WO2000006573A1 - Derives antiviral de purine substitues par alkyle et preparation de ces derives - Google Patents

Derives antiviral de purine substitues par alkyle et preparation de ces derives

Info

Publication number
WO2000006573A1
WO2000006573A1 PCT/SI1999/000021 SI9900021W WO0006573A1 WO 2000006573 A1 WO2000006573 A1 WO 2000006573A1 SI 9900021 W SI9900021 W SI 9900021W WO 0006573 A1 WO0006573 A1 WO 0006573A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
group
compounds
purine
acetyl
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/SI1999/000021
Other languages
English (en)
Inventor
Jože KOBE
Suzana JAKŠA
Genadij Kalayanov
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.)
Kemijski Institut
Original Assignee
Kemijski Institut
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 Kemijski Institut filed Critical Kemijski Institut
Priority to AU48175/99A priority Critical patent/AU4817599A/en
Publication of WO2000006573A1 publication Critical patent/WO2000006573A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a new process for the preparation of alkyl substituted purine derivatives, especially of N7 and N9 alkyl derivatives of purine. and to novel compounds, namely N7 alkyl derivatives of purine endowed with a potential biological, e.g. antiviral or antitumoural activity.
  • This new process enables the regioselective coupling of a specific alkyl group in 7 or 9 position of purine.
  • Purine derivatives in majority substituted in 9 position represent a plurality of important active substances endowed with antiviral activity. Inter alia, there are indicated: aciclovir, ganciclovir, and famciclovir and the like, which are still being researched. Recently, promising biological results for N7-substituted 2-amino purine possessing an acyclic component characteristic for ganciclovir (EP-A 448 006, EP-A 452 680), enhanced the palette of interesting active substances. Purine derivatives are usually prepared by coupling the side chain to the basic purine base. The basic problem and challenge are therefore an appropriate choice of the starting base (raw material), enabling the selective introduction of the selected side chain at the desired site, namely the N7 or N9 position.
  • the object of this invention is a new, regioselective process for the preparation of alkyl substituted purine derivatives, specifically N7 or N9 alkyl purine derivatives, starting from 7- or 9- benzyl guanine.
  • a further object of this invention are N7 alkyl purine derivatives, that are novel compounds endowed with a potential biological, e.g. antiviral or antitumoural activity.
  • the benzyl group may introduced in 7 position via the native nucleoside (guanosine) obtained by fermentation in a simple manner. (P. Brookes et al., J. Chem. Soc. ( C ) 2026, 1968 and P.K. Bridson et al.; Synthetic Commun.; 20, 2459, 1990).
  • the protection of a specific site means, of course, the possibility of performing a selective condensation to the remaining active 7 or 9 position.
  • R 2 represents a C 1 -C 12 linear or branched, saturated or unsaturated alkyl group, that may contain a 3-7 membered ring in the molecule, and also an ether, thioether, acetal, thioacetal, lactone, thiolactone, mono- or diacyl group, phosphorylmethoxy, phosphorylethoxy and phosphate groups,
  • R represents ring substituted p-methoxy, p-nitro, p-methyl benzyl groups
  • X represents chloro, bromo, iodo, p-toluene sulphonic groups or mesyloxy groups
  • R represents hydrogen, a CpC 6 alkyl group, a Ci-Cj ⁇ alkoxy group, a hydroxy group, a nitro group, an amino group, fluoro, chloro, bromo or iodo,
  • R 2 has the above meanings
  • This invention discloses the preferred example of the synthesis of penciclovir
  • R 4 represents a CpC 8 acyl group, a C Cio alkyl group or a C 7 -C 22 arylalkyl group.
  • the claimed process comprises the deoxygenation of the compounds of formulae 6 and 7 via the O6-sulphonylated intermediates of formulae 1 1 and 12
  • the compound of the formula 3 in conformance with this invention possesses a removable group, such as chloro, bromo, iodo, tozyl or mezyl groups, in the above mentioned linear or branched chain.
  • the alkyl group represents a side chain characteristic for potentially bioactive nucleoside active substances, and is bound to the purine ring.
  • the product of this composition has antiviral or antitumoural properties.
  • the reaction is preferably characterized by the following substituents without, however, limiting its scope.
  • R, R' and R" represent acetyl, benzoyl, benzyl or other standard protecting groups, and X has the same meanings as mentioned in the description of formulae 4 and 5.
  • N-substituted derivatives are known active substances.
  • N7-substituted derivatives are novel compounds.
  • the condensation reaction is performed in organic solvents, such as DMF, DMSO, 1 -methyl-2-pyrrolidone, preferably in 1 -methyl-2-pyrrolidone and at a temperature of 80 to 120 °C and is terminated within a few hours.
  • organic solvents such as DMF, DMSO, 1 -methyl-2-pyrrolidone, preferably in 1 -methyl-2-pyrrolidone and at a temperature of 80 to 120 °C and is terminated within a few hours.
  • the excess of the side chain (20 to 50%) is needed to improve the yield.
  • the compounds of formulae 4 and 5 are novel compounds, with the exception of the compounds disclosed in EP-A 728757 A.
  • the compounds of formulae 4 and 5 are obtained according to the above process, usually form salts. In the case, that the salt is not precipitating the debenzylation (hydrogenation) reaction may be performed on the crude product. Upon removal of the benzyl group the desired intermediates 6 and 7 are obtained. Conventional methods may be applied, such as the reduction in the presence of the palladium catalyst under hydrogen, or by means of formic acid or ammonium formate in standard solvents.
  • the claimed invention discloses and enables the regioselective preparation of alkylated purine derivatives directly from guanosine possesing substituents in position 9.
  • the 9-substituted derivatives are applicable as medicines.
  • the novel 7-substituted isomers, especially after the deoxygenation into 2-amino-7-alkil compounds represent a novel series of compounds endowed with potential biological activity e.g. an antiviral or an antitumoural activity.
  • Guanosine (56.6 g; 0.2 mole) was suspended in DMSO (150 mL) with stirring. The suspension was stirred for 20 min and then benzyl bromide (13 mL; 0.1 1 mole ) was added. The reaction mixture was stirred at room temperature for 24 hours, and the resulting solution was then transferred to a beaker. 10% HC1 (250 mL) was then added, and the mixture heated at 70° C for 2 hours, then cooled and filtered. The crystalline solid was washed with cold water, suspended in water and neutralized by addition of 6 M NaOH.
  • Acetyl-9-benzylguanine (0.5 g, 1.8 mmole) was suspended in l-methyl-2-pyrrolidone (5 mL ) and 4-acetoxy-3-acetoxymethyl-l -butyl tosylate (0.76 g, 2.1 mmole ) was added and heated at 120° C for 2 hours. Then additional 4-acetoxy— 3-acetoxymethyl-l -butyl tosylate ( 0.28g, 0.8 mmole ) was gradually added, and the heating at 120° C continued for 18 hours. The reaction mixture was allowed to cool and then poured into Et 2 O (20 mL ).

