Method for the treatment or prevention of Flavivirus infections using nucleoside analogues

Abstract

The present invention relates to a method for the treatment or prevention of Flavivirus infections using nucleoside analogues in a host comprising administering a therapeutically effective amount of a compound having the formula I or a pharmaceutically acceptable salt thereof.

1 . A method for the treatment or prevention of an hepatitis C infection in a host comprising administering to said host a therapeutically effective amount of a compound having the formula Ib or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 B is a nucleotide purine radical, a nucleotide pyrimidine radical or an analogue of a nucleotide purine radical or a nucleotide pyrimidine radical, wherein said analogue is derived by replacement of a CH moiety by a nitrogen atom in a nucleotide purine or pyrimidine radical, replacement of a nitrogen atom by a CH moiety in a nucleotide purine or pyrimidine radical or both; or derived by removal of ring substituents of said nucleotide purine radical or pyrimidine radical; or combinations thereof, and said analogue is optionally substituted by halogen hydroxyl, amino or C 1-6  alkyl;  
 Ra is 
 H, monophosphate, diphosphate, triphosphate, carbonyl which is substituted by a straight, branched or cyclic alkyl having up to 6 C atoms wherein the alkyl is unsubstituted or substituted by halogen, nitro CONH, COOH O-CQ-6 alkyl O—C 6  alkenyl O—C 6  alkynyl hydroxyl, amino or COOQ,  
 C 2-6  alkenyl which is unsubstituted or substituted by halogen nitro, CONH 2 , COOH, O—C_alkyl O—C_alkenyl, O—C, alkynyl, hydroxyl, amino, or COOQ,  
 C 2-6  alkynyl which is unsubstituted or substituted by halogen, nitro, CONH, COOH. O—C 1-6  alkyl O—C_alkenyl O—C 2-6  alkynyl, hydroxyl, amino, or COOQ,  
 C 6-10  aryl which is unsubstituted or mono- or di-substituted with OH SH, amino halogen or C 1-6  alkyl, or an  
                     
 
 Rc is in each case independently, H, 
 straight chain, branched chain or cyclic C 1-6  alkyl which is unsubstituted or substituted by or substituted by halogen, nitro, CONH. COOH, O—C 1-6  alkyl O—C —   6  alkenyl. O—C_) 6  alkynyl, hydroxyl, amino, or COOQ,  
 C 2-6  alkenyl which is unsubstituted or substituted by or substituted by halogen nitro, CONH 2 , COOH, O—C, alkyl, —C_alkenyl, —C_alkynyl hydroxyl, amino, or COOQ,  
 C 2-6  alkynyl which is unsubstituted or substituted by or substituted by halogen, nitro, CONH, COOH O—C, alkyl O—C, alkenyl O—C_alkynyl, hydroxyl amino, or COOQ,  
 C 6-10  aryl which is unsubstituted or mono- or di-substituted with OH, SH, amino, halogen or C 1-6  alkyl, or  
 a hydroxy protecting group; and  
 
 Z is ORb,  
 Rb is H, 
 straight chain, branched chain or cyclic C 1-6  alkyl which is unsubstituted or substituted by or substituted by halogen, nitro, CONH 2 , COOH, O—C_alkyl, O—C_alkenyl, O—C 1-6  alkynyl, hydroxyl, amino, or COOQ,  
 C 2-6  alkenyl which is unsubstituted or substituted by or substituted by halogen, nitro, CONH, COOH, —C 1-6 alkyl, O—C 2-6 alkenyl, O—C 2-6  alkynyl hydroxyl, amino, or COOQ,  
 C 2-6  alkynyl which is unsubstituted or substituted by or substituted by halogen, nitro CONH 2 , COOH, O—C_alkyl O—C_alkenyl O—C_alkynyl hydroxyl amino, or COOQ,  
 C 1-6  acyl, or  
 a hydroxy protecting group;  
 
 D 1  and D 2  are each independently N 3 , F, or H,  
 D 1  and D 2  can also be joined to be ═CH 2 , ═CF 2 , or C 3 -cycloalkyl which is unsubstituted or substituted by or substituted by halogen, nitro, CONH 2 , COOH, O—C 1-6  alkyl, O—C 2-6  alkenyl, O—C 7-6  alkynyl, hydroxyl, amino, or COOQ;  
 with the proviso that when B is adenine, Z is ORb, D 1  is H, D 2  is H and Rb is H, Ra is not triphosphate or H,  
 wherein said compound is not administered in conjunction with an interferon.  
 
