EPOTHILONE DERIVATIVES AND METHODS FOR MAKING AND USING THE SAME

摘要

The present invention relates to 16-membered macrocyclic compounds. In one aspect of the present invention, compounds of the formula (I), are provided wherein: R<1>, R<2>, R<3>, and R<10> are each independently hydrogen, methyl or ethyl; R<4> is hydrogen, hydroxyl, oxo, or NRR' where R and R' are independently hydrogen, C1-C10 aliphatic, aryl or alkylaryl; R<5> is hydrogen, oxo, or C1-C10 aliphatic, or optionally R<4> and R<5> together form a carbon-carbon double bond; R<6> is hydrogen, hydroxyl, oxo, C1-C10 aliphatic, C1-C10 alkylester, or halide; R<7> is hydrogen or C1-C10 aliphatic that is optionally substituted C1-C5 aliphatic, C1-C5 alkoxy, aryl, or a functional group selected from the group consisting of acetal, alcohol, aldehyde, amide, amine, carbamate, carboalkoxy, carbonate, carbodiimide, carboxylic acid, dioxolane and halogen, or optionally, R<6> and R<7> together form a 1,3-dioxane that is optionally substituted at the 2-position; R<8> and R<9> are both hydrogen or together form a carbon-carbon double bond or an epoxide; Ar is aryl; and, W is O or NR<11> where R<11> is hydrogen, C1-C10 aliphatic, aryl or alkylaryl provided that at least one of R<4>, R<5>, and R<6> is not hydrogen. These compounds are cytotoxic agents and can be used to treat cancer and non-cancer disorders characterized by cellular hyperproliferation.