐他汀偶联物（I）是新的。式（I）的雌二醇-达拉他汀偶联物是新的：A =式（i）的雌二醇基团：R1 = H，1-6C烷基，2-6C烯基，1-6C酰基，芳基羰基或芳基（1-6C）烷基羰基芳基＝任选地被卤素，1-6C烷基，1-6C烷氧基，1-6C酰基，CN，NO 2，NH 2，1-6C烷基氨基或二（1-6C烷基）氨基取代的苯基或萘基; R2 ＝ H，1-6C烷基，1-6C酰基，芳基羰基，芳基（1-6C）烷基羰基或与D的键;当R2是与D的键时，或当R2是H，1-6C烷基，1-6C酰基，芳基羰基或芳基（1-6C）烷基羰基时，与D的键时，R3 ＝ H; D ＝ -X-Y-Z-，其中X与E键合，Z与A键合; X = 1-6C亚烷基，-CO-Ra-或-P（O）（Rb）-O-Ra-; Ra = 1-6C亚烷基; Rb = 1-6C烷基; Y ＝羰基与Z键合的CO或NHCO。 Z ＝单键，-NH-Ra-或-Ra-CO-; E =式（ii）的dolastatin-15基团或式（iii）的dolastatin-10基团：R4 =异丙基或CH（Me）O，O原子与X相连：R5 =式E1或E2当R4是异丙基或当R4是CH（Me）O时的式E1'或E2'的基团时：R6 ＝ H，1-6C烷氧基或与X键合的O原子;当R 6为H或烷氧基时，R 7 ＝与X键合的O原子;当R 6为与X键合的O原子时，R 7 ＝ 1-6C烷氧基; R 8 ＝与X键合的O原子。 n = 1-4; R'6 = H或1-6C烷氧基; R'7 = 1-6C烷氧基; R'8 = H或1-6C烷氧基;当R 4为异丙基时，R 9 =式E3或E4的基团，或者当R 4为CH（Me）O时，R 9 =式E3'或E4'的基团：R10 = -CO-O-，O原子与X键合，或- CO-NH-，N原子键合到X上; R11 ＝与X键合的O原子; R'10 = H; R′11 ＝ H或1-6C烷氧基。制备方法（I）包括独立权利要求。
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