Novel cyclosporin derivatives for the treatment and prevention of a viral infection

Abstract

The present invention relates to a compound of the formula (I), (II), (III), (IV), (V), or (VI): or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing a viral infection using the same.

What is claimed is: 
     
         1 . A compound of the formula (IV) or (VI): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         R 1  is n-butyl or (E)-but-2-enyl; 
         R 2  is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; 
         W is O, or S; 
         each occurrence of R 3  is:
 (C 3 -C 6 )alkyl substituted by one or more groups R 4  each occurrence of which is independently selected from the group consisting of OR a ′, SR a ′, O(CH 2 ) m OH, O(CH 2 ) m O(CH 2 ) m OH, C(═O)(C 1 -C 6 )alkyl, C(═O)OH, C(═O)O(C 1 -C 6 )alkyl, —NR A R B , and —NR c (CH 2 ) m NR A R B ; wherein each occurrence R a ′ is independently H or alkyl; 
 (C 3 -C 6 )alkynyl substituted by one or more groups which may be the same or different selected from the group consisting of hydroxy, amino, monoalkylamino and dialkylamino; or 
 (C 3 -C 6 )alkenyl substituted by one or more groups which may be the same or different selected from the group consisting of hydroxy, amino, monoalkylamino and dialkylamino; 
 
         each occurrence of R 5  is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl; 
         each occurrence of R A  and R B  is independently:
 hydrogen; 
 (C 1 -C 6 )alkyl, optionally substituted by one or more groups R D  which may be the same or different; 
 (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl; 
 (C 3 -C 7 )cycloalkyl optionally substituted with (C 1 -C 6 )alkyl; 
 phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C 1 -C 6 )alkyl, —C(═O)O(C 1 -C 6 )alkyl, amino, alkylamino and dialkylamino; 
 or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may the same or different selected from nitrogen, sulfur and oxygen; 
 or R A  and R B , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; 
 
         each occurrence of R C  is independently hydrogen or (C 1 -C 6 )alkyl; 
         each occurrence of R D  is independently halogen, hydroxy, O(C 1 -C 4 )alkyl, C(═O)(C 1 -C 4 )alkyl, C(═O)O(C 1 -C 4 )alkyl; 
         m is an integer of 1, 2, 3, 4 or 5; 
         each occurrence R a  and R b  is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, phenyl or substituted phenyl, or R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycle or substituted heterocycle; and 
         n is an integer of 1, 2, 3, 4, 5, or 6. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 R 5  is:
 H; 
 (C 1 -C 6 )alkyl, optionally substituted by one or more groups R 6  which may be the same or different; 
 (C 2 -C 6 )alkenyl, optionally substituted by one or more groups which may be the same or different selected from hydroxy, (C 1 -C 6 )alkyl, aryl, (CH 2 ) p OR A , O(CH 2 ) m OH, O(CH 2 ) m O(CH 2 ) m OH, O(CH 2 ) m NR A R B , O(CH 2 ) m O(CH 2 ) m NR A R B , (CH 2 ) p NR A R B , (CH 2 ) p NR c (CH 2 ) m NR A R B , (CH 2 ) p NR c (CH 2 ) m NR c (CH 2 ) m NR A R B , (CH 2 ) p C(═O)NR A R B , (CH 2 ) p C(═O)OR A ; 
 (C 2 -C 6 )alkynyl, optionally substituted by one or one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; 
 (C 3 -C 7 )cycloalkyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; 
 phenyl or CH 2 -phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C 1 -C 6 )alkyl, (CH 2 ) p OR A , (CH 2 ) p NR A R B , (CH 2 ) p C(═O)NR A R B , (CH 2 ) p C(═O)OR A ; 
   each occurrence of R a  and R b  is independently H, (C 1 -C 6 )alkyl, phenyl, CH 2 -phenyl, (C 1 -C 6 )OH, (CH 2 ) p O(CH 2 ) m OH, (CH 2 ) p O(CH 2 ) m O(CH 2 ) m OH, or R a  and R b , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of (C 1 -C 6 )alkyl, phenyl and benzyl;   each occurrence of R 4  is independently halogen, hydroxy, aryl, O(CH 2 ) m OH, O(CH 2 ) m O(CH 2 ) m OH, C(═O)(C 1 -C 6 )alkyl, C(═O)OH, C(═O)O(C 1 -C 6 )alkyl, —NR A R B , or —NR c (CH 2 ) m NR A R B ;   each occurrence of R 6  is independently halogen, hydroxy, aryl, S(C 1 -C 6 )alkyl, SR A , OR A , O(CH 2 ) m OH, O(CH 2 ) m O(CH 2 ) m OH, C(═O)OR A , C(═O)NR A R B , NR A R B , O(CH 2 ) m NR A R B , O(CH 2 ) m O(CH 2 ) m NR A R B , NR c (CH 2 ) m NR A R B , or NR c (CH 2 ) m NR c (CH 2 ) m NR A R B , wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (C 1 -C 6 )alkyl, (CH 2 ) p OR A , (CH 2 ) p NR A R B , (CH 2 ) p C(═O)NR A R B  and (CH 2 ) p C(═O)OR A ;   each occurrence of R A  and R B  is independently:
 hydrogen; 
 (C 1 -C 6 )alkyl, optionally substituted by one or more groups R D  which may be the same or different; 
 (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl; 
 (C 3 -C 7 )cycloalkyl optionally substituted with (C 1 -C 6 )alkyl; 
 phenyl optionally substituted with from one to five groups which may be the same or different selected from halogen, —O(C 1 -C 6 )alkyl, —C(═O)O(C 1 -C 6 )alkyl, amino, alkylamino and dialkylamino; 
 or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may the same or different selected from nitrogen, sulfur and oxygen; 
 or R A  and R B , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; 
   each occurrence of R C  is independently hydrogen or (C 1 -C 6 )alkyl;   p is an integer of 0, 1, 2, 3, 4, or 5; and   m is an integer of 1, 2, 3, 4 or 5.   
     
