ALKYLATED RAPAMYCIN DERIVATIVES

摘要

This invention relates to compounds which possess immunosuppressive and/or anti tumor and/or antiinflammatory activity in vivo and/or inhibit thymocyte proliferation in vitro. These compounds are therefore useful in the treatment of transplantation rejection, autoimmune diseases such as lupus, rheumatoid arthritis, diabetes mellitus, multiple sclerosis and in the treatment of Candida albicans infections and also in treatment of diseases of inflammation. These compounds are represented by formula (I), wherein W and Y are OR1 and X and Z together form a bond or W and X are OR2 and Y and Z together form a bond, wherein: R1 is selected from -(CH¿2?)n-Ar where Ar is not phenyl, -(CH2CH2O)nCH3 where n is not 1, -CH2CH2CH2O(CH2CH2O)m-CH3, -(CH2)n-CH2CH(OR?3)CH¿2OR4 where R?3 and R4¿ are H, C¿1?-C10 alkyl, or R?3 and R4¿ together are ethylene, methylene or dimethylmethylene; -CH¿2?(CH2)n-OR?3¿ where R3 is not H, C¿1?-C10 alkyl, or C(O)C1-C10 alkyl; and -CH2(CH2)n-X where X is F, Cl, Br or I; R?2¿ is selected from H, C¿1?-C10 alkyl, Ar(CH2)n-, C3-C10 alkenyl, -(CH2CH2O)nCH3, -CH2CH2CH2O(CH2CH2O)m-CH3, -CH2(CH2)n-OR?3, -CH¿2(CH2)n-X where X is F, Cl, Br or I; and -(CH2)nCH2CH(OR5)CH2OR6 where R?5 and R6¿ are selected independently from H, C¿1?-C10 alkyl, -(CH2)n-Ar, -CONH(CH2)n-Ar or COC(CH3)2-(CH2)n-Ar, -COR?7¿ and -CO¿2R?7, where R7 is C1-C6 alkyl, C2-C6 alkenyl, or Ar; n = 1-10 independently; m = 1-5 independently; and Ar is selected independently from phenyl, pyridinyl, quinolinyl, indolyl, furanyl; 1,2,3-triazolyl and tetrazolyl, and a pharmaceutically acceptable acid addition salt where one can be formed.