Deuterated cyclosporine analogs and their use as immunomodulating agents

Abstract

Cyclosporine derivatives are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and cyclosporine derivatives. The cyclosporine derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by: (1) Chemical substitution and optionally deuterium substitution of amino acid 1; and (2) deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. Also disclosed are methods of producing the cyclosporine derivatives and method of producing immunosuppression with reduced toxicity with the disclosed cyclosporine derivatives.

1 . A cyclosporine A derivative with isotopic or chemical substitution in the amino acid position selected from the group consisting of 1, 3 and 9 or combinations thereof.  
     
     
         2 . A cyclosporine A derivative according to  claim 1  wherein one or more hydrogen atoms in the amino acid position selected from the group consisting of 1, 3 and 9 or combinations thereof are substituted with a deuterium atom and wherein said cyclosporine A derivative is optionally chemically substituted at the amino acid 9 position.  
     
     
         3 . The cyclosporin A derivative according to  claim 1  represented by the formula I:  
       
         
           
           
               
               
           
         
         (i) a deuterium or  
         (ii) a saturated or unsaturated straight or branched aliphatic carbon chain of from 1 to 16 carbon atoms and optionally containing one or more deuterium atoms or an ester, ketone or alcohol of said carbon chain and optionally containing one or more substituents selected from halogen, nitro, amino, amido, aromatic, and heterocyclic, or  
         (iii) an aromatic or heterocyclic group containing one or more deuterium atoms, or  
         (iv) a methyl group and  
         X, Y, and Z are hydrogen or deuterium provided that if R is methyl then at least one of X, Y or Z is deuterium and wherein R′ is an OH or acetate or other ester or is an O and together with a carbon adjacent to a double bond on amino acid 1 forms a heterocyclic ring.  
       
     
     
         4 . The cyclosporine A derivative of  claim 3  wherein R is a saturated or unsaturated aliphatic carbon chain of from 2 to 3 carbons.  
     
     
         5 . The cyclosporine A derivative of  claim 3  wherein R is a saturated or unsaturated aliphatic carbon chain of from 2 to 3 carbons containing one or more deuterium atoms.  
     
     
         6 . The cyclosporine A derivative of  claim 3  wherein R is methyl.  
     
     
         7 . The cyclosporine A derivative of  claim 4  wherein X, Y and Z are hydrogen.  
     
     
         8 . The cyclosporine A derivative of  claim 1  represented by formula 5g:  
       
         
           
           
               
               
           
         
       
     
     
         9 . The cyclosporine A derivative of  claim 1  represented by formula 5e:  
       
         
           
           
               
               
           
         
       
     
     
         10 . A pharmaceutical composition comprising the cyclosporine A derivative of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         11 . The cyclosporine A derivative of  claim 3  wherein X, Y and Z are H and R is a member selected from the group consisting of —D, —CHO, —CDO, —CD 3 , —CH═CD—CD 3 , —CD═CD—CD 3 , —CH═CH—CH═CD—CD 3 , —CD═CH—CD═CD—CD 3 , —CH═CH—CH═CD 2 , —CD═CH—CD═CD 2 , —CH═CD 2 , —CD═CD 2 , —CH═CH 2 , —CH═CH—CD 3 , —CH═CH—CH 3 , —CH═CH—CH═CH—CH 3 , and CH═CH—CH═CH 2 .  
     
     
         12 . A method of producing imnmunosuppression comprising: 
 administering to an animal in need thereof, an effective amount of a cyclosporine A derivative according to  claim 1.