Synthesis of Cyclosporin Analogs

摘要

The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISATX247, and derivatives thereof. ISATX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. Stereoselective pathways may utilize a Wittig reaction, or an organometallic reagent comprising inorganic elements such as boron, silicon, titanium, and lithium. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.

主权项

1. A method of preparing an isomeric mixture of cyclosporin A analogs modified at the 1-amino acid residue, wherein the synthetic pathway comprises the steps of:
a) protecting the β-alcohol of cyclosporin A by forming trimethylsilyl cyclosporine; b) oxidizing the trimethylsilyl cyclosporin A with ozone as the oxidizing agent following by work-up with a reducing agent; c) converting an intermediate trimethylsilyl cyclosporin A aldehyde to a mixture of (E) and (Z)-isomers of trimethylsilyl cyclosporin A-1,3-diene by reacting the intermediate with a phosphorus ylide prepared from a tributylallylphosphonium halide or triphenylphosphonium halide via a Witting reaction, optionally in the presence of a lithium halide; and d) preparing a mixture of (E) and (Z)-isomers of cyclosporin A analogs modified at the 1-amino acid residue by deprotecting the mixture of (E) and (Z)-isomers of trimethylsilyl cyclosporin A-1,3-diene.