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WO1996011204A1 - NOUVEAUX β-L-NUCLEOSIDES ET LEUR UTILISATION - Google Patents

NOUVEAUX β-L-NUCLEOSIDES ET LEUR UTILISATION Download PDF

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Publication number
WO1996011204A1
WO1996011204A1 PCT/DE1995/001412 DE9501412W WO9611204A1 WO 1996011204 A1 WO1996011204 A1 WO 1996011204A1 DE 9501412 W DE9501412 W DE 9501412W WO 9611204 A1 WO9611204 A1 WO 9611204A1
Authority
WO
WIPO (PCT)
Prior art keywords
dideoxy
nucleosides
fluoro
hbv
chem
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/DE1995/001412
Other languages
German (de)
English (en)
Inventor
Eckart Matthes
Martin Von Janta-Lipinski
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.)
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Original Assignee
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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 DE19518216A external-priority patent/DE19518216A1/de
Application filed by Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft filed Critical Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Publication of WO1996011204A1 publication Critical patent/WO1996011204A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07H19/06—Pyrimidine radicals
    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • C07H19/16—Purine radicals
    • 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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention relates to new ⁇ -L nucleosides of the general formula
  • R 1 H, methyl, halogen, formyl, hydroxymethyl, ethyl, chloroethyl;
  • R 2 H, OH
  • R 4 OH, 0-acetyl, O-palmitoyl, alkoxy-carbonyl, phosphonate,
  • Mono-, di-, triphosphate, or another protective group which can be converted into the hydroxyl group in a subsequent reaction, and their use as pharmaceutical active substances or agents for the prophylaxis and / or treatment of infections, in particular those caused by hepatitis B. Virus (HBV) or HIV (human immunodeficiency virus) are caused.
  • HBV Virus
  • HIV human immunodeficiency virus
  • HBV is the trigger agent for hepatitis B, an infectious disease that affects approximately 200 million people worldwide and whose chronic form is associated with an increased risk of primary liver carcinoma, which leads to around one million new tumor diseases per year in China alone.
  • EP 0 330 992 Cyclopentane derivatives of purines and pyrimidines.
  • ß-L-nucleoside analogs have been prepared or purified in pure form, such as. B.: ß-L-dideoxycytidine (L-ddC) (M. Mansuri et al, Bioorg. Med. Chem Lett. 1991, 1, 65-68), ß-L-5-fluoride dideoxycytidine (L-FddC) and ß-L-5-fluoro-dideoxyuridine (L-FddU) (T.-S. Lin et al. J. Med. Chem. 1994, 37, 798-803), ß-L-3-thiacytidine (L- 3TC) (CN Chang et al, J. Biol.
  • L-ddC ß-L-dideoxycytidine
  • L-FddC ß-L-5-fluoride dideoxycytidine
  • L-FddU ß-L-5-fluoro-dideoxyuridine
  • L- 3TC
  • the invention is based on the object of developing new antivirally active ⁇ -L nucleosides which are active against hepatitis B and HIV infections and which, with good tolerability and low toxicity, are highly effective against these infections.
  • ⁇ -L nucleosides have the general formula
  • B guanine, 2-aminopurine
  • R 1 H, methyl, halogen, formyl, hydroxymethyl, ethyl, chloroethyl;
  • R 2 H, OH;
  • Mono-, di-, triphosphate, or another protective group which can be converted into the hydroxy group in a subsequent reaction, mean high antiviral activity.
  • 3'-Fluorine-modified compounds of the formula I are particularly effective, among them ⁇ -L-2 ', 3'-dideoxy-3'-fluorocytidine, ⁇ -L-2', 3'-dideoxy-3'-fluoro-5- methylcytidine, ß-L-2 ', 3'-dideoxy-3' -fluoro-5-chlorocytidine and ß-L-2 ', 3'-dideoxy-3' - fluororguanosine.
  • Ss-L-5-methylcytosine arabinoside is also highly effective.
  • the compounds of the invention are prepared by processes known per se by condensation of the sugar part and heterocycle or by modification of the L-ribosyl radical.
  • L-Ribose acetylated and condensed with the heterocyclic base.
  • the resulting L-ribonucleoside is deoxygenated and then modified in the 3'-position, for example fluorinated.
  • the starting material L-ribose can be obtained in a simple manner by epimerization of L-arabinose, as a result of which the preparation of the compounds according to the invention is also economically viable.
  • HBV hepatitis B virus
  • L-FMetCdR is able to completely suppress the synthesis of HBV, the concentration of the inhibitor which reduces the amount of HBV-DNA released into the medium by 50% , is less than 0.2 ⁇ M.
  • a 50% inhibition of the proliferation of HepG2 2.2.15 cells (CD s -,) is only achieved at concentrations greater than 400 ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux β-L-nucléosides de pyrimidine et β-L-nucléosides de purine et leur utilisation comme principes actifs ou agents pharmaceutiques dans la prophylaxie et/ou le traitement d'infections, induites notamment par le virus de l'hépatite B et le virus du SIDA (VIH). La médecine et l'industrie pharmaceutique constituent les champs d'application de cette invention.
PCT/DE1995/001412 1994-10-07 1995-10-05 NOUVEAUX β-L-NUCLEOSIDES ET LEUR UTILISATION Ceased WO1996011204A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DEP4436995.6 1994-10-07
DE4436995 1994-10-07
DE19518216.2 1995-05-10
DE19518216A DE19518216A1 (de) 1994-10-07 1995-05-10 Neue ß-L-Nucleoside und ihre Verwendung

