Cyclosporin a analogs

Abstract

The present invention relates to novel cyclosporin analogs, processes for preparing them, pharmaceutical compositions containing them, and methods for using these analogs and the compositions containing them for the treatment of medical conditions, including but not limited to ocular conditions such as dry eye.

What is claimed is: 
     
         1 . A compound having Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is —C 1-6 alkyl, —OC 1-6 alkyl, —CH 2 F, —CH 2 OCH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 OH, —OCH 3 , —R 13 R 14 , 
       
       
         
           
           
               
               
           
         
         R 2  is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ; 
         R 3  is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ), or —CH 2 CH(R 7 )(CH 2 CH 3 ); 
         R 4  is —CH 3  or —CH 2 OH; 
         R 5  is —R 8 (CH 2 ) n (C═O) m —; 
         R 6  is —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 , or —CH 2 CH 2 CH 3 ; 
         R 7  is OC 1-5  alkyl; 
         R 8  is O, S, CH 2 O, CH 2 S, or CH 2 ; 
         R 9 , is —H, —C 1-5 alkyl, —C 2-4 fluoroalkyl, C 1-6 alkyl-heterocycle, cyanoalkyl, 
       
       
         
           
           
               
               
           
         
         C 3-8 cycloalkyl, heterocycle, aryl, or cycloalkenyl, or R 9  taken together with R 11 , R 10 , and the N to which R 9  and R 10  are attached forms a heterocycle; 
         R 10  is —H, —C 1-5 alkyl, —C 2-4 fluoroalkyl, C 1-6 alkyl-heterocycle, cyanoalkyl, 
       
       
         
           
           
               
               
           
         
         C 3-8 cycloalkyl, heterocycle, aryl, or cycloalkenyl, or R 10  taken together with R 11 , R 9 , and the N to which R 9  and R 10  are attached forms a heterocycle; 
         R 11  is O, NR 12 , S(O) q , CF 2 , CH(OC 1-6 alkyl), C 1-5 alkylene, divalent C 3-8 cycloalkyl, divalent heterocycle, carbonyl, or taken together with R 9 , R 10 , and the N to which R 9  and R 10  are attached forms a heterocycle; 
         R 12  is H, CH 3 , or C 1-5  alkyl; 
         R 13  is O, S, CH 2 O, CH 2 S, CH 2 SO, or CH 2 SO 2 ; 
         R 14  is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 NH(CH 2 CH 3 ), heterocycle, or aryl; 
         n is 0, 1, 2, 3 or 4; 
         m is 0 or 1; 
         p is 0 or 1; and 
         q is 0, 1 or 2; 
         wherein R 14  is optionally substituted with one or more groups independently selected from the group consisting of H, C 1-6 alkyl, halogen, hydroxyl, ester, sulfonamide, ketone, aldehyde, cycloalkyl, heterocycle, aryl, amine, heterocycle, amide, and guanidinyl; 
         wherein the heterocycle comprising R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached is monocyclic or polycyclic; 
         wherein “------” is a single bond or is absent; and 
         with the provisos that: 
         when R 8  is O, S, CH 2 O, or CH 2 S then n is 2, 3 or 4; 
         when p is 0 then R 11  and “------” are absent; and 
         when R 11  and “------” are absent then R 9  is not directly linked to R 10 . 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is —C 1-6 alkyl, —CH 2 F, —CH 2 OCH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 OH, —OCH 3 , —R 13 R 14 ,   
       
         
           
           
               
               
           
         
         R 2  is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ; 
         R 3  is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 (OH), —CH(CH 3 )(CH 2 CH 3 ), or —CH 2 CH(R 7 )(CH 2 CH 3 ); 
         R 4  is —CH 3 , or —CH 2 OH; 
         R 5  is —R 8 (CH 2 ) n (C═O) m — 
         R 6  is —CH 2 CH 3 , —CH(CH 3 )(OH), —CH(CH 3 ) 2 , or —CH 2 CH 2 CH 3 ; 
         R 7  is OC 1-5  alkyl; 
         R 8  is O, S, CH 2 O, CH 2 S, or CH 2 ; 
         R 9  is —H, —C 1-5 alkyl, 
       
       
         
           
           
               
               
           
         