     
     
         2 . A method according to  claim 1  wherein Z is OH.  
     
     
         3 . A method according to  claim 2  wherein D 1  is H and D 2  is F.  
     
     
         4 . A method according to  claim 2  wherein Ra is H, monophosphate, diphosphate, or triphosphate.  
     
     
         5 . A method according to  claim 2  wherein Ra is triphosphate.  
     
     
         6 . A method according to  claim 2  wherein Ra is H.  
     
     
         7 . A method according to  claim 3  wherein Ra is H, monophosphate, diphosphate, or triphosphate.  
     
     
         8 . A method according to  claim 3  wherein Ra is triphosphate.  
     
     
         9 . A method according to  claim 3  wherein Ra is H.  
     
     
         10 . A method according to  claim 2  wherein B is adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl, 3-carboxamido-1,2,4-triazol-1-yl, 3-deaza-adenin-9-yl, 3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl, 3-deaza-2-amino-purin-9-yl, 3-deaza-2-amino-6-chloro-purin-9-yl 3-deaza-2-6-diamino-purin-9-yl, 7-deaza-adenin-9-yl, 7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl, 7-deaza-2-amino-purin-9-yl, 7-deaza-2-amino-6-chloro-purin-9-yl, 7-deaza-2-6-diamino-purin-9-yl, 7-deaza-8-aza-adenin-9-yl, 7-deaza-8-aza-guanin-9-yl, 7-deaza-8-aza-inosin-9-yl, 7-deaza-8-aza-2-amino-purin-9-yl, 7-deaza-8-aza-2-amino-6-chloro-purin-9-yl, 7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl, 8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl, 8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl, 5-aza-thymin-1-yl, 5-aza-cytosin-1-yl, 5-aza-uracil-1-yl, 6-aza-thymin-1-yl, 6-aza-cytosin-1-yl, or 6-aza-uracil-1-yl; which in each case is unsubstituted or substituted by at least one of NHR 3 , C 1-6 alkyl, —OC 1-6 alkyl, Br, Cl, F, I or OH, wherein R 3  is H, C 1-6 alkyl or C 1-6 acyl.  
     
     
         11 . A method according to  claim 3  wherein B is chosen from adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl, 3-carboxamido-1,2,4-triazol-1-yl, 3-deaza-adenin-9-yl, 3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl, 3-deaza-2-amino-purin-9-yl, 3-deaza-2-amino-6-chloro-purin-9-yl 3-deaza-2-6-diamino-purin-9-yl, 7-deaza-adenin-9-yl, 7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl, 7-deaza-2-amino-purin-9-yl, 7-deaza-2-amino-6-chloro-purin-9-yl, 7-deaza-2-6-diamino-purin-9-yl, 7-deaza-8-aza-adenin-9-yl, 7-deaza-8-aza-guanin-9-yl, 7-deaza-8-aza-inosin-9-yl, 7-deaza-8-aza-2-amino-purin-9-yl, 7-deaza-8-aza-2-amino-6-chloro-purin-9-yl, 7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl, 8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl, 8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl, 5-aza-thymin-1-yl, 5-aza-cytosin-1-yl, 5-aza-uracil-1-yl, 6-aza-thymin-1-yl, 6-aza-cytosin-1-yl, or 6-aza-uracil-1-yl; which in each case is unsubstituted or substituted by at least one of NHR 3 , C 1-6 alkyl, —OC 1-6 alkyl, Br, Cl, F, I or OH, wherein R 3  is H, C 1-6 alkyl or C 1-6 acyl.  
     
     
         12 . A method according to  claim 2  wherein B is adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, 5-fluoro-cytosin-1-yl, uracil-1-yl, 5-fluorouracil or 1,2,4-triazole-3-carboxamide base.  
     
     
         13 . A method according to  claim 3  wherein B is adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, 5-fluoro-cytosin-1-yl, uracil-1-yl, 5-fluorouracil or 1,2,4-triazole-3-carboxamide base.  
     
