EP0779885A1 - Analogues de nucleosides antiviraux contenant une base benzimidazole substituee fixee a une chaine carbocyclique - Google Patents

Analogues de nucleosides antiviraux contenant une base benzimidazole substituee fixee a une chaine carbocyclique

Info

Publication number
EP0779885A1
EP0779885A1 EP95934402A EP95934402A EP0779885A1 EP 0779885 A1 EP0779885 A1 EP 0779885A1 EP 95934402 A EP95934402 A EP 95934402A EP 95934402 A EP95934402 A EP 95934402A EP 0779885 A1 EP0779885 A1 EP 0779885A1
Authority
EP
European Patent Office
Prior art keywords
dichloro
benzimidazol
cyclopentanediol
hydroxymethyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95934402A
Other languages
German (de)
English (en)
Inventor
Leroy B. Townsend
Susan Mary Daluge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wellcome Foundation Ltd
University of Michigan
Original Assignee
Wellcome Foundation Ltd
University of Michigan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/304,006 external-priority patent/US5534535A/en
Application filed by Wellcome Foundation Ltd, University of Michigan filed Critical Wellcome Foundation Ltd
Publication of EP0779885A1 publication Critical patent/EP0779885A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to certain purine nucleoside analogues containing a
  • hepadnaviruses each member of which selectively infects either mammalian or
  • avian hosts such as the woodchuck and the duck.
  • HBV is a viral pathogen of major consequence. It is most common
  • This carrier population serves as the source of infection of susceptible
  • the herpes group is the source of many common viral
  • CMV cytomegalovirus
  • Epstein-Barr Epstein-Barr
  • EBV varicella zoster virus
  • HSV herpes simplex virus
  • HHV6 human herpes virus 6
  • virus association of virus and host and, following a primary infection, virus may be
  • EBV causes infectious mononucleosis and is also suggested as the causative
  • VZV causes chicken pox and shingles.
  • Chicken pox is the primary disease
  • Shingles is the recurrent form of the disease which occurs in adults who were previously infected with
  • the clinical manifestations of shingles include neuralgia and a
  • inflammation may lead to paralysis or convulsions and coma can occur if the
  • VZV may
  • HSV 1 and HSV 2 are some of the most common infectious agents of man.
  • HSV infection is often
  • infections may be subclinical although they tend to be more severe than
  • HSV can lead to keratitis or cataracts. Infection in the newborn, in
  • HHV6 is the causative agent of roseola
  • novel compounds According to a first aspect of the present invention, novel compounds
  • R 1 is H, CH 3 or CH 2 OH;
  • R 2 is H or OH;
  • R 3 is H or OH; or
  • R 4 is amino, cyclopropylamino, cyclobutylamino, isopropylamino, r/-butylamino or -NR 8 R 9 where R 8 and R 9
  • R 5 is H and R 6 and R 7 are
  • Preferred compounds of formula (I) and (1-1) are those wherein R 4 is
  • Preferred compounds of Formula (I) and (1-1) are those of Formula (I A) or (IA-
  • R 2 is H or OH;
  • R 4 is amino, cyclopropylamino, isopropylamino, tert-
  • butylamino especially isopropyl or ten -butylamino, or
  • R 5 is H; and R 6 and R 7 are
  • Particularly preferred compounds of formula (I A) and (IA-1) are those wherein
  • R 4 is cyclopropylamino, isopropylamino or tert-butylamino;
  • R 5 is H; and
  • R 7 are both Cl; and the pharmaceutically acceptable derivatives thereof.
  • Enantiomers depicted by formula (I-l) are most preferred and preferably are
  • prophylaxis of viral infections such as herpes viral infections.
  • HBV hepatitis B virus
  • CMV cytomegalovirus
  • present invention are particularly useful for the treatment or prophylaxis of
  • hepatitis B or a herpes viral infection such as CMV which
  • a pharmaceutically acceptable derivative is meant any pharmaceutically or
  • a recipient is capable of providing (directly or indirectly) a compound according to the invention, or an antivirally active metabolite or residue thereof.
  • heterocyclic ring means a saturated, unsaturated or partially saturated
  • esters of the compounds of the invention include carboxylic acid esters
  • alkyl e.g. n-propyl, t-butyl, n-butyl, alkoxyalkyl (e.g.
  • aralkyl e.g. benzyl
  • aryloxyalkyl e.g. phenoxymethyl
  • sulfonate esters such as alkyl- or aralkylsulfonyl (e.g. methanesulfonyl);
  • amino acid esters e.g. L-valyl or L-isoleucyl
  • mono-, di- or triphosphate e.g. L-valyl or L-isoleucyl
  • the phosphate esters may be further esterified by, for example, a C ⁇ _20
  • moiety present advantageously contains 1 to 18 carbon atoms, particularly 3 to 6
  • any reference to any of the above compounds also includes a reference to a
  • Physiologically acceptable salts include salts of organic carboxylic acids such as
  • succinic acids organic sulfonic acids such as methanesulfonic, ethanesulfonic,
  • hydrochloric, sulfuric, phosphoric and sulfamic acids hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • viral infections or associated conditions such as acyclic nucleosides (e.g.
  • immunomodulatory agents such as thymosin, ribonucleotide
  • reductase inhibitors such as 2-acetylpyridine 5-[(2-
  • ingredient may be administered for therapy by any suitable route including oral,
  • parenteral including subcutaneous, intramuscular, intravenous and intradermal.
  • the desired dose is preferably
  • unit dosage forms for example, containing 10 to 1000 mg, preferably 20 to
  • the active ingredient should be administered to achieve peak plasma
  • concentrations of the active compound of from about 0.025 to about 100 ⁇ M, preferably about 0.1 to 70 ⁇ M, most preferably about 0.25 to 50 ⁇ M. This may
  • the active ingredient optionally in saline, or orally administered as a bolus
