Antiviral compounds and methods

Abstract

The invention relates to compounds having antiviral activity and methods utilizing the compounds to treat viral infections.

1 - 168 . (canceled) 
     
     
         169 . A method for the therapeutic or prophylactic treatment of a subject infected with or exposed to a virus, comprising administering to the subject a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3  and R 4  are independently hydrogen, 
       
       
         
           
           
               
               
           
         
         and wherein 
         X=hydrogen, hydroxy, nitro, halo, C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyl, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkyloxy, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo; 
         R a , R b , R c , R d , R e , R f , R h , R k , R L , R m , R n , R o , R p  independently=hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, 
       
       
         
           
           
               
               
           
         
         or PrS; 
         R g , R i  independently=hydrogen, hydroxy, halo, or C 1-5  alkyl; 
         R j =hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS. 
       
       
         
           
           
               
               
           
         
         and wherein 
         when R 1  is 
       
       
         
           
           
               
               
           
         
         R a  and R c  are amino, and R b  is halo, R 2 , R 3  or R 4  cannot be hydrogen, benzyl or substituted benzyl or BODIPY-Fl; 
         when R 1  is C 6 H 5 CH═CH, R 2  is hydrogen and R 3  is phenyl, R 4  cannot be phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, and R 3  is benzoyl, R 4  cannot be benzoyl; 
         when R 1  is phenyl, R 2  is substituted benzyl, R 3  is hydrogen and R 4  is hydrogen, R n , R o  and R p  cannot all be hydrogen; 
         when R 1  is phenyl, R 3  is hydrogen and R 4  is hydrogen, R 2  cannot be benzyl or phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, R 3  cannot be phenyl together with R 4  as benzoyl; and 
         when R 1  is phenyl, R 2  is hydrogen, R 3  and R 4  cannot both be benzyl. 
       
     
     
