Combination therapy of an hbv capsid assembly inhibitor and an interferon

Abstract

The present invention is directed to compositions and methods for treating hepatitis B virus infection. In particular, the present invention is directed to a combination therapy comprising administration of an HBV capsid assembly inhibitor and an interferon for use in the treatment of hepatitis B virus infections.

1 . (canceled) 
     
     
         2 . A pharmaceutical composition comprising an HBV capsid assembly inhibitor and an interferon, in a pharmaceutically acceptable carrier, wherein the HBV capsid assembly inhibitor is a compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1-6  alkyl or trifluoromethyl-C x H 2x —, wherein x is 1, 2, 3, 4, 5 or 6; 
         one of R 2  and R 3  is phenyl, which is once or twice or three times substituted by C 1-6  alkyl, cyano or halogen; and the other one is hydrogen or deuterium; 
         R 4  is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C 1-6 alkyl, C 1-6  alkylsulfanyl, halogen or cycloalkyl, wherein C 1-6 alkyl can be further optionally substituted with halogen; 
         A is 
       
       
         
           
           
               
               
           
         
       
       which is unsubstituted or substituted by groups selected from C 1-6  alkyl,
 deuterium and halogen; 
 or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof. 
 
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein the HBV capsid assembly inhibitor is selected from:
 (S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;   (R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; or   (2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid   or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.   
     
     
         4 . A pharmaceutical composition comprising an HBV capsid assembly inhibitor and an interferon, in a pharmaceutically acceptable carrier, wherein the HBV capsid assembly inhibitor is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 5  is C 1-6 alkyl; 
         R 6  is phenyl, which is once or twice or three times substituted by halogen or C 1-6 alkyl; 
         R 7  is hydrogen or C 1-6 alkyl; 
         R 8  is bicyclic bridged heterocyclyl; 
         or a pharmaceutically acceptable salt, or tautomerism isomer, or enantiomer, or diastereomer thereof. 
       
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the HBV capsid assembly inhibitor is selected from:
 2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid; and   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid;   or a pharmaceutically acceptable salt, or tautomerism isomer, or enantiomer, or diastereomer thereof.   
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The pharmaceutical composition according to  claim 2 , wherein the interferon is a non-conjugated interferon alfa or a pegylated alfa-type interferon. 
     
     
         9 . (canceled) 
     
     
         10 . The pharmaceutical composition according to  claim 2 , wherein the composition is selected from:
 (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Roferon A;   (R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester and Roferon A;   (2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Roferon A;   (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Intron A;   (R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester and Intron A;   (2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Intron A;   (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Pegasys;   (R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester and Pegasys;   (2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Pegasys;   (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Pegasys;   (R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester and Pegasys; and   (2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Pegasys;   in a pharmaceutically acceptable carrier.   
     
     
         11 . The pharmaceutical composition according to  claim 2 , wherein the composition consists of:
 (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Roferon A; or   (2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Pegasys;   in a pharmaceutically acceptable carrier.   
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . A kit comprising a container that contains an HBV capsid assembly inhibitor and an interferon, wherein the HBV capsid assembly inhibitor is a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1-6  alkyl or trifluoromethyl-C x H 2x —, wherein x is 1, 2, 3, 4, 5 or 6; 
         one of R 2  and R 3  is phenyl, which is once or twice or three times substituted by C 1-6  alkyl, cyano or halogen; and the other one is hydrogen or deuterium; 
         R 4  is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkylsulfanyl, halogen or cycloalkyl, wherein C 1-6 alkyl can be further optionally substituted with halogen; 
         A is 
       
       
         
           
           
               
               
           
         
       
       which is unsubstituted or substituted by groups selected from C 1-6 alkyl, deuterium and halogen;
 or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof. 
 
     
     
         22 . The kit according to  claim 21 , further comprising a sterile diluent. 
     
