Cyclosporin analogues and their pharmaceutical uses
View Patent ↗The compounds of the present invention are represented by Formula I, as shown below: or a pharmaceutically acceptable salt thereof, with X, R 0 , R 1 , and R 2 defined herein.
1. A compound of Formula Ia:
wherein:
X is OH or OAc;
R 0 is H or CH 2 OR 3 ;
R 1 is H or D;
R 2 is selected from the group consisting of:
halogen,
C 3 -C 6 unsubstituted cycloalkyl,
—CH═N—OR 4 , and
—CH═N—NR 4 R 5 ;
R 3 is selected from the group consisting of:
hydrogen,
alkanoyl,
alkenoyl,
alkynoyl,
aryloyl,
arylalkanoyl,
alkylaminocarbonyl,
arylaminocarbonyl,
arylalkylaminocarbonyl,
alkyloxycarbonyl,
aryloxycarbonyl, and
arylalkyloxycarbonyl;
R 4 and R 5 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,
arylalkyloxycarbonyl,
alkylsulfonyl, and
arylsulfonyl; and
R 4 together with R 5 results in the formation of a cyclic moiety of C 2 -C 6 optionally containing heteroatom or heteroatoms,
wherein the compound is a cis geometric isomer, a trans geometric isomer, or a mixture of the cis and the trans geometric isomers or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein X is OH or OAc, R 0 is H, CH 2 OH or CH 2 OAc, R 1 is H or D.
3. The compound according to claim 2 , wherein R 2 is selected from the group consisting of F, Cl, Br, and I.
4. A compound of Formula Ia:
wherein:
X is OH or OAc;
R 0 is H, CH 2 OH, or CH 2 OAc;
R 1 is H or D;
R 2 is selected from the group consisting of —CH═CHF, —CH═CHCl, —CH═CHBr, and —CH═CHI,
wherein the compound is a cis geometric isomer, a trans geometric isomer, or a mixture of the cis and the trans geometric isomers or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 2 , wherein R 2 is cyclopropyl.
6. The compound according to claim 2 , wherein R 2 is selected from the group consisting of —CH═N—OH, —CH═N—OCH 3 , —CH═N—OCH 2 CH 3 , —CH═N—NHCH 3 , and —CH═N—N(CH 3 ) 2 .
7. A compound of Formula Ib:
wherein:
X is OH or OAc;
R 0 is H or CH 2 OR 3 ;
R 1 is halogen;
R 2 is selected from the group consisting of:
hydrogen,
deuterium,
halogen,
C 2 -C 6 unsaturated straight or branched carbon chain, optionally containing halogen,
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:
hydrogen,
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 mixture of the cis and the trans geometric isomers or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carder and a therapeutically effective amount of the compound of claim 1 .
9. A pharmaceutical composition comprising a pharmaceutically acceptable carder and a therapeutically effective amount of the compound of claim 7 .