Antiviral agents and methods of treating viral infections

Abstract

The present invention relates to methods of treating viral or fungal infections using 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone (3-AP) and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP) and its prodrug forms and to pharmaceutical compositions comprising these compounds.

1 . A method of treating a viral infection in a patient comprising administering to said patient a pharmaceutical composition comprising an anti-viral effective amount of at least one compound according to the structure:  
     
       
         
         
             
             
         
       
       Where R 1  is H or a C 1 -C 3  alkyl group, preferably H or CH 3 ;  
       R 2  is H or CO 2 R 3 ;  
       R 3  is CHRR′ or  
       
         
           
           
               
               
           
         
       
       where R is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , i-propyl;  
       R′ is a free acid phosphate, phosphate salt or S—S—R″ group;  
       R″ is CH 2 CH 2 NHR 4 , CH 2 CH 2 OH, CH 2 COOR 5 , ortho- or para-substituted C 1 -C 3  alkylphenyl or ortho or para nitrophenyl;  
       R 4  is H or a C 1 -C 18  acyl group (preferably, a C 1 -C 4  group), benzoyl, or a substituted benzoyl group;  
       R 5  is H, a C 1 -C 18  alkyl group (preferably, a C 1 -C 3  group), phenyl, substituted phenyl, benzyl, or a substituted benzyl group;  
       R 6 , R 7 , R 8 , R 9  and R 10  are independently selected from H, a free acid phosphate, a phosphate salt, or an S—S—R″ group, a C 1 -C 3  alkyl group, F, Cl, Br, I, OCH 3 , OCF 3 , CF 3 , NO 2 , CN, SO 2 CF 3 , SO 2 CH 3 , COOCH 3 , SF 5 , COCH 3 , NH 2 , N(CH 3 ) 2 , SCH 3  or OH; With the proviso that when any two of R 6 , R 7 , R 8 , R 9  and R 10  are other than H, the other of R 6 , R 7 , R 8 , R 9  and R 10  are H, and with the proviso that no more than one of R 6 , R 7 , R 8 , R 9  and R 10  is a free acid phosphate, a phosphate salt or S—S—R″.  
     
   
   
       2 - 4 . (canceled)  
   
   
       5 . The method according to  claim 1  wherein R 1  and R 2  are H.  
   
   
       6 . The method according to  claim 1  wherein said viral infection is caused by an agent selected from the group consisting of human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.  
   
   
       7 . A method of treating a viral infection comprising administering in combination, at least one compound according to the structure:  
     
       
         
         
             
             
         
       
       Where R 1  is H or a C 1 -C 3  alkyl group, preferably H or CH 3 ;  
       R 2  is H or CO 2 R 3 ;  
       R 3  is CHRR′ or  
       
         
           
           
               
               
           
         
       
       where R is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , i-propyl;  
       R′ is a free acid phosphate, phosphate salt or S—S—R″ group;  
       R″ is CH 2 CH 2 NHR 4 , CH 2 CH 2 OH, CH 2 COOR 5 , ortho- or para-substituted C 1 -C 3  alkylphenyl or ortho or para nitrophenyl;  
       R 4  is H or a C 1 -C 18  acyl group (preferably, a C 1 -C 4  group), benzoyl, or a substituted benzoyl group;  
       R 5  is H, a C 1 -C 18  alkyl group (preferably, a C 1 -C 3  group), phenyl, substituted phenyl, benzyl, or a substituted benzyl group;  
       R 6 , R 7 , R 8 , R 9  and R 10  are independently selected from H, a free acid phosphate, a phosphate salt, or an S—S—R″ group, a C 1 -C 3  alkyl group, F, Cl, Br, I, OCH 3 , OCF 3 , CF 3 , NO 2 , CN, SO 2 CF 3 , SO 2 CH 3 , COOCH 3 , SF 5 , COCH 3 , NH 2 , N(CH 3 ) 2 , SCH 3  or OH; With the proviso that when any two of R 6 , R 7 , R 8 , R 9  and R 10  are other than H, the other of R 6 , R 7 , R 8 , R 9  and R 10  are H, and with the proviso that no more than one of R 6 , R 7 , R 8 , R 9  and R 10  is a free acid phosphate, a phosphate salt or S—S—R″ and at least one anti-viral agent which inhibits the growth or replication of viruses by a mechanism other than by inhibition of viral ribonucleotide reductase.  
     
   
   
       8 - 10 . (canceled)  
   
   
       11 . The method according to  claim 7  wherein R 1  and R 2  are H.  
   
   
       12 . The method according to  claim 7  wherein said viral infection is caused by an agent selected from the group consisting of human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.  
   
