SYNTHETIC DERIVATIVES OF RAPAMYCIN AS MULTIMERIZING AGENTS FOR CHIMERIC PROTEINS WITH IMMUNOPHILIN-DERIVED DOMAINS

摘要

New compounds are disclosed for multimerizing immunophilins and proteins containing immunophilin or immunophilin-related domains. The compounds are of the formula (I): M-L-Q, a resolved stereoisomer thereof or mixture of one or more such stereoisomers, and pharmaceutically acceptable salts thereof, wherein M is an immunophilin-binding group comprising a moiety of formula (II); G is independently selected from the group consisting of (a), (b), and (c); Q comprises a moiety of formula (II), a naturally occurring macrocyclic FKBP ligand or derivative thereof, or is a synthetic FKBP ligand of formula (III); n = 1 or 2; X = O, NH or CH2; B<1> and B<2> are independently H or aliphatic, heteroaliphatic, aryl or heteroaryl; Y = O, S, NH, -NH(C=O)-, -NH(C=O)-O-, -NH(SO2)- or NR<3>, or represents a covalent bond from R<2> to carbon 9; R<1>, R<2>, and R<3> are the same or different and are independently aliphatic, heteroaliphatic, aryl or heteroaryl; and, L is a linker moiety covalently linking monomers M to Q or covalently linking M<1> to M<2> through covalent bonds to either R<1>, R<2>, not necessarily the same in each of M<1> and M<2>.