         170 . The method according to  claim 169 , wherein the compound is selected from the group consisting of:
 (2-Bromocinnamoyl)guanidine,   (2-Chlorocinnamoyl)guanidine,   (2-Furanacryloyl)guanidine,   (2-Methoxycinnamoyl)guanidine,   (2-Nitrocinnamoyl)guanidine,   (3-Bromocinnamoyl)guanidine,   (3-Chlorocinnamoyl)guanidine,   (3-Methoxycinnamoyl)guanidine,   (3-Nitrocinnamoyl)guanidine,   (3-phenylpropanoyl)guanidine,   (4-Bromocinnamoyl)guanidine,   (4-Chlorocinnamoyl)guanidine,   (4-Hydroxycinnamoyl)guanidine,   (4-Methoxycinnamoyl)guanidine,   (4-Phenoxybenzoyl)guanidine,   (5-Phenyl-penta-2,4-dienoyl)guanidine,   (a-Methylcinnamoyl)guanidine,   (Phenylacetyl)guanidine,   (Quinoline-2-carbonyl)guanidine,   (trans-2-Phenylcyclopropanecarbonyl)guanidine,   [(4-Chlorophenoxy-acetyl]guanidine,   [(E)-3-(4-Dimethylaminophenyl)-2-methylacryloyl]guanidine,   [3-(3-Pyridyl)acryloyl]guanidine,   1-bromo-2-naphthoylguanidine,   1-naphthoylguanidine,   2-(1-naphthyl)acetoylguanidine,   2-(2-naphthyl)acetoylguanidine,   2-(cyclohex-1-en-1yl)cinnamoylguanidine,   2-(trifluoromethyl)cinnamoylguanidine,   2,3,5,6,-tetramethylcinnamoylguanidine,   2,3-difluorocinnamoylguanidine,   2,3-dimethylcinnamoylguanidine,   2,4,6-trimethylcinnamoylguanidine,   2,4-dichlorocinnamolyguanidine,   2,5-dimethylcinnamoylguanidine,   2,6-dichlorocinnamoylguanidine,   2′4 DichloroBenazamil HCl,   2-chloro-6-fluorocinnamoylguanidine,   2-cyclohexylcinnamoylguanidine,   2-ethoxycinnamoylguanidine,   2-ethylcinnamoylguanidine,   2-fluorocinnamoylguanidine,   2-methylcinnamoylguanidine,   2-naphthoylguanidine,   2-phenylcinnamoylguanidine,   2-t-butylcinnamoylguanidine,   3-(2-naphthyl)acryloylguanidine,   3-(cyclohex-1-en-1-yl)cinnamoylguanidine,   3-(trans-hept-1-en-1-yl)cinnamoylguanidine,   3-(trifluoromethoxy)cinnamoylguanidine,   3-(trifluoromethyl)cinnamoylguanidine,   3,4-(methylenedioxy)cinnamoylguanidine,   3,4,5-trimethoxycinnamoylguanidine,   3,4-dichlorocinnamoylguanidine,   3,4-difluorocinnamoylguanidine,   3-ethoxycinnamoylguanidine,   3-fluorocinnamoylguanidine,   3-isopropylcinnamoylguanidine hydrochloride,   3-methoxy-HMA,   3-methoxy-amiloride,   3-methylcinnamoylguanidine,   3-phenylcinnamoylguanidine,   3-t-butylcinnamoylguanidine,   4-(trifluoromethyl)cinnamoylguanidine,   4-ethoxycinnamoylguanidine,   4-fluorocinnamoylguanidine,   4-isopropylcinnamoylguanidine,   4-methylcinnamoylguanidine,   4-phenylbenzoylguanidine,   4-phenylcinnamoylguanidine,   4-t-butylcinnamoylguanidine,   5-(2′-bromophenyl)penta-2,4-dienoylguanidine,   5-(3′-bromophenyl)penta-2,4-dienoylguanidine,   5-(4-fluorophenyl)amiloride,   5-(N,N-Dimethyl)amiloride hydrochloride,   5-(N,N-hexamethylene)amiloride,   5-(N-Ethyl-N-isopropyl)amiloride,   5-(N-Methyl-N-isobutyl)amiloride,   5-bromo-2-fluorocinnamoylguanidine,   5-bromo-2-methoxycinnamoylguanidine,   5-tert-butylamino-amiloride,   6-bromo-2-naphthoylguanidine,   6-Iodoamiloride,   6-methoxy-2-naphthoylguanidine,   Benzamil hydrochloride,   Benzyoylguanidine,   cinnamoylguanidine hydrochloride,   Cinnamoylguanidine,   N-(2-naphthoyl)-N′-phenylguanidine,   N-(3-phenylpropanoyl)-N′-phenylguanidine,   N-(3-phenylpropanoyl)-N′-phenylguanidine,   N-(6-Hydroxy-2-naphthoyl)-N′-phenylguanidine,   N-(cinnamoyl)-N′phenylguanidine,   N,N′-Bis(3-phenylpropanoyl)guanidine,   N,N′-bis(3phenylpropanoyl)-N″-phenylguanidine,   N,N′-Bis(amidino)naphthalene-2,6-dicarboxamide,   N,N′-bis-(cinnamoyl)-N″-phenylguanidine,   N-amidino-3,5-diamino-6-phynyl-2-Pyrazinecarboxamide,   N-amidino-3-amino-5-hexamethyleneimino-6-phenyl-2-pyrazinecarboxamide,   N-amidino-3-amino-5-phenyl-6-chloro-2-pyrazinecarboxamide,   N-Benzoyl-N′-cinnamoylguanidine,   N-Cinnamoyl-N′,N′-dimethylguanidine,   Phenamil methanesulfonate salt,   trans-3-(1-naphthyl)acryloylguanidine and   trans-3-Furanacryoylguanidine,   or a pharmaceutically acceptable salt thereof.   
     
     
         171 . The method according to  claim 169 , wherein said virus is a Lentivirus. 
     
     
         172 . The method according to  claim 171 , wherein said Lentivirus is Human Immunodeficiency Virus (HIV). 
     
     
         173 . The method according to  claim 172 , wherein said HIV is HIV-1. 
     
     
         174 . The method according to  claim 169 , wherein said virus is a Coronavirus. 
     
     
         175 . The method according to  claim 174 , wherein said Coronavirus is the Severe Acute Respiratory Syndrome virus (SARS), human Coronavirus 229E, human Coronavirus OC43, porcine respiratory Coronavirus (PRCV) or bovine Coronvirus (BCV). 
     
     
         176 . The method according to  claim 174 , wherein said Coronavirus is any one of the coronavirus isolates listed in Table 1. 
     