         C 3-8  cycloalkyl, heterocycle, aryl, or cycloalkenyl, or taken together with R 11 , R 10 , and the N to which R 9  and R 10  are attached forms a heterocycle; 
         R 10  is —H, —C 1-5 alkyl, 
       
       
         
           
           
               
               
           
         
         C 3-8  cycloalkyl, heterocycle, aryl, or cycloalkenyl, or taken together with R 11 , R 9 , and the N to which R 9  and R 10  are attached forms a heterocycle; 
         R 11  is O, NR 12 , S(O) q , C 1-5 alkylene, divalent C 3-8 cycloalkyl, divalent heterocycle, carbonyl, or taken together with R 9 , R 10 , and the N to which R 9  and R 10  are attached forms a heterocycle; 
         R 12  is H, CH 3 , or C 1-5  alkyl; 
         R 13  is O, S, CH 2 O, CH 2 S, CH 2 SO, or CH 2 SO 2 ; 
         R 14  is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, CH 2 CH 2 N(CH 2 CH 3 ) 2 , CH 2 CH 2 NH(CH 2 CH 3 ), heterocycle, or aryl; 
         n is 0, 1, 2, 3 or 4; 
         m is 0 or 1; 
         p is 0 or 1; and 
         q is 0, 1 or 2; 
         wherein R 14  is optionally substituted with one or more groups independently selected from the group consisting of H, C 1-6 alkyl, halogen, hydroxyl, ester, sulfonamide, ketone, aldehyde, cycloalkyl, heterocycle, aryl, amine, heterocycle, amide, and guanidinyl; 
         wherein the heterocycle comprising R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached is monocyclic or polycyclic; 
         wherein “------” is a single bond or is absent; and 
         with the provisos that 
         when R 8  is O, S, CH 2 O, or CH 2 S then n is 2, 3 or 4; 
         when p is 0 then R 11  and “------” are absent; and 
         when R 11  and “------” are absent then R 9  is not directly linked to R 10 . 
       
     
     
         3 . A compound according to  claim 1 , with the further proviso that when R 2  is —CH 3 , and R 3  is —CH 2 CH(CH 3 ) 2 , and R 4  is —CH 3 , and R 6  is —CH 2 CH 3 , then the group 
       
         
           
           
               
               
           
         
       
       is not —CH 2 CH 2 CH 2 (C═O)N(CH 2 CH 3 ) 2 , —CH 2 CH 2 CH 2 (C═O)N(CH 3 ) 2 , —CH 2 CH 2 CH 2 (C═O)NH 2 , —CH 2 CH 2 CH 2 CH 2 CH 2 NH(C═O)CH 3 , —CH 2 CH 2 CH 2 CH 2 NH(C═O)CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 NH(C═O)CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 CH 2 NH(C═O)CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 2 NH(C═O)CH 3 , —CH 2 NHCH 2 COOH or —CH 2 NH(CH 2 ) 5 COOH. 
     
     
         4 . A compound according to  claim 1  with the further provisos that when m is 1, and R 2  is CH 3 , and R 3  is —CH 2 CH(CH 3 ) 2 , and R 4  is —CH 3 , and R 6  is —CH 2 CH 3  then neither R 9  nor R 10  is H or —C 1 -C 5 alkyl, and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached taken together do not form morpholinyl. 
     
     
         5 . The compound according to  claim 2 , wherein m is 0. 
     
     
         6 . The compound according to  claim 2 , wherein n is 0 or 3, m is 0, and p is 1. 
     
     
         7 . The compound according to  claim 2 , wherein p is 0 and R 9  is not directly linked to R 10 . 
     
     
         8 . The compound according to  claim 2 , wherein R 2  is —CH 3  or —CH 2 CH 3 , R 3  is —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) 2 , or —CH 2 C(CH 3 ) 2 (OH), R 4  is —CH 3 , R 6  is —CH 2 CH 3 , and R 8  is CH 2 . 
     
     
         9 . The compound according to  claim 2 , wherein R 2  is —CH 3 , R 3  is —CH 2 CH(CH 3 ) 2 , R 4  is —CH 3 , R 6  is —CH 2 CH 3 , and R 8  is CH 2 . 
     
