Cryptophycin derivatives and their use as anti-microtubule agents

摘要

The invention provides novel cryptophycin compounds which can be useful for disrupting the microtubulin system, as antineoplastic agents, and for the treatment of cancer. The invention further provides a formulation for administering the novel cryptophycin compounds. The compounds are of the formula <CHEM> wherein Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group; R<1> is halogen, SH, amino, monoalkylamino, dialkylamino, trialkylammonium, alkylthio, dialkylsulfonium, sulfate, or phosphate; R<2> is OH or SH; or R<1> and R<2> may be taken together to form an epoxide ring, and aziridine ring, an episulfide ring, a sulfate ring, or monoalkylphosphate ring; or R<1> and R<2> may be taken together to form a second bond between C18 and C19; R<3> is a lower alkyl group; R<4> is H; R<5> is H; R<4> and R<5> may be taken together to form a second bond between C13 and C14; R<6> is benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group; R<7> is H or a lower alkyl group; R<8> is H or a lower alkyl group; or R<7> and R<8> may optionally be taken together to form a cyclopropyl ring; R<9> is selected from the group consisting of H, a lower alkyl group, (C1-C3) alkylaryl, and aryl; R<10> is selected from the group consisting of H, a lower alkyl group, (C1-C3) alkylaryl, and aryl; R<11> is H; simple alkyl; phenyl, substituted phenyl, benzyl, substituted benzyl; X is O, NH or alkylamino; Y is C, O, NH, S, SO, SO2 or alkylamino; and a pharmaceutically acceptable salt or solvate thereof.