WO2001094348A1 - Agents antiviraux - Google Patents

Agents antiviraux Download PDF

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Publication number
WO2001094348A1
WO2001094348A1 PCT/AU2001/000686 AU0100686W WO0194348A1 WO 2001094348 A1 WO2001094348 A1 WO 2001094348A1 AU 0100686 W AU0100686 W AU 0100686W WO 0194348 A1 WO0194348 A1 WO 0194348A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
hydrogen
hydroxy
amino
Prior art date
Application number
PCT/AU2001/000686
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English (en)
Inventor
Sebastian Mario Marcuccio
Karen Elizabeth Jarvis
Original Assignee
Commonwealth Scientific And Industrial Research Organisation
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
Application filed by Commonwealth Scientific And Industrial Research Organisation filed Critical Commonwealth Scientific And Industrial Research Organisation
Priority to AU2001263668A priority Critical patent/AU2001263668A1/en
Publication of WO2001094348A1 publication Critical patent/WO2001094348A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • 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
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • Herpes Simplex virus (HSV) infections is recommended only in cases involving infection of slowly dividing host tissues, such as in keratoconjunctivitis. This is made necessary by the fact that idoxuridine (IUdR) and arabinoadenosine (ARA-A) can interfere with both viral DNA and host DNA, causing severe side effects. Severe systemic and neonatal HSV infections have been successfully treated with ARA-A, but extreme caution must be exercised in its use in order to prevent damage to blood-forming organs. Acyclovir is also approved for use against initial infections of herpes genitalis.
  • IdR idoxuridine
  • ARA-A arabinoadenosine
  • the drug is used to control localized herpes simplex infections for both genital and labial herpes in patients whose natural defences are impaired and unable to control the spread of the infection.
  • This drug reduces the length of time that live virions are present in the vesicles.
  • This viral shedding in the lesion allows the virus to be transferred from one person to another through sexual contact, and the disease is highly contagious when sores are present.
  • Another control attempt centers on the use of homologous vaccines made from attenuated HSV along with heterologous vaccines prepared from attenuated forms of viruses with cross-reacting antigens. For example, heterologous vaccination has been attempted with smallpox and polio vaccines.
  • Cytomegalic inclusion disease occurs most frequently in infants and a viral disease of the salivary glands and other tissues. It is caused by the intrauterine (congenital) or postnatal transmission of cytomegalovirus (CMV) Although rare, CID may also occur in adults receiving immunosuppressive therapy. Like other herpes viruses, CMV infections result in vesicular eruption of host tissue. The virus is not only found in the salivary glands but also the kidneys, liver, brain, lungs and eyes. Tissue destruction can be fatal or result in severe brain damage, blindness, deafness and heart defects. CMV is believed to be able to enter a latent period, as do other herpes viruses, resulting in a delay in the onset of symptoms of up to two years. At present, there is no treatment for this disease. A vaccine of attenuated CMV has been developed, but its value in preventing infection is questionable.
  • HBV Human Hepatitis B virus
  • Herpesvirus, Flavivirus and Hepadnavirus is highly desirable. Drugs which control or inhibit replication have proven to be effective in the control of some other viruses, however because of the difficulty of inhibiting viruses while leaving the non-infected cells unimpaired, few antiviral drugs are currently in widespread clinical use.
  • the antiviral activity and the preparation of purines which carry an acyclic radical in the 9-position are known. However, little is known about the antiviral activity of purines substituted in the 7-position.
  • substituted purines are inhibitors of replication of Hepatitis B virus and hence may be useful control agents for viral infections from a wide range of viruses including Herpesvirus, Flavivirus and Hepadnavirus when used alone or with one or more other antiviral agents.
  • R 3 is selected from hydrogen, halogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkenyloxyalkyl, mercapto, optionally substituted thio, optionally substituted amino, azide, optionally substituted aryloxy, optionally substituted acyl, optionally substituted acyloxy, carboxylic acid, optionally substituted carboxylic ester, optionally substituted carboxylic amide, optionally substituted thioester, optionally substituted sulphonyl, or -O- alkyl-P(O)(OR 5 )(OR 6 ) or -O-alkyl-P-alkyl-(O)(OR 5 ), wherein R 5 and R 6 are independently selected from hydrogen, alkyl, ammonium, triethylammonium or an alkali metal or alkaline earth metal ion;
  • n is an integer from 0 to 3
  • salts includes any pharmaceutically acceptable salt, ester, hydrate, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of the invention, or an antivirally active metabolite or residue thereof.
  • cyclic alkyl examples include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as "propyl", butyl” etc, it will be understood that this refers to straight, branched and cyclic isomers. An alkyl group may be optionally substituted by one or more optional substitutents as herein defined. Accordingly, "alkyl” as used herein is taken to refer to optionally substituted alkyl.
  • benzyl (wherein benzyl itself may be further substituted), phenoxy (wherein phenyl itself may be further substituted), benzyloxy (wherein benzyl itself may be further substituted), amino, alkylamino (eg C 1-6 alkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (eg C 1-6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH 3 ), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, -C(O)-alkyl (eg C 1-6 alkyl, such as acetyl), O-C(O)-alkyl (eg C ⁇ responsibly6alkyl, such as acetyloxy), benzoyl (where
  • amino examples include alkylamino, arylamino, dialkylamino, diarylamino, acyl amino, diacylamino, such as NH 2 , NHMe, NHEt, NHPr, NHBu, NMe 2 , NEt 2 , NPr 2 (n- and t ' -Pr), NHphenyl, Ndiphenyl, NHbenzyl, Ndibenzyl NHC(O)CH 3 and N(C(O)CH 3 ) 2 .
