FIELD: pharmacology.
SUBSTANCE: invention relates to new cytotoxic compounds of the formula 
where the dotted line indicates an optional bond; each X1 is -O-; each X2 is -NR-; R1 is selected from the group consisting of -R, -OR, -OCOR13, -OCONR14R15, -OCON(R14)NR(R15), =O (double bond with oxygen) and -NR14R15; R2 and R3 independently represent C1-6alkyl; R4 and R5 are independently selected from the group consisting of hydrogen and -OR; R6 and R7 are independently selected from the group, consisting of halogen, hydroxyl and C1-6alkyl optionally substituted with 1 to 3 substituents independently selected from hydroxyl and halogen, R6 and R7 together with the carbon atom to which they are attached, form a 3-5-membered heterocycloalkyl moiety containing 1 heteroatom of oxygen; R8 is hydrogen, C1-6alkyl or -OR; R9 is independently selected from -(C(R)2)m-C(O)OR, -(C(R)2)m-C(O)NR14R15, -(C(R)2)m-C(O)-SR and -(C(R)2)m-C(O)NR14N(R)R15; R13 is selected from the group consisting of hydrogen, C1-6alkyl, C3-8carbocyclyl, C3-8heterocyclyl, C1-6alkyl-C6-14aryl, C1-6alkyl-C5-14heteroaryl, where R13 is optionally substituted by -NRR or -SO2NRR; each R14 and R15 is independently selected from the group consisting of hydrogen, hydroxyl, -NRR, -NRNR2, -C3-10carbocyclyl, -C1-6alkylene-C3-10carbocyclyl, -C3-10heterocyclyl, -C1-6alkylene-C3-10heterocyclyl, - (CH2CH2O)1-6CH2CH2C(O)OR, - (CH2CH2O)1-6CH2CH2NRR, -C1-6alkyl, C6-14aryl, -C1-6alkylene-C6-14aryl and-C5-14heteroaryl; or R14 and R15 together with the atom or atoms to which they are attached form C3-10heterocyclyl ring, where R14, R15, or both, or the ring formed by R14 and R15, are optionally substituted by -(C(R)2)m-R18 group, where each R18 is independently selected from the groups: (1) -NRR, (2) -C(NRR)(C (O)OR), (3) -S-R, (4) aryl or heteroaryl optionally substituted with one or more halogens, -CF3, - (C(R)2)m-NRR, or - (C(R)2)m-SO2NRR, (5) -SO2R, (6) -S-S-C1-6alkyl-C(O)OR, (7) -SO2NRR, (8) -C(O)NRR, (9) -C(O)OR, (10) -C4-6cycloalkyl optionally substituted with -NRR, -SO2NRR or -NR-C(O)(CH2)0-6NRR, (11) -R, (12) -OR, (13) -N(R)NRR, (14) -C(O)N(R)NRR, (15) - (C(R)2)M-O-NRR and (16) -SSC1-6alkyl-NRR; each R is independently selected from the group consisting of hydrogen and -C1-6alkyl; and each m is independently 0, 1, 2 or 3; or pharmaceutically acceptable salts thereof, the invention also relates to a pharmaceutical composition based on these compounds for treatment of disease states, including cancer.
EFFECT: improved properties of compounds.
40 cl, 4 dwg, 10 tbl, 100 ex
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