Inhibitors and methods of inhibiting bacterial and viral pathogens

Abstract

Compounds, pharmaceutical compositions and methods for treating viral and bacterial infections, by administering certain thiourea compounds, specifically acylthiourea, carboximidoylthiourea and S-alkyl isothiourea derivatives and analogs, in therapeutically effective amounts are disclosed.

1 - 12 . (canceled) 
     
     
         13 . A method for the treatment or prophylaxis of a viral or bacterial infection or disease associated therewith, wherein the viral infection is caused by a virus family selected from the group consisting of: Bunyaviridae, Poxviridae, Arenaviridae, Picornaviridae, Togaviridae, Flaviviridae, Filoviridae, Paramyxoviridae, Orthomyxoviridae and Retroviridae, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of Formula I below or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of: H, chloro, methyl, methoxy, ethoxy, nitro and fluoro; 
         R 2  is selected from the group consisting of: H, chloro, methyl, methoxy, trifluoromethyl, propanoylamino and 2-methylpropanoylamino; 
         R 3  is selected from the group consisting of: H, methyl, amino, methylamino, dimethylamino, phenylamino and 3-pyridylamino; 
         R 4  is selected from the group consisting of: H, chloro, methyl, methoxy, trifluoromethyl and trifluoromethoxy; and 
         R 5  is selected from the group consisting of H and methyl. 
       
     
     
         14 . The method of  claim 13 , wherein R 1  is hydrogen. 
     
     
         15 . The method of  claim 13 , wherein R 1  is chloro. 
     
     
         16 . The method of  claim 13 , wherein R 2  is hydrogen. 
     
     
         17 . The method of  claim 13 , wherein R 2  is trifluoromethyl. 
     
     
         18 . The method of  claim 13 , wherein R 3  is amino. 
     
     
         19 . The method of  claim 13 , wherein R 3  is methylamino. 
     
     
         20 . The method of  claim 13 , wherein R 4  is hydrogen. 
     
     
         21 . The method of  claim 13 , wherein R 4  is methoxy. 
     
     
         22 . The method of  claim 13 , wherein R 5  is hydrogen. 
     
     
         23 . The method of  claim 13 , wherein the compound of Formula I is selected from the group consisting of: N-[(4-amino-3-methoxy-phenyl)carbamothioyl]-4-tert-butyl-benzamide; N-[(4-amino-2-chloro-phenyl)carbamothioyl]-4-tert-butyl-benzamide hydrochloride; 4-tert-butyl-N-[[2-chloro-4-(methylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[(2-chloro-5-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2-chloro-6-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[[2-chloro-3-(trifluoromethyl)phenyl]-carbamothioyl]benzamide; N-[(4-amino-3-methoxy-phenyl)carbamothioyl]-4-tert-butyl-benzamide hydrochloride; 4-tert-butyl-N-[(2-chloro-3-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[[4-(methylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[[2-chloro-4-(dimethylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[[2-chloro-5-(trifluoromethoxy)phenyl]-carbamothioyl]benzamide; 4-tert-butyl-N-[[4-(3-pyridylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[(2-chlorophenyl)carbamothioyl]-benzamide; 4-tert-butyl-N-(o-tolylcarbamothioyl)-benzamide; 4-tert-butyl-N-[[2-chloro-5-(trifluoromethyl)phenyl]-carbamothioyl]benzamide; N-[(4-anilinophenyl)-carbamothioyl]-4-tert-butyl-benzamide; 4-tert-butyl-N-[(3-chloro-2-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2,4-dimethylphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(4-dimethylaminophenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2,5-dichlorophenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2-methoxyphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(3-chlorophenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-(phenylcarbamothioyl)-benzamide; 4-tert-butyl-N-[(2,3-dimethylphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(3,4-dimethylphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2-ethoxyphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[[3-(2-methylpropanoylamino)-phenyl]carbamothioyl]-benzamide; 4-tert-butyl-N-[(2-nitrophenyl)carbamothioyl]-benzamide; 4-tert-butyl-N-(p-tolylcarbamothioyl)-benzamide; N-[(4-aminophenyl)-carbamothioyl]-4-tert-butyl-benzamide; 4-tert-butyl-N-[(2-fluorophenyl)carbamothioyl]-benzamide; 4-tert-butyl-N-[[3-(propanoylamino)phenyl]-carbamothioyl]benzamide; 4-tert-butyl-N-(m-tolylcarbamothioyl)-benzamide; 4-tert-butyl-N-[(3,5-dimethylphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(3-methoxyphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2,5-dimethylphenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(4-dimethylaminophenyl)-carbamothioyl]benzamide hydrochloride; and 4-tert-butyl-N-[(2,6-dimethylphenyl)-carbamothioyl]benzamide. 
     