     
         10 . The compound according to  claim 2 , wherein R 1  is —CH 3  or —CH 2 CH 3 , R 2  is —CH 3 , R 3  is —CH 2 CH(CH 3 ) 2 , R 4  is —CH 3 , R 6  is —CH 2 CH 3 , and R 8  is CH 2 . 
     
     
         11 . The compound according to  claim 2 , wherein R 1  is —CH 3 , R 2  is —CH 3 , R 3  is —CH 2 CH(CH 3 ) 2 , R 4  is —CH 3 , R 5  is —CH 2 CH 2 CH 2 —, R 6  is —CH 2 CH 3 , R 8  is CH 2 , n is 2, m is 0, and p=0. 
     
     
         12 . The compound according to  claim 2 , wherein p is 1 and R 9 , R 10 , R 11  and the N to which R 9  and R 10  are attached taken together form a heterocycle. 
     
     
         13 . The compound according to  claim 12 , wherein the heterocycle formed from R 9 , R 10 , R 11  and the N to which R 9  and R 10  are attached is selected from the group consisting of morpholinyl, piperazinonyl, N-methylpiperazinyl, 
       
         
           
           
               
               
           
         
       
       wherein “*” represents the point of attachment to R 5 . 
     
     
         14 . The compound according to  claim 2 , wherein R 1  is —CH 3  and R 6  is —CH 2 CH 3 . 
     
     
         15 . The compound according to  claim 2 , wherein R 1  is —CH 3 , R 6  is —CH 2 CH 3  or —CH(CH 3 ) 2 , R 8  is CH 2 , R 11  is O, p is 1, and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached taken together form morpholinyl. 
     
     
         16 . The compound according to  claim 2 , wherein R 1  is —CH 3 , R 6  is —CH 2 CH 3  or —CH(CH 3 ) 2 , R 8  is CH 2 , R 11  is NR 12 , R 12  is CH 3 , p is 1, and R 9 , R 10 , R 11  and the N to which R 9  and R 10  are attached taken together form N-methylpiperazinyl. 
     
     
         17 . The compound according to  claim 2 , wherein R 1  is —CH 3 , R 2  is —CH 3 , R 3  is —CH 2 CH(CH 3 ) 2 , R 4  is —CH 3 , R 5  is —CH 2 CH 2 CH 2 —, R 6  is —CH 2 CH 3 , R 8  is CH 2 , n is 2, m is 0, and p is 0. 
     
     
         18 . The compound according to  claim 2 , wherein R 1  is —CH 3 , R 2  is —CH 3 , R 3  is —CH 2 CH(CH 3 ) 2 , R 4  is —CH 3 , R 6  is —CH 2 CH 3 , R 8  is CH 2 , R 11  is O, n is 0 or 3, m is 0, p is 1, and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached taken together form: 
       
         
           
           
               
               
           
         
       
       wherein “*” represents the point of attachment to R 5 . 
     
     
         19 . The compound according to  claim 1 , wherein m is 0, and p is 0 or 1. 
     
     
         20 . The compound according to  claim 1 , wherein p is 1 and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached together form a heterocycle. 
     
     
         21 . The compound according to  claim 9 , wherein p is 1 and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached together form a heterocycle. 
     
     
         22 . The compound according to  claim 23 , wherein p is 1 and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached together form a heterocycle. 
     
     
         23 . The compound according to  claim 26 , wherein the heterocycle formed from R 9 , R 1 , R 11  and the N to which R 9  and R 10  are attached is selected from the group consisting of morpholinyl, piperazinonyl, N-methylpiperazinyl, 
       
         
           
           
               
               
           
         
       
       wherein “*” represents the point of attachment to R 5 . 
     
     
         24 . The compound according to  claim 1 , wherein R 1  is —CH 3 , —OCH 3  or —CH 2 OH; R 8  is CH 2 ; m is 0; p is 1, and R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached taken together form a heterocycle. 
     
     
         25 . The compound according to  claim 1 , wherein m is 0, p is 0 or 1, and R 1  is —C 1-6 alkyl or —OC 1-6  alkyl. 
     
     
         26 . The compound according to  claim 1 , wherein R 1  is CH 3 . 
     
