Patent EA-002305-B1 (EA)
Title: Benzimidazole derivatives
Inventor: DRACH JOHN CHARLES
IPC: C07D235/06
Filed: 1998-06-08
Abstract: 1. A compound of formula (I)   wherein: R<1> is halogen, hydroxy, azido, C1-8alkyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl, or -NR<19>R<20> (where R<19> and R<20> may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-6alkyl, heterocyleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, or R<19>R<20> together with the N atom to which they are attached from a 3, 4, 5 or 6 membered heterocyclic ring), OR<21> (where R<21> is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl), or -SR<22> (where R<22> is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl); R<2> is hydrogen or halogen; R<3> and R<4> may be the same or different and are hydrogen, halogen, C1-8alkyl, C6-14aryl, heterocycleC6-14aryl, C1-8alkoxy, haloC1-8alkyl or -SR<24> (where R<24> is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); Z is a substituent of formula (Ia), (Ib)   wherein: R<5> is hydrogen, C1-8alkyl, haloC1-8alkyl or C1-8alkoxy; R<6> is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl or C1-8alkoxy; R<7> is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or R<6> and R<7> together form a ketone or alkene; R<8>-R<11> may be the same or different and are hydrogen, hydroxy, halogen, C2-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or any of R<8> and R<9> or R<10> and R<11> together form a ketone or alkene; R<12>-R<14> may be the same or different and are hydrogen, hydroxy, C1-8 alkyl or hydroxyC1-8alkyl; or a pharmaceutically acceptable salt, ester or ester salt thereof, provided that a compound of formula (I) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-β-D-arabinopyranosyl)-benzimidazole-2-thione; further provided that when Z is a substituent of formula (Ia): a) R<2>, R<3>, and R<4> cannot all be hydrogen; and b) R<1> cannot be -NR<19>R<20> where R<19> and R<20> together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S; further provided that when Z is a substituent of formula (Ib): a) R<1> cannot be -NR<19>R<20> where R<19> and R<20> together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S; 2. A compound of formula (II)   wherein: R is halogen, hydroxy, azido, C1-8alkyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl, or -NR<19>R<20> (where R<19> and R<20> may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl, C6-14aryl, C6-14arylC1-6alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, or R<19>R<20> together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring), OR<21> (where R<21> is hydrogen, C1-8alkyl, C3-7cycloalkyl, or C6-14aryl), or -SR<22> (where R<22> is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl); R<2> is hydrogen or halogen; R<3> and R<4> may be the same or different and are hydrogen, halogen, C1-8alkyl, C6-14aryl, heterocycleC6-14aryl, C1-8alkoxy, haloC1-8alkyl or -SR<24> (where R<24> is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); R<5> is hydrogen, C1-8akyl, haloC1-8alkyl, C1-8alkoxy; R<6> is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy; R<7> is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or R<6> and R<7> together form a ketone or alkene; R<8> - R<11> may be the same or different and are hydrogen, hydroxy, halogen, C2-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or any of R<8> and R<9> or R<10> and R<11> together form a ketone or alkene; or a pharmaceutically acceptable salt, ester or ester salt thereof, provided that a compound of formula (II) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-β-D-arabinopyranosyl)-benzimidazole-2-thione; further provided that: a) R<2>, R<3>, and R<4> cannot all be hydrogen; and b) R<1> cannot be -NR<19>R<20> where R<19> and R<20> together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S. 3. A compound of formula (III)   wherein: R<1> is halogen, hydroxy, azido, C1-8alkyl, C1-8alkoxy, C2-6alkenyl, C2-6alkynyl, C6-14arylC2-6alkenyl, C6-14arylC2-6alkynyl, or -NR<19>R<20> (where R<19> and R<20> may be the same or different and are hydrogen, C1-8alkyl, cyanoC1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C3-7cycloalkyl, C1-8alkylC3-7cycloalkyl, C2-6alkenyl, C3-7cycloalkylC1-8alkyl, C2-6alkynyl C6-14aryl, C6-14arylC1-6alkyl, heterocycleC1-8alkyl, C1-8alkylcarbonyl, C6-14arylsulfonyl, or R<19>R<20> together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring), OR<21> (where R<21> is hydrogen, C1-8alkyl, C3-7cycloalkyl, or C6-14aryl), or SR<22> (where R<22> is