     
         24 . The method of  claim 23 , wherein the compound of Formula I is 4-tert-butyl-N-[(2-chloro-5-methyl-phenyl)-carbamothioyl]benzamide. 
     
     
         25 . The method of  claim 13 , wherein the mammal is a human. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 13 , wherein said Bunyaviridae is selected from the group consisting of Rift Valley fever virus, La Crosse virus and Andes virus. 
     
     
         28 . The method of  claim 13 , wherein said Poxviridae is selected from the vaccinia virus and monkeypox virus. 
     
     
         29 . The method of  claim 13 , wherein said Arenaviridae is selected from the group consisting of Tacaribe virus and lymphocytic choriomeningitis virus. 
     
     
         30 . The method of  claim 13 , wherein said Picornaviridae is Encephalomyocarditis virus. 
     
     
         31 . The method of  claim 13 , wherein said Togaviridae is Sindbis virus. 
     
     
         32 . The method of  claim 13 , wherein said Flaviviridae is Dengue virus. 
     
     
         33 . The method of  claim 13 , wherein said Filoviridae is selected from the group consisting of Ebola virus and Zaire strain. 
     
     
         34 . The method of  claim 13 , wherein said Orthomyxoviridae is an influenza virus. 
     
     
         35 . The method of  claim 34 , wherein said influenza virus is H1N1 virus. 
     
     
         36 . The method of  claim 13 , wherein said Retroviridae is a Human Immunodeficiency virus. 
     
     
         37 . The method of  claim 13 , which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon. 
     
     
         38 . The method of  claim 37 , wherein said antiviral agent is Ribavirin. 
     
     
         39 . The method of  claim 37 , wherein said antiviral agent is cidofovir. 
     
     
         40 . The method of  claim 37 , wherein said interferon is pegylated. 
     
     
         41 . The method of  claim 13 , wherein said bacterial infection is caused by a bacteria family selected from the group consisting of Chlamydiaceae and Coxiellaceae. 
     
     
         42 . The method of  claim 41 , wherein said Chlamydiaceae is selected from the group consisting of  Chlamydophila caviae  and  Chlamydophila muridarum.    
     
     
         43 . The method of  claim 41 , wherein said Coxiellaceae is  Coxiella burnetti.    
     
     
         44 . The method of  claim 13 , A wherein the compound of Formula I is selected from the group consisting of: N-[(4-amino-3-methoxy-phenyl)carbamothioyl]-4-tert-butyl-benzamide; N-[(4-amino-2-chloro-phenyl)carbamothioyl]-4-tert-butyl-benzamide hydrochloride; 4-tert-butyl-N-[[2-chloro-4-(methylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[(2-chloro-5-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[(2-chloro-6-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[[2-chloro-3-(trifluoromethyl)phenyl]-carbamothioyl]benzamide; N-[(4-amino-3-methoxy-phenyl)carbamothioyl]-4-tert-butyl-benzamide hydrochloride; 4-tert-butyl-N-[(2-chloro-3-methyl-phenyl)-carbamothioyl]benzamide; 4-tert-butyl-N-[[4-(methylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[[2-chloro-4-(dimethylamino)phenyl]-carbamothioyl]benzamide hydrochloride; 4-tert-butyl-N-[[2-chloro-5-(trifluoromethoxy)phenyl]-carbamothioyl]benzamide; and 4-tert-butyl-N-[[4-(3-pyridylamino)phenyl]-carbamothioyl]benzamide hydrochloride. 
     
     
         45 . The method of  claim 44 , wherein the compound of Formula I is 4 tert-butyl-N-[(2-chloro-5-methyl-phenyl)-carbamothioyl]benzamide. 
     
     
         46 - 175 . (canceled)