Deuterated cyclosporin analogs and their use as immunomodulating agents

A method for making a cyclosporin A derivative having the structure:

• wherein R is an unsaturated straight or branched aliphatic carbon chain of from 2 to 3 carbons, the method comprising the steps of:
• (a) protecting the β-alcohol of cyclosporin A, thereby forming an intermediate acetyl cyclosporin A;
• (b) oxidizing the acetyl cyclosporin A to produce an intermediate acetyl cyclosporin A aldehyde;
• (c) treating the intermediate acetyl cyclosporin A aldehyde in a Wittig reaction with a phosphorus ylide formed by treating an alkyl or aryl triphenyl phosphonium halide with a base to produce an acetyl cyclosporin A derivative;
• and
• (d) hydrolyzing the acetyl cyclosporin A derivative with a base.

A method for making a cyclosporine A derivative having the structure:

• wherein R is a saturated or unsaturated, straight or branched, aliphatic carbon chain of from 2 to 3 carbons that is substituted with one or more deuterium atoms, the method comprising the steps of:
• (a) protecting the β-alcohol of cyclosporin A, thereby forming an intermediate acetyl cyclosporin A;
• (b) oxidizing the acetyl cyclosporin A to produce an intermediate acetyl cyclosporin A aldehyde;
• (c) treating the intermediate acetyl cyclosporin A aldehyde in a Wittig reaction with a phosphorus ylide formed by treating an alkyl or aryl triphenyl phosphonium halide with a base to produce an acetyl cyclosporine A derivative;
• and
• (d) hydrolyzing the acetyl cyclosporin A derivative with a base.

A method for making a cyclosporin A derivative having the structure:

• wherein R is a member selected from the group consisting of —D, —CH═CD—CD3, —CD═CD—CD3, —CH═CH—CH═CD—CD3, —CD═CH—CD═CD—CD3, —CH═CH—CH═CD2, —CD═CH-CD═CD2, —CH═CD2, —CD═CD2, —CH═CH2, —CH═CH—CD3, —CH═CH—CH3, —CH═CH—CH═CH—CH3, and —CH═CH—CH═CH2,
• the method comprising the steps of:
• (a) protecting the B-alcohol of cyclosporin A, thereby forming an intermediate acetyl cyclosporin A;
• (b) oxidizing the acetyl cyclosporin A to produce an intermediate acetyl cyclosporin A aldehyde;
• (c) treating the intermediate acetyl cyclosporin A aldehyde in a Wittig reaction with a phosphorus ylide formed by treating an alkyl or aryl triphenyl phosphonium halide with a base to produce an acetyl cyclosporine A derivative;
• and
• (d) hydrolyzing the acetyl cyclosporin A derivative with a base.