Benzimidazole compounds and antiviral uses thereof

Abstract

The present invention relates to novel benzimidazole compounds that have useful antiviral activity. More specifically, the invention encompasses benzimidazole compounds that inhibit membrane fusion associated events such as viral transmission, reduce viral load or otherwise treat viral infections. The invention also encompasses the use of benzimidazole compounds as inhibitors of membrane fusion associated events, such as viral transmission. In another embodiment, the invention encompasses processes for making benzimidazole compounds, methods of using the benzimidazole compounds and compositions comprising the benzimidazole compounds. Finally, the invention provides methods for treating, preventing or ameliorating symptoms associated with respiratory infection, particularly that caused by Respiratory Syncytial Virus utilizing the novel benzimidazole compounds of the invention.

1 . A compound of the Formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable prodrug, salt, solvate, hydrate, clathrate, enantiomer, diastereomer, racemate or mixture of stereoisomer thereof, wherein: 
 R 1  and R 2  are each independently: hydrogen, saturated or unsaturated straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloaryl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted arylalkyl; wherein, if present, the substituent is at least one alkanoyl, imide, alkyl, hydroxy, halide, methoxy, ethoxy, carboxylic acid, cyano, amine, amide, alkylamine, acetal, acetylene, aminal, amino acid, amino acid ester, azo, diazo, azide, carbamate, carboxylic acid ester, carboalkoxy ester, cyanohydrin, diazonium salt, glucoside, glucuronide, halocarbon, polyhalocarbon, halocarbonoxy, polyhalocarbonoxy, hydroxylamine, ketone, lactone, nitrile, nitrile oxide, N-oxides, nucleoside linked, oxime, phosphate, phosphinate, phosphonate, phosphonic acid, quaternary ammonium salt, sulfoxide, sulfone, sulfonate ester, sulfinate ester, sulfonic acid, thioacetal, thiocarboxylic acid, thiol, or thioaryl;  
 R 3  is hydrogen, halide, saturated or unsaturated straight or branched substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; wherein, if present the substiuent is at least one alkanoyl, imide, alkyl, hydroxy, halide, methoxy, ethoxy, carboxylic acid, amine, amide, alkylamine, acetal, acetylene, aminal, amino acid, amino acid ester, azo, diazo, azide, carbamate, carboxylic acid ester, carboalkoxy ester, cyanohydrin, diazonium salt, glucoside, glucuronide, halocarbon, polyhalocarbon, halocarbonoxy, polyhalocarbonoxy, hydroxylamine, ketone, lactone, nitrile, nitrile oxide, N-oxides, nucleoside linked, oxime, phosphate, phosphinate, phosphonate, phosphonic acid, quaternary ammonium salt, sulfoxide, sulfone, sulfonate ester, sulfinate ester, sulfonic acid, thioacetal, thiocarboxylic acid, thiol, or thioaryl;  
 R 4 , R 4′  , R 8 , and R 8′  are each independently hydrogen, halide, saturated or unsaturated straight or branched substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl; wherein, if present the substituent is at least one alkanoyl, imide, amine, alkylamine, amide, carboxylic acid, ester, nitro, sulfide, sulfonyl, sulfonamide, acetal, acetylene, aminal, amino acid, amino acid ester, azo, diazo, azide, carbamate, carboxylic acid ester, carboalkoxy ester, cyanohydrin, diazonium salt, glucoside, glucuronide, halocarbon, polyhalocarbon, halocarbonoxy, polyhalocarbonoxy, hydroxylamine, ketone, lactone, nitrile, nitrile oxide, N-oxides, nucleoside linked, oxime, phosphate, phosphinate, phosphonate, phosphonic acid, quaternary ammonium salt, sulfoxide, sulfone, sulfonate ester, sulfinate ester, sulfonic acid, thioacetal, thiocarboxylic acid, thiol, or thioaryl;  
 X is a bond, straight chain or branched substituted or unsubstituted alkyl, -(alkyl)N—, -(alkyl)O—, —C═N—, carbonyl, phosphorus, or sulfur;  
 Y is nitrogen;  
 n=1 is an integer from 0 to about 1;  
 with the proviso that compounds of Formula I do not include a compound where R 1 , R 2 , R 3 , R 4 , R 4′ , R 8 , R 8′  are hydrogen, X is a bond, and n=0; or a compound where R 3 , R 4 , R 4′ , R 8 , and R 8′  are hydrogen, X is a bond, n=0, one of R 1  or R 2  is a hydrogen, and the other is a 4-piperidinyl or N-substituted 4-piperidinyl.  
 
   
   
       2 - 25 . (canceled)  
   
   
       26 . The compound according to  claim 1  having Formula III:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable prodrug, salt, solvate, hydrate, enantiomer, diastereomer, racemate or mixture of stereoisomer thereof, wherein: 
 R 1  and R 2  are each independently: hydrogen, saturated or unsaturated straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloaryl, substituted or unsubstituted heteroaryl, alkanoyl, or imide, wherein, if present, the substituent is at least one alkyl, alkanoyl, imide, alkoxy, carboxylic acid, amine, amide, alkylamine, cyano, halide, hydroxy, nitro, thiol, acetal, acetylene, aminal, amino acid, amino acid ester, azo, diazo, azide, carbamate, carboxylic acid ester, carboalkoxy ester, cyanohydrin, diazonium salt, glucoside, glucuronide, halocarbon, polyhalocarbon, halocarbonoxy, polyhalocarbonoxy, hydroxylamine, lactone, nitrile, nitrile oxide, N-oxides, nucleoside linked, oxime, quaternary ammonium salt, sulfoxide, sulfone, sulfonate ester, sulfinate ester, sulfonic acid, thioacetal, thiocarboxylic acid, thiol, or thioaryl;  
 R 4 , R 4′ , R 5 , R 5′ , R 8 , R 8′ , R 9 , and R 9′  are each independently hydrogen, halide, saturated or unsaturated straight or branched substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloaryl or substituted or unsubstituted heteroaryl; wherein, if present, the substituent is at least one alkanoyl, imide, alkyl, hydroxy, halide, methoxy, ethoxy, carboxylic acid, cyano, amine, alkylamine, amide, carboxylic acid, ester, nitro, sulfide, sulfonyl, sulfonamide, acetal, acetylene, aminal, amino acid, amino acid ester, azo, diazo, azide, carbamate, carboxylic acid ester, carboalkoxy ester, cyanohydrin, diazonium salt, glucoside, glucuronide, halocarbon, polyhalocarbon, halocarbonoxy, polyhalocarbonoxy, hydroxylamine, ketone, lactone, nitrile, nitrile oxide, N-oxides, nucleoside linked, oxime, phosphate, phosphinate, phosphonate, phosphonic acid, quaternary ammonium salt, sulfoxide, sulfone, sulfonate ester, sulfinate ester, sulfonic acid, thioacetal, thiocarboxylic acid, thiol, or thioaryl; and  
 R 6  is hydrogen, saturated or unsaturated straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloaryl or substituted or unsubstituted heteroaryl; wherein, if present, the substituent is at least one alkanoyl, imide, alkyl, hydroxy, halide, methoxy, ethoxy, carboxylic acid, cyano, nitro, thiol, alkanoyl, imide, acetal, acetylene, aminal, amino acid, azo, diazo, carbamate, carboalkoxy ester, cyanohydrin, glucoside, glucuronide, halocarbon, polyhalocarbon, halocarbonoxy, polyhalocarbonoxy, ketone, nitrile, nitrile oxide, N-oxides, nucleoside linked, oxime, sulfone, or sulfonic acid.  
 
   
   
       27 . The compound according to  claim 26 , wherein: 
 R 1 , and R 2  are each independently saturated or unsaturated straight or branched substituted or unsubstituted C 1 -C 11  alkyl, C 1 -C 12  alkoxy, substituted or unsubstituted C 1 -C 11  alkylamino, substituted or unsubstituted 3 to 10 membered cycloalkyl, substituted or unsubstituted 3 to 10 membered heterocycloalkyl, substituted or unsubstituted 5 to 12 membered aryl, substituted or unsubstituted 5 to 12 membered arylalkyl, substituted or unsubstituted 4 to 13 membered heteroaryl, alkanoyl, or imide, wherein, if present, the substituent is at least one C 1 -C 4  alkyl, cyano, fluoride, chloride, bromide, hydroxy, nitro, or thiol.    
   
   
       28 . The compound according to  claim 26 , wherein: 
 R 4 , R 4′ , R 5 , R 5 ′, R 8 , R 8 ′, R 9 , and R 9′  are each independently hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, amine, C 1 -C 4  alkylamine, C 1 -C 4  amide, carboxylic acid, ester, halide, hydroxy, nitro, C 1 -C 4  sulfide, C 1 -C 4  sulfonyl, or sulfonamide.    
   