     
         177 . The method according to  claim 169 , wherein said virus is the Hepatitis C virus. 
     
     
         178 . The method according to  claim 169 , wherein said virus is Equine Arteritis virus. 
     
     
         179 . A method for preventing the infection of a cell exposed to a virus or for reducing, retarding or otherwise inhibiting growth and/or replication of a virus in a cell infected with said virus comprising contacting the cell with a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3  and R 4  are independently hydrogen, 
       
       
         
           
           
               
               
           
         
         and wherein 
         X=hydrogen, hydroxy, nitro, halo, C 1-6 alkyl, C 1-6 alkyloxy, C 3-6 cycloalkyl, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkyloxy, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo; 
         R a , R b , R c , R d , R e , R f , R h , R k , R L , R m , R n , R o , R p  independently=hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, 
       
       
         
           
           
               
               
           
         
         or PrS; 
         R g , R i  independently=hydrogen, hydroxy, halo, or C 1-5  alkyl; 
         R j =hydrogen, amino, halo, C 1-5 alkyl, C 1-5 alkyloxy, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS, 
       
       
         
           
           
               
               
           
         
         and wherein 
         when R 1  is 
       
       
         
           
           
               
               
           
         
         R a  and R c  are amino, and R b  is halo, R 2 , R 3  or R 4  cannot be hydrogen, benzyl or substituted benzyl or BODIPY-Fl; 
         when R 1  is C 6 H 5 CH═CH, R 2  is hydrogen and R 3  is phenyl, R 4  cannot be phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, and R 3  is benzoyl, R 4  cannot be benzoyl; 
         when R 1  is phenyl, R 2  is substituted benzyl, R 3  is hydrogen and R 4  is hydrogen, R n , R o  and R p  cannot all be hydrogen; 
         when R 1  is phenyl, R 3  is hydrogen and R 4  is hydrogen, R 2  cannot be benzyl or phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, R 3  cannot be phenyl together with R 4  as benzoyl; and 
         when R 1  is phenyl, R 2  is hydrogen, R 3  and R 4  cannot both be benzyl. 
       
     
     