  • blood levels may be maintained by a continuous infusion to provide about 0.01
  • present invention comprise at least one active ingredient, as defined above,
  • Formulations include those suitable for oral, rectal, nasal, topical
  • transdermal buccal and sublingual including transdermal buccal and sublingual), vaginal or parenteral (including transdermal buccal and sublingual), vaginal or parenteral (including transdermal buccal and sublingual), vaginal or parenteral (including transdermal buccal and sublingual), vaginal or parenteral (including transdermal buccal and sublingual), vaginal or parenteral (including transdermal buccal and sublingual), vaginal or parenteral (including
  • formulations may conveniently be presented in unit dosage form and may be
  • formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both,
  • compositions suitable for transdermal administration may be presented as
  • patches suitably contain the
  • concentration of the active compound is about 1% to 25%, preferably about 3%
  • the active compound may be delivered
  • Formulations of the present invention suitable for oral administration may be any suitable for oral administration.
  • the active ingredient as a powder or granules; as a
  • a tablet may be made by compression or molding, optionally with one or more
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder
  • binder e.g. povidone, gelatin,
  • hydroxypropylmethyl cellulose hydroxypropylmethyl cellulose
  • lubricant inert diluent, preservative
  • disintegrant e.g. sodium starch glycollate, cross-linked povidone, cross-linked
  • tablets may be made by molding in a suitable machine a mixture of the
  • the tablets may
  • Tablets may optionally be provided with an enteric coating, to
  • Formulations suitable for topical administration in the mouth include lozenges
  • pastilles comprising the active ingredient in an inert basis such as
  • 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,
  • Formulations suitable for parenteral administration include aqueous and non-
  • aqueous isotonic sterile injection solutions which may contain anti-oxidants,
  • suspensions which may include suspending agents and thickening agents.
  • formulations may be presented in unit-dose or multidose sealed containers, for
  • ampules and vials may be stored in a freeze-dried (lyophilized)
  • solutions and suspensions may be prepared from sterile powders, granules and
  • Preferred unit dosage formulations are those containing a daily dose or unit
  • formulations of this invention may include other agents conventional
  • those suitable for oral administration may include such further agents as
  • sweeteners thickeners and flavoring agents.
  • the present invention further includes the following process, depicted
  • Base e.g., 2 CC >3 or t ⁇ ethylammo Solvent such as t-butanol. dioxane. dimethytforrnarnide
  • L is a leaving group, e.g., halogen, in particular Chloro
  • R 4 C(OR) 3 wherein R 4 is H, Ci-4 alkyl or C 1-4 perfluoroalkyl
  • R is Ci-4 alkyl, preferably at ambient temperature and in an acidic
  • Rl, R ⁇ and R ⁇ are as defined above and L is a leaving group
  • organosulphonyloxy e.g. p-toluenesulphonyloxy or
  • the present invention is intended to encompass both the racemates and the
  • a compound of formula (I) or (I-l) may be converted into a pharmaceutically
  • esterifying agent e.g. an acid
  • Active ingredient 100 Lactose 200 Starch 50 Povidone 5 Magnesium stearate 4
  • lactose used in formulation E was of the direct
  • Active Ingredient 250 Pregelatinised Starch NF15
  • the formulation was prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and
  • a capsule formulation was prepared by admixing the ingredients of Formulation D in Example 1 above and filling into a two-part hard gelatin capsule.
  • Capsules were prepared by melting the macrogol 4000 BP, dispersing the active
  • Capsules were prepared by dispersing the active ingredient in the lecithin and
  • the following controlled release capsule formulation was prepared by extruding
  • ingredients a, b and c using an extruder, followed by spheronisation of the
  • the active ingredient was dissolved in the glycofurol.
  • the benzyl alcohol was then added and dissolved, and water added to 3 ml. The mixture was then
  • the active ingredient was dissolved in a mixture of the glycerol and most of the
  • the volume was made up with purified water and mixed well.
  • Witepsol HI 5 was melted in a steam-jacketed pan at 45 °C
  • the active ingredient was sifted through a 2001 m sieve and added to
  • Witepsol HI 5 was added to the suspension and stirred to ensure a
  • HCMV Human cytomegalovirus
  • P5A cell line in 96-well plates are applied to microtiter plate
  • HBV surface antigen HBV surface antigen
  • virus particles are then denatured to release HBV DNA strands
  • Quantitation is achieved through fitting of a standard curve to
  • HBV producer cells 2500 cells/well, were seeded in 96-
  • One primer is biotinylated at the 5-prime end
  • primers were purchased from Synthecell Corp., Rockville, MD
  • IC50 (the median inhibitory concentration) is the amount of compound which produces a 50 percent decrease in HBV
  • metaperiodate (8.98 g, 42.3 meq) and ruthenium trichloride (44 mg, 0.21 meq) were added. Additional sodium metaperiodate (179 mg) was added
  • 1,4-dioxane 130 mL-water (10 mL) at reflux with 4M sulfuric acid (2.3 mL).
  • thermometer A dry, 2L, three-neck flask was equipped with a mechanical stirrer, thermometer
  • Example were evaporated to an oily solid (136.64 g), which was added to the
  • chloroform layer was dried (sodium sulfate) and then concentrated to an oil in
  • Example 19 This solid was reduced with Raney nickel/ hydrogen(45 psi) in
  • bromosuccinimide (2.10 g, 1 1.5 mmol) was added all at once. After 5 minutes of

