WO1994008456A1 - Benzimidazoles polysubstitues utilises comme agents antiviraux - Google Patents

Benzimidazoles polysubstitues utilises comme agents antiviraux Download PDF

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Publication number
WO1994008456A1
WO1994008456A1 PCT/US1993/010104 US9310104W WO9408456A1 WO 1994008456 A1 WO1994008456 A1 WO 1994008456A1 US 9310104 W US9310104 W US 9310104W WO 9408456 A1 WO9408456 A1 WO 9408456A1
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compound
ribofuranosyl
text
solution
meoh
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PCT/US1993/010104
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English (en)
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Leroy B. Townsend
John C. Drach
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The Regents Of The University Of Michigan
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Priority claimed from US07/964,345 external-priority patent/US5360795A/en
Application filed by The Regents Of The University Of Michigan filed Critical The Regents Of The University Of Michigan
Priority to AU54470/94A priority Critical patent/AU5447094A/en
Publication of WO1994008456A1 publication Critical patent/WO1994008456A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals

Definitions

  • the present invention relates generally to polysubstituted benzimidazoles and, more particularly, to novel polysubstituted benzimidazoles and compositions, their preparation and their use as antiviral agents, particularly against human cytomegalovirus and herpes simplex virus.
  • Benzimidazole nucleosides are particularly attractive as potential antiviral agents because of their stability toward some major pathways of bioactive purine (bicyclic) nucleoside inactivation, e.g., deamination by adenosine deaminase and glycosidic bond cleavage by purine nucleoside phosphorylases.
  • Benzimidazole nucleosides such as DRB have, however, demonstrated only marginal levels of activity or generally unacceptable levels of cytotoxicity, or both, thereby greatly diminishing their usefulness in the treatment of viral infections. It would thus be desirable to provide polysubstituted benzimidazoles and compositions thereof having good antiviral properties, preferably with a low degree of cytotoxicity.
  • the present invention relates to novel antiviral compositions comprising a polysubstituted benzimidazole and a pharmaceutically acceptable carrier and methods of treatment therewith, wherein the polysubstituted benzimidazole is selected from the group consisting of compounds having the following formula and pharmaceutically acceptable salts and formulations thereof:
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 45 in the text);
  • R, is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is ⁇ -D-ribofuranosyl (denoted compound 52 in the text);
  • R 1 is H
  • R 2 is NO 2
  • R 3 is NO 2
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 61 in the text);
  • R- is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 81 in the text);
  • R is H, R 2 is Cl, R 3 is Cl ⁇ R 4 is H, R 5 is I and R 6 is ⁇ -D-ribofuranosyl (denoted compound 83a in the text);
  • R 1 is Br, R 2 is Br, R 3 is H, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 85 in the text);
  • R 1 is H, R 2 is Br, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 95 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Br, R 4 is H, R 5 is Ci and R 6 is ⁇ -D-ribofuranosyl (denoted compound 99 in the text);
  • R 1 is H, R 2 is I, R 3 is l, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 107 in the text) ;
  • R, is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 2'-deoxy-ribofuranosyl (denoted compound 111 in the text);
  • R- is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 2'-deoxy-ribofuranosyl (denoted compound 112 in the text); R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is H (denoted compound 7 in the text);
  • R is H, R 2 is Cl, R 3 is F, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 12c in the text);
  • R is Cl
  • R 2 is Cl
  • R 3 is Cl
  • R 4 is H
  • R 5 is Cl
  • R 6 is H (denoted compound 13 in the text);
  • R is H
  • R 2 is NO 2
  • R 3 is H
  • R 4 is H
  • R 5 is Cl
  • R 6 is H (denoted compound 19 in the text);
  • R is H, R 2 is I, R 3 is NO 2 , R 4 is H, R 5 is Cl and R 6 is H (denoted compound 26 in the text); R t is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 32 in the text);
  • R is H, R 2 is I, R 3 is I, R 4 is H, R 5 is Cl and F ⁇ is H (denoted compound 41 in the text);
  • R is Cl
  • R 2 is H
  • R 3 is CF 3
  • R 4 is H
  • R 5 is Cl
  • R 6 is H (denoted compound 41c in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 44 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is SCH 2 C 6 H 5 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 54 in the text); ⁇ is H, R 2 is Br, R 3 is Br,_R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 57 in the text);
  • R is H, R 2 is F, R 3 is F, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 65 in the text);
  • R 1 is H, R 2 is Cl, R 3 is F, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 65a in the text);
  • R 1 is H
  • R 2 is H
  • R 3 is Cl
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 67 in the text);
  • R is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is CF 3 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 81b in the text);
  • R is Cl, R 2 is H, R 3 is CF 3 , R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 81c in the text);
  • R. is H, R 2 is Br, R 3 is H, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 87 in the text);
  • R T is H, R 2 is H, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 90 in the text);
  • R. is Cl, R 2 is Cl.
  • R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 92 in the text);
  • R is Br
  • R 2 is Br
  • R 3 is Br
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 103 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is 2'-deoxy- ⁇ -D-ribofuranosyl (denoted compound 113 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-arabinofuranosyl (denoted compound 134 in the text); R. is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is Cl and R 6 is (1 ,3-dihydroxy-2- propoxy)methyl (denoted compound 155 in the text);
  • R is Cl
  • R 2 is Cl
  • R 3 is Cl
  • R 4 is Cl
  • R 5 is NH 2
  • R 6 is (1 ,3-dihydroxy-2- propoxy)methyl (denoted compound 156 in the text);
  • R. is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is Cl and R 6 is 2-hydroxyethoxymethyl (denoted compound 166 in the text);
  • R T is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is OCH 3 and R 6 is 2-hydroxyethoxymethyl (denoted compound 166a in the text);
  • R is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is NH 2 and R 6 is 2-hydroxyethoxymethyl (denoted compound 167 in the text); R j is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is benzyl (denoted compound
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 5-O-acetyl- ⁇ -D-ribofuranosyl (denoted compound 42a in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 5-O-acety I- ⁇ -D-ribofuranosyl (denoted compound 52b in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 2,3,5-tri-O-acetyl- ⁇ -D- ribofuranosyl (denoted compound 42 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 2,3,5-tri-O-acetyl- ⁇ -D- ribofuranosyl (denoted compound 52a in the text);
  • R, is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-5'-deoxyribofuranosyl (denoted compound 210 in the text);
  • R 1 is H
  • R 2 is Cl
  • R 3 is Cl
  • R 4 is H
  • R 5 is Br
  • R 6 is ⁇ -D-5'-deoxyribofuranosyl (denoted compound 211 in the text); and operative combinations thereof.
  • pharmaceutically acceptable carrier any composition, solvent, dispersion medium, coating, delivery vehicle or the like, which can be employed to administer the compounds and compositions of the present invention without undue adverse physiological effects.
  • operative combination is meant any chemically compatible combination of the compounds which does not eliminate the antiviral activity of the composition.
  • the present invention also relates to a method of antiviral treatment generally comprising the step of administering to the viral host a therapeutically effective amount of a polysubstituted benzimidazole selected from the above-described group.
  • therapeutically effective amount is meant an amount generally effective to achieve the desired antiviral effect.
  • the present invention further relates to the use of a polysubstituted benzimidazole selected from the above-described group in the manufacturing of medicaments for antiviral use.