         180 . The method according to  claim 179 , wherein the compound is selected from:
 (2-Bromocinnamoyl)guanidine,   (2-Chlorocinnamoyl)guanidine,   (2-Furanacryloyl)guanidine,   (2-Methoxycinnamoyl)guanidine,   (2-Nitrocinnamoyl)guanidine,   (3-Bromocinnamoyl)guanidine,   (3-Chlorocinnamoyl)guanidine,   (3-Methoxycinnamoyl)guanidine,   (3-Nitrocinnamoyl)guanidine,   (3-phenylpropanoyl)guanidine,   (4-Bromocinnamoyl)guanidine,   (4-Chlorocinnamoyl)guanidine,   (4-Hydroxycinnamoyl)guanidine,   (4-Methoxycinnamoyl)guanidine,   (4-Phenoxybenzoyl)guanidine,   (5-Phenyl-penta-2,4-dienoyl)guanidine,   (a-Methylcinnamoyl)guanidine,   (Phenylacetyl)guanidine,   (Quinoline-2-carbonyl)guanidine,   (trans-2-Phenylcyclopropanecarbonyl)guanidine,   [(4-Chlorophenoxy-acetyl]guanidine,   [(E)-3-(4-Dimethylaminophenyl)-2-methylacryloyl]guanidine,   [3-(3-Pyridyl)acryloyl]guanidine,   1-bromo-2-naphthoylguanidine,   1-naphthoylguanidine,   2-(1-naphthyl)acetoylguanidine,   2-(2-naphthyl)acetoylguanidine,   2-(cyclohex-1-en-1yl)cinnamoylguanidine,   2-(trifluoromethyl)cinnamoylguanidine,   2,3,5,6,-tetramethylcinnamoylguanidine,   2,3-difluorocinnamoylguanidine,   2,3-dimethylcinnamoylguanidine,   2,4,6-trimethylcinnamoylguanidine,   2,4-dichlorocinnamolyguanidine,   2,5-dimethylcinnamoylguanidine,   2,6-dichlorocinnamoylguanidine,   2′4 DichloroBenazamil HCl,   2-chloro-6-fluorocinnamoylguanidine,   2-cyclohexylcinnamoylguanidine,   2-ethoxycinnamoylguanidine,   2-ethylcinnamoylguanidine,   2-fluorocinnamoylguanidine,   2-methylcinnamoylguanidine,   2-naphthoylguanidine,   2-phenylcinnamoylguanidine,   2-t-butylcinnamoylguanidine,   3-(2-naphthyl)acryloylguanidine,   3-(cyclohex-1-en-1-yl)cinnamoylguanidine,   3-(trans-hept-1-en-1-yl)cinnamoylguanidine,   3-(trifluoromethoxy)cinnamoylguanidine,   3-(trifluoromethyl)cinnamoylguanidine,   3,4-(methylenedioxy)cinnamoylguanidine,   3,4,5-trimethoxycinnamoylguanidine,   3,4-dichlorocinnamoylguanidine,   3,4-difluorocinnamoylguanidine,   3-ethoxycinnamoylguanidine,   3-fluorocinnamoylguanidine,   3-isopropylcinnamoylguanidine hydrochloride,   3-methoxy-HMA,   3-methoxy-amiloride,   3-methylcinnamoylguanidine,   3-phenylcinnamoylguanidine,   3-t-butylcinnamoylguanidine,   4-(trifluoromethyl)cinnamoylguanidine,   4-ethoxycinnamoylguanidine,   4-fluorocinnamoylguanidine,   4-isopropylcinnamoylguanidine,   4-methylcinnamoylguanidine,   4-phenylbenzoylguanidine,   4-phenylcinnamoylguanidine,   4-t-butylcinnamoylguanidine,   5-(2′-bromophenyl)penta-2,4-dienoylguanidine,   5-(3′-bromophenyl)penta-2,4-dienoylguanidine,   5-(4-fluorophenyl)amiloride,   5-(N,N-Dimethyl)amiloride hydrochloride,   5-(N,N-hexamethylene)amiloride,   5-(N-Ethyl-N-isopropyl)amiloride,   5-(N-Methyl-N-isobutyl)amiloride,   5-bromo-2-fluorocinnamoylguanidine,   5-bromo-2-methoxycinnamoylguanidine,   5-tert-butylamino-amiloride,   6-bromo-2-naphthoylguanidine,   6-Iodoamiloride,   6-methoxy-2-naphthoylguanidine,   Benzamil hydrochloride,   Benzyoylguanidine,   cinnamoylguanidine hydrochloride,   Cinnamoylguanidine,   N-(2-naphthoyl)-N′-phenylguanidine,   N-(3-phenylpropanoyl)-N′-phenylguanidine,   N-(3-phenylpropanoyl)-N′-phenylguanidine,   N-(6-Hydroxy-2-naphthoyl)-N′-phenylguanidine,   N-(cinnamoyl)-N′phenylguanidine,   N,N′-Bis(3-phenylpropanoyl)guanidine,   N,N′-bis(3phenylpropanoyl)-N″-phenylguanidine,   N,N′-Bis(amidino)naphthalene-2,6-dicarboxamide,   N,N′-bis-(cinnamoyl)-N″-phenylguanidine,   N-amidino-3,5-diamino-6-phynyl-2-Pyrazinecarboxamide,   N-amidino-3-amino-5-hexamethyleneimino-6-phenyl-2-pyrazinecarboxamide,   N-amidino-3-amino-5-phenyl-6-chloro-2-pyrazinecarboxamide,   N-Benzoyl-N′-cinnamoylguanidine,   N-Cinnamoyl-N′,N′-dimethylguanidine,   Phenamil methanesulfonate salt,   trans-3-(1-naphthyl)acryloylguanidine and   trans-3-Furanacryoylguanidine,   or a pharmaceutically acceptable salt thereof.   
     
     
         181 . The method according to  claim 179 , wherein said virus is a Lentivirus, Human Immunodeficiency Virus (HIV), a Coronavirus, the Hepatitis C virus or Equine Arteritis virus. 
     