     
         27 . A compound according to  claim 1 , wherein the heterocycle formed from R 9 , R 10 , and the N to which R 9  and R 10  are attached is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein “*” indicates the point of attachment to R 5 . 
     
     
         28 . A compound according to  claim 24 , wherein the heterocycle formed by R 9 , R 10 , R 11 , and the N to which R 9  and R 10  are attached taken together is substituted by an alkyl, halogen, or haloalkyl. 
     
     
         29 . A compound according to  claim 28 , wherein said substituted heterocycle is substituted by
 —CF 3  or fluorine.   
     
     
         30 . A compound according to  claim 1  selected from the group consisting of:
 [(3R,4R,5S)-4-(hydroxy)-3-methyl-5-(methylamino)-1-(morpholin-4-yl) hexanoic acid] 1 [(R)-Me-Sar] 3  cyclosporin A (Compound F); 
 [(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-(4-methylpiperazino)-hexanoic acid] 1 [(R)-Me-Sar] 3  cyclosporin A (Compound L); 
 [(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-N-diethylamino-hexanoic acid] 1 [(R)-Me-Sar] 3  cyclosporin A (Compound M); 
 [(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-(N-3-piperazinone)-hexanoic acid] 1 [(R)-Me-Sar] 3  cyclosporin A (Compound N); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-{1H-imidazol-4-yl}-ethylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound AK); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-methoxyethylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound AF); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-methoxyethyl)methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound AG); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(N-(3aR*,6aS*)-2-methyloctahydropyrrolo[3,4-c]pyrrolo)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound O); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(1,4-dioxan-2-ylmethyl)methylamino-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound AJ); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(thiomorpholino)-hexanoic acid] 1 [(R)-Me-Sar] 3  cyclosporin A (Compound J); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(1,1-dioxo-thiomorpholino)-hexanoic acid] 1 [(R)-Me-Sar] 3  cyclosporin A (Compound P); 
 [[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-homomorpholino-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound X); 
 [(6R,7R,8S)-7-hydroxy-6-methyl-8-(methylamino)-1-N-morpholino-nonanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound G); 
 [(6R,7R,8S)-7-Hydroxy-6-methyl-8-(methylamino)-1-N-diethylamino-nonanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound AH); 
 [(6R,7R,8S)-7-Hydroxy-6-methyl-8-(methylamino)-1-N-(2-methoxy)ethylamino-nonanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound AI); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-N-morpholino-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound H); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(4-methylpiperazin-1-yl)-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound T); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-diethylamino-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound U); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(2-{sulfonic acid dimethylamide}-ethylamino)-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound W); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(2-{1H-imidazol-4-yl}-ethylamino)-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound Y); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-({1,1-dioxo}thiomorpholin-4-yl)-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound Z); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(N-(3aR*,6aS*)-2-methyloctahydropyrrolo[3,4-c]pyrrolo)-1-oxo-octanoic acid]1[(R)-methyl-Sar]3 cyclosporin A (Compound ZZ); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(2-methoxyethylamino)-1-oxo-octanoic acid]1[(R)-methyl-Sar]3 cyclosporin A (Compound ZY); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(1,4-dioxan-2-ylmethyl)amino)-1-oxo-octanoic acid]1[(R)-methyl-Sar]3 cyclosporin A (Compound ZX); 
 [(5R,6R,7S)-6-Hydroxy-5-methyl-7-(methylamino)-1-piperidino-1-oxo-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound Q); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-2-(N,N-diethylamino)ethoxy-hexanoic acid] 1 [(S)-thio-isopropyl-Sar] 3  cyclosporin A (Compound AL); 
 [(3R,4R,5S)-4-hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-ethyl-Sar] 3  cyclosporin A (Compound AB); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-methoxy-Sar] 3  cyclosporin A (Compound B); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-methoxymethylene-Sar] 3  cyclosporin A (Compound D); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-hydroxymethyl-Sar] 3  cyclosporin A (Compound V); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(R)-2-diethylamino ethyl oxymethyl-Sar] 3  cyclosporin A (Compound S); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-homomorpholino-hexanoic acid] 1 [(R)-2-diethylamino ethyl oxymethyl-Sar] 3  cyclosporin A (Compound AD); 
 [(5R,6R,7S)-1-(dimethylamino)-6-hydroxy-5-methyl-7-(methylamino)-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound KF); 
 [(5R,6R,7S)-6-hydroxy-5-methyl-7-(methylamino)-1-(N-morpholino)-octanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound KG); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-N-morpholino-hexanoic acid] 1 [(S)-2-diethylaminoethylthiomethyl-Sar] 3  cyclosporin A (Compound AC); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({pyridin-2-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DA); 