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

Abstract

Cette invention concerne un nouveau procédé de préparation de dérivés de purine substitués par alkyle, notamment de dérivés alkyle N7 et N9 de purine. Cette invention concerne également de nouveaux composés, précisément des dérivés alkyle N7 de purine, qui possèdent un potentiel biologique tel qu'une action antivirale ou antitumorale. Ce nouveau procédé permet de coupler un groupe alkyle spécifique de manière sélective envers les régions dans la position 7 ou 9 de la purine.
PCT/SI1999/000021 1998-07-29 1999-07-28 Derives antiviral de purine substitues par alkyle et preparation de ces derives Ceased WO2000006573A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48175/99A AU4817599A (en) 1998-07-29 1999-07-28 Antiviral alkyl substituted purine derivatives and their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-9800216 1998-07-29
SI9800216A SI20022A (sl) 1998-07-29 1998-07-29 Alkilno substituirani purinovi derivati in njihova priprava

Publications (1)

Publication Number Publication Date
WO2000006573A1 true WO2000006573A1 (fr) 2000-02-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SI1999/000021 Ceased WO2000006573A1 (fr) 1998-07-29 1999-07-28 Derives antiviral de purine substitues par alkyle et preparation de ces derives

Country Status (3)

Country Link
AU (1) AU4817599A (fr)
SI (1) SI20022A (fr)
WO (1) WO2000006573A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001094348A1 (fr) * 2000-06-08 2001-12-13 Commonwealth Scientific And Industrial Research Organisation Agents antiviraux
WO2002090358A1 (fr) * 2001-05-04 2002-11-14 Pharmacia Italia S.P.A. Halogenures de 7,9-guaninium disubstitue utilises comme des inhibiteurs de telomerase
US6761767B2 (en) 2001-08-30 2004-07-13 Ajinomoto Co., Inc. Production method of famciclovir and production and crystallization method of intermediate therefor
US7473780B2 (en) * 2004-05-18 2009-01-06 Teva Pharmeceutical Industries Ltd. Drying process for preparing crystalline solid famciclovir
US7544672B2 (en) 2005-03-30 2009-06-09 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US7601835B2 (en) * 2005-05-20 2009-10-13 Arrow International Limited Preparation of famciclovir and other purine derivatives
EP2145888A1 (fr) 2003-09-18 2010-01-20 Conforma Therapeutics Corporation Dérivés de déazapurine en tant qu'inhibiteurs de l'HSP90
WO2014145464A1 (fr) * 2013-03-15 2014-09-18 The Board Of Trustees Of The University Of Alabama Sels d'analogues de nucléosides ayant une solubilité améliorée et leurs procédés de formation
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182024A2 (fr) * 1984-09-20 1986-05-28 Beecham Group Plc Dérivés de purine et leur utilisation pharmaceutique
EP0728757A1 (fr) * 1995-02-21 1996-08-28 Ajinomoto Co., Inc. Procédé de préparation de dérivés de purine
WO1999012927A1 (fr) * 1997-09-11 1999-03-18 Commonwealth Scientific And Industrial Research Organisation Acyclonucleosides de purine utilises comme agents antiviraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182024A2 (fr) * 1984-09-20 1986-05-28 Beecham Group Plc Dérivés de purine et leur utilisation pharmaceutique
EP0728757A1 (fr) * 1995-02-21 1996-08-28 Ajinomoto Co., Inc. Procédé de préparation de dérivés de purine
WO1999012927A1 (fr) * 1997-09-11 1999-03-18 Commonwealth Scientific And Industrial Research Organisation Acyclonucleosides de purine utilises comme agents antiviraux