     
         182 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3  and R 4  are independently hydrogen, 
       
       
         
           
           
               
               
           
         
         and wherein 
         X=hydrogen, C 2-6 alkyl, C 3-6 cycloalkyl, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo; 
         R d , R e , R f , R h , R L , R m , R n , R o , R p  independently=hydrogen, amino, C 2-5 alkyl, aryl, substituted aryl, aryl-substituted amino, 
       
       
         
           
           
               
               
           
         
         or PrS; 
         R g , R i  independently=hydrogen, hydroxy, or C 1-5  alkyl; 
         R k =amino, C 1-5 alkyl, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, 
       
       
         
           
           
               
               
           
         
         or PrS; 
         R j =hydrogen, amino, C 1-5 alkyl, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS, 
       
       
         
           
           
               
               
           
         
         and wherein 
         when R 1  is C 6 H 5 CH═CH, R 2  is hydrogen and R 3  is phenyl, R 4  cannot be phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, and R 3  is benzoyl, R 4  cannot be benzoyl; 
         when R 1  is phenyl, R 2  is substituted benzyl, R 3  is hydrogen and R 4  is hydrogen, R n , R o  and R p  cannot all be hydrogen; 
         when R 1  is phenyl, R 3  is hydrogen and R 4  is hydrogen, R 2  cannot be benzyl or phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, R 3  cannot be phenyl together with R 4  as benzoyl; and 
         when R 1  is phenyl, R 2  is hydrogen, R 3  and R 4  cannot both be benzyl. 
       
     
     
         183 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2 , R 3  and R 4  are independently hydrogen, 
       
       
         
           
           
               
               
           
         
         and wherein 
         X=hydrogen, C 2-6 alkyl, C 3-6 cycloalkyl, phenyl, C 1-6 alkeneyl, C 3-6 cycloalkeneyl, C 1-6 alkeneoxy, or benzo; 
         R d , R e , R f , R h , R L , R m , R n R o , R p  independently=hydrogen, amino, C 2-5 alkyl, aryl, substituted aryl, aryl-substituted amino, 
       
       
         
           
           
               
               
           
         
         or PrS; 
         R g , R i  independently=hydrogen, hydroxy, or C 1-5  alkyl; 
         R k =hydrogen, amino, C 1-5 alkyl, aryl, substituted aryl, substituted amino, mono or dialkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, 
       
       
         
           
           
               
               
           
         
         or PrS; 
         R j =amino, C 1-5 alkyl, hydroxy, aryl, substituted aryl, substituted amino, alkyl-substituted amino, cycloalkyl-substituted amino, aryl-substituted amino, PrS, 
       
       
         
           
           
               
               
           
         
         and wherein 
         when R 1  is C 6 H 5 CH═CH, R 2  is hydrogen and R 3  is phenyl, R 4  cannot be phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, and R 3  is benzoyl, R 4  cannot be benzoyl; 
         when R 1  is phenyl, R 2  is substituted benzyl, R 3  is hydrogen and R 4  is hydrogen, R n , R o  and R p  cannot all be hydrogen; 
         when R 1  is phenyl, R 3  is hydrogen and R 4  is hydrogen, R 2  cannot be benzyl or phenyl; 
         when R 1  is phenyl, R 2  is hydrogen, R 3  cannot be phenyl together with R 4  as benzoyl; and 
         when R 1  is phenyl, R 2  is hydrogen, R 3  and R 4  cannot both be benzyl. 
       
     
     
         184 . A compound according to  claim 183 , selected from the group consisting of:
 cinnamoylguanidine,   4-phenylbenzoylguanidine,   N-(cinnamoyl)-N′phenylguanidine,   N,N′-bis-(cinnamoyl)-N″-phenylguanidine,   N-(6-Hydroxy-2-naphthoyl)-N′-phenylguanidine,   N,N′-Bis(amidino)naphthalene-2,6-dicarboxamide,   N″-Cinnamoyl-N,N′-diphenylguanidine,   (Phenylacetyl)guanidine,   benzyoylguanidine,   N-benzoyl-N′-cinnamoylguanidine,   [(E)-3-(4-Dimethylaminophenyl)-2-methylacryloyl]guanidine,   (5-Phenyl-penta-2,4-dienoyl)guanidine,   [3-(3-Pyridyl)acryloyl]guanidine,   (4-Hydroxycinnamoyl)guanidine,   (Quinoline-2-carbonyl)guanidine,   or a pharmaceutically acceptable salt thereof.   
     
     
         185 . A pharmaceutical composition comprising a compound according to  claim 183  and optionally one or more pharmaceutical acceptable carriers or derivatives. 
     
     
         186 . The pharmaceutical composition according to  claim 185 , further comprising one or more other antiviral agents.