  • the present invention also relates to compositions comprising a polysubstituted benzimidazole selected from the above-described group in combination with other antiviral agents outside the group.
  • the present invention further relates to the novel polysubstituted benzimidazoles used in the compositions and treatments of the present invention and methods of their making.
  • Novel benzimidazoles include compounds 52, 61 , 83a, 85, 95, 99, 107, 111 , 112, 7, 12c, 13, 19, 26, 32, 41 , 41 c, 57, 65, 65a, 67, 81 b, 81 c, 87, 90, 92, 103, 113, 134, 182,
  • Figures 1 and 2 are synthesis schemes and substituent charts of polysubstituted benzimidazoles in accordance with and illustrating the principles of the present invention.
  • Figure 3 is a dose response curve comparing the activity against human cytomegalovirus of two polysubstituted benzimidazole nucleosides (compounds 45 and 111) to the known drug ganciclovir in accordance with the principles of the present invention.
  • Figure 4 is a graph illustrating the low degree of cytotoxicity (cell growth inhibition) of a polysubstituted benzimidazole nucleoside (compound 45) in accordance with the principles of the present invention.
  • Figure 5 is a graph illustrating the reversibility of the cytotoxic effects produced by a very high level of a polysubstituted benzimidazole nucleoside (compound 45) in accordance with the principles of the present invention.
  • Figure 6 is a graph illustrating the cytotoxic effects of DRB on cell growth and its irreversibilrty.
  • Figure 7 is a synthetic path to 5'-deoxy ribonucleosides from the corresponding ribonucleosides.
  • Figure 8 is a synthesis scheme for a polysubstituted benzimidazole nucleoside (compound 210) from D-ribose.
  • Table 1 illustrates the antiviral activity and cytotoxicity of polysubstituted benzimidazoles in accordance with the principles of the present invention.
  • Table 2 illustrates the effects of a polysubstituted benzimidazole nucleoside on the replication of selected herpes viruses in accordance with the principles of the present invention.
  • Table 3 illustrates the antiviral activity and cytotoxicity of polysubstituted benzimidazoles in accordance with the principles of the present invention.
  • Table 4 illustrates the antiviral activity and cytotoxicity of a polysubstituted benzimidazole nucleoside (compound 45) and its 5'-deoxy analog (compound 210) in accordance with the principles of the present invention.
  • Novel antiviral compositions of the present invention comprise a polysubstituted benzimidazole and a pharmaceutically acceptable carrier, wherein the polysubstituted benzimidazole is selected from the group consisting of compounds having the following formula and pharmaceutically acceptable salts and formulations thereof:
  • w erein is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 45 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is ⁇ -D-ribofuranosyl (denoted compound 52 in the text);
  • R is H, R 2 is NO 2 , R 3 is NO 2 , R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 61 in the text);
  • R is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 81 in the text);
  • R n is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is I and R 6 is ⁇ -D-ribofuranosyl (denoted compound 83a in the text);
  • R t is Br, R 2 is Br, R 3 is H, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 85 in the text);
  • R is H, R 2 is Br, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 95 in the text);
  • R. is H, R 2 is Cl, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 99 in the text);
  • R n is H, R 2 is I, R 3 is I, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 107 in the text);
  • R n is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 2'-deoxy-ribofuranosyl (denoted compound 111 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 2'-deoxy-ribofuranosyl (denoted compound 112 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is H (denoted compound 7 in the text); _
  • R 1 is H, R 2 is Cl, R 3 is F, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 12c in the text);
  • R 1 is Cl, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 13 in the text);
  • R 1 is H, R 2 is NO 2 , R 3 is H, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 19 in the text);
  • R is H, R 2 is I, R 3 is NO 2 , R 4 is H, R 5 is Cl and R 6 is H (denoted compound 26 in the text);
  • R 1 is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 32 in the text); R, is H, R 2 is I, R 3 is I, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 41 in the text);
  • R is Cl, R 2 is H, R 3 is CF 3 , R 4 is H, R 5 is Cl and R 6 is H (denoted compound 41c in the text); R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 44 in the text);
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is SCH 2 C 6 H 5 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 54 in the text);
  • R is H, R 2 is Br, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 57 in the text);
  • R 1 is H
  • R 2 is F
  • R 3 is F
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 65 in the text);
  • R is H, R 2 is Cl, R 3 is F, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 65a in the text);
  • R. is H, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 67 in the text);
  • R 1 is Cl
  • R 2 is H
  • R 3 is Cl
  • R 4 is H
  • R 5 is CF 3
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 81b in the text);
  • R is Cl
  • R g is H
  • R 3 is CF 3
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 81c in the text);
  • R is H, R 2 is Br, R 3 is H, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 87 in the text);
  • R is H, R 2 is H, R 3 is Br, R 4 is H, R 5 is Ci and R 6 is ⁇ -D-ribofuranosyl (denoted compound 90 in the text);
  • R, is Cl, R 2 is Cl, R 3 is CI 1 _R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 92 in the text);
  • R is Br, R 2 is Br, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 103 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is 2'-deoxy- ⁇ -D-ribofuranosyl (denoted compound 113 in the text);
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-arabinofuranosyl (denoted compound 134 in the text);
  • R 1 is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is Cl and R 6 is (1 ,3-dihydroxy-2- propoxy)methyl (denoted compound 155 in the text);
  • R, is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is NH 2 and R 6 is (1 ,3-dihydroxy-2- propoxy)methyl (denoted compound 156 in the text);
  • R 1 is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is Cl and R 6 is 2-hydroxyethoxymethyl ⁇ denoted compound 166 in the text);
  • R, is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is OCH 3 and R 6 is 2-hydroxyethoxymethyl
  • R. is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is NH 2 and R 6 is 2-hydroxyethoxymethyI (denoted compound 167 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is benzyl (denoted compound 182 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 5-O-acetyl- ⁇ -D-ribofuranosyl (denoted compound 42a in the text);
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 5-O-acetyl- ⁇ -D-ribofuranosyl (denoted compound 52b in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and Rg is 2,3,5-tri-O-acetyl- ⁇ -D- ribofuranosyl (denoted compound 42 in the text);
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 2,3,5-tri-O-acetyl- ⁇ -D- ribofuranosyl (denoted compound 52a in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-5'-deoxyribofuranosyl (denoted compound 210 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is ⁇ -D-5'-deoxyribofuranosyl (denoted compound 211 in the text); and operative combinations thereof.
  • R 6 ⁇ -D-ribofuranosyl (denoted compound 67 in the text);
  • compositions and methods of the present invention include:
  • the present invention also comprises novel polysubstituted benzimidazoles, and, as later described, their synthesis and use in medicaments and methods of treatment.
  • Novel polysubstituted benzimidazoles of the present invention include compounds 52, 61 ,
  • Preferred novel compounds of the present invention include compounds 52, 85, 111 , 65, 65a, 81 c, 87, 90, 92, 182, 210 and 211.
  • antiviral treatment in accordance with the present invention encompasses the treatment of viral infections, as well as prophylactic treatment which may be desired in certain situations, e.g. in immuno-compromised patients, such as bone marrow transplant patients.
  • the polysubstituted benzimidazoles of the invention have been demonstrated as particularly effective against viruses of the herpes family. They are thus useful in treatment against human cytomegalovirus (HCMV) and herpes simplex viruses types 1 and 2.
