Cyclosporin analogs for the treatment of lung diseases

Abstract

the present invention relates to a cyclosporin analog of the following formula (I) or a pro-drug or pharmaceutically acceptable salt thereof: In formula I, the formula for residue A is: where X is absent, —C1-C6 alkyl-, or —C3-C6 cycloalkyl-; Y is selected from the groups: —C(O)—O—R1; —C(O)—S—R1; —C(O)—OCH2-OC(O)R2; —C(S)—O—R1; and —C(S)—S—R1; where R1 is hydrogen, C1-C6 alkyl optionally substituted with halogen, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio or halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio and where R2 is C1-C6 alkyl optionally substituted with halogen, C1-C6 alkoxy, C1-C6 alkylthio heterocyclics or aryl; B is -αAbu-, -Val-, -Thr- or -Nva-; and U is -(D)Ala-, -(D)Ser- or -[O-(2-hydroxyethyl)(D)Ser]-, or -[O-acyl(D)Ser]- or -[O-(2-acyloxyethyl)(D)Ser]-. In a second embodiment, the present invention relates to the use of the cyclosporin analogs of the present invention or a pro-drug or pharmaceutically acceptable salt thereof in pharmaceutical compositions for the treatment of asthma and other diseases characterized by airflow obstruction in a subject. In a third embodiment, the present invention relates to processes for the production of novel cyclosporin analogs of the present invention. The present invention also contemplates method(s) of treatment of asthma and other diseases characterized by airflow obstruction in a subject by administering to the subject therapeutically effective amounts of the cyclosporin analogs of the present invention with or without the concurrent use of other drugs or pharmaceutically acceptable carriers or excipients.

What is claimed is:  
     
         1 . A cyclosporin analog of formula (I) or a pro-drug or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein, 
 (a) A is of the formula:  
                     
 wherein  
 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, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio;  
 ii. —C(O)—S—R1 where R1 is hydrogen, C1-C6 alkyl optionally substituted with halogen, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio;  
 iii. —C(O)—OCH2-OC(O)R2 where R2 is C1-C6 alkyl, optionally substituted with halogen, C1-C6 alkoxy, C1-C6 alkylthio, heterocyclics or aryl;  
 iv. —C(S)—O—R1 where R1 is hydrogen, C1-C6 alkyl optionally substituted with halogen, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio; and  
 v. C(S)—S—R1 where R1 is hydrogen, C1-C6 alkyl optionally substituted with halogen, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio.  
 
 (b) B is -αAbu-, -Val-, -Thr- or -Nva-; and  
 (c) U is -(D)Ala-, -(D)Ser- or -[O-(2-hydroxyethyl)(D)Ser]-; or -[O-acyl(D)Ser]- or -[O-(2-acyloxyethyl)(D)Ser]-.  
 
     
     
         2 . A cyclosporin analog according to  claim 1  or a pro-drug or a pharmaceutically acceptable salt thereof, wherein in formula (I), B is -αAbu-, and U is -(D)Ala-.  
     
     
         3 . A cyclosporin analog according to  claim 1  or a pro-drug or a pharmaceutically acceptable salt thereof, wherein in formula I: 
 (i) A is of the formula A1 or A2, wherein: 
 X is absent; and  
 Y is selected from a group consisting of: 
 i. —C(O)—O—R1 where R1 is hydrogen, C1-C6 alkyl optionally substituted with halogen, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio;  
 ii. —C(O)—S—R1 where R1 is hydrogen, C1-C6 alkyl optionally substituted with halogen, heterocyclics, aryl, C1-C6 alkoxy or C1-C6 alkylthio, halogen substituted C1-C6 alkoxy, halogen substituted C1-C6 alkylthio; and  
 iii. C(O)—OCH 2 —OC(O)R2 where R2 is C1-C6 alkyl optionally substituted with halogen, C1-C6 alkoxy, C1-C6, alkylthio, heterocyclics or aryl;  
 
 
 (ii) B is -αAbu-; and  
 (iii) U is -(D)Ala-.  
 
     
     
         4 . A cyclosporin analog according to  claim 1  or a pro-drug or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 3 ;  
 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=—COOCH 2 CH 2 CH 3 ;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 Ph;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 F;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCHF 2 ;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCF 3 ;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 CF 3 ;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 Cl;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 OCH 3 ;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOCH 2 OCH 2 CH 2 OCH 3 ;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—C(═O)SCH 2 Ph;  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is —CH 2 CH 2 CH 2 —, Y=—COOCH 3 ; and  
 Compound of Formula (I) wherein B=-αAbu-, U=-(D)Ala-, X is absent, Y=—COOFmoc.  
 
     
     
         5 . A chemical process for preparing a cyclosporin analog of formula I as claimed in  claim 1 , comprising: 
 a. reacting a compound of formula I, wherein A=-MeBmt- with: 
 i. an olefin of formula CH 2 ═CH—X—Y, wherein X and Y are as defined in  claim 1;  and  
 ii. a catalyst;  
 in the presence of a lithium salt in an organic solvent; and  
   b. hydrogenating the product of step a in an organic solvent under hydrogen with a catalyst;    and optionally converting the product of said reaction into a pharmaceutically acceptable salt.    
     
     
         6 . The chemical process as claimed in  claim 5 , wherein the catalyst in step (a) (ii) is Grubb's ruthenium alkylidene, Nolan's catalyst, a benzylidene catalyst or a molybdenum catalyst.  
     
     
         7 . The chemical process as claimed in  claim 5 , wherein step (b) is performed at room temperature.  
     
     
         8 . The chemical process as claimed in  claim 7 , wherein the catalyst in step (b) is Palladium on carbon.  
     
     
         9 . A pharmaceutical composition, said composition comprising at least one cyclosporin analog of formula 1 as claimed in  claim 1 , said cyclosporin analog being present alone or in combination with a pharmaceutically acceptable carrier or excipient.  
     
     
         10 . A method for treating diseases characterized by airflow obstruction in a subject in need of treatment which comprises the step of administering to said subject a therapeutically effective amount of at least one cyclosporin analog of formula I as claimed in  claim 1 .  
     
     
         11 . The method of  claim 10 , wherein said disease is asthma.  
     
     
         12 . The method of  claim 10 , wherein the step of administering the cyclosporin analog of formula I is done by topical administration.