Abstract

Cette invention se rapporte à des analogues de nucléosides antiviraux, qui contiennent une base benzimidazole substituée fixée à une chaîne carbocyclique à la place du résidu de sucre habituel. Ces composés sont représentés par les formules (I) et (I-1), où R1 représente H, CH¿3? ou CH2OH; R?2¿ représente H ou OH; R3 représente H ou OH; ou R2 et R3 forment ensemble une liaison; R4 représente amino, cyclopropylamino, cyclobutylamino, isopropylamino, tert-butylamino ou -NR?8R9, où R8 et R9¿ forment, avec l'atome d'azote auquel ils sont liés, une chaîne hétérocyclique à 4, 5 ou 6 éléments; R5 représente H; et R6 et R7 représentent Cl, à l'exclusion du composé (±)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxyméthyl)-1,2-cyclopentanediol, et à condition qu'au moins l'un des éléments R?1, R2 et R3¿ représente ou contienne OH. Ces composés ont une action contre les infections par le virus de l'herpès, en particulier le cytomégalovirus, et également contre les infections par le virus de l'hépatite B.
EP95934402A 1994-09-09 1995-09-11 Analogues de nucleosides antiviraux contenant une base benzimidazole substituee fixee a une chaine carbocyclique Withdrawn EP0779885A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/304,006 US5534535A (en) 1992-03-09 1994-09-09 Therapeutic nucleosides
US304006 1994-09-09
PCT/US1995/011366 WO1996007646A1 (fr) 1994-09-09 1995-09-11 Analogues de nucleosides antiviraux contenant une base benzimidazole substituee fixee a une chaine carbocyclique

