Cyclosporine analogue mixtures and their use as immunomodulating agents

Abstract

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 ISA TX 247, and derivatives thereof. Mixtures of ISA TX 247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISA TX 247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. 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.

1 . A composition comprising an isomeric mixture of a cyclosporine analogues modified at the 1-amino acid residue with a 1,3-diene substituent, wherein the isomeric mixture comprises greater than about 90% of the E-isomer and less than about 10% of the Z-isomer, wherein the isomers are the E- and Z-isomers as specified below: