Use of substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections

Abstract

N-Substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of Formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections, the compounds of Formula I may be used alone, or in combination with another antiviral agents selected from among nucleosides, nucleotides, immunomodulators, immunostimulants or various combinations of such other agents.

1 - 90 . (canceled)  
   
   
       91 . A pharmaceutical composition comprising a salt of a basic N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound and an antiviral compound, wherein said antiviral compound is a biologically active acid selected from the group consisting of a nucleoside containing a carboxylic acid moiety and a nucleotide, said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound corresponding to Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       R is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl, tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aralkenyl, aralkynyl, substituted aralkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heteroarylalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, heterocycloalkenyl, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkyloxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, alkanoylaminoalkyl, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl or R 5 , wherein  
         R 5 ═R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein:  
       R 1  is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;  
       R 2  is independently alkylene, alkenylene, alkynylene or haloalkylene;  
       R 3  is independently alkylene, alkenylene, alkynylene or haloalkylene;  
       R 4  is independently alkylene, alkenylene, alkynylene or haloalkylene;  
       R 6  is independently alkylene, alkenylene, alknylene or haloalkylene;  
       X 1  is independently oxygen, sulfur, sulfoxide or sulfone;  
       X 2  is independently oxygen, sulfur, sulfoxide or sulfone;  
       X 3  is independently oxygen, sulfur, sulfoxide or sulfone;  
       X 4  is independently oxygen, sulfur, sulfoxide or sulfone;  
       m, n and p are independently 0, 1, 2, or 3; and m+n+p≦3  
       A, B, C, and D are independently hydrido, lower alkyl, lowerhaloalkyl or acyl;  
       D and R taken together may form a five or six membered ring when R is carbonyl or alkylcarbonyl;  
       A and B taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;  
       B and C taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring; and  
       C and D taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;  
       wherein the main chain in R contains between one and twenty atoms; and  
       the main chain of R 5  contains between four and twenty atoms.  
     
   
   
       92 . The pharmaceutical composition of  claim 91  further comprising a pharmaceutically acceptable carrier, diluent or excipient.  
   
   
       93 . The pharmaceutical composition of  claim 91  wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl or R 5 .  
   
   
       94 . The pharmaceutical composition of  claim 91  wherein all of any X 1 , X 2 , X 3 , and X 4  linkages are oxygen: (m+n+p)≧2; and R 1  is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 , and R 4  groups are unsubstituted alkylene.  
   
   
       95 . The pharmaceutical composition of  claim 91  wherein the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol is N-(8,8,8-trifluorooctyl)-1,5-dideoxy-1,5-imino-D-glucitol.