     
         23 . The kit according to  claim 21 , further comprising a package insert comprising printed instructions directing the use of a combined treatment of the HBV capsid assembly inhibitor and the interferon as a method for treatment or prophylaxis of hepatitis B virus infection. 
     
     
         24 . The kit according to  claim 21 , wherein the HBV capsid assembly inhibitor is selected from the group consisting of:
 (S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;   (R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; and   (2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;   or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.   
     
     
         25 . The kit according to  claim 21 , wherein the interferon is a non-conjugated interferon alfa or a pegylated alfa-type interferon. 
     
     
         26 . The kit according to  claim 21 , wherein the HBV capsid assembly inhibitor and the interferon used in the container are selected from the group consisting of:
 (S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Roferon A;   (2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Pegasys;   in a pharmaceutically acceptable carrier.   
     
     
         27 . A method for treatment or prophylaxis of hepatitis B virus infection, the method comprising:
 administering to a subject an effective first amount of an HBV capsid assembly inhibitor, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;   and a second amount of an interferon, wherein the HBV capsid assembly inhibitor is a compound of formula (I)   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1-6  alkyl or trifluoromethyl-C x H 2x —, wherein x is 1, 2, 3, 4, 5 or 6; 
         one of R 2  and R 3  is phenyl, which is once or twice or three times substituted by C 1-6  alkyl, cyano or halogen; and the other one is hydrogen or deuterium; 
         R 4  is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkylsulfanyl, halogen or cycloalkyl, wherein C 1-6 alkyl can be further optionally substituted with halogen; 
         A is 
       
       
         
           
           
               
               
           
         
       
       which is unsubstituted or substituted by groups selected from C 1-6 alkyl, deuterium and halogen;
 or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof. 
 
     
     
         28 . The method according to  claim 27 , wherein the HBV capsid assembly inhibitor is selected from the group consisting of:
 (S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;   (R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; and   (2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid;   or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof.   
     
     
         29 . The method according to  claim 27 , wherein the interferon is a non-conjugated interferon alfa or a pegylated alfa-type interferon. 
     
     
         30 . The method according to  claim 27 , wherein the HBV capsid assembly inhibitor and the interferon used in the subject are:
 (S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid and Roferon A; or   (2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid and Pegasys;   in a pharmaceutically acceptable carrier.   
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . The pharmaceutical composition according to  claim 2 , wherein the interferon is Roferon A, Intron A, Pegasys or PegIntron. 
     
     
         35 . The pharmaceutical composition according to  claim 2 , wherein the interferon is Roferon A or Pegasys. 
     
     
         36 . The kit according to  claim 25 , wherein the interferon is Roferon A, Intron A, Pegasys or PegIntron. 
     
     
         37 . The kit according to  claim 25 , wherein the interferon is Roferon A or Pegasys. 
     
     
         38 . The method according to  claim 27 , wherein the interferon is Roferon A, Intron A, Pegasys or PegIntron. 
     
     
         39 . The method according to  claim 27 , wherein the interferon is Roferon A or Pegasys. 
     
     
         40 . The method according to  claim 27 , wherein the HBV capsid assembly inhibitor and the interferon are co-administered in the same formulation or different formulations. 
     
     
         41 . The method according to  claim 27 , wherein the HBV capsid assembly inhibitor and the interferon are administered to a subject by the same route or different routes. 
     
     
         42 . The method according to  claim 27 , wherein the HBV capsid assembly inhibitor and the interferon are administered to a subject by parenteral or oral administration. 
     
     
         43 . The method according to  claim 27 , wherein the HBV capsid assembly inhibitor and the interferon are administered simultaneously or sequentially. 
     
     
         44 . The pharmaceutical composition according to  claim 4 , wherein the composition is selected from:
 2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and Roferon A;   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and Roferon A;   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and Intron A;   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and Intron A;   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and Pegasys;   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and Pegasys;   2-[(1R,3S,5S)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and PegIntron; and   2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]acetic acid and PegIntron;   in a pharmaceutically acceptable carrier.