     
         14 . A method according to  claim 1  wherein the compound of formula I is: 
 3′-deoxycytidine;  
 3′-deoxycytidine-5′triphosphate;  
 5-Fluoro-3′-deoxycytidine;  
 5-Fluoro-3′-deoxycytidine-5′triphosphate;  
 3′-deoxyuridine;  
 3′-deoxyuridine-5′triphosphate;  
 5-Fluoro-3′-deoxyuridine;  
 5-Fluoro-3′-deoxyuridine-5′triphosphate;  
 3′-deoxythymidine;  
 3′-deoxythymidine-5′triphosphate;  
 3′-deoxyguanosine;  
 3′-deoxyguanosine-5′triphosphate;  
 2-N-acetyl-3′-deoxyguanosine;  
 2-N-acetyl-3′-deoxyguanosine-5′triphosphate;  
 5-Methyl-3′-deoxycytidine;  
 5-Methyl-3′-deoxycytidine-5′triphosphate;  
 5-Iodo-3′-deoxycytidine;  
 5-Iodo-3′-deoxycytidine-5′triphosphate;  
 5-Chloro-3′-deoxycytidine;  
 5-Chloro-3′-deoxycytidine-5′triphosphate;  
 3′-fluoro-3′-deoxyguanosine;  
 3′-fluoro-3′-deoxyguanosine-5′triphosphate;  
 3′-fluoro 3′-deoxycytidine;  
 3′-fluoro 3′-deoxycytidine-5′triphosphate;  
 5-Iodo-3′-deoxycytidine;  
 5-Iodo-3′-deoxycytidine-5′triphosphate;  
 5-Chloro-3′-deoxyuridine;  
 5-Chloro-3′-deoxyuridine-5′triphosphate;  
 5-Bromo-3′-deoxyuridine;  
 5-Bromo-3′-deoxyuridine-5′triphosphate;  
 6-Chloro-3′-deoxyguanosine;  
 6-Chloro-3′-deoxyguanosine-5′triphosphate;  
 3′-spirocyclopropyl-3′-deoxyguanosine;  
 3′-spirocyclopropyl-3′-deoxyguanosine-5′triphosphate;  
 3′-difluoro-spirocyclopropyl-3′-deoxyguanosine;  
 3′-difluoro-spirocyclopropyl-3′-deoxyguanosine-5′triphosphate;  
 3′-methylene-3′-deoxyguanosine;  
 3′-methylene-3′-deoxyguanosine-5′triphosphate;  
 3′-difluromethylene 3′-deoxyguanosine;  
 3′-difluromethylene 3′-deoxyguanosine-5′triphosphate;  
 3′-spirocyclopropyl-3′-deoxycytidine;  
 3′-spirocyclopropyl-3′-deoxycytidine-5′triphosphate;  
 3′-difluoro-spirocyclopropyl-3′-deoxycytidine;  
 3′-difluoro-spirocyclopropyl-3′-deoxycytidine-5′triphosphate;  
 3′-methylene-3′-deoxycytidine;  
 3′-methylene-3′-deoxycytidine-5′triphosphate;  
 3′-difluromethylene 3′-deoxycytidine;  
 3′-difluromethylene 3′-deoxycytidine-5′triphosphate;  
 9-β-D-xylofuranosyl-guanosine;  
 9-β-D-xylofuranosyl-guanosine-5′triphosphate;  
 9-β-D-xylofuranosyl-cytidine;  
 9-β-D-xylofuranosyl-cytidine-5′triphosphate;  
 3′-azido-3′-deoxycytidine;  
 3′-azido-3′-deoxycytidine 5′triphosphate; and or a pharmaceutically acceptable salts thereof.  
 
     
     
         15 . A method according to claim  1 I wherein said compound is used in combination with at least one further therapeutic agent chosen from ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.  
     
     
         16 . A The method according to  claim 2 , wherein said compound is used in combination with at least one further therapeutic agent chosen from ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.  
     
     
         17 . A The method according to  claim 3 , wherein said compound is used in combination with at least one further therapeutic agent chosen from ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.  
     
     
         18 . A The method according to  claim 14 , wherein said compound is used in combination with at least one further therapeutic agent chosen from ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), glycyrrhizin and silybum marianum.  
     
     
         19 . A method according to  claim 1 , wherein said method is a method of treatment.  
     
