Anti-viral drug

Abstract

An antiviral compound for use in the treatment of positive-sense, single-stranded RNA (herein after ssRNA] virus infections different from the West Nile Fever virus infections wherein said antiviral compound is of general formula (I) [compound S(A), herein after] or a pharmaceutically acceptable salt thereof (I) formula (I) wherein—R 1 is selected from an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, a cycloalkyl group having 3 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, an aryl group, an alkylaryl group, or a cycloheteroalkyl group having 3 to 12 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms optionally substituted by a halogen atom or hydroxyl group, a cycloalkyl group having 3 to 6 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, a phenyl, a benzyl, a morpholine, or an imidazolyl, more preferably an alkyl group having 1 to 4 carbon atoms, a cyclohexyl, a phenyl or a benzyl.

1 - 45 . (canceled) 
     
     
         46 . A method of treatment of positive-sense, single-stranded RNA (ssRNA) virus infection different from the West Nile Fever virus infection, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an subject in need thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group; a cycloalkyl group having 3 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, an aryl group, an alkylaryl group, or a cycloheteroalkyl group having 3 to 12 carbon atoms; and 
         the positive-sense, single-stranded ssRNA virus is a virus different from the West Nile Fever virus and is selected from the ssRNA viruses belonging to the Orders Nidovirales, Picornavirales, or Tymovirales; ssRNA viruses belonging to the unassigned families selected from the group consisting of Flaviviridae, Astroviridae, and Caliciviridae; wherein the Flaviviridae is selected from the group consisting of Hepacivirus, Pegivirus, Pestivirus, and Flavivirus, and wherein the Flavivirus is Zika virus. 
       
     
     
         47 . The method of  claim 46 , wherein R 1  is an alkyl group having 1 to 8 carbon atoms optionally substituted by a halogen atom or hydroxyl group, a cycloalkyl group having 3 to 6 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, a phenyl, a benzyl, a morpholinyl, or an imidazolyl. 
     
     
         48 . The method of  claim 46 , wherein R 1  is a methyl group. 
     
     
         49 . The method of  claim 46 , wherein the positive-sense, single-stranded ssRNA virus is a virus belonging to the Order Nidovirales. 
     
     
         50 . The method of  claim 46  wherein the positive-sense, single-stranded ssRNA virus is a virus belonging to the Coronaviridae family. 
     
     
         51 . The method of  claim 46  wherein the positive-sense, single-stranded ssRNA virus is a coronavirus selected from the group consisting of an alpha coronavirus, a beta coronavirus, a gamma coronavirus, and a delta coronavirus 
     
     
         52 . The method of  claim 46 , wherein the positive-sense, single-stranded ssRNA virus is a beta coronavirus. 
     
     
         53 . The method of  claim 46 , wherein the positive-sense, single-stranded ssRNA virus is a SARS-CoV or a MERS-CoV. 
     
     
         54 . The method of  claim 46 , wherein the compound is administered with one or more pharmaceutically acceptable carriers selected from fillers, expanders, binders, moisturizers, disintegrants, surfactants, and lubricants; one or more diluents; one or more excipients; one or more additional ingredients selected from buffers, isotonizing agents, chelating agents, coloring agents, preservatives, perfumes, flavors, sweeteners, or other drugs; or combinations thereof. 
     
     
         55 . The method of  claim 46 , wherein the compound of formula (I) is administered in a solid dosage form selected from a tablet, pill, pulve, powder, granule, and capsule; in a liquid dosage form selected from a solution, suspension, emulsion, syrup, or elixir; or as an ointment. 
     
     
         56 . A process for the manufacture of an antiviral compound of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein
 R 1  is an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, a cycloalkyl group having 3 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, an aryl group, an alkylaryl group, or a cycloheteroalkyl group having 3 to 12 carbon atoms, 
 
         comprising the steps of:
 (a) diazotizing a compound of formula (II): 
 
       
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen, thereby forming a diazonium compound of formula (III) or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         
           (b) condensing the compound of formula (III) or a pharmaceutically acceptable salt thereof with at least one α-nitroester of formula (IV): 
         
       
       
         
           
           
               
               
           
         
         wherein
 R 3  is:
 —(CO)—OR 5 , wherein R 5  is an alkyl group having 1 to 24 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group; 
 —(CO)—R 6 , wherein R 6  is an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group, or 
 —O—(CO)—Y, wherein Y is an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group; and 
 
 R 4  is an alkyl group having 1 to 24 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group; or an alkenyl group; 
 
         thereby forming a compound of formula (I). 
       
