WO1991019727A1 - 5-hydrogenophosphonates et 5'-methylphosphonates de nucleosides modifies du sucre, compositions et utilisations de ces produits pour traiter des infections virales - Google Patents

5-hydrogenophosphonates et 5'-methylphosphonates de nucleosides modifies du sucre, compositions et utilisations de ces produits pour traiter des infections virales Download PDF

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Publication number
WO1991019727A1
WO1991019727A1 PCT/US1991/004362 US9104362W WO9119727A1 WO 1991019727 A1 WO1991019727 A1 WO 1991019727A1 US 9104362 W US9104362 W US 9104362W WO 9119727 A1 WO9119727 A1 WO 9119727A1
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WIPO (PCT)
Prior art keywords
dideoxy
hydrogen
pentofuranosyl
azido
carbons
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PCT/US1991/004362
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English (en)
Inventor
Alexander A. Krayevsky
Natalie B. Tarussova
Jasenka Matulic-Adamic
Kyoichi A. Watanabe
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Memorial Sloan Kettering Cancer Center
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Memorial Sloan Kettering Cancer Center
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Publication of WO1991019727A1 publication Critical patent/WO1991019727A1/fr
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    • 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

Definitions

  • nucleosides are converted into their corresponding 5'-mono-nucleotides by the action of cellular nucleoside kinase(s) followed by stepwise phosphorylation catalyzed by cellular nucleotide kinases to their corresponding 5'-triphosphates.
  • nucleoside 5'-triphosphates inhibit proviral DNA synthesis catalyzed by HIV reverse transcriptase (RT) by incorporation to the 3' position of the growing DNA terminal.
  • RT HIV reverse transcriptase
  • nucleosides are poor substrates for deoxynucleoside kinase(s) due to rather restricted structural requirement of the enzyme(s). Conversion of the 5'-monophosphate of these nucleosides into their corresponding 5'-triphosphates usually occurs readily in the cell. Nucleoside-5'-monophosphates cannot be used for treatment of AIDS, because they can hardly penetrate the cell membrane due to strong acidic nature.
  • Nucleoside-5'-hydrogenphosphonates weak acidic compounds, however, may penetrate cell membrane and may be oxidized to their corresponding phosphates and then further converted into the corresponding triphosphates in the cell, or the 5'-hydrogen-phosphonates may serve as substrates for nucleotide kinases forming the triphosphate analogues, pyrophosphorylhydrogenphosphonates, which then inhibit the viral DNA synthesis catalyzed by the reverse transcriptase.
  • the present invention provides a compound having the structure :
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 3 is hydrogen or an alkyl group of one to four carbons
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • Z is a hydrogen, a hydroxy, or an amino group.
  • the present invention also provides a compound having the structure:
  • R 3 is hydrogen or an alkyl group of one to four carbons
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • Z is a hydrogen, a hydroxy, or an amino group.
  • the present invention provides a compound having the structure:
  • R 3 is hydrogen or an alkyl group of one to four carbons
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • Z is a hydrogen, a hydroxy, or an amino group.
  • the present invention provides a compound having the structure:
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, and R is hydrogen or an alkyl group of one to four carbons.
  • the invention provides a compound having the structure:
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, and
  • R is hydrogen or an alkyl group of one to four carbons.
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, and R is hydrogen or an alkyl group of one to four carbons.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically effective amount of a compound according to the subject invention and a pharmaceutically acceptable carrier. Finally, the invention provides methods for treating viral infections. Detailed Description Of The Invention
  • the present invention provides a compound having the structure:
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 3 is hydrogen or an alkyl group of one to four carbons
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • Z is a hydrogen, a hydroxy, or an amino group.
  • the present invention also provides a compound having the structure:
  • R 3 is hydrogen or an alkyl group of one to four carbons
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • Z is a hydrogen, a hydroxy, or an amino group.
  • the present invention provides a compound having the structure:
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 3 is hydrogen or an alkyl group of one to four carbons
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • Z is a hydrogen, hydroxy, or an amino group.
  • the present invention also provides a compound of structures
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, halogen or an alkyl group of one to four carbons.
  • the present invention provides a compound having the structure:
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, and R is hydrogen or an alkyl group of one to four carbons.
  • the invention provides a compound having the structure:
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, and
  • R is hydrogen or an alkyl group of one to four carbons.
  • X is a hydroxy, a thiol, or an amino group
  • Y is hydrogen, a halogen or an alkyl group of one to four carbons
  • R 1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
  • R 2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, and R is hydrogen or an alkyl group of one to four carbons.
  • Compounds of structures I, II or III may be used to suppress viral replication and treat infection.
  • the subject invention also provides a pharmaceutical composition which comprises a pharmaceutically effective amount of a compound of structures I, II or III or a pharmaceutically acceptable metal addition salt thereof and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier encompasses any of the standard pharmaceutical carriers such as sterile solutions, tablets, coated tablets and capsules. Typically such carriers, contain excipients such as starch, milk, sugar, certain types of clay, gelatin, steric acid, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavor and color additives or other ingredients. Compositions comprising such carriers are formulated by well known conventional methods. However, the compositions comprising the compound of structures I, II or III or a metal salt thereof, are previously unknown.
  • This invention further concerns a method of treating a viral infection so as to render the infection incapable of viral replication which comprises contacting the viral infection with an effective amount of a compound of structure I, II or III.
  • this invention provides a method of treating a viral infection which comprises contacting the viral infection with an effective amount of the pharmaceutical composition described above, i.e. 1 to 200 mg/kg of body weight of a subject.
  • This invention also provides a method of treating a subject which comprises administering to the subject an effective amount of the pharmaceutical composition described above.
  • the administration of the compound may be effected by any of the well known methods, including but not limited to oral, intravenous, intramuscular, and subcutaneous.
  • the method of delivery, the amount to be and the frequency of delivery, are expected to vary according to the situation, the carrier used, and result desired. However, those variables are readily determinable by one skilled in the art.
  • the term "subject” includes but is not limited to domestic animals and human beings.
  • This invention further provides a method of treating a subject having a viral infection which comprises administering to the subject an effective amount of the compound to suppress the viral replication.
  • a subject may be any warm-blooded animal, preferably human.
  • the viral infection may be any viral infection, including but not limited to human immunodeficiency virus, hepititis virus or cytomegalo virus.
  • nucleoside-5 '-hydrogenphosphonates are prepared:
  • Example 2 To a solution of 1-(2,3-Dideoxy-2,3-didehydro- ⁇ -D-glyceropentofuranosyl) thymine (45 mg, 0.2 mmol) in trimethylphosphate (2 mL) ) are added 0.6 M solution of phosphorous acid tri-n-butyl-ammonium salt in pyridine (0.5 mL) and N,N'-dicyclohexyl carbodimide (125 mg, 0.6 mmol). The mixture is stirred for 8 hours at room temperature, and then is centrifuged for 10 minutes. The supernatant is removed by decantation. The solid is twice washed by dispersion in water (1 mL each) followed by centrifugation.