  • R and R' group which is not hydrogen may be optionally substituted as described above.
  • reactive groups such as free hydroxy, mercapto or amino groups may be temporarily or permanently protected by a protecting group.
  • Protected compounds of the invention may useful as intermediates in the preparation of compounds suitable for use in the therapeutic methods of the invention and accordingly, the protected derivatives of the compounds of Formula (I), or salts, derivatives, prodrugs, tautomers or isomers thereof, are also considered to be within the scope of the invention.
  • Suitable protecting groups including for example alkyl, acyl and silyl groups. Methods for the installation and removal of protecting groups are known to the skilled person and are described in Protective Groups in Organic Synthesis, T. Greene and P. Wutz, John Wiley and Son, 3 rd Edition, 1991.
  • an “effective amount” of the compound, analogue or derivative as used in accordance with this invention is an amount sufficient to inhibit, slow, interrupt, halt, prevent or arrest viral growth or replication. Suitable “effective amounts” may depend on the age, gender, weight and general health of the patient and can be determined by the attending physician or veterinarian.
  • nucleoside anti-viral agent which inhibits reverse transcriptase
  • the two different modes of action provide an unexpectedly superior anti- viral treatment. This appears to be due to a synergistic effect between the compound of formula (I) and the nucleoside antiviral agent.
  • suitable nucleoside anti-viral agents include those described above.
  • the agent is 3TC, adefovir, dipivoxil, BMS_200475, emtricitabine ((- )FTC), B-L-Fd4C, clevudine, (L-FMAU), DAPD and nabi-3700.001.
  • compositions of the present invention comprise at least one active ingredient, together with one or more pharmaceutically acceptable carriers or diluents, and optionally other antiviral or other therapeutic agents.
  • Each carrier must be pharmaceutically "acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.
  • Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compositions 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 compositions 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.
  • compositions 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.
  • Compositions suitable for parenteral administration include aqueous and non- aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • compositions 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.
  • 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.
  • parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zerin, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha- tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • the leaving groups may be of any suitable known type, such as, for example, halogen, silyl, methylate or sulfates, such as tosylate, mesylate, or brosylate, and those leaving groups disclosed in Jerry March “Advanced Organic Chemistry Reactions, Mechanisms and Structure", Fourth Edition 1992, p 357.
  • Example 1 7-[4-Acetoxy-3-(acetoxymethyl)but-l-yl]-2-amino-6-chloropurine.
  • formulation A may be prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • Formulation B mg/capsule or tablet Active ingredient 250
  • This formulation may be prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.
  • a capsule formulation may be prepared by admixing the ingredients of Formulation B in Example 4 above and filling into a two-part hard gelatin capsule.
  • Formulation, B (intra) may be prepared in a similar manner.
  • the following controlled release capsule formulation may be prepared by extruding ingredients a, b and c using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets may then be coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule. mg/capsule
  • the active ingredient may be dissolved in most of the water at 35-40 °C and the pH adjusted to between 5.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate.
  • the batch may then be made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule générale (I), dans laquelle R1 représente un hydrogène, un halogène, un azide, un alcoxy éventuellement substitué, un aryloxy éventuellement substitué, un mercapto, un thio éventuellement substitué, un amino éventuellement substitué, un hydrazino éventuellement substitué, ou un séléno éventuellement substitué ; R2 représente un hydrogène, un halogène, un hydroxy, un azide, un mercapto, un thio éventuellement substitué, ou un amino éventuellement substitué ; R3 représente un élément sélectionné dans le groupe comprenant un hydrogène, un halogène, un hydroxy, un alkyle éventuellement substitué, un alcoxy éventuellement substitué, un alcényle éventuellement substitué, un alcényloxy éventuellement substitué, un alcényloxyalkyle éventuellement substitué, un mercapto, un thio éventuellement substitué, un amino éventuellement substitué, un azide, un aryloxy éventuellement substitué, un acyle éventuellement substitué, un acyloxy éventuellement substitué, un acide carboxylique, un ester carboxylique éventuellement substitué, un amide carboxylique éventuellement substitué, un thioester éventuellement substitué, un sulphonyl éventuellement substitué, ou un -O-alkyl-P(O)(OR5)(OR6) ou un -O-alkyl-P-alkyl-(O)(OR?5), R5 et R6¿ représentant indépendamment des éléments sélectionnés dans le groupe comprenant un hydrogène, un alkyle, un ammonium, un triéthylammonium ou un ion de métal alcalin ou de métal alcalino-terreux ; R4 et l'atome d'oxygène auquel il est rattaché formant un groupe hydroxy, un ester, un carbonate, un carbamate, ou un thiocarbonate ainsi que ses sels ou un -O-alkyl-P(O)(OR5)(OR6) ou un -O-alkyl-P-alkyl(O)(OR?5)(OR6), R5 et R6¿ représentant les éléments décrits ci-dessus ; et n représente un entier compris entre 0 et 3. L'invention concerne également des sels, des dérivés, des promédicaments, des tautomères et/ou des isomères de ce composé.
PCT/AU2001/000686 2000-06-08 2001-06-08 Agents antiviraux WO2001094348A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001263668A AU2001263668A1 (en) 2000-06-08 2001-06-08 Antiviral agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPQ8067 2000-06-08
AUPQ8067A AUPQ806700A0 (en) 2000-06-08 2000-06-08 Antiviral agents

