Cyclosporin alkynes and their utility as pharmaceutical agents

1. 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 2 ;

R 1 is selected from the group consisting of:

hydrogen;

halogen;

C 2 -C 6 saturated or unsaturated, straight or branched carbon chain;

C 2 -C 6 saturated or unsaturated, straight or branched carbon chain containing substitution or substitutions selected from the group consisting of deuterium, halogen, nitrogen, sulfur, and silicon atom or atoms;

C 2 -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 ester, and amide;

C 2 -C 4 saturated or unsaturated, straight or branched carbon chain containing an aryl or a heteroaryl;

C 3 -C 6 -substituted and unsubstituted cycloalkyl;

substituted and unsubstituted aryl;

substituted and unsubstituted heteroaryl;

—CH 2 OH;

—CHO;

—CH═N—OR 3 ; and

—CH═N—NR 3 R 4 ;

R 2 is selected from the group consisting of:

alkanoyl;

alkenoyl;

alkynoyl;

aryloyl;

arylalkanoyl;

alkylaminocarbonyl;

arylaminocarbonyl;

arylalkylaminocarbonyl;

alkyloxycarbonyl;

aryloxycarbonyl; and

arylalkyloxycarbonyl;

R 3 or R 4 are the same or different and independently selected from the group consisting of:

hydrogen;

C 1 -C 6 saturated straight or branched carbon chain;

C 3 -C 6 unsaturated straight or branched carbon chain;

C 3 -C 6 -substituted and unsubstituted cycloalkyl;

C 1 -C 4 carbon chain containing an aryl or heteroaryl;

substituted and unsubstituted aryl;

substituted and unsubstituted heteroaryl;

alkanoyl;

alkenoyl;

alkynoyl;

aryloyl;

arylalkanoyl;

alkylaminocarbonyl;

arylaminocarbonyl;

arylalkylaminocarbonyl;

alkyloxycarbonyl;

aryloxycarbonyl; and

arylalkyloxycarbonyl; and

R 3 together with R 4 results in the formation of a cyclic moiety of C 2 -C 6 optionally containing heteroatom or heteroatoms,

or a pharmaceutically acceptable salt thereof

to said mammal under conditions effective to suppress immune response in a mammal.

2. A method of treating a chronic inflammatory or autoimmune disease in a mammal comprising:

administering to a mammal in need thereof 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 2 ;

R 1 is selected from the group consisting of:

hydrogen;

halogen;

C 2 -C 6 saturated or unsaturated, straight or branched carbon chain;

C 2 -C 6 saturated or unsaturated, straight or branched carbon chain containing substitution or substitutions selected from the group consisting of deuterium, halogen, nitrogen, sulfur, and silicon atom or atoms;

C 2 -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 ester, and amide;

C 2 -C 4 saturated or unsaturated, straight or branched carbon chain containing an aryl or a heteroaryl;

C 3 -C 6 -substituted and unsubstituted cycloalkyl;

substituted and unsubstituted aryl;

substituted and unsubstituted heteroaryl;

—CH 2 OH;

—CHO;

—CH═N—OR 3 ; and

—CH═N—NR 3 R 4 ;

R 2 is selected from the group consisting of:

alkanoyl;

alkenoyl;

alkynoyl;

aryloyl;

arylalkanoyl;

alkylaminocarbonyl;

arylaminocarbonyl;

arylalkylaminocarbonyl;

alkyloxycarbonyl;

aryloxycarbonyl; and

arylalkyloxycarbonyl;

R 3 or R 4 are the same or different and independently selected from the group consisting of:

hydrogen;

C 1 -C 6 saturated straight or branched carbon chain;

C 3 -C 6 unsaturated straight or branched carbon chain;

C 3 -C 6 -substituted and unsubstituted cycloalkyl;

C 1 -C 4 carbon chain containing an aryl or heteroaryl;

substituted and unsubstituted aryl;

substituted and unsubstituted heteroaryl;

alkanoyl;

alkenoyl;

alkynoyl;

aryloyl;

arylalkanoyl;

alkylaminocarbonyl;

arylaminocarbonyl;

arylalkylaminocarbonyl;

alkyloxycarbonyl;

aryloxycarbonyl; and

arylalkyloxycarbonyl; and

R 3 together with R 4 results in the formation of a cyclic moiety of C 2 -C 6 optionally containing heteroatom or heteroatoms,

or a pharmaceutically acceptable salt thereof

under conditions effective to treat the chronic inflammatory or autoimmune disease.

3. The method of claim 2 , wherein the chronic inflammatory or autoimmune disease is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, psoriasis, and ulcerative colitis.

4. A method of treating ocular allergy and dry eye in a mammal comprising:

administering to a mammal in need thereof 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 2 ;

R 1 is selected from the group consisting of:

hydrogen;

halogen;

C 2 -C 6 saturated or unsaturated, straight or branched carbon chain;

C 2 -C 6 saturated or unsaturated, straight or branched carbon chain containing substitution or substitutions selected from the group consisting of deuterium, halogen, nitrogen, sulfur, and silicon atom or atoms;

C 2 -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 ester, and amide;

C 2 -C 4 saturated or unsaturated, straight or branched carbon chain containing an aryl or a heteroaryl;

C 3 -C 6 -substituted and unsubstituted cycloalkyl;

substituted and unsubstituted aryl;

substituted and unsubstituted heteroaryl;

—CH 2 OH;

—CHO;

—CH═N—OR 3 ; and

—CH═N—NR 3 R 4 ;

R 2 is selected from the group consisting of:

alkanoyl;

alkenoyl;

alkynoyl;

aryloyl;

arylalkanoyl;

alkylaminocarbonyl;

arylaminocarbonyl;

arylalkylaminocarbonyl;

alkyloxycarbonyl;

aryloxycarbonyl; and

arylalkyloxycarbonyl;

R 3 or R 4 are the same or different and independently selected from the group consisting of:

hydrogen;

C 1 -C 6 saturated straight or branched carbon chain;

C 3 -C 6 unsaturated straight or branched carbon chain;

C 3 -C 6 -substituted and unsubstituted cycloalkyl;

C 1 -C 4 carbon chain containing an aryl or heteroaryl;

substituted and unsubstituted aryl;

substituted and unsubstituted heteroaryl;

alkanoyl;

alkenoyl;

alkynoyl;

aryloyl;

arylalkanoyl;

alkylaminocarbonyl;

arylaminocarbonyl;

arylalkylaminocarbonyl;

alkyloxycarbonyl;

aryloxycarbonyl; and

arylalkyloxycarbonyl; and

R 3 together with R 4 results in the formation of a cyclic moiety of C 2 -C 6 optionally containing heteroatom or heteroatoms,

or a pharmaceutically acceptable salt thereof

under conditions effective to treat ocular allergy and dry eye.