   
       13 . The method according to  claim 7  wherein said anti-viral agent is selected from the group consisting of acyclic nucleosides, interferons, reverse transcriptase inhibitors, nucleoside transport inhibitors 2′,3′-dideoxynucleosides, 3TC, AZT, 2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, 2′,3′-dideoxythymidine, 2′,3′-dideoxy-2′,3′-didehydrothymidine and 2′,3′-dideoxy-2′,3′-didehydrocytidine, β-LFddC, β-LFd4C, β-Ld4C, tenofovir DF, adefovir, dipivoxil, immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoetin, ampligen, thymodulin, thymopentin, foscarnet, ribavirin and inhibitors of HIV binding to CD4 receptors such as soluble CD4, CD4 fragments, CD4 hybrid molecules and glycosylation inhibitors such as 2-deoxy-D-glucose, castanospermine and 1-deoxynojirimycin.  
   
   
       14 . (canceled)  
   
   
       15 . A pharmaceutical composition comprising an anti-viral effective amount of at least one compound according to the structure:  
     
       
         
         
             
             
         
       
       Where R 1  is H or a C 1 -C 3  alkyl group, preferably H or CH 3 ;  
       R 2  is H or CO 2 R 3 ;  
       R 3  is CHRR′ or  
       
         
           
           
               
               
           
         
       
       where R is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , i-propyl;  
       R′ is a free acid phosphate, phosphate salt or S—S—R″ group;  
       R″ is CH 2 CH 2 NHR 4 , CH 2 CH 2 OH, CH 2 COOR 5 , ortho- or para-substituted C 1 -C 3  alkylphenyl or ortho or para nitrophenyl;  
       R 4  is H or a C 1 -C 18  acyl group (preferably, a C 1 -C 4  group), benzoyl, or a substituted benzoyl group;  
       R 5  is H, a C 1 -C 18  alkyl group (preferably, a C 1 -C 3  group), phenyl, substituted phenyl, benzyl, or a substituted benzyl group;  
       R 6 , R 7 , R 8 , R 9  and R 10  are independently selected from H, a free acid phosphate, a phosphate salt, or an S—S—R″ group, a C 1 -C 3  alkyl group, F, Cl, Br, I, OCH 3 , OCF 3 , CF 3 , NO 2 , CN, SO 2 CF 3 , SO 2 CH 3 , COOCH 3 , SF 5 , COCH 3 , NH 2 , N(CH 3 ) 2 , SCH 3  or OH; With the proviso that when any two of R 6 , R 7 , R 8 , R 9  and R 10  are other than H, the other of R 6 , R 7 , R 8 , R 9  and R 10  are H, and with the proviso that no more than one of R 6 , R 7 , R 8 , R 9  and R 10  is a free acid phosphate, a phosphate salt or S—S—R″ and at least one other anti-viral agent which inhibits the growth or replication of viruses by a mechanism other than by inhibition of viral ribonucleotide reductase.  
     
   
   
       16 - 18 . (canceled)  
   
   
       19 . The composition according to  claim 15  wherein said composition is used to treat a viral infection caused by an agent selected from the group consisting of human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus) and flaviviruses, including Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.  
   
   
       20 . The composition according to  claim 15  wherein said other anti-viral agent is selected from the group consisting of acyclic nucleosides such as acyclovir or ganciclovir, interferons such as alpha, beta or gamma-interferon, reverse transcriptase inhibitors and nucleoside transport inhibitors such as dipyridamole, 2′,3′-dideoxynucleosides, 3TC, AZT, 2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, 2′,3′-dideoxythymidine, 2′,3′-dideoxy-2′,3′-didehydrothymidine and 2′,3′-dideoxy-2′,3′-didehydrocytidine, β-LFddC, β-LFd4C, β-Ld4C, tenofovir DF, adefovir, dipivoxil, immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoetin, ampligen, thymodulin, thymopentin, foscarnet, ribavirin and inhibitors of HIV binding to CD4 receptors e.g. soluble CD4, CD4 fragments, CD4 hybrid molecules, glycosylation inhibitors such as 2-deoxy-D-glucose, castanospermine and 1-deoxynojirimycin.  
   
   
       21 . The composition according to  claim 15  wherein R 1  and R 2  are H.  
   
   
       22 . The composition according to  claim 21  wherein said other anti-viral agent is selected from the group consisting of 3TC, DDI, D4T, P-LFd4C, β-LFddC, AZT, acyclovir and gancyclovir.  
   
   
       23 . The composition according to  claim 21  wherein said other anti-viral agent is selected from the group consisting of 3TC, DDI, D4T and AZT.  
   
   
       24 - 35 . (canceled)  
   
   
       36 . A method of treating an HIV infection in a patient in need thereof comprising administering to said patient in combination, an effective amount of at least one compound according to the structure:  
     
       
         
         
             
             
         
       
       Where R 1  and R 2  are both H, with an effective amount of at least one anti-HIV agent selected from the group consisting of ddI and D4T, said administration producing a synergistic effect in treating said patient.  
     
   
   
       37 . The method according to  claim 36  wherein said anti-HIV agent is ddI.  
   
   
       38 . The method according to  claim 36  wherein said anti-HIV agent is D4T.  
   
   
       39 . A method of treating an HSV infection in a patient in need thereof comprising administering in combination, an effective amount of at least one compound according to the structure:  
     
       
         
         
             
             
         
       
       Where R 1  and R 2  are both H, with an effective amount of acyclovir.