Publications (1)

Publication Number Publication Date
WO2001094348A1 true WO2001094348A1 (fr) 2001-12-13

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AU (1) AUPQ806700A0 (fr)
WO (1) WO2001094348A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253412B1 (fr) * 1986-07-18 1990-10-31 Ceskoslovenska akademie ved Dérivés N-phosphonométhoxyalkyliques de bases de pyrimidine et de purine, leur procédé de préparation, compositions pharmaceutiques les contenant avec activité antivirale
US5075445A (en) * 1983-08-18 1991-12-24 Beecham Group P.L.C. Guanine derivatives
US5684153A (en) * 1984-08-16 1997-11-04 Beecham Group Plc Process for the preparation of purine derivatives
WO2000006573A1 (fr) * 1998-07-29 2000-02-10 Kemijski inštitut Derives antiviral de purine substitues par alkyle et preparation de ces derives
WO2000008025A1 (fr) * 1998-08-06 2000-02-17 Medivir Ab Synthese de derives de nucleoside acyclique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5075445A (en) * 1983-08-18 1991-12-24 Beecham Group P.L.C. Guanine derivatives
US5684153A (en) * 1984-08-16 1997-11-04 Beecham Group Plc Process for the preparation of purine derivatives
EP0253412B1 (fr) * 1986-07-18 1990-10-31 Ceskoslovenska akademie ved Dérivés N-phosphonométhoxyalkyliques de bases de pyrimidine et de purine, leur procédé de préparation, compositions pharmaceutiques les contenant avec activité antivirale
WO2000006573A1 (fr) * 1998-07-29 2000-02-10 Kemijski inštitut Derives antiviral de purine substitues par alkyle et preparation de ces derives
WO2000008025A1 (fr) * 1998-08-06 2000-02-17 Medivir Ab Synthese de derives de nucleoside acyclique

