Cyclosporin alkyne analogues and their pharmaceutical uses

Abstract

The compounds of the present invention are represented by the chemical structure found in Formula I: or a pharmaceutically acceptable salt thereof, with X, R 0 , R 1 , and R 2 defined herein.

1 - 10 . (canceled) 
     
     
         11 . A method of suppressing or reducing immune response in a mammal comprising:
 administering a therapeutically effective amount of a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 X is OH or OAc; 
 R 0  is H, CH 2 OH, or CH 2 OR 3 , 
 R 1  is hydrogen, deuterium, or methyl; 
 R 2  is selected from the group consisting of: 
 hydrogen; 
 halogen; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a substitution or substitutions selected from the group consisting of deuterium, halogen, nitrogen, sulfur, and silicon; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a function group or function groups selected from the group consisting of alcohol, ether, aldehyde, ketone, carboxylic acid, ester, and amide; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a function group of oxime or hydrazone; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing an aryl or a heteroaryl group; 
 C 3 -C 6  substituted and unsubstituted cycloalkyl; 
 substituted and unsubstituted aryl; and 
 substituted and unsubstituted heteroaryl; and 
 R 3  is selected from the group consisting of: 
 alkanoyl, 
 alkenoyl, 
 alkynoyl, 
 aryloyl, 
 arylalkanoyl, 
 alkylaminocarbonyl, 
 arylaminocarbonyl, 
 arylalkylaminocarbonyl, 
 alkyloxycarbonyl, 
 aryloxycarbonyl, and 
 arylalkyloxycarbonyl, 
 wherein the compound is a cis geometric isomer, a trans geometric isomer, or a pharmaceutically acceptable salt thereof 
 
       to said mammal under conditions effective to suppress immune response in a mammal. 
     
     
         12 . A method of treating a mammal with a chronic inflammatory or autoimmune disease comprising:
 administering a therapeutically effective amount of a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 X is OH or OAc; 
 R 0  is H, CH 2 OH, or CH 2 OR 3 ; 
 R 1  is hydrogen, deuterium, or methyl; 
 R 2  is selected from the group consisting of:
 hydrogen; 
 halogen; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a substitution or substitutions selected from the group consisting of deuterium halogen, nitrogen, sulfur, and silicon; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a function group or function groups selected from the group consisting of alcohol, ether, aldehyde, ketone, carboxylic acid, ester, and amide; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a function group of oxime or hydrazone; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing an aryl or a heteroaryl group; 
 C 3 -C 6  substituted and unsubstituted cycloalkyl; 
 substituted and unsubstituted al; and 
 substituted and unsubstituted heteroaryl; and 
 
 R 3  is selected from the group consisting of
 alkanoyl, 
 alkenoyl, 
 alkynoyl, 
 aryloyl, 
 arylalkanoyl, 
 alkylaminocarbonyl, 
 arylaminocarbonyl, 
 arylalkylaminocarbonyl, 
 alkyloxycarbonyl, 
 aryloxycarbonyl, and 
 arylalkyloxycarbonyl, 
 wherein the compound is a cis geometric isomer, a trans geometric isomer, or a pharmaceutically acceptable salt thereof 
 
 
       to the mammal under conditions effective to treat the chronic inflammatory or autoimmune disease. 
     
     
         13 . The method of  claim 12 , wherein the chronic inflammatory or autoimmune disease is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, psoriasis, and ulcerative colitis. 
     
     
         14 . A method of treating a mammal with ocular allergy and dry eye comprising:
 administering a therapeutically effective amount of a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 X is OH or OAc; 
 R 0  is H, CH 2 OH, or CH 2 OR 3 , 
 R 1  is hydrogen, deuterium, or methyl; 
 R 2  is selected from the group consisting of:
 hydrogen; 
 halogen; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a substitution or substitutions selected from the group consisting of deuterium halogen, nitrogen, sulfur, and silicon; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a function group or function groups selected from the group consisting of alcohol, ether, aldehyde, ketone, carboxylic acid, ester, and amide; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing a function group of oxime or hydrazone; 
 C 1 -C 6  saturated or unsaturated, straight or branched carbon chain containing an aryl or a heteroaryl group; 
 C 3 -C 6  substituted and unsubstituted cycloalkyl; 
 substituted and unsubstituted heteroaryl; and 
 
 R 3  is selected from the group consisting of
 alkanoyl, 
 alkenoyl, 
 alkynoyl, 
 aryloyl, 
 arylalkanoyl, 
 alkylaminocarbonyl, 
 arylaminocarbonyl, 
 arylalkylaminocarbonyl, 
 alkyloxycarbonyl 
 aryloxycarbonyl, and 
 arylalkyloxycarbonyl, 
 wherein the compound is a cis geometric isomer, a trans geometric isomer, or a pharmaceutically acceptable salt thereof 
 
 
       to the mammal under conditions effective to treat ocular allergy and dry eye.