  • Other viruses contemplated to be treated within the scope of the present invention include, but are not limited to: varicella-zoster virus (varicella; zoster, chickenpox; shingles); Epstein- Barr virus (infectious mononucleosis; glandular fever; and Burkittis lymphoma); HHV6; human immunodeficiency virus (HIV) and hepatitis viruses.
  • the compounds and compositions of the present invention can be used in the manufacture of medicaments and in antiviral treatment of humans and other animals by administration in accordance with conventional procedures, such as an active ingredient in pharmaceutical compositions.
  • the compounds of the invention can be provided as pharmaceutically acceptable formulations and/or "prodrugs,” including but not limited to esters, especially carboxylic acid esters (perferably C 1 to C 20 ), such as 5'- acetyl and 2',3',5'-triacetyl prodrugs (e.g. compounds 42a, 52b, 42 and 52a) and pharmaceutical salts such as thiolate, citrate and acetate salts.
  • the pharmaceutical compositions can be administered topically, orally, or parentally and may take the form of tablets, lozenges, granules, capsules, pills, ampoules or suppositories. They may also take the form of ointments, gels, pastes, creams, sprays, lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or nonaqueous diluents, syrups, granulates or powders.
  • the pharmaceutical compositions can also contain other pharmaceutically active compounds or a plurality of compounds of the invention.
  • a compound of the formula of the present invention also referred to herein as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, buccai and subiingual), vaginal, parental (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary. It will also be appreciated that the preferred route will vary with the condition and age of the recipient and the nature of the infection.
  • a suitable dose for each of the above-named viral infections is in the range of about 0.1 to about 250 mg per kilogram body weight of the recipient per day, preferably in the range of about 1 to about 100 mg per kilogram body weight per day and most preferably in the range of about 5 to about 20 mg per kilogram body weight per day.
  • ail weights of active ingredient are calculated as the parent compound of the formula of the present invention for salts or esters thereof, the weights would be increased proportionately.
  • the desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
  • sub-doses amy be administered in unit dosage forms, for example, containing about 10 to about 1000 mg, preferably about 20 to about 500 mg, and most preferably about 100 to about 400 mg of active ingredient per unit dtosage form. It will be appreciated that appropriate dosages of the compounds and compositions of the invention may depend on the type and severity of the viral infection and can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the antiviral treatments of the present invention.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.25 to about 100 ⁇ M, preferably about 0.5 to about 70 ⁇ M, most preferably about 1 to about 50 ⁇ M. This may be achieved, for example, by the intravenous injection of about 0.1 to about 5% solution of the active ingredient, optionally in saline, or orally administered, for example, as a tablet, capsule or syrup containing about 0.1 to about 250 mg per kilogram of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg per kilogram of the active ingredient.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising at least one active ingredient, as defined above, together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic agents.
  • Each carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and_ intradermal) and pulmonary administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a watei-in-oil liquid emulsion.
  • the active ingredient may also be presented a bolus, etectuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylemthyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycollate, cross- linked povidone, cross-linked sodium carboxmethyl cellulose) surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol or oil.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active ingredients and optionally one or more excipients or diluents.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, about 0.075 to about 20% w/w, preferably about 0.2 to about 25% w/w and most preferably about 0.5 to about 10% w/w.
  • the active ingredient may be employed with either a paraffinic or a water- miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulphoxide and related analogues.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in an known manner. While this phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at lease one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulation in a concentration of about 0.5 to about 20%, advantageously about 0.5 to about 10% particularly about 1.5% w/w.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration as, for example, a nasal spray or a nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other micorparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily subdose, as herein above-recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention my include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable of oral administration my include such further agents as sweeteners, thickeners and flavoring agents.
  • the present invention also comprises methods of synthesis of polysubstituted benzimidazoles of the invention.
  • the present invention provides a process for the preparation of polysubstituted benzimidazoles of the following formula:
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 45 in the text);
  • R is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is ⁇ -D-ribofuranosyl (denoted compound 52 in the text);
  • R 1 is H
  • R 2 is NO 2
  • R 3 is NO 2
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 61 in the text);
  • R is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 81 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is I and R 6 is ⁇ -D-ribofuranosyl (denoted compound 83a in the text);
  • R is Br, R 2 is Br, R 3 is H, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 85 in the text);
  • R is H, R 2 is Br, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 95 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 99 in the text);
  • R 1 is H, R 2 is I, R 3 is I, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 107 in the text);
  • R T is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 2'-deoxy-ribofuranosyl (denoted compound 111 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 2'-deoxy-ribofuranosyl (denoted compound 112 in the text);
  • R 1 is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is H (denoted compound 7 in the text); R 1 is H, R 2 is Cl, R 3 is F, R 4 is H, R 5 is Ci and R 6 is H (denoted compound 12c in the text);
  • R is Cl, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 13 in the text);
  • R is H, R 2 is NO 2 , R 3 is H, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 19 in the text);
  • R is H, R 2 is I, R 3 is NO 2 , R 4 is H, R 5 is Cl and R 6 is H (denoted compound 26 in the text);
  • R 1 is Cl, R 2 is H, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 32 in the text);
  • R 1 is H, R 2 is I, R 3 is I, R 4 is H, R 5 is Cl and R 6 is H (denoted compound 41 in the text);
  • R n is Cl, R 2 is H, R 3 is CF 3 , R 4 is H, R 5 is Cl and R 6 is H (denoted compound 41c in the text); R, is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 44 in the text);
  • R- is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is SCH 2 C 6 H 5 and R 6 is ⁇ -D-ribofuranosyl (denoted compound 54 in the text);
  • R. is H, R 2 is Br, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 57 in the text);
  • R is H, R 2 is F, R 3 is F, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 65 in the text);
  • R 1 is H, R 2 is Cl, R 3 is F, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 65a in the text);
  • R j is H, R 2 is H, R 3 is CI,_R 4 is H, R 5 is Ci and R 6 is ⁇ -D-ribofuranosyl (denoted compound 67 in the text);
  • R 1 is Cl
  • R g is H
  • R 3 is Cl
  • R 4 is H
  • R 5 is CF 3
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 81b in the text);
  • R 1 is Cl
  • R 2 is H
  • R 3 is CF 3
  • R 4 is H
  • R 5 is Cl
  • R 6 is ⁇ -D-ribofuranosyl (denoted compound 81c in the text);
  • R 1 is H, R 2 is Br, R 3 is H, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 87 in the text);
  • R 1 is H, R 2 is H, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 90 in the text);
  • R- is Cl, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Ci and R 6 is ⁇ -D-ribofuranosyl (denoted compound 92 in the text);
  • R 1 is Br, R 2 is Br, R 3 is Br, R 4 is H, R 5 is Cl and R 6 is ⁇ -D-ribofuranosyl (denoted compound 103 in the text); R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is NH 2 and R 6 is 2'-deoxy- ⁇ -D-ribofuranosyl
  • R is Cl
  • R 2 is Cl
  • R 3 is Cl
  • R 4 is Cl
  • R 5 is Cl
  • R 6 is (1 ,3-dihydroxy-2- propoxy)methyl (denoted compound 155 in the text);
  • R t is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is NH 2 and R 6 is (1 ,3-dihydroxy-2- propoxy)methyl (denoted compound 156 in the text);
  • R n is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is Cl and R 6 is 2-hydroxyethoxymethyl (denoted compound 166 in the text); R, is Cl, R 2 is Cl, R 3 is Cl, R 4 is Cl, R 5 is OCH 3 and R 6 is 2-hydroxyethoxymethyl
  • R is Cl
  • R 2 is Cl
  • R 3 is Cl
  • R 4 is Cl
  • R 5 is NH 2
  • Rg is 2-hydroxyethoxymethyl (denoted compound 167 in the text);
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 5-O-acety I- ⁇ -D-ribofuranosyl (denoted compound 42a in the text);
  • R. is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 5-O-acetyl- ⁇ -D-ribofuranosyl (denoted compound 52b in the text);
  • R, is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Cl and R 6 is 2,3,5-tri-O-acetyl- ⁇ -D- ribofuranosyl (denoted compound 42 in the text);
  • R, is H, R 2 is Cl, R 3 is Cl, R 4 is H, R 5 is Br and R 6 is 2,3,5-tri-O-acetyl- ⁇ -D- ribofuranosyl (denoted compound 52a in the text); which comprises reacting a compound of the following formula:
  • R R g , R 3 , R 4 and R 5 are defined as above, with a protected compound of formula R 6 a X, shown below, in which R 6 a represents a protected carbohydrate or carbohydrate-like moiety and X represents a leaving group, and subsequently removing the protecting group from the moiety to form the desired compound.
  • the compound of formula R 6 a X is represented by the formula:
  • X represents a leaving group such as a halo (e.g. chloro) or C,. 4 aikanoyioxy (e.g. acetoxy) group and R represents a hydroxy protecting group, for example, an acyl group such as C, ⁇ alkanoyl (e.g. acetyl or aroyl, e.g. benzoyl, e.g. p_-nitrobenzoyl arid the like.
  • the reaction of the compound of formula II with the compound of formula R 6 a X may be effected in the presence of BSA, TMSOTf, BSTFA and the like, advantageously in a solvent such as acetonitrile, dichloroethane and the like.
  • the removal of the protecting groups in the above process according to the invention may be effected, for example, by treatment with methanolic ammonia, boron trihalide ⁇ sodium carbonate, potassium cyanide and the like. Additionally, compounds of formula II may be reacted with compounds of the formula:
  • R' aralkyl to prepare a compound of general formula I, whe-ein R 6 is benzyl rather than a carbohydrate or carbohydrate-like moiety, and wherein, e.g. R. is H, R 2 , R 3 is Cl, R 4 is H and R 5 is NH 2 or Cl.
  • the compounds of the present invention can be synthesized in accordance with the representative procedures described vide infra.
  • the appropriate benzimidazole was prepared and then condensed with the appropriate precursor for the ultimate R g group as represented by the schemes and substituent charts of Figures 1 and 2.
  • the solvents, reagents and reaction conditions for the preparation of some representative starting materials, intermediate and target compounds are presented in detail below.
  • the compound numbering in this section and specification refers to the reaction scheme and chart numbers of the compounds.
  • a CuCI 2 saturated aqueous solution (15 ml) was diluted to 25 ml with water.
  • Sodium nitrite (1.035g, 5 mmole) was dissolved in 5 ml of water and slowly added to the CuCI 2 solution.
  • 2-amino-5,6-dichlorobenzimidazole(4) (0.935g, 5 mmole) was slowly added in small portions.
  • the mixture was stirred at room temperature for 1 hr. Excess CuCI 2 solution was added and the mixture was heated on a steam bath for 1 hr.
  • 5,6-Dichlorcbenzimidazole-2-thione (3) was prepared according to the method of Van Allen and Deacon, as described in Van Allen, J.A. et al., Org. Syn. IV:569. Carbon disulfide (84.5 mL, 107.0 g, 1.4 M) was added to a solution of KOH (92.4 g, of 85% purity, 78.5 g, 1.4 M) in EtOH (1.5 L) and the resulting yellow solution was stirred without heating until a white precipitate was obtained. To obtain the product in good yield, potassium ethyl xanthate must be prepared in situ.
  • the 80 hr time period was for convenience alone, since the reaction is probably complete within 24 hr.
  • the reaction mixture was filtered through Celite.
  • the filter cake was washed with MeOH (250 mL) and H 2 O (750 mL) and the filter cake was discarded.
  • the filtrate was diluted with H 2 O (1.5 L), adjusted to pH 10 with cone. NH 4 OH (1750 mL) and then allowed to stand overnight at 5°C.
  • the precipitate (yellow leaflets) was collected by filtration, washed with H 2 O and then dried under reduced pressure at 50°C for 60 hr. Crude yield: 265 g.
  • 2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr 2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3 x 100 ml), dried with MgSO 4 , concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole (7).
  • Powdered 2-amino-5,6-dichlorobenzimidazole (3) (20.2 g, 0.1 M) was added in one portion and the mixture stirred without heating. Gas evolution was almost immediate and very vigorous; the reaction was exothermic to the point that a gentle reflux was maintained. During this time, an orange solid began to separate. After 25 min, the rate of reflux began to decrease, and after 35 min was very slow. The mixture was then heated under reflux until gas evolution had almost ceased. The mixture was cooled for 20 min in an ice bath then treated with 48% aqueous HBr (100 mL) giving a black suspension. After stirring for 20 min, H 2 O was added and an orange precipitate was obtained. Stirring was continued for 30 min and then the precipitate was removed by filtration.
  • 2,5,6-Trichlorobenzimidazole 700 mg, 0.0032 moles was dissolved in acetonitrile and BSTFA (1 ml, 0.0038 moles) was added. The mixture was heated at 75°C for 20 minutes. TMSTf (1 ml, 0.0051 moles) and 1-0-acetyl-2,3,5-tri-O-benzoyl- ⁇ -D-ribofuranose (1.9 g, 0.0038 moles) were added while heating was continued for 45 min. The acetonitrile was removed under reduced pressure and the protected nucleoside was separated on a silica column, eluting with chloroform. The benzoyl protecting groups were removed by overnight treatment at room temperature with methanolic ammonia.
  • the solid product was triturated with H 2 O (800 mL, 20 min), MeOH (500 mL, 30 min), and then recrystallized from EtOH/MeOH (1 L/1 L) to give 52.4 g of 45 as white crystals ⁇ 2 crops, the 2nd crop (2.8 g) was obtained by evaporation of the mother liquid and recrystallization of the residue two more times from EtOH/MeOH ⁇ . Recrystallization was accomplished by dissolving the crude product in a minimum amount of boiling EtOH, diluting it immediately with an equal amount of hot MeOH and allowing it to slowly cool.
  • 2-Bromo-5,6-dich!orobenzimidazole (7) (1g, 3.8 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60°C.
  • BSA (1.03 ml, 4.2 mmole) was ad_ded and the mixture was stirred for 10 minutes.
  • 1 ,2,3,5-Tetra-O-acetyl- ⁇ -D- ribofuranose (1.21 g, 3.8 mmole) and TMSTf (0.81 ml, 4.2 mmole) were added to the clear solution and the mixture was stirred for 10 min.
  • the reaction mixture was stirred at room temperature for 1 hr. A solution of KI/H 2 O (0.537 g/5 mL) was added dropwise and stirring was continued at room temperature for 3 h and then 100°C for 15 min.
  • the reaction mixture was extracted with EtOAc (50 mL x 2).
  • the EtOAc solution was washed with Na 2 S 2 O 3 /H 2 O (1 g/50 mL), sat. NaHCO 3 (50 mL), sat. NaCl solution (50 mL), dried (Na 2 SO 4 ), and evaporated. The residue was recrystallized from MeOH to give 0.169 g of a yellowish crystalline compound.
  • the brown solid was dissolved in a mixture of Cone. H 2 S0 4 /ice-H 2 0 (14 mL/20 mL) at 0°C. To this mixture, was added dropwise a solution of NaNO 2 /H 2 O (0.994 g, 13.688 mmol/5 mL). The reaction mixture was stirred at 0°C for 1 hr. A solution of urea/H 2 O (0.411 g/3 mL) was added and stirring was continued at 0°C for 10 min. A solution of KI/H 2 O (2.272 g/5 mL) was added and stirring was continued at room temperature for 18 h. The reaction mixture was extracted with EtOAc (100 mL x 2).
  • the filter cake was washed with portions of H 2 0 (100 ml) and air dried. The filtrate and washings were combined and extracted with EtOAc (100 ml x 2). The EtOAc solution was dried (Na ⁇ SO ⁇ and evaporated to give a solid. This was combined with the major part of the solid product and was coevaporated with EtOH (2x). The resulting solid was suspended in 100 ml of CHCI 3 and the suspension was filtered. The filter cake was washed with portions of CHCI 3 , and air dried to give 6.62 grams of 34 as a yellowish solid. The filtrate and washings were evaporated and the residue was again suspended in a small amount of CHCI 3 .
  • 2-Amino-5(6)-chlorobenzimidazole (34) (10.06 grams, 60 mmoles) was added portionwise to an aqueous solution of cupric chloride (120 grams) and sodium nitrite (12.42 grams) while stirring. The reaction mixture was stirred for one hour at room temperature. At this time the reaction mixture was extracted with EtOAc (200 ml x 3) to provide a brownish discoloration of the organic phase. The EtOAc phase was washed with saturated NaCl solution, dried with Na 2 S0 4 , and evaporated in vacuo to reveal a brown precipitate which was added to a silica column.
  • 2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60°C.
  • BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes.
  • 1 ,2,3,5-tetra-O-acetyl- ⁇ -D- ri ⁇ furanose 5.09 g, 16 mmole
  • TMSTf (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60°C for 1 hr.
  • the EtOAc solution was extracted with saturated NaHC0 3 solution (300 ml x 2), saturated NaCl solution (50 ml), dried (Na ⁇ SOJ, and evaporated in vacuo.
  • the resulting yellowish-brown syrup was dissolved in a minimum volume of chloroform and transferred to a silica column (30 x 3 cm).
  • the column was eluted with CHCI 3 while ultimately increasing solvent polarity to 1 % MeOH/CHCI 3 .
  • the first spot eluted from the column was collected and evaporated in vacuo to reveal an oily yellow residue.
  • the syrup was coevaporated with EtOH (25 ml x 2) to reveal a white precipitate.
  • This solution was cooled to ⁇ 20°C and treated with 7.0 g (22 mmole of 1 ,2,3,5-tetra-O-acetyl-b-D-ribofuranose and 4.638 mL (24 mmole) of TMSOTf at roo temperature for 2 h.
  • the reaction mixture was diluted with 200 mL of CHCI 3 .
  • the CHCI solution was washed with sat. NaHC0 3 solution (200 mL x 2), sat. NaCl solution (200 mL) dried (Na 2 S0 4 ), and evaporated.
  • 1 -(2,3,5-Tri-0-benzyl- ⁇ -D-ribofuranosyl)-2.4.5.6-tetrachlorobenzimidazole (91 a) an 1 -(2,3,5-Tri-0-benzyl-c(-D-ribofuranosyl)-2,4,5,6-tetrachlorobenzimidazole
  • HCl gas wa allowed to pass through a solution of 1 -0-p-nitrobenzoyl-2,3,5-tri-0-benzyl- ⁇ - ribofuranose (1.479 g, 2.6 mmol) in 10 mL of dry CH 2 CI 2 at 0°C for 15 min.
  • Compound 110a (6.0 g, prepared from 10 mmol of 110) was treated with 150 mL of NH 3 /MeOH at room temperature for 2 days. The reaction mixture was evaporated and coevaporated with MeOH. The resulting solid was triturated with CHCI 3 (50 mL). The CHCI 3 suspension was kept at 0°C for 1 hr and was then filtered. The solid was washed with portions of CHCI 3 and then recrystallized from MeOH to give 2.462 g (2 crops) of 110b as white needles. The CHCI 3 filtrate was concentrated to 20 mL and kept in a freezer ( ⁇ -15°C) overnight.
  • the title compound was prepared from 2,4,5,6,7-pentachlorobenzimidazole (14) (0.29 g, 1.0 mmole), CH 3 CN (35 mL), NaH (97%, oil dispersion, 0.033 g, 1.4 mmole) and [(1 ,3-bis(benzyloxy)-2-propoxy]methylchloride (0.49 g, 1.5 mmole ) in CH 3 CN (10 mL) to afford an oil.
  • the resulting oil was purified by flash column chromatography (2 x 20 cm) (230-400 mesh) prepared with wet Si0 2 in hexane.
  • 5'-Deoxy TC could not be phosphorylated at the 5'-position and should therefore be inactive as antiviral agent if activation at the 5'-position is required. If, on the other hand, the 5'-deo analog demonstrated activity against HCMV it could be concluded that TCRB acts by non-"classical antiviral" mechanism that does not involve activation at the 5'-position.
  • the silica gel used for chromatography was silica gel 60 230-400 mesh (E. Merck, Darmstadt, West Germany).
  • Thin Layer Chromatography (TLC) was performed on pre-scored SilicAR 7GF plates (Analtech, Newark, DE, USA). TLC plates were developed in the following solvent systems: system 1 (2% MeOH/CHCI 3 ), system 2 (10% MeOH/CHCI 3 ), system 3 (50% EtOAc/hexane).
  • system 1 2% MeOH/CHCI 3
  • system 2 10% MeOH/CHCI 3
  • system 3 50% EtOAc/hexane
  • Compounds were visualized by illuminating under UV light (254nm) or by spraying with 20% methanolic sulfuric acid followed by charring on a hot plate. Evaporations were carried out under reduced pressure (water aspirator) with the bath temperature below 40 °C, unless specified otherwise.
  • IR spectra were obtained on a Nicoiet 5DXB FT-IR spectrophotometer. UV spectra were performed on a Hewlett-Packard 8450-A UV/VIS spectrophotometer. Nuclear magnetic resonance (NMR) spectra were determined at 360 MHz with a Bruker WP 360 SY. The chemical shift values are expressed in ⁇ values (parts per million) relative to the standard chemical shift of the solvent DMSO- dg. Elemental analyses were performed by M-H-W Laboratories, Phoenix, AZ. b. Synthetic Method Methyl 2.3-O-isopropylidene- ⁇ -D-ribofuranoside (202)
  • D-Ribose (25g, 0.17 moles) was dissolved in 500 mL acetone containing 50 mL of 2,2- dimethoxypropane and 90 mL methanol. 10 mL of methanol saturated with HCl at 0 °C was added and the mixture was stirred at room temperature overnight. The mixture was neutralized with the addition of 15 mL pyridine and partitioned between 500 mL H 2 0 and 200 mL_ether. The layers were separated and the aqueous layer extracted with two more 200 mL ether portions.
  • the ether portions were combined, dried over magnesium sulfate, gravity filtered, and concentrated to a thick, yellow syrup which was not purified further and immediately deiodinated.
  • the thick, yellow oil (6.5 g, 21 mmol) was dissolved in methanol (60 mL) and placed in a hydrogenator apparatus at 40 psi in the presence of 10% Palladium on charcoal (0.75g) and triethylamine (3.2 mL) and a small piece of dry ice. After four hrs, the mixture was filtered through Celite and the filtrate was concentrated to a small volume under reduced pressure.
  • the thick solution was suspended in methylene chloride (200 mL) and extracted with water (2 x 50 mL) and saturated sodium bicarbonate solution (50 mL). The methylene chloride layer was dried over magnesium sulfate, filtered, and concentrated to a thick syrup. This thick syrup was suspended in 0.04 N HCl and heated at reflux for two hours. The solution was allowed to cool to room temperature, concentrated to a small volume, and added to an ion exchange column (9.7 x 17 cm). The columrvwas washed with two column volumes of water.
  • the collected aqueous fractions were pooled, concentrated to a colorless syrup, suspended in pyridine (1200 mL), and allowed to stir at room temperature for 72 hrs in the presence of acetic anhydride (180 mL). The solution was then treated with cold aqueous sodium bicarbonate (300 mL) and extracted with chloroform (5 x 100 mL). The chloroform extracts were dried over MgS0 4 , and concentrated under reduced pressure. The remaining thick syrup was repeatedly evaporated with toluene to remove traces of pyridine.
  • 2,5,6-Trichlorobenzimidazole 500 mg, 2.26 mmol was suspended in dry acetonitrile (90 mL) and treated with BSA (0.56 mL, 2.26 mmol). After 15 minutes, 1 ,2,3-tri-0-acetyl-5- deoxyribose (621 mg, 2.26 mmol) was added along with TMSTf (0.45 mL, 2.26 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was concentrated under reduced pressure and applied to a silica gel column (3.5 x 9 cm) and eluted with dichloromethane.
  • MeOH/CHCI 3 indicated the disappearance of the protected nucleoside and complete formation of a more polar compound.
  • the aqueous alcoholic solution was neutralized with the addition of glacial acetic acid and then concentrated under reduced pressure to about
  • KB cells a human epidermoid neoplastic cell line
  • MEM minimal essential medium
  • ECM(E) Earle salts
  • the sodium bicarbonate concentration was varied to meet the buffering capacity required.
  • BSC-1 Africann green monkey kidney cells were grown and passaged in Dulbecco modified MEM(E) supplemented with 5%tryptose phosphate broth and 5% horse serum.
  • Cultures of human foreskin fibroblasts (HFF) were grown in medium consisting of MEM(E) with 10% fetal bovine serum.
  • HFF cells were passaged at 1 :2 to 1 :10 dilutions according to conventional procedures by using 0.05% trypsin plus 0.02% EDTA in a HEPES buffered salt solution. HFF cells were passaged only at 1 :2 dilutions.
  • HSV-1 The HF strain of HSV-1 was used in selected experiments and was obtained from Dr. G.H. Cohen, University of Pennsylvania.
  • the Towne strain, plaque-purified isolate P 0 , of HCMV was a gift of Dr. Mark Stinski, University of Iowa.
  • High titer HSV-1 stocks were prepared as follows: Nearly confluent monolayer cultures of KB cells were grown in 32 oz. glass bottles containing MEM(E) buffered with 25 mM HEPES and supplemented with 5% fetal bovine serum and 0.127 g/liter L-arginine (VGM, virus growth medium). The cultures were infected at a low input multiplicity to reduce the formation of defective virus. After cell cytopathology reached "three to four plus", the cells were harvested by vigorous shaking, and concentrated by centrifugation (800 x g for 5 min.). The resulting virus pools were stored at -76°C until retrieved for use in experiments.
  • S ⁇ ock HCMV was prepared by infecting HFF cells at a multiplicity of infection (m.o.i.) of less that 0.01 plaque-forming units (p.f.u.) per cell.
  • Cell growth medium was changed every tour days until cytopathoiogy was evident in all cells (approximately 21 days).
  • Supernatant fluids were retained as the virus stock.
  • the remaining cells were disrupted by three cycles of freeze-thawing and the cell plus medium held as an additional source of virus. Storage was in liquid nitrogen.
  • HSV-1 was titered using monolayer cultures of BSC-1 cells.
  • Cells were planted at 3 x 10 5 cells/well using 6-well cluster dishes.
  • MEM(E) supplemented with 10% fetal bovine serum was employed as medium.
  • cells were 90% confluent and were inoculated in triplicate using at least three ten-fold dilutions with 0.2 ml of the virus suspension to be assayed and incubated in a humidified 4% CO 2 -90% air atmosphere for one hour to permit viral adsorption.
  • the cell sheet was overlayed with 5 ml of MEM(E) with 5% serum plus 0.5% methocel (4000 CPS) and incubated an additional two to three days.
  • Cells were fixed and stained with 0.1 % crystal violet in 20% methanol and macroscopic plaques enumerated.
  • HCMV was titered in 24-well cluster dishes which were planted to contain 5 x 10 4 HFF cells/well, grown as described above. When the cells were 70 to 80% confluent, 0.2 ml of the virus suspension was added per well and adsorbed as described above. At least three ten-fold dilutions of each preparation were used. Following virus adsorption, the cell sheets were overlayed with 0.5% methocel (4000 CPS) in maintenance medium [MEM(E) with 1.1 g/liter NaHC0 3 , 100 units/ml penicillin G, 100 ⁇ g/ml streptomycin, and 5% fetal bovine serum]. The cultures were incubated in a humidified atmosphere of 4% C0 2 -96% air.
  • Viral foci were visible 5 to 7 days after infection using at least 10-fold magnification. Cells were fixed and stained by a 10-minute exposure to a 0.1% solution of crystal violet in 20% methanol 7 to 12 days after infection. Microscopic foci were enumerated at 20-fold magnification using a Nikon Profile Projector.
  • (2) Assays for Antiviral Activity (a) HSV-1 Plaque reduction experiments with HSV-1 were performed using monolayer cultures of BSC-1 cells. The assay was performed exactly as described above except that the 0.2 ml virus suspension contained approximately 100 p.f.u. of HSV-1.
  • the cell sheet was rinsed twice with 2 ml of VGM without serum to remove unadsorbed virus and 5 ml of VGM containing drugs at three to five selected concentrations added in duplicate. Following an 18-to 20-hr incubation at 37°C, infected monolayers were treated with EDTA- trypsin to suspend the cells; aliquots were removed, subjected to three cycles of freezing and thawing, and stored at -76°C for subsequent virus assay. Virus was titered on BSC-1 cells as described above. ELISA techniques according to standard procedures were also used to determine activity against HSV-1.
  • KB or HFF cells were planted using a Costar Transplate-96 (Costar, Cambridge, Massachusetts) in Costar 96-well cluster dishes at a concentration of 10,000 to 12,000 cells per well.
  • Cells were suspended in 200 ⁇ l of medium [MEM(H) plus 0.7 g/liter NaHC0 3 supplemented with 10% calf serum] per well. After incubation of 16 to 24 hours at 37°C in a humidified atmosphere of 4% C0 2 in air, 150 ⁇ l of medium was removed per well.
  • One- hundred ⁇ l of medium with or without compounds in twice their final concentrations was added to each well using a Titertek Multichannel Pipette. Final concentrations of compounds ranged from 0.1 to 320 ⁇ l of medium containing radioactive precursors also was added to each well to give a final concentration to 1 to 3 ⁇ Ci/ml of labeled precursor.
  • [ H]Thd was diluted with unlabeled dThd to give a final concentration of 3 to 6 ⁇ M.
  • Liquid scintillation solution was added, and radioactivity determined in a Beckman model LS8100 Liquid scintillation spectrometer. All samples were counted for 2.0 min each, with three round of counting. Counts per minute were determined following the application of statistical methods to eliminate count rates which fell outside distribution limits defined by Chauvenetys rejection criterion.
  • Cytotoxicity produced in HFF and BSC-1 cells was estimated by visual scoring of cells not affected by virus infection in the HCMV and HSV-1 plaque reduction assays. Cytopathology was estimated at 35- and 60-fold magnification and scored on a zero to four plus basis. Weils were scored on the day of staining. (4) Cell Growth Rates
  • a plating efficiency assay was used to confirm and extend results described above. Briefly, KB cells were suspended in growth medium and an aliquot containing 1000 cells was added to a 140 x 25 mm petri dish. Growth medium (40 ml) containing selected concentrations of test compounds was added and the cultures incubated in a humidified atmosphere of 4% C0 2 -96% air, 37°C for 14 days. Medium then was decanted and colonies fixed with methanol and stained with 0.1% crystal violet in 20% methanol. Macroscopic colonies greater than 1 mm in diameter were enumerated. Drug effects were calculated as a percentage of reduction in number of colonies formed in the presence of each drug concentration compared to the number of colonies formed in the absence of drugs. Dose-response curves were generated and l 50 concentrations for inhibition of plating/colony formation were calculated.
  • Table 1 summarizes test results from antiviral and cytotoxicity evaluation of the benzimidazoles.
  • These halogen-substituted compounds were active against HCMV, with a halogen at R 5 being essential for antiviral activity and low cytotoxicity.
  • compounds 45 and 52 were active against HCMV in the sub- or low micromolar range and did not produce cytotoxicity in uninfected cells at concentrations up to 100 ⁇ M.
  • This potent and selective antiviral activity against HCMV is in sharp contrast to the low, apparent activity against this virus of the dichloro compound commonly referred to as DRB which compound was initially described by Tamm (I. Tamm, Science 120:847-848, 1954).
  • Other compounds showing good or better activity than compound 45 against HCMV and low cytotoxicity are compounds 52, 85, 95, 99 and compound 111 (the deoxyribosyl analog of compound 45).
  • Other compounds with activity include compounds 61 , 81 , 83a, and 107. All compounds except 81 , 95, and 99 also had activity against HSV-1.
  • Table 3 summarizes test results from antiviral and cytotoxicity evaluation of benzimidazoles and related compounds. These compounds are active against HCMV and some also are active against HSV-1. For example, compounds 57, 65, 65a, 87, 90, 103, 113, 134, 155, 156, 182, 92, 81 c and 54 were active against HCMV in the low-micromolar range in either plaque or yield reduction assays. Although some comounds also showed cytotoxic effects in some assays, activity against HCMV was separated from cytotoxicity. All other compounds presented in Table 3 also were active against HCMV but to a lesser extent. In addition to activity against HCMV, compounds 44, 65a, 113, 134, 182, 54, 19, 12c, 13 and 26 also are active against HSV-1.
  • Average percent inhibition of DNA, RNA and protein synthesis or cell growth determined in KB cells as described in the text.
  • Figure 6 shows the effects of the known compound DRB were fully inhibitory to uninfected cells at 100 ⁇ M and these effects could not be reversed by removal of the drug from culture, thereby establishing the cytoxicity of this compound.
  • the lack of cytotoxicity of compound 45 was further established by plating efficiency experiments. In these experiments, which measure both the ability of cells to grow and to attach to a substrate, compound 45 had no effect at 100 ⁇ M.
  • Compounds of the invention provide additional advantages when used in combination with other antiviral drugs.
  • combination of compound 45 with the known antiviral drug ganciclovir results in greater activity (i.e. synergy) against human cytomegalovirus (HCMV) than the use of either agent alone when used at concentrations (approximately 0.1 to 10 ⁇ M) most likely achieved in vivo by the administration of therapeutic amounts of each drug.
  • HCMV human cytomegalovirus
  • compound 45 also is synergistic against HCMV when used with another known antiviral drug, acyclovir.
  • the combination of compound 52 with ganciclovir or acyclovir results in synergistic activitiy against HCMV.
  • Compounds of the invention could thus be used to treat HCMV infections in AIDS patients already receiving the antiviral drug zidovudine (AZT).
  • AZT antiviral drug zidovudine
  • Combination of either compound 45 or 52 with AZT provides the advantage of less toxicity over the combination of ganciclovir with AZT.
  • the combination of compound 45 or 52 with AZT produces less cytotoxicity (i.e. antagonism) in cultured human cells than either agent used alone.
  • cytotoxicity i.e. antagonism
  • combination of ganciclovir with AZT produces greater cytotoxicity in human cells than the use of either of these drugs alone.
  • Prodrugs of polysubstituted benzimidazoles can be useful for oral administration.
  • ester prodrugs of compounds 45 (compounds 42 and 42a) and 52 (compounds 52a and 52b), respectively, have been prepared and are active against HCMV.
  • 5'-deoxy TCRB (210) was active against HCMV in the plaque reduction assay. In fact, 5'-deoxy TCRB was not only active, but approximately 10 times more active than TCRB. It was very clear that the phosphorylation of the hydroxyl group at the 5'-position was not necessary for antiviral activity and since phosphorylation at this particular position is not possible. TCRB is apparently not acting as a "classical antiviral" nucleoside. The fact that the 5'-deoxy analog is active at all is important because it tells us that these new halogenated benzimidazole ribonucleosides have a mode of action dissimilar to most other nucleoside analog antiviral agents.
  • HFF cells Diploid human foreskin fibroblasts (HFF cells) were grown in minimal essential medium with Earle salts [MEM(E)] supplemented with 10% fetal bovine serum. HFF cells (approximately 100,000 cells per plate) were planted in MEME on 24 well plates and incubated for 24 h. A plaque-purified isolate, P 0 , of the Towne strain of HCMV was used in the experiments.
  • HCMV plaque reduction assays were performed on monolayer cultures of HFF cells with the virus inoculum (200 mL) containing approximately 100 plaque forming units (PFU) of virus.
  • the compounds to be assayed were dissolved in the overlay medium and selected concentrations were prepared (100 ⁇ M, 10 ⁇ M, 1 ⁇ M, and 0.1 ⁇ M solutions).
  • PFU plaque forming units
  • 1 mL of the selected concentrations of drug were added to the wells.
  • the plates were then incubated for 10 days at 37 °C/C0 2 . After removal of the MEME/methocel, the cells were stained with crystal violet.
  • the plaques were counted and IC 50 s for the compounds were calculated based on their ability to reduce the formation of plaques in this assay.
  • Ganciclovir was used as a standard in each set of plaque reduction assay experiments.

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Abstract

L'invention se rapporte à des nouveaux benzimidazoles polysubstitués, à des compositions les contenant et à leur utilisation pour le traitement d'infections virales. Les benzimidazoles polysubstitués et les compositions de la présente invention présentent des caractéristiques antivirales par rapport aux virus de la famille de l'herpès, en particulier le cytomégalovirus humain (HCMV) et les virus de l'herpès (HSV).
PCT/US1993/010104 1992-10-21 1993-10-20 Benzimidazoles polysubstitues utilises comme agents antiviraux WO1994008456A1 (fr)

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US08/050,470 US5574058A (en) 1990-11-01 1993-05-03 Polysubstituted benzimidazoles as antiviral agents
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WO1996001833A1 (fr) * 1994-07-07 1996-01-25 The Wellcome Foundation Limited Composes therapeutiques
WO1997007125A1 (fr) * 1995-08-18 1997-02-27 The Regents Of The University Of Michigan Benzimidazoles de ribofuranosyle 5'-substitues utilises comme agents antiviraux
WO1997025337A1 (fr) * 1996-01-05 1997-07-17 Glaxo Group Limited Composes therapeutiques
WO1998035977A1 (fr) * 1997-02-13 1998-08-20 Glaxo Group Limited Derives de benzimidazole
US5998398A (en) * 1996-01-05 1999-12-07 Glaxo Wellcome Inc. 2-amino-5,6-dichlorobenzimidazole derivatives having antiviral activity
US6214801B1 (en) 1996-01-23 2001-04-10 The Regents Of The University Of Michigan Imidazo[1,2-a]pyridine C-nucleosides as antiviral agents
US6455506B1 (en) 1997-07-30 2002-09-24 Smithkline Beecham Corporation Lyxofuranosyl benzimidazoles as antiviral agents
US6455507B1 (en) 1997-06-10 2002-09-24 Smithkline Beecham Corporation Benzimidazole derivatives
US6469160B1 (en) * 1998-04-07 2002-10-22 Smithkline Beecham Corporation Crystalline forms of an antiviral benzimidazole compound
US6482939B1 (en) 1998-04-07 2002-11-19 Smithkline Beecham Corporation Form vi 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)-1h-bezimimidazole
EP0984967B1 (fr) * 1996-03-15 2004-02-25 Biochem Pharma Inc Derives de la naphthyridine et leurs analogues inhibiteurs du cytomegalovirus
EP2681200A4 (fr) * 2011-03-03 2015-05-27 Zalicus Pharmaceuticals Ltd Inhibiteurs de type benzimidazole du canal sodique

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CANCER TREATMENT REPORTS, Volume 60, No. 10, issued October 1976, SMITH et al., "Inhibitors of Hypoxanthine Metabolism in Ehrlich Ascites Tumor Cells In Vitro", page 1575. *

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US6307043B1 (en) 1994-07-07 2001-10-23 Glaxo Wellcome Inc. Benzimidazole and its ribonucleoside
WO1996001833A1 (fr) * 1994-07-07 1996-01-25 The Wellcome Foundation Limited Composes therapeutiques
MD1838G2 (ro) * 1994-07-07 2002-08-31 Зэ Уелкэм Фаундейшэн Лимитид Derivaţi de 5,6-diclorbenzimidazol, procedeu de obţinere a lor, compoziţie farmaceutică şi metodă de tratament sau de prevenire a infecţiei virotice herpetice
AP736A (en) * 1994-07-07 1999-03-09 The Wellcome Foundation Ltd Benzimidazole derivatives and their use in medical therapy particularly for the treatment of virus infections.
US5998605A (en) * 1994-07-07 1999-12-07 Glaxo Wellcome Inc. Antiviral benzimidazole nucleoside analogues and method for their preparation
US6077832A (en) * 1994-07-07 2000-06-20 Glaxo Wellcome Inc. Antiviral benzimidazole nucleoside analogues and a method for their preparation
AU721277B2 (en) * 1995-08-18 2000-06-29 Regents Of The University Of Michigan, The 5'-substituted-ribofuranosyl benzimidazoles as antiviral agents
US5874413A (en) * 1995-08-18 1999-02-23 University Of Michigan 5'-substituted-ribofuranosyl benzimidazoles as antiviral agents
WO1997007125A1 (fr) * 1995-08-18 1997-02-27 The Regents Of The University Of Michigan Benzimidazoles de ribofuranosyle 5'-substitues utilises comme agents antiviraux
WO1997025337A1 (fr) * 1996-01-05 1997-07-17 Glaxo Group Limited Composes therapeutiques
US6617315B1 (en) 1996-01-05 2003-09-09 Stanley Dawes Chamberlain Therapeutic compounds
US5998398A (en) * 1996-01-05 1999-12-07 Glaxo Wellcome Inc. 2-amino-5,6-dichlorobenzimidazole derivatives having antiviral activity
US6204249B1 (en) 1996-01-05 2001-03-20 Glaxo Wellcome Inc. L-benzimidazole nucleosides
US6214801B1 (en) 1996-01-23 2001-04-10 The Regents Of The University Of Michigan Imidazo[1,2-a]pyridine C-nucleosides as antiviral agents
EP0984967B1 (fr) * 1996-03-15 2004-02-25 Biochem Pharma Inc Derives de la naphthyridine et leurs analogues inhibiteurs du cytomegalovirus
US6413938B1 (en) 1997-02-13 2002-07-02 The Regents Of The University Of Michigan Benzimidazole derivatives for the treatment of viral infections
WO1998035977A1 (fr) * 1997-02-13 1998-08-20 Glaxo Group Limited Derives de benzimidazole
US6455507B1 (en) 1997-06-10 2002-09-24 Smithkline Beecham Corporation Benzimidazole derivatives
US6455506B1 (en) 1997-07-30 2002-09-24 Smithkline Beecham Corporation Lyxofuranosyl benzimidazoles as antiviral agents
US6482939B1 (en) 1998-04-07 2002-11-19 Smithkline Beecham Corporation Form vi 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)-1h-bezimimidazole
US6469160B1 (en) * 1998-04-07 2002-10-22 Smithkline Beecham Corporation Crystalline forms of an antiviral benzimidazole compound
US7297683B2 (en) 1998-04-07 2007-11-20 Smithkline Beecham Corporation Crystalline forms of an antiviral benzimidazole compound
US7714123B2 (en) 1998-04-07 2010-05-11 Glaxosmithkline Llc Crystalline forms of an antiviral benzimidazole compound
US9163052B2 (en) 1998-04-07 2015-10-20 Glaxosmithkline Llc Crystalline forms of an antiviral benzimidazole compound
EP2681200A4 (fr) * 2011-03-03 2015-05-27 Zalicus Pharmaceuticals Ltd Inhibiteurs de type benzimidazole du canal sodique
US9688615B2 (en) 2011-03-03 2017-06-27 Degiacomo, Interim Trustee, Mark G. Benzimidazole inhibitors of the sodium channel

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