N4-acylcytosine-1,3-dioxolane nucleosides for treatment of viral infections

Abstract

The present invention is directed to a compound, method and composition of treating or preventing viral infections, in particular, human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections, in human patients or other animal hosts, comprising the administration of N 4 -acylcytosine-1,3-dioxolane and pharmaceutically acceptable salts, prodrugs, and other derivatives thereof.

1. A compound of the formula: 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein
 i) R 1  is chosen from hydrogen and  halogen;  
 ii) R 2  is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6  where R 6  is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;  
 iii) R 3  is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;  
 iv) R 3′  is chosen from H, halogen, methyl, or ethyl; and  
 v) R 4  is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.  
 
     
     
       2. The compound of  claim 1  wherein R 1  is fluorine. 
     
     
       3. The compound of  claim 1  wherein R 3  is fluorine and R 3′  is H. 
     
     
       4. A compound selected from the group consisting of β-D-N 4 -p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β-D-N 4 -p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β-D-N 4 -p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane. 
     
     
       5. A compound selected from the following, or its pharmaceutically acceptable salt:
 β-D-5-fluoro-N 4 -(4-iodobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -p-toluoylcytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -(m-toluoyl)cylidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-5-fluoro-N 4 -(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 β-D-N 4 -(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 and β-D-N 4 -(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       6. The compound of  claim 5  wherein the compound is: β-D-5-fluoro-N 4 -(iodobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
     
     
       7. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -(4-fluorobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       8. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(4-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       9. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(4-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       10. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -(3-fluorobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       11. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(3-chlorobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       12. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(3-bromobenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       13. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -(4-nitrobenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       14. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -p-toluoylcytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       15. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -(m-toluoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       16. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(4-ethylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       17. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -(4-propylbenzoyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       18. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(4-tert-butylbenzoyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       19. The compound of  claim 5  wherein the compound is:
 β-D-N 4 -(cyclohexane-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       20. The compound of  claim 5  wherein the compound is:
 β-D-5-fluoro-N 4 -(2-thiophenecarbonyl)cytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       21. The compound of  claim 5  wherein the compound is;
 β-D-N 4 -(benzo-[b]-thiophene-2-carbonyl)-5-fluorocytidine-1,3-dioxolane of the structure: 
                 
 
 
     
     
       22. A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound of  claim 1  in a pharmaceutically acceptable carrier or diluent. 
     
     
       23. A pharmaceutical composition that includes an effective HIV or HBV treatment amount of a compound selected from the group consisting of β-D-N 4 -p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β-D-N 4 -p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β-D-N 4 -p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane. 
     
     
       24. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of the formula: 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein
 iv) R 1  is chosen from hydrogen and  halogen;  
 v) R 2  is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6  where R 6  is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;  
 vi) R 3  is chosen from H,  halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;  
 vii) R 3′  is chosen from H, halogen, methyl, or ethyl; and  
 viii) R 4  is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,  
 
       in a pharmaceutically acceptable carrier. 
     
     
       25. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of the formula: 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein
 ix) R 1  is chosen from hydrogen and  halogen;  
 x) R 2  is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6  where R 6  is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;  
 xi) R 3  is chosen from H,  halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;  
 xii) R 3′  is chosen from H, halogen, methyl, or ethyl; and  
 xiii) R 4  is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,  
 
       in a pharmaceutically acceptable carrier. 
     
     
       26. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of the formula: 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein
 xiv) R 1  is chosen from hydrogen and  halogen;  
 xv) R 2  is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6  where R 6  is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;  
 xvi) R 3  is chosen from H,  halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;  
 xvii) R 3′  is chosen from H, halogen, methyl, or ethyl; and  
 xviii) R 4  is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,  
 
       in a pharmaceutically acceptable carrier in combination with another anti-HIV agent. 
     
     
       27. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of the formula: 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein
 xix) R 1  is chosen from hydrogen and  halogen;  
 xx) R 2  is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C 6 H 4 R 6  where R 6  is chosen from halogen, CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;  
 xxi) R 3  is chosen from H,  halogen, CN, CF 3 , N 3 , NO 2 , alkyl, alkenyl, and alkynyl;  
 xxii) R 3′  is chosen from H, halogen, methyl, or ethyl; and  
 xxiii) R 4  is H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol,  
 
       in a pharmaceutically acceptable carrier in combination with another anti-HIV  anti- HBV  agent. 
     