   
       29 . The compound according to  claim 26 , wherein: 
 R 6  is a saturated or unsaturated straight or branched substituted or unsubstituted C 1 -C 8  alkyl, C 1 -C 4  alkoxy, substituted or unsubstituted C 2 -C 6  alkylamino, substituted or unsubstituted 3 to 6 membered cycloalkyl, substituted or unsubstituted 4 to 5 membered heterocycloalkyl having at least one oxygen, nitrogen, or sulfur atom within the ring, substituted or unsubstituted 5 to 16 membered aryl, substituted or unsubstituted 5 to 10 membered arylalkyl, substituted or unsubstituted 4 to 6 membered heteroaryl having at least one oxygen, nitrogen, or sulfur atom in the ring, C 1 -C 4  alkanoyl, or imide, wherein, if present, the substituent is at least one C 1 -C 4  alkyl, cyano, fluoride, chloride, bromide, hydroxy, nitro, or thiol.    
   
   
       30 . The compound according to  claim 26 , wherein: 
 R 1  and R 2  are each independently hydrogen, methyl, ethyl, propyl, isopropyl, sec-butyl, 3-methylbutyl, 2-methyl-2-propenyl, 2-propynyl, pentyl, hexyl, 2-butylyl, 2-hydroxy-2-(4-hydroxyphenyl)ethyl, 2-(2-pyridinyl)ethyl, 2-hydroxy-2-(3,4-dihydroxyphenyl)ethyl, 3-pyridinylmethyl, 2,5-difluorobenzyl, 4-trifluoromethoxyphenylmethyl, 3-methoxypropyl, 2-hydroxyethyl, 4-phenylbutyl, 2-phosphonatethyl, 3-(2-methyl)ethoxypropyl, 2-(2-thiophenyl)ethyl, N-benzyl-4-piperidinyl, 3-(1-pyrrolidinyl)propyl, 2-(N,N-diethyl)ethyl, tetrahydrofuranylmethyl, cyclopentyl, or cyclohexyl.    
   
   
       31 . The compound according to  claim 26 , wherein R 6  is hydrogen.  
   
   
       32 . The compound according to  claim 26 , wherein the compound of Formula III is an enantiomer or diastereomer.  
   
   
       33 . The compound according to  claim 26 , wherein R 4 , R 5 ′, R 8 ′, and R 9′  are hydrogen.  
   
   
       34 . The compound according to  claim 26 , wherein at least one of R 4 , R 4′ , R 8 , and R 8′  is not hydrogen.  
   
   
       35 . The compound according to  claim 26 , wherein at least two of R 4 , R 4′ , R 8 , and R 8′  are not hydrogen.  
   
   
       36 . The compound according to  claim 26 , wherein at least one of R 5 , R 5 ′, R 9 , and R 9′  is not hydrogen.  
   
   
       37 . The compound according to  claim 26  having Formula XII:  
     
       
         
         
             
             
         
       
     
   
   
       38 - 63 . (canceled)  
   
   
       64 . A pharmaceutical composition comprising the compound according to  claim 26  and a pharmaceutically acceptable carrier.  
   
   
       65 - 66 . (canceled)  
   
   
       67 . A method of treating, preventing, or ameliorating one or more symptoms associated with a respiratory syncytial virus (RSV) infection in a mammal comprising administering to the mammal a therapeutically or prophylactically effective amount of the compound of  claim 26  and a pharmaceutically acceptable carrier.  
   
   
       68 . The method of treating, preventing, or ameliorating a viral infection according to  claim 67 , wherein the compound is administered orally, parenterally, transdermally, or mucosally.  
   
   
       69 . The method of treating, preventing, or ameliorating a viral infection according to  claim 67 , wherein the compound is administered in an amount from about 10 mg/kg/day to about 15 mg/kg/day.  
   
   
       70 . The method of treating, preventing, or ameliorating a viral infection according to  claim 67 , wherein the mammal is a human subject.  
   
   
       71 . The method of treating, preventing, or ameliorating a viral infection according to  claim 67 , wherein the human subject is a human infant.  
   
   
       72 . A method of inhibiting membrane fusion associated events characteristic of a viral infection in a mammal comprising administering the compound of  claim 26  and a pharmaceutically acceptable carrier.  
   
   
       73 . A method of treating, preventing, or ameliorating one or more symptoms associated with a HPIV infection in a mammal comprising administering to the mammal a therapeutically or prophylactically effective amount of the compound of  claim 26  and a pharmaceutically acceptable carrier.  
   
   
       74 . The compound of  claim 26  which is a pharmaceutically acceptable salt, solvate, hydrate, enantiomer, diastereomer, racemate or mixture of stereisomers.