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BORYSKI,J. ET AL: "A Facile Syntehsis of 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (Ganciclovir) from Guanosine", SYNTHESIS, no. 4, 1999, STUTTGART, pages 625 - 628, XP002126579 *
BRAND,B ET AL.: "Convenient Syntesis of 9-[4-Hydroxy-3-(hydroxymethylbutyl]-guanine (penciclovir) and 9-[4-Acetoxy-3-(acetoxymethyl)butyl]2-amino-9H-purine (Famciclovir)", TETRAHEDRON, vol. 55, 1999, OXFORD, pages 5239 - 5252, XP002126581 *
CHINESE J.CHEM., vol. 9, no. 6, November 1991 (1991-11-01), PEKING, pages 536 - 5542, XP002126147 *
CUNDY D J ET AL: "3-[(3'-hydroxymethyl)-4'-hydroxybutyl]imidazo[4,5-b]pyridines--novel antiviral agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,GB,OXFORD, vol. 7, no. 6, pages 669-674, XP004136106, ISSN: 0960-894X *
GEEN,G.A. ET AL.: "The effect of the C-6 substituent on the Regioselectivity of N-Alkylation of 2-aminopurines", TETRAHEDRON, vol. 46, no. 19, 1990, OXFORD, pages 6903 - 6914, XP002126578 *
GEEN,G.R. ET AL.: "Regiospecific Michael Additions with 2-Amino-purines", TETRAHEDRON LETT., vol. 33, no. 32, 1992, OXFORD, pages 4609 - 4612, XP002126148 *
HAINES D R ET AL: "Synthesis and biological activity of unsaturated carboacyclic purine nucleoside analogs", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 30, no. 5, pages 943-947, XP002109313, ISSN: 0022-2623 *
KIM,D.K. ET AL.: "Synthesis and Evaluation of 2-Amino-9-(1,3-Dihydroxy-2-propoxymethyl)-6-fluoropurine Mono- and Diesters as Potential Prodrugs of Ganciclovir", J.MED.CHEM., vol. 42, no. 2, 1999, WASHINGTON, pages 324 - 328, XP002126580 *
KJELLBERG J ET AL: "STUDIES ON THE ALKYLATION OF DERIVATIVES OF GUANINE", NUCLEOSIDES & NUCLEOTIDES,XX,XX, vol. 8, no. 2, pages 225-256, XP000616145, ISSN: 0732-8311 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001094348A1 (fr) * 2000-06-08 2001-12-13 Commonwealth Scientific And Industrial Research Organisation Agents antiviraux
WO2002090358A1 (fr) * 2001-05-04 2002-11-14 Pharmacia Italia S.P.A. Halogenures de 7,9-guaninium disubstitue utilises comme des inhibiteurs de telomerase
US6761767B2 (en) 2001-08-30 2004-07-13 Ajinomoto Co., Inc. Production method of famciclovir and production and crystallization method of intermediate therefor
EP2145888A1 (fr) 2003-09-18 2010-01-20 Conforma Therapeutics Corporation Dérivés de déazapurine en tant qu'inhibiteurs de l'HSP90
US7473780B2 (en) * 2004-05-18 2009-01-06 Teva Pharmeceutical Industries Ltd. Drying process for preparing crystalline solid famciclovir
US7544672B2 (en) 2005-03-30 2009-06-09 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US8093229B2 (en) 2005-03-30 2012-01-10 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US7601835B2 (en) * 2005-05-20 2009-10-13 Arrow International Limited Preparation of famciclovir and other purine derivatives
AU2006248745B2 (en) * 2005-05-20 2011-06-23 Arrow International Limited Preparation of famciclovir and other purine derivatives
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US12398162B2 (en) 2011-12-22 2025-08-26 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
WO2014145464A1 (fr) * 2013-03-15 2014-09-18 The Board Of Trustees Of The University Of Alabama Sels d'analogues de nucléosides ayant une solubilité améliorée et leurs procédés de formation

Also Published As

Publication number Publication date
SI20022A (sl) 2000-02-29
AU4817599A (en) 2000-02-21

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