Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy for treating hepatitis virus infections

Abstract

Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immunostimulating agents.

What is claimed is:  
     
         1 . A method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal a first amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 1  to C 20 , and  
 W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and  
 a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof,  
 wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.  
 
     
     
         2 . The method of  claim 1 , wherein R is a branched or straight chain alkyl having a chain length of C 1  to C 20 , and W, X, Y, and Z are each hydrogen.  
     
     
         3 . The method of  claim 2 , wherein R is a straight chain alkyl having a chain length of C 1  to C 20 .  
     
     
         4 . The method of  claim 3 , wherein R is a straight chain alkyl having a chain length of C 2  to C 14 .  
     
     
         5 . The method of  claim 4 , wherein R is a straight chain alkyl having a chain length of C 6  to C 12 .  
     
     
         6 . The method of  claim 5 , wherein R is nonyl.  
     
     
         7 . The method of  claim 1 , wherein R is a branched or straight chain alkyl having a chain length of C 1  to C 20 , and W, X, Y, and Z are each alkanoyl.  
     
     
         8 . The method of  claim 7 , wherein R is a straight chain alkyl having a chain length of C 1  to C 20 .  
     
     
         9 . The method of  claim 8 , wherein R is a straight chain alkyl having a chain length of C 2  to C 14 .  
     
     
         10 . The method of  claim 9 , wherein R is a straight chain alkyl having a chain length of C 6  to C 12 .  
     
     
         11 . The method of  claim 10 , wherein R is nonyl.  
     
     
         12 . The method of  claim 7 , wherein said alkanoyl has a chain length of C 1  to C 20 .  
     
     
         13 . The method of  claim 7 , wherein said alkanoyl has a chain length of C 2  to C 14 .  
     
     
         14 . The method of  claim 7 , wherein said alkanoyl has a chain length of C 3  to C 10 .  
     
     
         15 . The method of  claim 7 , wherein said alkanoyl is butanoyl.  
     
     
         16 . The method of  claim 7 , wherein R is nonyl and W, X, Y, and Z are each butanoyl.  
     
     
         17 . The method of  claim 1 , wherein 
 R is a straight chain alkyl having a chain length of C 1  to C 20 ,    W, X, Y, and Z are each hydrogen, and    said antiviral compound is a nucleoside antiviral compound.    
     
     
         18 . The method of  claim 1 , wherein 
 R is a straight chain alkyl having a chain length of C 1  to C 20 ,    W, X, Y, and Z are each butanoyl, and    said antiviral compound is a nucleoside antiviral compound.    
     
     
         19 . The method of  claim 1 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of: 
 N-(n-hexyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-heptyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-octyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-octyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-dodecyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(5-methylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(3-propylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-pentylpentylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-butylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(7-methyloctyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(8-methylnonyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(9-methyldecyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(10-methylundecyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(6-cyclohexylhexyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(4-cyclohexylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(2-cyclohexylethyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-cyclohexylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-phenylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(3-(4-methyl)-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(6-phenylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-dodecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(5-methylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(3-propylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-pentylpentylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-butylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(7-methyloctyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(8-methylnonyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(9-methyldecyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(10-methylundecyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(6-cyclohexylhexyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(4-cyclohexylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(2-cyclohexylethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-cyclohexylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-phenylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(3-(4-methyl)-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate; and    N-(6-phenylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and    said nucleoside or nucleotide antiviral compound is selected from the group consisting of:    (+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;    (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC);    (−)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine (FTC);    (−)2′,3′, dideoxy-3′-thiacytidine [(−)-SddC];    1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);    1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine triphosphate (FIACTP);    1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-methyluarcil (FMAU);    1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide;    2′,3′-dideoxy-3′-fluoro-5-methyl-dexocytidine (FddMeCyt);    2′,3′-dideoxy-3′-chloro-5-methyl-dexocytidine (ClddMeCyt);    2′,3′-dideoxy-3′-amino-5-methyl-dexocytidine (AddMeCyt);    2′,3′-dideoxy-3′-fluoro-5-methyl-cytidine (FddMeCyt);    2′,3′-dideoxy-3′-chloro-5-methyl-cytidine (ClddMeCyt);    2′,3′-dideoxy-3′-amino-5-methyl-cytidine (AddMeCyt);    2′,3′-dideoxy-3′-fluorothymidine (FddThd);    2′,3′-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);    2′,3′-dideoxy-beta-L-5-thiacytidine;    2′,3′-dideoxy-beta-L-5-cytidine (beta-L-ddC);    2′-deoxy-3′-thia-5-fluorocytosine;    3′-amino-5-methyl-dexocytidine (AddMeCyt);    3′-azido-3′-deoxythymidine (AZT);    3′-chloro-5-methyl-dexocytidine (ClddMeCyt);    9-(2-phosphonyl-methoxyethyl)-2′,6′-diaminopurine-2′,3′-dideoxyriboside;    9-(2-phosphonylmethoxyethyl)adenine (PMEA); acyclovir triphosphate (ACVTP);    D-carbocyclic-2′-deoxyguanosine (CdG);    dideoxy-cytidine;    dideoxy-cytosine (ddC);    dideoxy-guanine (ddG);    dideoxy-inosine (ddI);    E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate;    fluoro-arabinofuranosyl-iodouracil;    stavudine;    2-deoxy-3′-thia-5-fluorocytidine;    2′,3′-dideoxy-guanine; and    2′,3′-dideoxy-guanosine.    
     