Publications (1)

Publication Number Publication Date
EP0779885A1 true EP0779885A1 (fr) 1997-06-25

Family

ID=23174626

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95934402A Withdrawn EP0779885A1 (fr) 1994-09-09 1995-09-11 Analogues de nucleosides antiviraux contenant une base benzimidazole substituee fixee a une chaine carbocyclique

Country Status (17)

Country Link
EP (1) EP0779885A1 (fr)
JP (1) JPH10505092A (fr)
CN (1) CN1164855A (fr)
AP (1) AP741A (fr)
AU (1) AU3692895A (fr)
BR (1) BR9508826A (fr)
CA (1) CA2199502A1 (fr)
CZ (1) CZ71297A3 (fr)
FI (1) FI970959A (fr)
HU (1) HUT77440A (fr)
IS (1) IS4436A (fr)
NO (1) NO971070L (fr)
NZ (1) NZ294095A (fr)
OA (1) OA10601A (fr)
PL (1) PL319440A1 (fr)
SK (1) SK29197A3 (fr)
WO (1) WO1996007646A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5912356A (en) * 1995-09-11 1999-06-15 Glaxo Wellcome Inc. Antiviral nucleoside analogues containing a substituted benzimidazole base attached to a carbocyclic ring
GB9600142D0 (en) * 1996-01-05 1996-03-06 Wellcome Found Chemical compounds
JP2001512453A (ja) 1997-02-13 2001-08-21 グラックス グループ リミテッド ベンゾイミダゾール誘導体
EP1000080A1 (fr) 1997-07-30 2000-05-17 The Regents of The University of Michigan Benzimidazoles de lyxofuranosyle en tant qu'agents antiviraux
TR200103147T1 (tr) 1999-12-27 2002-06-21 Japan Tobacco Inc. Kaynaşık halkalı bileşikler ve bunların ilaç olarak kullanımı.
US6770666B2 (en) 1999-12-27 2004-08-03 Japan Tobacco Inc. Fused-ring compounds and use thereof as drugs
GB0008939D0 (en) 2000-04-11 2000-05-31 Glaxo Group Ltd Process for preparing substituted benzimidazole compounds
AR035543A1 (es) * 2001-06-26 2004-06-16 Japan Tobacco Inc Agente terapeutico para la hepatitis c que comprende un compuesto de anillo condensado, compuesto de anillo condensado, composicion farmaceutica que lo comprende, compuestos de benzimidazol, tiazol y bifenilo utiles como intermediarios para producir dichos compuestos, uso del compuesto de anillo con
CN1834090B (zh) * 2005-03-18 2011-06-29 中国科学院上海药物研究所 苯并咪唑类化合物、其制备方法以及用途
ES2757928T3 (es) 2007-08-02 2020-04-30 Millennium Pharm Inc Proceso para la síntesis de inhibidores de enzimas activadoras E1

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9205071D0 (en) * 1992-03-09 1992-04-22 Wellcome Found Therapeutic nucleosides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9607646A1 *

Also Published As

Publication number Publication date
AP9700940A0 (en) 1997-04-30
NO971070L (no) 1997-05-07
CZ71297A3 (en) 1997-08-13
FI970959A0 (fi) 1997-03-06
FI970959A (fi) 1997-05-06
AU3692895A (en) 1996-03-27
BR9508826A (pt) 1997-09-30
IS4436A (is) 1997-03-07
MX9701789A (es) 1997-10-31
CN1164855A (zh) 1997-11-12
NZ294095A (en) 1998-08-26
WO1996007646A1 (fr) 1996-03-14
PL319440A1 (en) 1997-08-04
SK29197A3 (en) 1997-10-08
OA10601A (en) 2002-09-03
JPH10505092A (ja) 1998-05-19
AP741A (en) 1999-04-26
NO971070D0 (no) 1997-03-07
CA2199502A1 (fr) 1996-03-14
HUT77440A (hu) 1998-04-28

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