  • the combined supernatants are concentrated to dryness in vacuo.
  • the residue is dissolved in a minimal amoun, of pyridine and applied to a silica gel plate (20 x 20 x 0.15 cm), and the plate is developed in system 1.
  • the UV absorbing band corresponding to the nucleoside-5'-phosphonate is scraped, and then extracted with system 1 (30 mL).
  • the solvent is removed by evaporation in vacuo, and the residue is reevaporated with water (2 mL) .
  • the residue is dried azeotropically be evaporation with ethanol (2 mL x 2) in vacuo.
  • 1-(2,3-Dideoxy-2,3-didehydro-5-O-hydrogenphosphonvl- ⁇ -D-glycero-pentofuranosyl) thymine (25 mg, 42% yield) is obtained as colorless foam.
  • nucleoside-5'-hydrogen phosphonates were prepared:
  • Table 3 lists the 1 H NMR parameters for some representative nucleoside-5'-hydrogenphosphonates.
  • 1-(2,3-dideoxy-5-O-methylphosphonyl- ⁇ -D-glycero-pentofuranosyl) cytosine is isolated by preparative layer chromatography on a silica gel plate as Example 1 (29 mg, 42% yield, as a colorless foam).
  • the following nucleoside-5'-methylphosphonates are prepared:
  • 1-(2,3-Anhydro-5-O-methylphosphonyl- ⁇ -D-lyxof uranosyl) cytosine is isolated by preparative layer chromatography on a silica gel plate as Example 1 (28 mg, 46% yield, as a colorless foam).
  • the following nucleoside-5'-methylphosphonates are prepared:
  • Table 4 lists the ⁇ NMR parameters for some of these nucleoside-5'-methylphosphonates.
  • Anti-HIV-1 Assay Anti-HIV-1 activities of the compounds were tested in MT4 cells. The cells were infected with HIV1 at 200 TCID50 viruses per 10 6 cells. After an absorption period of one hour at 37oC unabsorbed viruses were removed by washing with fresh medium without fetal calf serum. The cells were suspended in fresh medium and distributed into 12-well microculture plates (10 6 cells 5/3ml/well). Then, various concentrations of test compounds were added. The cell cultures were incubated at 37' in a humidified atmosphere of 5% C02 HIV-1 P24 core antigen and RT activity in the supernatants of the test cell cultures were detected on day-4. Anti-HIV-1 effects of compounds were evaluated by the inhibitory concentration was calculated by the medianeffect plot using a computer software.
  • Cytotoxicity Assay The Cytotoxicity of the compounds was determined in MT4 cells in 96-well microplates by XTT-microculture tetrazolium assay.
  • Table 7 lists the Anti-Hiv-1 effect and cytotoxicity of hydrogen-phosphates of pyrimidine nucleosides in MT4 cells.
  • Table 8 lists the Anti-Hiv-1 effect and cytotoxicity of hydrogen-phosphates of pyrimidine nucleosides in MT4 cells.
  • Table 9 lists the Anti-Hiv-1 Activity of AZT-HP, FLT-HP and ddt-HP based on Reversetranscriptase assay on day-4 in MT4 cells.
  • Table 10 lists the Dose-Effect relationships of inhibiting HIV-1 replication in MT4 cells. /
  • HIV at 10 micromolar concentration. Even at 1.0 micromolar concentration, these compounds inhibit HIV replication to a significant extent. The cytotoxicity of these compounds against uninfected cells is much less than that of the nucleosides used for standard.
  • AZT-HP AZT-HP
  • FLT-HP FLT-HP
  • ddT-HP ddT-HP
  • AZT-HP gave EC50 (50% antiviral effective concentration) of 0.072 ⁇ M and IC50 (50% inhibitory concentration of cell growth) of 2,500 ⁇ M.
  • a selectively index of 34,700 was achieved.
  • FLT-HP showed EC50 of 0.135 ⁇ M and IC50 of >5,000 ⁇ M. Its selectively index was >37,000.
  • the EC50 and IC50 of ddT-HP were 0.084 ⁇ M and 3410 ⁇ M, respectively, with a selectivity index of 40,000.
  • AZT, FLT and ddT gave their ED50, IC50 and selectively index as following: AZT, 0.005 ⁇ M, 154 ⁇ M and 30,800; FLT, 0.004 ⁇ M, 190 ⁇ M and 47,500; and ddT 1.88 ⁇ M and >5,000 ⁇ M and >2,660.
  • AZT-HP and FLT-HP shows lower anti-HIV-1 activity than that of AZT and FLT, their selectivity indices were close to that of AZT and FLT. Their selectivity indices were close to that of AZT and FLT because of their low cytotoxicity.
  • Anti viral activity of ddT-HP was more than 20-folds higher than ddT and it still shows low cytotoxicity. Thus ddT-HP gives a good selectivity index.

