Deuterated cyclosporine analogs and their use as immunomodulating agents

A cyclosporin A derivative having the structure of Formula (II):

• wherein the configuration of the MeBmt residue is as shown in FIG. 3, compound 5 and
• R is an unsaturated straight or branched aliphatic carbon chain of from 2 to 3 carbons,
• prepared by the method comprising the steps of:
• (a) protecting the β-alcohol of cyclosporin A, thereby forming an intermediate acetyl cyclosporin A;
• (a) oxidizing the acetyl cyclosporin A to produce an intermediate acetyl cyclosporin A aldehyde;
• (b) treating the intermediate acetyl cyclosporin A aldehyde in a Wittig reaction with a phosphorus ylide having the structural formula
• RCH═PPh3
• wherein
• R is as defined above
• to produce an acetyl cyclosporin A derivative having the structure of Formula (I):
• wherein R is as defined above and the configuration of the MeBmt residue is as shown in FIG. 3, compound 5;
• and
• (c) hydrolyzing the acetyl cyclosporin A derivative having the structure of Formula (I) with a base.

A cyclosporine A derivative having the structure of Formula (II):

• wherein the configuration of the MeBmt residue is as shown in FIG. 3, compound 5 and
• 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, prepared by the method comprising the steps of:
• (a) protecting the 13-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 having the structural formula
• RCH═PPh3
• wherein
• R is as defined above
• to produce an acetyl cyclosporine A derivative having the structure of Formula (I):
• wherein R is as defined above and the configuration of the MeBmt residue is as shown in FIG. 3, compound 5;
• and
• (d) hydrolyzing the acetyl cyclosporin A derivative having the structure of Formula (I) with a base.

A cyclosporin A derivative having the structure of Formula (II):

• wherein the configuration of the MeBmt residue is as shown in FIG. 3, compound 5 and
• 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═CHCH═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
• prepared by the method comprising the steps of:
• (a) protecting the 0-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 having the structural formula
• RCH═PPh3
• wherein
• R is as defined above
• to produce an acetyl cyclosporin A derivative having the structure of Formula (I):
• wherein R is as defined above and the configuration of the MeBmt residue is as shown in FIG. 3, compound 5;
• and
• (d) hydrolyzing the acetyl cyclosporin A derivative having the structure of Formula (I) with a base.