     
     
         57 . The process of  claim 56 , wherein R 1  is a methyl group. 
     
     
         58 . The process of  claim 56 , wherein R 3  is —(CO)—OR 5 , wherein R 5  is an alkyl group having 1 to 24 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group. 
     
     
         59 . The process of  claim 56 , wherein R 3  is —(CO)—OR 5 ′, wherein R 5  is an alkyl group having 1 to 6 carbon atoms. 
     
     
         60 . The process of  claim 56 , wherein the product of step (b) is 7-mercapto-3-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-4(1H)-one or a pharmaceutically acceptable salt thereof, and the process further comprises the step of contacting the product of step (b) with an alkylating agent of formula (V): R 1 —X or formula (VI) R 1 —Z in a suitable solvent, wherein X is a halogen atom or an oxygen containing functional group selected from OTs and OTMS, and Z is a sulfate group (O—S(═O) 2 —O) or a carbonate group (O—C(═O)—O). 
     
     
         61 . A process for the manufacture of an antiviral compound (A) of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein
 R 1  is selected from an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, a cycloalkyl group having 3 to 12 carbon atoms which is optionally substituted by a halogen atom or hydroxyl group, an aryl group, an alkylaryl group, or a cycloheteroalkyl group having 3 to 12 carbon atoms, 
 
         comprising the steps of:
 (a) diazotizing a compound of formula (II): 
 
       
       
         
           
           
               
               
           
         
         wherein R 2  is equal to R 1 , as defined here above, thereby forming a diazonium compound of formula (III) or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
         
           (b) condensing the diazonium compound of formula (III) or a pharmaceutically acceptable salt thereof, as obtained in step (a), with at least one α-nitroester of formula (IV): 
         
       
       
         
           
           
               
               
           
         
         wherein R 3  is:
 —(CO)—R 6 , wherein R 6  is an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group, or 
 —O—(CO)—Y, wherein Y is an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group or an aralkyl group; and 
 
         R 4  is an alkyl group having 1 to 24 carbon atoms which is optionally substituted by a hydroxyl group, an amino group, a halogen atom, an aryl group, or an aralkyl group; or an alkenyl group. 
       
     
     
         62 . The process of  claim 61 , wherein R 3  is —(CO)—R 6 , wherein R 6  is an alkyl group having 1 to 6 carbon atoms. 
     
     
         63 . The process of  claim 56 , wherein the molar ratio of the diazonium compound of formula (III) to the α-nitroester of formula (IV) in step (b) is from 0.5:2 to 2:0.5. 
     
     
         64 . The process of  claim 56 , wherein the step (b) is carried out in the presence of at least one pharmaceutically acceptable non-toxic inorganic or organic base. 
     
     
         65 . The process of  claim 56 , wherein step (b) is carried out in a solvent selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol, iso-butyl alcohol, dimethylether, diethylether, dipropylether, diisopropylether, di-tert-butylether, diisobutylether, dibutylether, di-sec-butylether, dioxane, tetrahydrofuran, dimethoxymethane, dimethoxyethane, dimethoxypropane, dimethylketone, diethylketone, dipropylketone, methylethylketone, dimethylsulfoxide, dimethylsulfone, diphenylsulfone, diethylsulfoxide, diethylsulfone, diisopropylsulfone, tetrahydrothiophene-1, sulfolane, tetrahydrothiophene-1-monoxide, dimethylacetamide, dimethylformamide, N-methyl pyrrolidinone, and mixtures thereof. 
     
     
         66 . A process for the manufacture of the compound (B) of formula (II R1 ) 
       
         
           
           
               
               
           
         
         comprising condensing aminoguanidine with a thio compound of formula (VII): 
       
       
         
           
           
               
               
           
         
         wherein R 1  is selected from an alkyl group having 1 to 12 carbon atoms which is optionally substituted by a halogen atom or a hydroxyl group, a cycloalkyl group having 3 to 12 carbon atoms which is optionally substituted by a halogen atom or a hydroxyl group, an aryl group, an alkylaryl group, or a cycloheteroalkyl group having 3 to 12 carbon atoms.