     
         3 . The compound of  claim 1 , wherein R 1  is n-butyl. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is (E)-but-2-enyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is ethyl. 
     
     
         6 . The compound of  claim 1 , wherein W is O. 
     
     
         7 . The compound of  claim 1 , wherein W is S. 
     
     
         8 . The compound of  claim 1 , wherein R 3  is —(CH 2 ) n NR A R B , wherein n is an integer of 3, 4, 5 or 6; and wherein each occurrence of R A  and R B  is independently hydrogen; (C 1 -C 4 )alkyl, optionally substituted by one or more groups R D  which may be the same or different, in which each occurrence of R D  is independently halogen, hydroxy, O(C 1 -C 4 )alkyl, C(═O)(C 1 -C 4 )alkyl, C(═O)O(C 1 -C 4 )alkyl; or R A  and R B , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl and benzyl. 
     
     
         9 . The compound of  claim 1 , wherein R 3  is —(CH 2 ) n NR A R B , wherein n is an integer of 3, 4, 5 or 6; and wherein R A  and R B , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (C 1 -C 4 )alkyl, phenyl and benzyl. 
     
     
         10 . The compound of  claim 1 , wherein R 3  is 3-monoalkylaminobutyl or 3-dialkylaminobutyl, wherein said alkyl is (C 1 -C 4 )alkyl. 
     
     
         11 . The compound of  claim 1 , wherein R 5  is H or methyl. 
     
     
         12 . The compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
         in which n is an integer of 3, 4, 5 or 6. 
       
     
     
         13 . The compound of  claim 1 , wherein R 5  is H, CH 2 —S—(C 1 -C 6 )alky, CH 2 —O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, benzyl, (C 2 -C 6 )OH, (C 1 -C 6 )-monoalkyl amine, (C 1 -C 6 )-dialkyl amine, or (C 1 -C 6 )-cyclic amine. 
     
     
         14 . The compound of  claim 1 , wherein each occurrence R a  and R b  is independently H, (C 1 -C 6 )alkyl, phenyl, CH 2 -phenyl, (C 1 -C 6 )OH, (CH 2 ) p O(CH 2 ) m OH, or (CH 2 ) p O(CH 2 ) m O(CH 2 ) m OH. 
     
     
         15 . The compound of  claim 1 , wherein R a  and R b , together with the nitrogen atom to which they are attached, form a heterocycle selected from 
       
         
           
           
               
               
           
         
         in which R c  is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH 2 CMe 3 , Ph, or CH 2 Ph. 
       
     
     
         16 . The compound of  claim 1 , wherein each occurrence R a ′ is independently H, Me or Et. 
     
     
         17 . The compound of  claim 1 , having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein ∥ represents a single bond or a double bond; 
         W is O or S; 
         R 5  is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 CMe 3 , phenyl, CH 2 -phenyl, 
       
       
         
           
           
               
               
           
         
         each R d  is independently R a , OR a , CH 2 OR a , 
       
       
         
           
           
               
               
           
         
         each R e  is independently H, Me, Et, OR a , CH 2 OR a , CH 2 CH 2 OR a , 
       
       
         
           
           
               
               
           
         
         each of R a  and R b  is independently H, methyl, ethyl, n-propyl, propyl, n-butyl, i-butyl, t-butyl, CH 2 CMe 3 , phenyl, CH 2 -phenyl, 
       
       
         
           
           
               
               
           
         
         or R a  and R b , together with the nitrogen atom to which they are attached 
       
       
         
           
           
               
               
           
         
         form a heterocycle selected from 
       
       
         
           
           
               
               
           
         
         R e  is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 CMe 3 , phenyl, or CH 2 -phenyl; 
         each n is independently 2, 3, 4, 5 or 6; and 
         each n 1  is independently 1, 2, 3, 4, 5 or 6. 
       