     
         20 . The method of  claim 1 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol and N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and said nucleoside antiviral compound is (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC).  
     
     
         21 . The method of  claim 20 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol and said nucleoside antiviral compound is (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC).  
     
     
         22 . The method of  claim 1 , wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 0.1 mg/kg/day to about 100 mg/kg/day.  
     
     
         23 . The method of  claim 22 , wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 1 mg/kg/day to about 75 mg/kg/day.  
     
     
         24 . The method of  claim 23 , wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 5 mg/kg/day to about 50 mg/kg/day.  
     
     
         25 . The method of  claim 1 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 0.1 mg/person/day to about 500 mg/person/day.  
     
     
         26 . The method of  claim 25 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 10 mg/person/day to about 300 mg/person/day.  
     
     
         27 . The method of  claim 26 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 25 mg/person/day to about 200 mg/person/day.  
     
     
         28 . The method of  claim 27 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 50 mg/person/day to about 150 mg/person/day.  
     
     
         29 . The method of  claim 1 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 1 mg/person/day to about 50 mg/person/day.  
     
     
         30 . The method of  claim 1 , wherein said hepatitis virus infection is a hepatitis B virus infection.  
     
     
         31 . A method of treating a hepatitis B virus infection in a mammal, comprising administering to said mammal from about 0.1 mg/kg/day to about 100 mg/kg/day of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 1  to C 20 , and  
 W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and  
 from about 0.1 mg/person/day to about 500 mg/person/day of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral, and mixtures thereof.  
 
     
     
         32 . The method of  claim 31 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol and N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and said nucleoside antiviral agent is (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC).  
     
     
         33 . The method of  claim 32 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol.  
     
     
         34 . A method of treating a hepatitis B virus infection in a human patient, comprising administering to said human patient from about 0.1 mg/kg/day to about 100 mg/kg/day of N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol and from about 0.1 mg/person/day to about 500 mg/person/day of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate.  
     
     
         35 . A composition, comprising an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 1  to C 20 , and  
 W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and  
 an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof.  
 
     
     
         36 . A pharmaceutical composition, comprising a first amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I:  
       wherein: 
 R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 1  to C 20 , and  
 W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and  
 a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof, and  
 a pharmaceutically acceptable carrier, diluent, or excipient.  
 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.  
     
     
         38 . The pharmaceutical composition of  claim 36 , wherein R is a branched or straight chain alkyl having a chain length of C 1  to C 20 , and W, X, Y, and Z are each hydrogen.  
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein R is a straight chain alkyl having a chain length of C 1  to C 20 .  
     
     
         40 . The pharmaceutical composition of  claim 39  wherein R is a straight chain alkyl having a chain length of C 2  to C 14 .  
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein R is a straight chain alkyl having a chain length of C 6  to C 12 .  
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein R is nonyl.  
     
     
         43 . The pharmaceutical composition of  claim 36 , wherein R is a branched or straight chain alkyl having a chain length of C 1  to C 20 , and W, X, Y, and Z are each alkanoyl.  
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein R is a straight chain alkyl having a chain length of C 1  to C 20 .  
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein R is a straight chain alkyl having a chain length of C 2  to C 14 .  
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein R is a straight chain alkyl having a chain length of C 6  to C 12 .  
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein R is nonyl.  
     
     
         48 . The pharmaceutical composition of  claim 43 , wherein said alkanoyl has a chain length of C 1  to C 20 .  
     
     
         49 . The pharmaceutical composition of  claim 43 , wherein said alkanoyl has a chain length of C 2  to C 14 .  
     
     
         50 . The pharmaceutical composition of  claim 43 , wherein said alkanoyl has a chain length of C 3  to C 10 .  
     
     
         51 . The pharmaceutical composition of  claim 43 , wherein said alkanoyl is butanoyl.  
     
     
         52 . The pharmaceutical composition of  claim 43 , wherein R is nonyl and W, X, Y, and Z are each butanoyl.  
     
     
         53 . The pharmaceutical composition of  claim 36 , wherein 
 R is a straight chain alkyl having a chain length of C 1  to C 20 ,    W, X, Y, and Z are each hydrogen, and    said antiviral compound is a nucleoside antiviral compound.    
     
     
         54 . The pharmaceutical composition of  claim 36 , wherein 
 R is a straight chain alkyl having a chain length of C 1  to C 20 ,    W, X, Y, and Z are each butanoyl, and    said antiviral compound is a nucleoside antiviral compound.    
     
     
         55 . The pharmaceutical composition of  claim 36 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of: 
 N-(n-hexyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-heptyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-octyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-octyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-dodecyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(5-methylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(3-propylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-pentylpentylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-butylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(7-methyloctyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(8-methylnonyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(9-methyldecyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(10-methylundecyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(6-cyclohexylhexyl-)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(4-cyclohexylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(2-cyclohexylethyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-cyclohexylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(1-phenylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(3-(4-methyl)-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(6-phenylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol;    N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-decyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-undecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(n-dodecyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(2-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(4-ethylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(5-methylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(3-propylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-pentylpentylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-butylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(7-methyloctyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(8-methylnonyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(9-methyldecyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(10-methylundecyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(6-cyclohexylhexyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(4-cyclohexylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(2-cyclohexylethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-cyclohexylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(1-phenylmethyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate;    N-(3-(4-methyl)-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate; and    N-(6-phenylhexyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and    said nucleoside or nucleotide antiviral compound is selected from the group consisting of:    (+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;    (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC);    (−)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine (FTC);    (−)2′,3′, dideoxy-3′-thiacytidine [(−)-SddC];    1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);    1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine triphosphate (FIACTP);    1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-methyluarcil (FMAU);    1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide;    2′,3′-dideoxy-3′-fluoro-5-methyl-dexocytidine (FddMeCyt);    2′,3′-dideoxy-3′-chloro-5-methyl-dexocytidine (ClddMeCyt);    2′,3′-dideoxy-3′-amino-5-methyl-dexocytidine (AddMeCyt);    2′,3′-dideoxy-3′-fluoro-5-methyl-cytidine (FddMeCyt);    2′,3′-dideoxy-3′-chloro-5-methyl-cytidine (ClddMeCyt);    2′,3′-dideoxy-3′-amino-5-methyl-cytidine (AddMeCyt);    2′,3′-dideoxy-3′-fluorothymidine (FddThd);    2′,3′-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);    2′,3′-dideoxy-beta-L-5-thiacytidine;    2′,3′-dideoxy-beta-L-5-cytidine (beta-L-ddC);    2′-deoxy-3′-thia-5-fluorocytosine;    3′-amino-5-methyl-dexocytidine (AddMeCyt);    3′-azido-3′-deoxythymidine (AZT);    3′-chloro-5-methyl-dexocytidine (ClddMeCyt);    9-(2-phosphonyl-methoxyethyl)-2′,6′-diaminopurine-2′,3′-dideoxyriboside;    9-(2-phosphonylmethoxyethyl)adenine (PMEA);    acyclovir triphosphate (ACVTP);    D-carbocyclic-2′-deoxyguanosine (CdG);    dideoxy-cytidine;    dideoxy-cytosine (ddC);    dideoxy-guanine (ddG);    dideoxy-inosine (ddI);    E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate;    fluoro-arabinofuranosyl-iodouracil;    stavudine;    2-deoxy-3′-thia-5-fluorocytidine;    2′,3′-dideoxy-guanine; and    2′,3′-dideoxy-guanosine.    
     
     
         56 . The pharmaceutical composition of  claim 36 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol and N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and said nucleoside antiviral compound is (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC).  
     
     
         57 . The pharmaceutical composition of  claim 56 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol.  
     
     
         58 . The pharmaceutical composition of  claim 36 , wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 0.1 mg to about 100 mg.  
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 1 mg to about 75 mg.  
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein said first amount of said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is in the range of from about 5 mg to about 50 mg.  
     
     
         61 . The pharmaceutical composition of  claim 36 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 0.1 mg to about 500 mg.  
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 10 mg to about 300 mg.  
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 25 mg to about 200 mg.  
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 50 mg to about 150 mg.  
     
     
         65 . The pharmaceutical composition of  claim 36 , wherein said second amount of said nucleoside or nucleotide antiviral compound, or mixture thereof, is in the range of from about 1 mg to about 50 mg.  
     
     
         66 . A pharmaceutical composition for treating a hepatitis B virus infection in a mammal, comprising from about 0.1 mg to about 100 mg of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 1  to C 20 , and  
 W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl; and  
 from about 0.1 mg to about 500 mg of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral, and mixtures thereof.  
 
     
     
         67 . The pharmaceutical composition of  claim 66 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol and N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate, and said nucleoside antiviral agent is (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate.  
     
     
         68 . The pharmaceutical composition of  claim 67 , wherein said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol.  
     
     
         69 . A pharmaceutical composition for treating a hepatitis B virus infection in a human patient, comprising from about 0.1 mg to about 100 mg of N-(n-nonyl-)-1,5-dideoxy-1,5-imino-D-glucitol and from about 0.1 mg to about 500 mg of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate.