Therapeutic compounds

Abstract

The present invention relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.

1 . A compound of formula (I)  
                   
       wherein R represents hydrogen, a halo atom, —NR 1 R 2  where R 1  and R 2 , which may be the same or different, are each independently selected from hydrogen, C 1-6  alkyl, cyanoC 1-6  alkyl, hydroxyC 1-6 alkyl, haloC 1-6  alkyl, C 3-7 cycloalkyl, C 1-6 alkylC 3-7 cycloalkyl, C 2-6  alkenyl, C 3-7 cycloalkylC 1-6 alkyl, C 2-6 alkynyl, aryl, arylC 1-6 alkyl, heterocyclicC 1-6  alkyl, —COC 1-6 alkyl or R 1 R 2  together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring and pharmaceutically acceptable derivatives thereof.  
     
     
         2 . A compound according to    claim 1   , in the form of a β-anomer.  
     
     
         3 . A compound according to    claim 1   , in the form of an α-anomer.  
     
     
         4 . A compound according to    claim 1    of formula (Ib)  
                 
 
       wherein R represents a halo atom or —NR 1 R 2  wherein R 1  represents hydrogen and R 2  is selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-7 cycloallkyl, C 1-6 alkylC 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, arylalkyl, R 1  and R 2 , which may be the same or different, are both C 1-6  alkyl, or R 1 R 2  together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring and pharmaceutically acceptable derivatives thereof.  
     
     
         5 . A compound according to any of    claims 1    to    4    wherein R represents —NR 1 R 2  wherein R 1  represents hydrogen and R 2  is selected from C 1-6 alkyl, C 3-7 cycloalkyl and haloC 1-6 alkyl and pharmaceutically acceptable derivatives thereof.  
     
     
         6 . A compound according to any of    claims 1    to    5    wherein R represents isopropylamino, isobutylamino, sec-butylamino, cyclopropylamino, cyclopentylamino or 2-fluoro-1-methylethylamino and pharmaceutically acceptable derivatives thereof.  
     
     
         7 . A compound according to    claim 1    selected from 5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole, 2-yclopropylamino-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole and 5,6-dichloro-2-((2-fluoro-1-methyl-ethylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole and pharmaceutically acceptable derivatives thereof.  
     
     
         8 . 5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole  
     
     
         9 . A pharmaceutically acceptable derivative of a compound according to any of    claims 1    to    8   .  
     
     
         10 . A derivative according to    claim 9    in the form of a salt.  
     
     
         11 . A derivative according to    claim 9    in the form of an ester.  
     
     
         12 . A derivative according to    claim 10    wherein the salt is selected from salts of organic carboxylic acids, organic sulphonic acids and inorganic acids.  
     
     
         13 . A derivative according to    claim 11    wherein the ester is selected from carboxylic acid, sulphonate, amino acid, phosphate and mono-, di- or tri-phosphate esters  
     
     
         14 . A pharmaceutical formulation comprising a compound of formula (I) as defined in any of    claims 1    to    13    or a pharmaceutically acceptable derivative thereof, together with pharmaceutically acceptable carrier therefore.  
     
     
         15 . A compound according to any of    claims 1    to    13    or a formulation according to    claim 14    for use in therapy.  
     
     
         16 . Use of a compound according to any of    claims 1    to    13    for the manufacture of a medicament for the treatment or prophylaxis of a viral infection.  
     
     
         17 . Use according to    claim 16    wherein the viral infection is a herpes virus infection.  
     
     
         18 . Use according to    claim 17    wherein the herpes virus infection is an infection selected from herpes simplex virus 1, herpes simplex virus 2, varicella zoster virus, cytomegalovirus, Epstein Barr virus, human herpes virus 6 and human herpes virus 7.  
     
     
         19 . Use of a compound according to any of    claims 1    to    13   , for the manufacture of a medicament for simultaneous or sequential administration with at least one other therapeutic agent for the treatment or prophylaxis of a viral infection.  
     
     
         20 . A method of treatment or prevention of the symptoms or effects of a virus infection is an infected animal which comprises treating said animal with a therapeutically effective amount of a compound as defined according to any of    claims 1    to    13   .  
     
     
         21 . A method according to    claim 20    wherein the virus infection is a herpes virus infection.  
     
     
         22 . A method according to    claim 21    wherein the herpes virus infection is selected from herpes simplex virus 1, herpes simplex virus 2, varicella zoster virus, cytomegalovirus, Epstein Barr virus, human herpes virus 6 and human herpes virus 7.  
     
     
         23 . A process for the preparation of a compound of formula (I) as defined in any of    claims 1    to    13    which process comprises: 
 (A) reacting a compound of formula (II)  
                 
 
 wherein L is hydrogen and R 3 , R 4  and R 5  are each a hydroxy or a protected hydroxy group, with a suitable halogenating agent or when L is a suitable leaving atom or group and R 3 , R 4  and R 5  are as hereinbefore defined, with an amine of formula H—NR 1 R 2  (wherein R 1  and R 2  are as defined in    claim 1   ); or  
 (B) reacting a compound of formula (III)  
                 
 
 wherein R is as defined in    claim 1   , with a compound of formula (IV)  
                 
 
 wherein R 3 , R 4  and R 5  are each a hydroxy or a protected hydroxy group and L 1  is a suitable leaving group in the α- or β-position;  
 and thereafter or simultaneously therewith effecting one or more of the following further steps may be additionally performed in any desired or necessary order: 
 (i) removing any remaining protecting group(s);  
 (ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or a protected form thereof;  
 (iii) converting the compound of formula (I) or a protected form thereof into a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;  
 (iv) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into the compound of formula (I) or a protected form thereof;  
 (v) converting a pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof into another pharmaceutically acceptable derivative of the compound of formula (I) or a protected form thereof;  
 (vi) where necessary, separating the alpha and beta anomers of the compound of formula (I) or of a protected derivative thereof or of a pharmaceutically acceptable derivative of a compound of formula (I)  
 
 
     
     
         24 . A compound of formula (II)  
                   
       wherein L is hydrogen or a suitable leaving atom or group and R 3 , R 4  and R 5  are each a hydroxy or a protected hydroxy group.  
     
     
         25 . A compound according to    claim 24    wherein L is hydrogen or a halo atom and R 3 , R 4  and R 5  are each a hydroxy or a protected hydroxy group, preferably OC(O)CH 3 .  
     
     
         26 . 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole.  
     
     
         27 . 2-bromo-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole  
     
     
         28 . A compound according to formula (V)  
                   
       wherein X is —NR 1 R 2  wherein R 1  and R 2  are as defined in    claim 1    with the proviso that R 1  and R 2  are not both hydrogen or methyl.  
     
     
         29 . A compound according to    claim 28    selected from 
 2-(cyclopropylamino)-5,6-dichloro-1H-benzimidazole;  
 5,6-dichloro-2-(isopropylamino)-1H-benzimidazole; and  
 5,6-dichloro-2-(2-fluoro-1-methyl-ethylamino)-1H-benzimidazole.