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  • 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)
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Abstract

Composés possédant la structure (I), (II) ou (III), dans laquelle R représente (a) ou (b) R1 représente hydrogène, halogène, un groupe azido, amino ou alkyle ayant un à quatre carbones, R2 représente hydrogène, halogène un groupe azido, un groupe amino ou un groupe alkyle ayant un à quatre carbones, R3 représente hydrogène ou un groupe alkyle ayant un à quatre carbones, X représente un groupe hydroxy, thiol, ou amino, Y représente hydrogène, un groupe halogène ou alkyle ayant un à quatre carbones, et Z représente un groupe hydrogène, hydroxy, ou amino. On décrit aussi des compositions pharmaceutiques comprenant une quantité pharmaceutiquement efficace d'un composé selon la présente invention et un porteur pharmaceutiquement acceptable. On décrit enfin des procédés pour éliminer l'infection virale.
PCT/US1991/004362 1990-06-19 1991-06-19 5-hydrogenophosphonates et 5'-methylphosphonates de nucleosides modifies du sucre, compositions et utilisations de ces produits pour traiter des infections virales Ceased WO1991019727A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017651A3 (fr) * 1992-03-04 1993-11-25 Max Delbrueck Centrum Analogues nucleosidiques antiviraux, leur fabrication et leur utilisation
US5508270A (en) * 1993-03-06 1996-04-16 Ciba-Geigy Corporation Nucleoside phosphinate compounds and compositions
EP0805683A4 (fr) * 1995-01-27 1999-09-01 Univ Emory Nucleosides de 5-carboxamido ou 5-fluoro]-pyrimidine insaturee en 2',3' ou modifiee en 3'
US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
WO2006062434A1 (fr) * 2004-11-25 2006-06-15 Kukhanova Marina Konstantinovn Preparations antivirales modifiees 5'- phosphonate azidothymidine-potentielles
US7115584B2 (en) 1999-01-22 2006-10-03 Emory University HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
EP1964569A3 (fr) * 2000-04-13 2009-07-22 Pharmasset, Inc. Dérivés de nucléoside substitué 3'-Or 2'-hydroxymethyl pour le traitement des infections virales
US7635690B2 (en) 1999-01-22 2009-12-22 Emory University HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816570A (en) * 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816570A (en) * 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF EXPERIMENTAL MEDICINE, Volume 166, issued October 1987, USA, D.R. RICHMAN et al., "Failure of Dideoxynucleosides to Inhibit Human Immunodeficiency Virus Replication in Cultured Human Macrophages", pages 1144-1149. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017651A3 (fr) * 1992-03-04 1993-11-25 Max Delbrueck Centrum Analogues nucleosidiques antiviraux, leur fabrication et leur utilisation
US5508270A (en) * 1993-03-06 1996-04-16 Ciba-Geigy Corporation Nucleoside phosphinate compounds and compositions
US7419966B2 (en) * 1995-01-27 2008-09-02 Emory University [5-carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US6232300B1 (en) 1995-01-27 2001-05-15 Emory University Treatment of HIV by administration of β-D-2′, 3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D4FC)
US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US6680303B2 (en) 1995-01-27 2004-01-20 Emory University 3′,5-difluoro-2′,3′-didehydropyrimidine nucleosides and methods of treatment therewith
EP0805683A4 (fr) * 1995-01-27 1999-09-01 Univ Emory Nucleosides de 5-carboxamido ou 5-fluoro]-pyrimidine insaturee en 2',3' ou modifiee en 3'
US7115584B2 (en) 1999-01-22 2006-10-03 Emory University HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
US7635690B2 (en) 1999-01-22 2009-12-22 Emory University HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine
EP1964569A3 (fr) * 2000-04-13 2009-07-22 Pharmasset, Inc. Dérivés de nucléoside substitué 3'-Or 2'-hydroxymethyl pour le traitement des infections virales
WO2006062434A1 (fr) * 2004-11-25 2006-06-15 Kukhanova Marina Konstantinovn Preparations antivirales modifiees 5'- phosphonate azidothymidine-potentielles
RU2322450C2 (ru) * 2004-11-25 2008-04-20 Закрытое акционерное общество "Производственно-коммерческая Ассоциация АЗТ" Модифицированные 5'-фосфонаты азт в качестве активных компонентов для потенциальных противовирусных препаратов
US7999099B2 (en) * 2004-11-25 2011-08-16 Marina Konstantinovna Kukhanova Modified 5′-phosphonate azidothymidine—potential anti-viral preparations
KR101323698B1 (ko) 2004-11-25 2013-10-30 마리나 콘스탄티노브나 쿠카노바 Ａｚｔ의 변형된 5'-포스포네이트 - 잠재적 항바이러스제

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