Publications (1)

Publication Number Publication Date
WO1996011204A1 true WO1996011204A1 (fr) 1996-04-18

Family

ID=25941105

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1995/001412 Ceased WO1996011204A1 (fr) 1994-10-07 1995-10-05 NOUVEAUX β-L-NUCLEOSIDES ET LEUR UTILISATION

Country Status (1)

Country Link
WO (1) WO1996011204A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6566344B1 (en) 1998-08-10 2003-05-20 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6569837B1 (en) 1998-08-10 2003-05-27 Idenix Pharmaceuticals Inc. β-L-2′-deoxy pyrimidine nucleosides for the treatment of hepatitis B
US6596700B2 (en) 2000-05-26 2003-07-22 Idenix Pharmaceuticals Inc. Methods of treating hepatitis delta virus infection with β-L-2'-deoxy-nucleosides
US6787526B1 (en) 2000-05-26 2004-09-07 Idenix Pharmaceuticals, Inc. Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides
US6875751B2 (en) 2000-06-15 2005-04-05 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US7186700B2 (en) 2002-09-13 2007-03-06 Idenix Pharmaceuticals, Inc. β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US7323451B2 (en) 2002-08-06 2008-01-29 Idenix Pharmaceuticals, Inc. Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7582748B2 (en) 2003-03-20 2009-09-01 Microbiologica Quimica E Farmaceutical Ltd. Methods of manufacture of 2′-deoxy-β-L-nucleosides
US7595390B2 (en) 2003-04-28 2009-09-29 Novartis Ag Industrially scalable nucleoside synthesis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0254268A2 (fr) * 1986-07-24 1988-01-27 The Wellcome Foundation Limited Nucléosides fluorées, leur préparation et leur utilisation pharmaceutique contre le SIDA

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0254268A2 (fr) * 1986-07-24 1988-01-27 The Wellcome Foundation Limited Nucléosides fluorées, leur préparation et leur utilisation pharmaceutique contre le SIDA

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
D.T.GISH ET AL.: "Nucleic Acids. 12. Synthesis of the L-Enantiomer of 1-beta-Arabinofuranosylcytosine and of O2,O2'-Anhydro-1-beta-D-arabinofuranosylcytosine.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 14, no. 9, WASHINGTON US, pages 882 - 883 *
R.L.TOLMAN ET AL.: "Synthesis of 1-beta-L-Arabinofuranosylcytosine the Enantiomer of Cytosine Arabinoside.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 14, no. 11, WASHINGTON US, pages 1112 *
S.SPADARI ET AL.: "L-Thymidine Is Phosphorylated by Herpes Simplex Virus Type I Thymidine Kinase and Inhibits Viral Growth.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 22, 30 October 1992 (1992-10-30), WASHINGTON US, pages 4214 - 4220 *
T-S LIN ET AL.: "Synthesis and Biological Evaluation of 2',3'-Dideoxy-L-Pyrimidine Nucleosides as Potential Antiviral Agents Against Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV).", JOURNAL OF MEDICINAL CHEMISTRY, vol. 37, no. 6, 18 March 1994 (1994-03-18), WASHINGTON US, pages 798 - 803 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7795238B2 (en) 1998-08-10 2010-09-14 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6569837B1 (en) 1998-08-10 2003-05-27 Idenix Pharmaceuticals Inc. β-L-2′-deoxy pyrimidine nucleosides for the treatment of hepatitis B
US6946450B2 (en) 1998-08-10 2005-09-20 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US9290533B2 (en) 1998-08-10 2016-03-22 Novartis Ag β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US7304043B2 (en) 1998-08-10 2007-12-04 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
US6566344B1 (en) 1998-08-10 2003-05-20 Idenix Pharmaceuticals, Inc. β-L-2′-deoxy-nucleosides for the treatment of hepatitis B
EP2415776A1 (fr) * 1998-08-10 2012-02-08 IDENIX Pharmaceuticals, Inc. Bêta-L-2'-désoxy-nucléosides pour le traitement de l'hépatite B
US6596700B2 (en) 2000-05-26 2003-07-22 Idenix Pharmaceuticals Inc. Methods of treating hepatitis delta virus infection with β-L-2'-deoxy-nucleosides
US6787526B1 (en) 2000-05-26 2004-09-07 Idenix Pharmaceuticals, Inc. Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides
US6875751B2 (en) 2000-06-15 2005-04-05 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US7585851B2 (en) 2000-06-15 2009-09-08 Idenix Pharmaceuticals, Inc. 3′-prodrugs of 2′-deoxy-β-L-nucleosides
US7323451B2 (en) 2002-08-06 2008-01-29 Idenix Pharmaceuticals, Inc. Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7589079B2 (en) 2002-08-06 2009-09-15 Novartis Ag Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7858594B2 (en) 2002-08-06 2010-12-28 Novartis Pharma Ag Crystalline and amorphous forms of beta-L-2′-deoxythymidine
US7928086B2 (en) 2002-09-13 2011-04-19 Novartis Ag β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US8158606B2 (en) 2002-09-13 2012-04-17 Novartis, Ag β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US7186700B2 (en) 2002-09-13 2007-03-06 Idenix Pharmaceuticals, Inc. β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
US7582748B2 (en) 2003-03-20 2009-09-01 Microbiologica Quimica E Farmaceutical Ltd. Methods of manufacture of 2′-deoxy-β-L-nucleosides
US7595390B2 (en) 2003-04-28 2009-09-29 Novartis Ag Industrially scalable nucleoside synthesis

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