Treatment of EBV and KHSV Infection and Associated Abnormal Cellular Proliferation

Abstract

A method and composition for the treatment, prevention and/or prophylaxis of a host, and in particular, a human, infected with Epstein-Barr virus (EBV), is provided that includes administering an effective amount of a 5-substituted uracil nucleoside or its pharmaceutically acceptable salt or prodrug, optionally in a pharmaceutically acceptable diluent or excipient.

1 . A method for treating a host infected with Epstein-Barr virus or KHSV comprising administering an effective amount of a compound of the general formula (I), (II) or (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         i) X is O, S, NR 4 , CH 2 , CHF or CF 2 ; 
         ii) R 1  is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, hal0 alkynyl , cycloalkyl, CN, CF 3 , N 3 , NO 2 , aryl, heteroaryl, heteroaryl, acyl or COR 5  where R 5  is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl; 
         iii) R 2  and R 2 ′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R 2  and R 2 ′ is H; 
         iv) R 3  is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH 2 OR 4 ; 
         v) R 4  is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl; 
         vi) Y is chosen from H, OH, halogen (F, Cl, Br, I), N 3 , CN, or OR 2 ′; and 
         vii) Z is 0 or S. 
       
     
     
         2 - 14 . (canceled) 
     
     
         15 . The method of  claim 1  wherein the compound administered is a β-L isomer and is at least 95% pure. 
     
     
         16 . The method of  claim 1  wherein the compound administered is a β-D isomer and is at least 95% pure. 
     
     
         17 . The method of  claim 1  wherein the host is a human. 
     
     
         18 . A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell carries the Epstein-Barr virus or KHSV genome, comprising administering an effective amount of a compound of the general formula (I), (II) or (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         (i) X is O, S, NR 4 , CH 2 , CHF or CF 2 ; 
         ii) R 1  is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N 3 , NO 2 , aryl, heteroaryl, heteroaryl, acyl or COR 5  where R 5  is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl; 
         iii) R 2  and R 2 ′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester including alkyl or aryl alkyl sulfonyl including methanesulfonyl; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R 2  and R 2 ′ is H; 
         iv) R 3  is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH 2 OR 4 ; 
         v) R 4  is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl; 
         yl) Y is chosen from H, OH, halogen (F, Cl, Br, I), N 3 , CN, or OR 2 ′; and 
         vii) Z is 0 or S. 
       
     
     
         19 - 41 . (canceled) 
     
     
         42 . The method of  claim 18  wherein the compound administered is a β-L isomer and is at least 95% pure. 
     
     
         43 . The method of  claim 18  wherein the compound administered is a β-D isomer and is at least 95% pure. 
     
     
         44 . The method of  claim 18  wherein the host is a human. 
     
     
         45 . A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell does not carry the EBV or KHSV genome, comprising
 (i) administering the EBV-TK or KHSV-TK gene to the cell or surrounding cells in a manner that allows the enzyme to be expressed in the cell, and then   (ii) administering an effective amount of a compound of the general formula (I), (II) or (III):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         i) X is O, S, NR 4 , CH 2 , CHF or CF 2 ; 
         ii) R 1  is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF 3 , N 3 , NO 2 , aryl, heteroaryl, heteroaryl, acyl or COR 5  where R 5  is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl; 
         iii) R 2  and R 2 ′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R 2  and R 2 ′ is H; 
         iv) R 3  is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH 2 OR 4 ; 
         v) R 4  is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl; 
         yl) Y is chosen from H, OH, halogen (F, Cl, Br, I), N3, CN, or OR 2 ; and 
         vii) Z is O or S. 
       
     
     
         46 - 56 . (canceled) 
     
     
         57 . The method of  claim 45  wherein the compound administered is a β-L isomer and is at least 95% pure. 
     
     
         58 . The method of  claim 45  wherein the compound administered is a β-D isomer and is at least 95% pure. 
     
     
         59 . The method of  claim 45  wherein the host is a human. 
     
     
         60 . A pharmaceutical composition comprising an effective amount to treat a cell carrying the Epstein-Barr virus or KHSV of a compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         i) X is O, S, NR 4 , CH 2 , CHF or CF 2 ; 
         ii) R 1  is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF 3 , N 3 , NO 2 , aryl, heteroaryl, heteroaryl, acyl or COR 5  where R 5  is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl; 
         iii) R 2  and R 2 ′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester including alkyl or aryl alkyl sulfonyl including methanesulfonyl; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R 2  and R 2 ′ is H; 
         iv) R 3  is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH 2 OR 4 ; 
         v) R 4  is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl; 
         vi) Y is chosen from H, OH, halogen (F, Cl, Br, I), N3, CN, or OR 2 ′; and 
         vii) Z is 0 or S. 
       
     
     
         61 - 72 . (canceled) 
     
     
         73 . The pharmaceutical composition of  claim 60  of  claim 1  wherein the compound administered is a β-L isomer and is at least 95% pure. 
     
     
         74 . The pharmaceutical composition of  claim 60  of  claim 1  wherein the compound administered is a β-D isomer and is at least 95% pure. 
     
     
         75 . An immortalized human embryonic kidney cell transfected with the EBV-TK or KHSV-TK gene. 
     
     
         76 - 78 . (canceled) 
     
     
         79 . A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell does not carry the EBV or KHSV genome, comprising (i) administering a cell that carries and expresses the EBV-TK or KHSV-TK gene to a location that will enable a bystander effect on the abnormal cell, and then
 (ii) administering an effective amount of a compound of the general formula (I), (II) or (III).   
     
     
         80 . (canceled) 
     
     
         81 . The method of  claim 1  wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil. 
     
     
         82 . The method of  claim 1  wherein the host exhibits acute mononucleoisis or oral hairy leukoplakia. 
     
     
         83 . The method of  claim 18  wherein the host exhibits nasopharyngeal carcinoma, a B-cell lymphoma, B-cell lymphoproliferative disorder, Hodgkins disease, a T-lymphoma, an NK/monocytoid/dendritic cell malignancy, a sporadic epithelial carcinoma, a leiomyosarcoma, a multicentric leiomyosarcoma, Kaposi's sarcoma, multicentric Castleman's Disease, or germanotrophic lymphoma. 
     
     
         84 . The method of  claim 18  wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil. 
     
     
         85 . The method of  claim 45  wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil. 
     
     
         86 . The pharmaceutical composition of  claim 60  wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.