hydrogen, C1-8alkyl, hydroxyC1-8alkyl, C3-7cycloalkyl, or C6-14aryl); R<2> is hydrogen or halogen; R<3> and R<4> may be the same or different and are hydrogen, halogen, C1-8alkyl, C6-14aryl, heterocycleC6-14aryl, C1-8alkoxy, haloC1-8alkyl or -SR<24> (where R<24> is hydrogen, C1-8alkyl, C6-14aryl, or C6-14arylC1-8alkyl); R<5> is hydrogen, C1-8alkyl, haloC1-8alkyl, C1-8alkoxy; R<6> is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy; R<7> is hydrogen, hydroxy, halogen, C1-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or R<6> and R<7> together form a ketone or alkene; R<8>-R<11> may be the same or different and are hydrogen, hydroxy, halogen, C2-8alkyl, hydroxyC1-8alkyl, haloC1-8alkyl, C1-8alkoxy, or any of R<8> and R<9> or R<10> and R<11> together form a ketone or alkene; or a pharmaceutically acceptable salt, ester or ester salt thereof, provided that a compound of formula (III) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-β-D-arabinopyranosyl)-benzimidazole-2-thione; further provided that: a) R<2>, R<3> and R<4> cannot all be hydrogen; and b) R<1> cannot be -NR<19>R<20> where R<19> and R<20> together with the N atom to which they are attached form a 5 membered heterocyclic ring containing S. 4. A compound of Formula (I)   wherein Z is a substituent of Formula (Ia) or (Ib)   and wherein R<1> is halogen; R<2> is hydrogen; R<3> and R<4> are halogen; R<5> and R<7> are hydrogen; R<6> is hydroxy or hydrogen; R<8> and R<10> are hydroxy; R<9> and R<11> are hydrogen; R<12> is hydrogen, C1-8 alkyl, or hyroxyC1-8 alkyl; R<13> is hydroxy; R<14> is hydrogen or hydroxy; or a pharmaceutically acceptable salt, ester or ester salt thereof. 5. A compound of Formula (II)   wherein R<1> is halogen; R<2> is hydrogen; R<3> and R<4> are halogen; R<5> and R<7> are hydrogen; R<6> is hydroxy or hydrogen; R<8> and R<10> are hydroxy; R<9> and R<11> are hydrogen; or a pharmaceutically acceptable salt, ester or ester salt thereof. 6. A compound of Formula (III)   wherein R<1> is halogen; R<2> is hydrogen; R<3> and R<4> are halogen; R<5> and R<7> are hydrogen; R<6> is hydroxy or hydrogen; R<8> and R<10> are hydroxy; R<9> and R<11> are hydrogen; or a pharmaceutically acceptable salt, ester or ester salt thereof. 7. A compound selected from the group consisting of (3S,4R,5R,6S)-2-Bromo-5,6-dichloro-1-(tetrahydro-4,5-dihydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole; (+-)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexanol; (+-)-(1R*, 2S*, 3R*)-3-(2-bromo-5,6-dichloro-1H-benzimidazol-l-yl)-1,2-cyclohexanediol; 2-Bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole; 5,6-Dichloro-N-(1-methylethyl)-1-β-D-ribopyranosyl-1H-benzimidazol-2-amine; 2-Bromo-5,6-dichloro-4-fluoro-l-β-D-ribopyranosyl-lH-benzimidazole; 2-Bromo-5,6,-dichloro-l-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazole; 2-Bromo-5,6-dichloro-1-β-L-ribopyranosyl-1H-benzimidazole; 2-Bromo-6-chloro-5-methyl-l-β-D-ribopyranosyl-1H-benzimidazole; 2-Bromo-5,6-dichloro-1-(4-deoxy-β-D-erythro-pentopyranosyl)-1Hbenzimidazole; or a pharmaceutically acceptable salt, ester or ester salt thereof. 8. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 7, together with carrier thereof acceptable for pharmaceutical use. 9. Use of a compound according to any one of Claims 1 to 7 for the manufacture of a medicament for the treatment or prophylaxis of a viral infection. 10. A method of treatment of a virus infection in an animal which comprises treating said animal with a therapeutically effective amount of a compound as defined according to any one of Claims 1 to 7. 11. A method according to Claim 10 wherein the virus infection is a herpes virus infection. 12. A method according to Claim 10 wherein the virus infection is a cytomegalovirus infection. 13. A method according to Claim 10 wherein the virus infection is a Hepatitis B virus infection. 14. A compound formula (XI):   or a pharmaceutically acceptable salt, ester or ester salt thereof. 15. 2-Bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole or a pharmaceutically acceptable salt, ester or ester salt thereof. 16. A pharmaceutical formulation comprising 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole together with a pharmaceutically acceptable carrier therefor. 17. Use of a compound according to Claims 14 or 15 for the manufacture of a medicament for the treatment or prophylaxis of a viral infection. 18. A method of treatment or prevention of the symptoms or effects of a virus infection in an infected animal which comprises treating said animal with a therapeutically