     
     
         18 . The compound of  claim 1 , wherein R 3  is (C 3 -C 6 )alkyl substituted by one or more groups R 4  each occurrence of which is independently selected from the group consisting of OR a ′ and SR a . 
     
     
         19 . The compound of  claim 1 , having the following chemical structure: 
       
         
           
           
               
               
           
         
         wherein ∥ represents a single bond or a double bond; 
         W is O or S; 
         each of R a  and R b  is independently H, methyl, ethyl, n-propyl, propyl, n-butyl, i-butyl, t-butyl, CH 2 CMe 3 , phenyl, CH 2 -phenyl, 
       
       
         
           
           
               
               
           
         
         or R a  and R b , together with the nitrogen atom to which they are attached 
       
       
         
           
           
               
               
           
         
         form a heterocycle selected from 
       
       
         
           
           
               
               
           
         
         R c  is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 CMe 3 , phenyl, or CH 2 -phenyl; 
         each n is independently 2, 3, 4, 5 or 6; and 
         each n 1  is independently 1, 2, 3, 4, 5 or 6. 
       
     
     
         20 . The compound of  claim 1 , wherein R 5  is H, 
     
     
         21 . The compound of  claim 1 , selected from the group consisting of:
 [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-iso-propoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-iso-propoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3-[(β-iso-propoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-iso-propoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-[(β-iso-propoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-iso-propoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-pentan-3-yloxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-pentan-3-yloxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3-[(β-pentan-3-yloxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-pentan-3-yloxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-[(β-pentan-3-yloxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-pentan-3-yloxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-iso-butoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-iso-butoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3-[(β-iso-butoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-iso-butoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-[(β-iso-butoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-iso-butoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-2-ethylbutoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-2-ethylbutoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3-[(β-2-ethylbutoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-2-ethylbutoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-([β-2-ethylbutoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-2-ethylbutoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[β-(2-methoxyethoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[β-(2-methoxyethoxy)-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[β-[2-(2-methoxyethoxy)ethoxy]-NMeSer]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[β-[2-(2-methoxyethoxy)ethoxy]-NMeSer]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-iso-propylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-iso-propylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino) propylthio-Sar]-3-[(β-iso-propylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-iso-propylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-[(β-iso-propylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-iso-propylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-pentan-3-ylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-pentan-3-ylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3[(β-pentan-3-ylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-pentan-3-ylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-[(β-pentan-3-ylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-pentan-3-ylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-iso-butylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[(β-iso-butylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3-[(β-iso-butylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-iso-butylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-[(β-iso-butylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-iso-butylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Dimethylamino)propylthio-Sar]-3-[(β-2-ethylbutylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-([β-2-ethylbutylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-iso-Propyl-N-ethylamino)propylthio-Sar]-3-[(β-2-ethylbutylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Pyrrolidinyl)propylthio-Sar]-3-[(β-2-ethylbutylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Piperidinyl)propylthio-Sar]-3-([β-2-ethylbutylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[(β-2-ethylbutylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[β-(2-methoxyethylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[β-(2-methoxyethylthio)-NMeCys]-4-cyclosporin;   [(R)-3-(N, N-Diethylamino)propylthio-Sar]-3-[β-[2-(2-methoxyethoxy)ethylthio]-NMeCys]-4-cyclosporin; and   [(R)-3-(N-Morpholino)propylthio-Sar]-3-[β-[2-(2-methoxyethoxy)ethylthio]-NMeCys]-4-cyclosporin;   [β-(2-Methoxyethylthio)-NMeCys]-4-cyclosporin;   or a pharmaceutically acceptable salt thereof.   
     
     
         22 . A pharmaceutical composition comprising at least one compound of  claim 1  and a pharmaceutically-acceptable carrier or diluent. 
     
     
         23 . A method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         24 . A method for treating or preventing hepatitis C virus infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         25 . A method for treating or preventing hepatitis B virus infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound of  claim 1 . 
     
     
         26 . A method for treating or preventing HIV virus infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound of  claim 1 .