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
BRAND B. ET AL.: "Convenient syntheses of 9-(4-hydroxy-3-(hydroxymethyl)butyl)-guanine (penciclovir) and 9-(4-acetoxy-3-(acetoxymethyl)butyl)-2-amino-9H-purine (famiciclovir)", TETRAHEDRON, vol. 55, 1999, pages 5239 - 5252, ISSN 0040-4020 *
GEEN G.R. ET AL.: "The effect of the C-6 substituent on the regioselectivity of N-alkylation of 2-aminopurines", TETRAHEDRON, vol. 46, no. 19, 1990, pages 6903 - 6914, ISSN 0040-4020 *
HANNAH J. ET AL.: "Carba-acylonucleoside antiherpetic agents", J. HETEROCYCLIC CHEM., vol. 26, 1989, pages 1261 - 1271, ISSN 022-152X *
HOCKOVA D. ET AL.: "7-(1-cyanobut-3-en-1-yl)-N6-(N,N-dimethylamino)methylene)-adenine as a starting compound for the synthesis of alpha-branched acyclic analogues of N7-isomer of adenine", COLLECT. CZECH. CHEM. COMMUN., vol. 64, 1999, pages 1316 - 1324 *
HOLY A. ET AL.: "Structure-antiviral activity relationship in the series of pyrimidine and purine N-(2-(2-phosphonomethoxy)ethyl) nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base", J. MED. CHEM., vol. 42, 1999, pages 2064 - 2086, ISSN 022-2633 *
HOLY A. ET AL.: "Synthesis of 3-(hydroxy-2-phosphonylmethoxypropyl) derivatives of heterocyclic bases", COLLECT. CZECH. CHEM. COMMUN., vol. 54, 1989, pages 2470 - 2501, XP000917997 *
HOLY A. ET AL.: "Synthesis of N-(2-(2-phosphonylethoxy)ethyl) derivatives of heterocyclic bases", COLLECT. CZECH. CHEM. COMMUN., vol. 54, 1989, pages 809 - 818 *
HOLY A. ET AL.: "Synthesis of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases", COLLECT. CZECH. CHEM. COMMUN., vol. 54, 1989, pages 2190 - 2210 *
KJELLBERG J. ET AL.: "Regioselective alkylation of 6-(beta-methoxyethoxy)guanine to give the 9-alkylguanine derivative", TETRAHEDRON LETTERS, vol. 27, no. 7, 1986, pages 877 - 880 *
KJELLBERG J. ET AL.: "Studies on the alkylation of derivatives of guanine", NUCLEOSIDES AND NUCLEOTIDES, vol. 8, no. 2, 1989, pages 225 - 256, ISSN 0732-8311, XP000616145 *
PLATZER N. ET AL.: "Easy alkylation of purine bases by solid-liquid phase transfer catalysts without solvent. Structural analysis by 2D heteronuclear 1H13C correlated NMR spectroscopy", TETRAHEDRON, vol. 43, no. 9, 1987, pages 2101 - 2108, ISSN 0040-4020 *
SESSLER J.L. ET AL.: "The synthesis of 2-amino 7-substituted purines", NUCLEOSIDES AND NUCLEOTIDES, vol. 8, no. 3, 1989, pages 431 - 448, ISSN 0732-8311 *
XU H. ET AL.: "Synthesis, properties and pharmacokinetic studies of N2-phenylguanine derivatives as inhibitors of herpes simplex virus thymidine kinases", J. MED. CHEM., vol. 38, 1995, pages 49 - 57, ISSN 022-2633, XP002053656 *

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