Cyclosporins for the treatment of respiratory diseases

Abstract

The present invention relates to novel semisynthetic cyclosporin analogs of formula (I): wherein A is X is absent, —C1-C6 alkyl-, or —C3-C6 cycloalkyl- Y is selected from the group consisting of: (i) C(O)—O—R1, where R1 is hydrogen, C1-C6-alkyl, optionally substituted with halogen, heterocyclic, aryl, C1-C6-alkoxy, C1-C6-alkylthio, halogen-substituted C1-C6-alkoxy, or halogen-substituted C1-C6-alkylthio; (ii) C(O)—S—R1, where R1 is as previously defined; (iii) C(O)—OCH 2 —OC(O)R2, where R2 is C1-C6-alkyl, optionally substituted with halogen, C1-C6-alkoxy; C1-C6-alkylthio, heterocyclic or aryl; (iv) C(S)—O—R1, where R1 is as previously defined, and (v) C(S)—S—R1, where R1 is as previously defined; B is -αAbu-, -Val-, -Thr- or -Nva-; and U is -(D)Ala-, -(D)Ser-, —[O-(2-hydroxyethyl)(D)Ser]-, —[O-acyl(D)Ser]- or —[O-(2-acyloxyethyl)(D)Ser]-.

What is claimed is:  
     
         1 . A cyclosporin represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 A is  
                     
 X is absent, —C1-C6 alkyl-, or —C3-C6 cycloalkyl- 
 Y is selected from the group consisting of: 
 (i) C(O)—O—R1, where R1 is hydrogen, C1-C6 alkyl, optionally substituted with halogen, heterocyclic, aryl, C1-C6-alkoxy, C1-C6 alkylthio, halogen-substituted C1-C6 alkoxy, or halogen-substituted C1-C6 alkylthio;  
 (ii) C(O)—S—R1, where R1 is as previously defined;  
 (iii) C(O)—OCH2—OC(O)R2, where R2 is C1-C6 alkyl, optionally substituted with halogen, C1-C6 alkoxy, C1-C6 alkylthio, heterocyclic or aryl;  
 (iv) C(S)—O—R1, where R1 is as previously defined, and  
 (v) C(S)—S—R1, where R1 is as previously defined;  
 
 B is -αAbu-, -Val-, -Thr- or -Nva-; and  
 U is -(D)Ala-, -(D)Ser-, —[O-(2-hydroxyethyl)(D)Ser]-, —[O-acyl(D)Ser]- or —[O-(2-acyloxyethyl)(D)Ser]-,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A cyclosporin according to  claim 1  wherein B is -αAbu-, and U is -(D)Ala- 
     
     
         3  A cyclosporin according to  claim 1 , wherein B is -αAbu-, U is -(D)Ala-, X is absent, and Y is selected from a group consisting of: 
 C(O)—O—R1 where R1 is hydrogen, C1-C6 alkyl, optionally substituted with halogen, heterocyclic, aryl, C1-C6-alkoxy, C1-C6-alkylthio, halogen-substituted C1-C6 alkoxy, or halogen-substituted C1-C6 alkylthio;  
 C(O)—S—R1 where R1 is as previously defined 
 C(O)—OCH2—OC(O)R2 where R2 is C1-C6 alkyl, optionally substituted with halogen, C1-C6-alkoxy, C1-C6-alkylthio, heterocyclic or aryl  
 
 
     
     
         4 . A cyclosporin according to  claim 1  which is selected from the group consisting of: 
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOH  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOEt  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2CH2CH3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2Ph  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2F  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCHF2  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCF3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2CF3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2Cl  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2OCH3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOCH2OCH2CH2OCH3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=C(O)SCH2Ph  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is —CH2CH2CH2—, Y=COOCH3  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=COOFmoc.  
 
     
     
         5 . A process for preparing a cyclosporin compound represented by formula I as defined in  claim 1 , comprising reacting a compound of formula 1 wherein A=-MeBmt- and B and U are as defined in  claim 1  with an olefin represented by the formula CH 2 ═CH—X—Y, wherein X and Y are as defined in  claim 1 , with a catalyst in the presence of a lithium salt in an organic solvent.  
     
     
         6 . The process as defined in  claim 5  wherein said catalyst is Grubb's ruthenium alkylidene catalyst, Nolan's catalyst, a benzylidene catalyst or a molybdenum catalyst.  
     
     
         7 . The process as defined in  claim 5  wherein the reaction is carried out at from room temperature to about 100° C. for 1 to 7 days.  
     
     
         8 . A pharmaceutical composition for topical administration comprising a cyclosporin compound of  claim 1  together with a pharmaceutically acceptable diluent or carrier therefor.  
     
     
         9 . A method for treating inflammatory or obstructive airways disease in a subject in need of said treatment, which comprises topically administering to said subject a therapeutically effective amount of a cyclosporin compound of  claim 1 .  
     
     
         10 . The method of  claim 9  wherein said step of topically administering is by inhalation.  
     
     
         11 . The method of  claim 9 , wherein said airways disease is asthma, allegic rhinitis, bronchitis, COPD, chronic bronchitis or cystic fibrosis.