 [(3R,4R,5S)-1-(Bis{pyridin-2-ylmethyl}amino)-4-hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DB); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(methyl-phenyl-amino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DC); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(methyl-pyridin-2-yl-amino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DD); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-sulfamoyl-ethyl)-methyl-amino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DE); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({pyridin-3-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DF); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({pyrimidin-2-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DG); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({pyrazin-2-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DH); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({3-methyl-3H-imidazol-4-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DI); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({2-methyl-2H-pyrazol-3-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DJ); 
 [(3R,4R,5S)-1-({2-Cyano-propyl}-methyl-amino)-4-hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DK); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({pyridin-4-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DL); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({1-methyl-1H-pyrazol-4-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DM); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({3,3,3-trifluoropropyl}-methyl-amino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DN); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({1-methyl-3-trifluoromethyl-2H-pyrazol-5-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DO); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({5-fluoro-pyridin-2-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DP); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({5-chloro-pyridin-2-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DQ); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-({3-trifluoromethyl-pyridin-2-ylmethyl}-methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DR); 
 [(3R,4R,5S)-1-(3,3-Dimethyl-morpholin-4-yl)-4-hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DS); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-methylamino-((R)-3-methyl-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DT); 
 [(3R,4R,5S)-1-(5,6-Dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-Hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DU); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DV); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-((S)-3-methyl-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DW); 
 [(3R,4R,5S)-1-(2,3-Dihydro-benzo[1,4]oxazin-4-yl)-4-Hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DX); 
 [(3R,4R,5S)-1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-Hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DY); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-phenyl-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound DZ); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(piperidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EA); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(pyrrolidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EF); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-trifluoromethyl-piperidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EB); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(3-trifluoromethyl-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EC); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-([1,2]oxazinan-2-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound ED); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2-trifluoromethyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EE); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(pyrrolidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EF); 
 [[(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(4-methyl-[1,4]diazepan-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EG); 
 [[(3R,4R,5S)-4-Hydroxy-1-(3-methoxy-azetidin-1-yl)-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EH); 
 [(4R,5R,6S)-5-Hydroxy-4-methyl-6-(methylamino)-1-(morpholin-4-yl)-heptanoic acid] 1  cyclosporin A (Compound EI); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-1-(morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3 [Ethyl-Val] 4  cyclosporin A (Compound EJ); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2,2,6,6-tetrafluoro-morpholin-4-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EK); 
 [(3R,4R,5S)-(3,3-Difluoro-pyrrolidin-1-yl)-4-Hydroxy-3-methyl-5-(methylamino)-1-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EL); 
 [(3R,4R,5S)-(3,3-Difluoro-azetidin-1-yl)-4-hydroxy-3-methyl-5-(methylamino)-1-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EM); 
 [(3R,4R,5S)-(4,4-Difluoro-piperidin-1-yl)-4-hydroxy-3-methyl-5-(methylamino)-1-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EN); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound ER); 
 [(3R,4R,5S)-4-Hydroxy-3-methyl-5-(methylamino)-1-(2,2,6,6-tetrafluoro-morpholin-4-yl)-hexanoic acid] 1 [(R)-hydroxymethyl-Sar] 3  cyclosporin A (Compound EO); 
 (3R,4R,5S)-1-(3,3-Difluoro-pyrrolidin-1-yl)-4-hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-hydroxymethyl-Sar] 3  cyclosporin A (Compound EP); and 
 (3R,4R,5S)-1-[Bis-(3,3,3-trifluoro-propyl)-amino]-[(4-Hydroxy-3-methyl-5-(methylamino)-hexanoic acid] 1 [(R)-methyl-Sar] 3  cyclosporin A (Compound EQ). 
 
     
     
         31 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.