Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane

Abstract

A method and composition for the treatment of HIV and HBV infections in humans is disclosed that includes administering an effective amount of 2-hydroxymethyl-5-(5-fluorocytosin- 1 -yl)-1,3-oxathiolane, a pharmaceutically acceptable derivative thereof, including a 5′ or N 4 alkylated or acylated derivative, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. A process for the resolution of a racemic mixture of nucleoside enantiomers is also disclosed that includes the step of exposing the racemic mixture to an enzyme that preferentially catalyzes a reaction in one of the enantiomers.

1 . (±)-β-D,L-2-Hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative, or physiologically acceptable salt.  
     
     
         2 . (−)-β-L-2-Hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative, or physiologically acceptable salt.  
     
     
         3 . (+)-β-D-2-Hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative, or its physiologically acceptable salt.  
     
     
         4 . The compound of  claim 1  of the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently alkyl; a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl; alkoxyalkyl; aralkyl; aryloxyalkyl; aryl including phenyl optionally substituted with halogen, C 1  to C 4  alkyl or C 1  to C 4  alkoxy; sulfonate ester; alkyl or aralkyl sulphonyl; the mono, di or triphosphate ester, or an amino acid ester, and one of R 1  or R 2  can be hydrogen.  
     
     
         5 . The compound of  claim 2  of the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently alkyl; a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl; alkoxyalkyl; aralkyl; aryloxyalkyl; aryl including phenyl optionally substituted with halogen, C 1  to C 4  alkyl or C 1  to C 4  alkoxy; sulfonate ester; alkyl or aralkyl sulphonyl; the mono, di or triphosphate ester, or an amino acid ester, and one of R 1  or R 2  can be hydrogen.  
     
     
         6 . The compound of  claim 3  of the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently alkyl; a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl; alkoxyalkyl; aralkyl; aryloxyalkyl; aryl including phenyl optionally substituted with halogen, C 1  to C 4  alkyl or C 1  to C 4  alkoxy; sulfonate ester; alkyl or aralkyl sulphonyl; the mono, di or triphosphate ester, or an amino acid ester, and one of R 1  or R 2  can be hydrogen.  
     
     
         7 . The compound of  claim 4 , wherein R 1  and R 2  are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, t-pentyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl, and one of R 1  and R 2  can be hydrogen.  
     
     
         8 . The compound of  claim 5 , wherein R 1  and R 2  are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, t-pentyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl, and one of R 1  and R 2  can be hydrogen.  
     
     
         9 . The compound of  claim 6 , wherein R 1  and R 2  are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, t-pentyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl, and one of R 1  and R 2  can be hydrogen.  
     
     
         10 . The compound of  claim 7 , wherein R 1  is n-butyl and R 2  is hydrogen.  
     
     
         11 . The compound of  claim 8 , wherein R 1  is n-butyl and R 2  is hydrogen.  
     
     
         12 . The compound of  claim 9 , wherein R 1  is n-butyl and R 2  is hydrogen.  
     
     
         13 . A pharmaceutical composition comprising an effective amount to treat HIV or HBV infection in humans of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, in the racemic form, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         14 . A pharmaceutical composition comprising an effective amount to treat HIV or HBV infection in humans of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         15 . A pharmaceutical composition comprising an effective amount to treat HIV or HBV infection in humans of (+)-β-D-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the physiologically acceptable derivative is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently alkyl; a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl; alkoxyalkyl; aralkyl; aryloxyalkyl; aryl including phenyl optionally substituted with halogen, C 1  to C 4  alkyl or C 1  to C 4  alkoxy; sulfonate ester; alkyl or aralkyl sulphonyl; the mono di or triphosphate ester, or an amino acid ester, and one of R 1  or R 2  can be hydrogen.  
     
     
         17 . The pharmaceutical composition of  claim 14 , wherein the physiologically acceptable derivative is of the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently alkyl; a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl; alkoxyalkyl; aralkyl; aryloxyalkyl; aryl including phenyl optionally substituted with halogen, C 1  to C 4  alkyl or C 1  to C 4  alkoxy; sulfonate ester; alkyl or aralkyl sulphonyl; the mono, di or triphosphate ester, or an amino acid ester, and one of R 1  or R 2  can be hydrogen.  
       
     
     
         18 . The pharmaceutical composition of  claim 15 , wherein the physiologically acceptable derivative is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently alkyl; a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl; alkoxyalkyl; aralkyl; aryloxyalkyl; aryl including phenyl optionally substituted with halogen, C 1  to C 4  alkyl or C 1  to C 4  alkoxy; sulfonate ester; alkyl or aralkyl sulphonyl; the mono, di or triphosphate ester, or an amino acid ester, and one of R 1  or R 2  can be hydrogen.  
     
     
         19 . The pharmaceutical composition of  claim 13 , wherein R 1  and R 2  are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, t-pentyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl, and one of R 1  and R 2  can be hydrogen.  
     
     
         20 . The pharmaceutical composition of  claim 14 , wherein R 1  and R 2  are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, t-pentyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl, and one of R 1  and R 2  can be hydrogen.  
     
     
         21 . The pharmaceutical composition of  claim 15 , wherein R 1  and R 2  are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, amyl, t-pentyl, 3-methylbutyryl, hydrogen succinate, 3-chlorobenzoate, cyclopentyl, cyclohexyl, benzoyl, acetyl, pivaloyl, mesylate, propionyl, butyryl, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, amino acids including but not limited to alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl, and one of R 1  and R 2  can be hydrogen.  
     
     
         22 . The pharmaceutical composition of  claim 13 , wherein R 1  is n-butyl and R 2  is hydrogen.  
     
     
         23 . The pharmaceutical composition compound of  claim 14 , wherein R 1  is n-butyl and R 2  is hydrogen.  
     
     
         24 . The pharmaceutical composition of  claim 15 , wherein R 1  is n-butyl and R 2  is hydrogen.  
     
     
         25 . A method for treating HIV infection in humans comprising administering an effective amount of (+)-β-D,L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         26 . A method for treating HIV infection in humans comprising administering an effective amount of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         27 . A method for treating HIV infection in humans comprising administering an effective amount of (+)-β-D-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         28 . A method for treating HBV infection in a human or other host animal comprising administering an effective amount of (±)-β-D,L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a pharmaceutically acceptable carrier.  
     
     
         29 . A method for treating HBV infection in humans or other host animals comprising administering an effective amount of (−)-β-L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a physiologically acceptable carrier.  
     
     
         30 . A method for treating HBV infection in humans or other host animals comprising administering an effective amount of (+)-β-D-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, or its physiologically acceptable derivative or physiologically acceptable salt, in a physiologically acceptable carrier.  
     
     
         31 . The method of claims  25 ,  26 ,  27 ,  28 ,  29 , or  30 , wherein the carrier is suitable for oral delivery.  
     
     
         32 . The method of claims  25 ,  26 ,  27 ,  28 ,  29 , or  30 , wherein the carrier comprises a capsule.  
     
     
         33 . The method of claims  25 ,  26 ,  27 ,  28 ,  29 , or  30 , wherein the carrier is in the form of a tablet.  
     
     
         34 . The method of claims  25 ,  26 ,  27 ,  28 ,  29  or  30 , wherein the administration is parenteral.