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WO2008131502A2 - Nouveaux composés antiviraux - Google Patents

Nouveaux composés antiviraux Download PDF

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Publication number
WO2008131502A2
WO2008131502A2 PCT/BE2008/000033 BE2008000033W WO2008131502A2 WO 2008131502 A2 WO2008131502 A2 WO 2008131502A2 BE 2008000033 W BE2008000033 W BE 2008000033W WO 2008131502 A2 WO2008131502 A2 WO 2008131502A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compounds
purine
substituted
aryl
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.)
Ceased
Application number
PCT/BE2008/000033
Other languages
English (en)
Other versions
WO2008131502A3 (fr
Inventor
Armando De Palma
Antonin Holy
Hubert Hrebabecky
Johan Neyts
Michal Sala
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.)
Katholieke Universiteit Leuven
Czech Academy of Sciences CAS
Institute of Organic Chemistry and Biochemistry CAS
Original Assignee
Katholieke Universiteit Leuven
Czech Academy of Sciences CAS
Institute of Organic Chemistry and Biochemistry CAS
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 Katholieke Universiteit Leuven, Czech Academy of Sciences CAS, Institute of Organic Chemistry and Biochemistry CAS filed Critical Katholieke Universiteit Leuven
Publication of WO2008131502A2 publication Critical patent/WO2008131502A2/fr
Publication of WO2008131502A3 publication Critical patent/WO2008131502A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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

Definitions

  • the icosahedral capsid of the virus is formed by 60 protomers, each one assembled by the 4 structural proteins, designated VP 1-4.
  • the non-structural region comprises two proteases, the viral RNA-dependent RNA polymerase (RdRp) and 4 other mature proteins that either cleaved or as a precursor, are involved in viral replication.
  • RdRp viral RNA-dependent RNA polymerase
  • the compounds of the invention are employed for the treatment or prophylaxis of viral infections, more particularly Picornaviridae infections.
  • the active ingredients of the compound(s) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra- arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals corresponds to an amount which ensures a plasma level of between l ⁇ g/ml and 100 mg/ml, optionally of 10 mg/ml.
  • the effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • ED x is the dose of the first or respectively second drug used alone (Ia, 2a), or in combination with the second or respectively first drug (Ic, 2c), which is needed to produce a given effect.
  • Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against viral infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother.
  • the term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds according to the formulae of the application are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable nontoxic salts containing, for example, Na+, Li+, K+, Ca+2 and Mg+2. Such salts may include those derived by combination of appropriate cations s ⁇ ch as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative.
  • Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX 4 + (wherein X typically is independently selected from H or a C 1 -C 4 alkyl group).
  • a suitable cation such as Na+ and NX 4 + (wherein X typically is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • the compounds of the present invention can have different isomeric forms, including stereoisomers and tautomers, and during the synthesis as provided herein normally one isomeric form is prepared (except for some isomeric impurities). AU the atoms in the compounds of the present invention can be in the R or S form. For some specific
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, hie, p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compounds of the invention.
  • 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 solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • 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 for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), 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 as nasal drops include aqueous or oily solutions of the active ingredient.
  • the pro-drugs of the present invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms.
  • the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus.
  • a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used.
  • Table 1 Structures of example compounds of the invention and their respective codes.
  • EXAMPLE 4 Synthesis of 9-(l-Adamantyl)-6-chloro-9H-purine (2) and related compounds of the invention.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une série de nouveaux composés qui présentent une activité antivirale, notamment à l'encontre de virus de la famille des picornaviridés (Picornaviridae). Cette invention concerne les nouveaux composés, des procédés de préparation de ceux-ci, des compositions pharmaceutiques les comprenant, ainsi que ces composés utilisés comme médicament, en particulier comme médicament antiviral.
PCT/BE2008/000033 2007-04-27 2008-04-28 Nouveaux composés antiviraux Ceased WO2008131502A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0708258.9 2007-04-27
GBGB0708258.9A GB0708258D0 (en) 2007-04-27 2007-04-27 New anti-viral nulceoside analogs

Publications (2)

Publication Number Publication Date
WO2008131502A2 true WO2008131502A2 (fr) 2008-11-06
WO2008131502A3 WO2008131502A3 (fr) 2009-03-05

Family

ID=38170862

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BE2008/000033 Ceased WO2008131502A2 (fr) 2007-04-27 2008-04-28 Nouveaux composés antiviraux

Country Status (2)

Country Link
GB (1) GB0708258D0 (fr)
WO (1) WO2008131502A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10189841B2 (en) 2015-11-20 2019-01-29 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5250535A (en) * 1982-02-01 1993-10-05 Syntex Inc. Substituted 9-(1 or 3-monoacyloxy or 1,3-diacyloxy-2-propoxymethyl) purines as antiviral agent
JPH06102662B2 (ja) * 1989-09-01 1994-12-14 協和醗酵工業株式会社 キサンチン誘導体
ES2199289T3 (es) * 1995-07-26 2004-02-16 Kyowa Hakko Kogyo Co., Ltd. Dispersion solida de derivados de xantina.
JP4667543B2 (ja) * 1996-07-03 2011-04-13 大日本住友製薬株式会社 新規プリン誘導体

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10189841B2 (en) 2015-11-20 2019-01-29 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors
US10399980B2 (en) 2015-11-20 2019-09-03 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors
US11161848B2 (en) 2015-11-20 2021-11-02 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors
US12043623B2 (en) 2015-11-20 2024-07-23 Forma Therapeutics, Inc. Purinones as ubiquitin-specific protease 1 inhibitors

Also Published As

Publication number Publication date
WO2008131502A3 (fr) 2009-03-05
GB0708258D0 (en) 2007-06-06

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