     
       28. The method of claims  24 ,  25 ,  26  or  27  wherein R 1  is fluorine. 
     
     
       29. The method of claims  24 ,  25 ,  26 , or  27  wherein R 3  is fluorine and R 3′  is H. 
     
     
       30. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound selected from the group consisting of β-D-N 4 -p-iodobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-fluoro-benzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-chlorobenzoyl-5-fluoro-cytidine-1,3-dioxolane, β-D-N 4 -p-bromobenzoyl-5-fluorocytidine-1,3-dioxolane, β-D-N 4 -p-ethyl-benzoyl-5-fluorocytidine-1,3-dioxolane, and β-D-N 4 -p-t-butylbenzoyl-5-fluoro-cytidine-1,3-dioxolane. 
     
     
       31. A method for the treatment of a host infected with HBV that includes administering an effective amount of a compound of one of  claim 5  or  6 - 21   according to any one of claims  5 -   21   in a pharmaceutically acceptable carrier. 
     
     
       32. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of one of  claim 5  or  6 - 21   according to any one of claims  5 -   21   in a pharmaceutically acceptable carrier. 
     
     
       33. A method for the treatment of a host infected with HIV that includes administering an effective amount of a compound of one of  claim 5  or  6 - 21   according to any one of claims  5 -   21   in a pharmaceutically acceptable carrier in combination with another anti-HIV agent. 
     
     
       34. A method for the treatment of a host infected with HBV that includes  comprises administrating an effective amount of a compound of one of  claim 5  or  6 - 21   according to any one of claims  5 -   21   in a pharmaceutically acceptable carrier in combination with another anti-HBV agent. 
     
     
       35. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of the formula:
                   
       
         or a pharmaceutically acceptable salt thereof, wherein  
           i )  R   1    is hydrogen;    
           ii )  R   2    is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C   6   H   4   R   6    where R   6    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;    
           iii )  R   3    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, alkenyl, and alkynyl;    
           iv )  R   3′    is chosen from H, halogen, methyl, or ethyl; and    
           v )  R   4    is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.   
       
     
     
       36. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound in a pharmaceutically acceptable carrier in combination with another anti- HBV agent, wherein the compound has the formula:                     
       
         or a pharmaceutically acceptable salt thereof, wherein  
           i )  R   1    is hydrogen;    
           ii )  R   2    is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C   6   H   4   R   6    where R   6    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;    
           iii )  R   3    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, alkenyl, and alkynyl;    
           iv )  R   3′    is chosen from H, halogen, methyl, or ethyl; and    
           v )  R   4    is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.   
       
     
     
       37. A compound of the formula:
                   
       
         or a pharmaceutically acceptable salt thereof, wherein  
           i )  R   1    is hydrogen;    
           ii )  R   2    is chosen from alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, heteroaryl, and C   6   H   4   R   6    where R   6    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl;    
           iii )  R   3    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, alkenyl, and alkynyl;    
           iv )  R   3′    is chosen from H, halogen, methyl, or ethyl; and    
           v )  R   4    is chosen from H, phosphate, carbonyl substituted with alkyl, alkenyl, alkynyl, aryl, sulfonate ester, a lipid, an amino acid, a peptide, or cholesterol.   
       
     
     
       38. The compound of  claim 37  wherein R 2    is C   6   H   4   R   6    where R   6    is chosen from halogen, CN, CF   3   , N   3   , NO   2   , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, and aryl.   
     
     
       39. A pharmaceutical composition that comprises an effective HIV or HBV treatment amount of a compound of  claim 37  in a pharmaceutically acceptable carrier or diluent. 
     
     
       40. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of  claim 37 . 
     
     
       41. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of  claim 37 . 
     
     
       42. A method for the treatment of a host infected with HIV that comprises administering an effective amount of a compound of  claim 37  in a pharmaceutically acceptable carrier in combination with another anti- HIV agent.   
     
     
       43. A method for the treatment of a host infected with HBV that comprises administering an effective amount of a compound of  claim 37  in a pharmaceutically acceptable carrier in combination with another anti- HBV agent.