     
         20 . A method according to  claim 19 , wherein 
 Ra is H, monophosphate, diphosphate, triphosphate, carbonyl substituted by C 1-6  alkyl, C 2-6 , C 2-6  alkynyl, or C 6-10  aryl or                          Rc is, in each case independently, H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl or a hydroxy protecting group selected from acetyl-2-thioethyl ester, pivaloyloxymethyl ester and isopropyloxycarbonyloxymethyl ester; and    Rb is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  acyl, or a hydroxy protecting group selected from acetyl-2-thioethyl ester, pivaloyloxymethyl ester and isopropyloxycarbonyloxymethyl ester.    
     
     
         21 . A method according to  claim 19 , wherein B is adenin-9-yl, guanin-9-yl, inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl, or 3-carboxamido-1,2,4-triazol-1-yl, which in each case is unsubstituted or substituted by at least one of NHR 3 , C 1-6 alkyl, —OC 1-6 alkyl, Br, Cl, F, I or OH, wherein R 3  is H, C 1-6 alkyl or C 1-6 acyl.  
     
     
         22 . A method according to  claim 19 , wherein B is adenin-9-yl, guanin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl, which in each case is unsubstituted or substituted by at least one of NHR 3 , C 1-6 alkyl, —OC 1-6 alkyl, Br, Cl, F, I or OH, wherein R 3  is H, C 1-6 alkyl or C 1-6 acyl.  
     
     
         23 . A method according to  claim 19 , wherein B is guanin-9-yl, cytosin-1-yl, uracil-1-yl, which in each case is unsubstituted or substituted by at least one of NHR 3 , C 1-6 alkyl, —OC 1-6 alkyl, Br, Cl, F, I or OH, wherein R 3  is H, C 1-6 alkyl or C 1-6 acyl.  
     
     
         24 . A method according to  claim 19 , wherein B is guanin-9-yl, cytosin-1-yl, 5′-fluoro-cytosin-1-yl, 5′-fluorouracil-1-yl or uracil-1-yl.  
     
     
         25 . A method according to  claim 19 , wherein B is  
       
         
           
           
               
               
           
         
       
       wherein 
 X is H, halogen or NHR 10 ;  
 R 10  is H, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl;  
 Y is H, halogen or NHR 11 ;  
 R 11  is H, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl;  
 Y 2  is H, halogen or NHR 12 ;  
 R 12  is H, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl;  
 R 9  is H, hydroxy protecting group, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl;  
 Y 3  is H, halogen or NHR 13 ;  
 R 13  is H, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl;  
 R 7  is H, halogen, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl; and  
 R 8  is H, halogen, C 1-6 acyl, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl.  
 
     
     
         26 . A method according to  claim 25 , wherein X is H, F, or NHR 10 , R 10  is H, Y is H, F, or NHR 1 , R 11  is H, Y 2  is H, F, or NHR 12 , R 12  is H, R 9  is H, Y 3  is H, F, or NHR 13 R 13  is H, R 7  is H, F, or C 1-6  alkyl, and R 8  is H, F, or C 1-6  alkyl.  
     
     
         27 . A method according to  claim 19 , wherein Z is F or ORb, and ORb is H or methyl.  
     
     
         28 . A method according to  claim 19 , wherein D 1  and D 2  are N 3 , F, or H in which D 1  and D 2  are not both H, or D 1  and D 2  together form cyclopropyl, difluorocyclopropyl-═CH 2 , or ═CF 2 .  
     
     
         29 . A method according to  claim 19 , wherein said compound is administered in an amount of 0.01 to about 750 mg/kg of body weight per day.  
     
     
         30 . A method according to  claim 19 , wherein said compound is administered in unit dosages containing 10 to 1500 mg of said compound per unit dosage.  
     
     
         31 . A method according to  claim 15 , wherein said compound and said further therapeutic agent are each administered as a formulation which further contains a pharmaceutically acceptable carrier.  
     
     
         32 . A method according to  claim 31 , wherein said compound and said further therapeutic agent are sequentially administered, in separate or combined pharmaceutical formulations.  
     
     
         33 . A method according to  claim 31 , wherein said compound and said further therapeutic agent are simultaneously administered, in separate or combined pharmaceutical formulations.  
     
     
         34 . A method according to  claim 1 , wherein said host is a human.  
     
     
         35 . A method according to  claim 19 , wherein said host is a human.  
     
     
         36 . A method according to  claim 2 , wherein said host is a human.  
     
     
         37 . A method according to  claim 3 , wherein said host is a human.  
     
     
         38 . A method according to  claim 14 , wherein said host is a human.