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

Abstract

The present invention relates to a compound of the formula (I): 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.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       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, isobutyl or n-butyl; 
 W is O or S; 
 R 3  is alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, or cycloalkenyl or substituted cycloalkenyl; and 
 R 5  is H or methyl. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 R 3  is:   (C 1 -C 6 )alkyl, optionally substituted by one or more groups R 4  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 halogen, hydroxy, amino, monoalkylamino and dialkylamino;   (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; or   (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;   R 4  is halogen, hydroxy, 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 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 6 )alkyl, C(═O)(C 1 -C 6 )alkyl, C(═O)O(C 1 -C 6 )alkyl or —NR E R F ;   each occurrence of R E  and R F  is independently hydrogen or (C 1 -C 6 )alkyl;
 R 5  is H or methyl; and 
 m is an integer of 2, 3 or 4. 
   
     
     
         3 . The compound of  claim 1 , wherein R 1  is n-butyl or (E)-but-2-enyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is ethyl. 
     
     
         5 . The compound of  claim 1 , wherein W is O. 
     
     
         6 . The compound of  claim 1 , wherein W is S. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is —(CH 2 ) n NR A R B , wherein n is an integer of 2, 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. 
     
     
         8 . The compound of  claim 1 , wherein R 3  is —(CH 2 ) n NR A R B , wherein n is an integer of 2, 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. 
     
     
         9 . The compound of  claim 1 , wherein R 3  is 2-aminoethyl, 2-aminobutyl, 3-aminobutyl, 2-monoalkylaminoethyl, 2-monoalkylaminobutyl, 3-monoalkylaminobutyl, 2-dialkylaminoethyl, 2-dialkylaminobutyl, or 3-dialkylaminobutyl. 
     
     
         10 . The compound of  claim 1 , wherein R 3  is dimethylaminoethyl, diethylaminoethyl, methylethylaminoethyl, methyl-iso-butylaminoethyl, ethyl-iso-butylaminoethyl, methyl-tert-butylaminoethyl, or ethyl-tert-butylamino ethyl. 
     
     
         11 . The compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
       in which n is an integer of 2, 3, 4, 5 or 6. 
     
     
         12 . The compound of  claim 1 , wherein R 5  is H. 
     
     
         13 . The compound of  claim 1 , wherein R 5  is methyl. 
     
     
         14 . The compound of  claim 1 , wherein the compound having the following chemical structure: 
       
         
           
           
               
               
           
         
       
       wherein W is S or O; and
 R a  is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 CMe 3 , phenyl, CH 2 -phenyl, 
 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein the compound having the following chemical structure: 
       
         
           
           
               
               
           
         
       
       wherein W is S or O;
 R a  is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 
 CH 2 CMe 3 , phenyl, CH 2 -phenyl, 
 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound of  claim 1 , selected from the group consisting of:
 [(R)-Methylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-Ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-n-Propylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-iso-Butylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-iso-Pentylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-(4-Methyl)-Pentylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-Hydroxyethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-Methoxyethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-Ethoxyethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-iso-Butoxyethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-Hydroxyethoxy)ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-Methoxyethoxy)ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-Ethoxyethoxy)ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-iso-Butoxyethoxy)ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-Hydroxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-Methoxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-Ethoxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-iso-Butoxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-Methoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-Ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-n-Propoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-iso-Butoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-iso-Pentyloxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-(4-Methyl)-Pentyloxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-Hydroxyethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-Methoxyethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-Ethoxyethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-iso-Butoxyethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-Hydroxyethoxy)ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-Methoxyethoxy)ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-Ethoxyethoxy)ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-(2-iso-Butoxyethoxy)ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-Methoxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-Ethoxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-2-[2-(2-iso-Butoxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylisoleucine]-4-cyclosporin;   [(R)-Methylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-Ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-n-Propylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-iso-Butylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-iso-Pentylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-(4-Methyl)-Pentylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-Hydroxyethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-Methoxyethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-Ethoxyethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-iso-Butoxyethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-Hydroxyethoxy)ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-Methoxyethoxy)ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-Ethoxyethoxy)ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-iso-Butoxyethoxy)ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-Hydroxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-Methoxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-Ethoxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-iso-Butoxyethoxy)ethoxy]ethylthio-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-Methoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-Ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-n-Propoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-iso-Butoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-iso-Pentyloxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-(4-Methyl)-Pentyloxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-Hydroxyethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-Methoxyethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-Ethoxyethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-iso-Butoxyethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-Hydroxyethoxy)ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-Methoxyethoxy)ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-Ethoxyethoxy)ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-(2-iso-Butoxyethoxy)ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-Methoxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin;   [(R)-2-[2-(2-Ethoxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin; and   [(R)-2-[2-(2-iso-Butoxyethoxy)ethoxy]ethoxy-Sar]-3-[N-methylvaline]-4-cyclosporin, or pharmaceutically acceptable salt thereof.   
     
     
         17 . A pharmaceutical composition comprising at least one compound according to  claim 1  and a pharmaceutically-acceptable carrier or diluent. 
     
     
         18 . A method for treating 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 according to  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the viral infection is a HIV infection, a hepatitis C virus infection or a hepatitis B virus infection. 
     
     
         20 . The method of  claim 18 , wherein the mammalian species is human.