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WO1991019727A1 - 5'-hydrogenphosphonates and 5'-methylphosphonates of sugar modified nucleosides, compositions and uses thereof - Google Patents

5'-hydrogenphosphonates and 5'-methylphosphonates of sugar modified nucleosides, compositions and uses thereof 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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Prior art keywords
dideoxy
hydrogen
pentofuranosyl
azido
carbons
Prior art date
Application number
PCT/US1991/004362
Other languages
French (fr)
Inventor
Alexander A. Krayevsky
Natalie B. Tarussova
Jasenka Matulic-Adamic
Kyoichi A. Watanabe
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Sloan-Kettering Institute For Cancer Research
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Publication of WO1991019727A1 publication Critical patent/WO1991019727A1/en

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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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Abstract

The present invention concerns compounds having one of the structures (I), (II), (III), wherein R is (a) or (b), R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, R2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons, R3 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, and Z is a hydrogen, hydroxy, or an amino group. 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 to suppress viral infection.

Description

5'-Hvdrogenphosphonates and 5'-Methylyphosphonates of Sugar Modified Nucleosides, Compositions and Uses Thereof
The invention described herein was made in the course of work under Grant Nos. CA-08748 and AI-26056 from the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.
Background Of The Invention
The only clinically available agent for the treatment of acquired immune deficiency syndrome (AIDS) in the United States is 3'-azido-3,-deoxythymidine (AZT). [Mitsuya et al., Proc. Nat Aσad. Sci., USA, 1985 82., 7096] Several 2',3'-dideoxynucleosides are also reported [Mitsuya et al.. Proc. Nat. Acad. Sci., USA, 1986, 83, 1911] as active against human immune deficiency virus (HIV) , the responsible pathogen that causes AIDS. These 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. These nucleoside 5'-triphosphates inhibit proviral DNA synthesis catalyzed by HIV reverse transcriptase (RT) by incorporation to the 3' position of the growing DNA terminal.
Many 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.
Summarv Of The Invention
The present invention provides a compound having the structure :
wherein R is
Figure imgf000005_0001
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
The present invention also provides a compound having the structure:
wherein
Figure imgf000006_0001
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
Further, the present invention provides a compound having the structure:
Figure imgf000007_0001
wherein
Figure imgf000007_0002
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
The present invention provides a compound having the structure:
Figure imgf000008_0001
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
Also, the invention provides a compound having the structure:
Figure imgf000008_0002
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons. R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
Further, the invention provides a compound having the structure:
Figure imgf000009_0001
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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:
wherein R is Λ
Figure imgf000010_0001
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group. The present invention also provides a compound having the structure:
wherein R is
Figure imgf000011_0001
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
Further, the present invention provides a compound having the structure:
wherein R is
Figure imgf000011_0002
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R3 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, and
Z is a hydrogen, hydroxy, or an amino group.
The present invention also provides a compound of structures
I, II or III wherein R is:
Figure imgf000012_0001
wherein 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:
Figure imgf000013_0001
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
Also, the invention provides a compound having the structure:
Figure imgf000013_0002
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons. R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
Further, the invention provides a compound having the structure:
Figure imgf000014_0001
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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 following compounds are examples of compounds useful in accordance with the present invention:
1-(2,3-Dideoxy-5'-O-hydrogenphosphonvl-β-D-glvceropentofuranosyl) cytosine. 1-(2,3-Dideoxy-5'-3-hydrogenphosphonyl-β-D-glyceropentofuranosyl) thymine,
1-(2,3-Dideoxy-5'-O-hvdroαenphosphonvl-β-D-qlvceropentofuranosy1) uracil,
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl)-5- fluorouracil,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl)-5- fluorouracil,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosy1) thymine,
1-(3-Azido-2,3-dideoxy-5'-O-hvdrogenphosphonγl-β-D-erythropentofurcnosyl) uracil,
1-(3-Azido-2,3-dideoxy-5•-O-hydrogenphosphony1-β-D-erythropentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-0-hydrogenphosphonyl-β-D-erythropentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-O-hydroαenphosphonyl-β-D-erythropentofuranosyl) uracil,
1-(2, 3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosyl) cytosine,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D-threopentofuranosyl) thymine,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D-threopentofuranosyl) uracil,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β- D -threo- pentofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl) uracil,
1-(3-Azido-2,3-dideo.xy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl)-5-fluorouracil. The following compounds are still further examples of compounds of the present invention:
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogen-phosphonyl-β-D- glycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-2, 3-didehydro-5'-O-hydrogen-phosphonyl-β-D- glycero-pentofuranosyl) thymine,
1-(2,3-Dideoxy-2, 3-didehydro-5'-O-hydrogen-phosphonyl-β-D- glycero-pentofuranosyl) uracil,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl) cytosine,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl) thymine,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl) uracil.
1-(2,3-Dideoxy-5'-O-methylPhosphonvl-β-D-glyceropentof uranosyl) cytosine,
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D-glyceropentof uranosyl) thymine,
1-(2,3-Dideoxy-5'-O-methylphosphonvl-β-D-glyceropentofuranosyl) uracil,
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D-lyxofuranosyl)-5- fluorouracil,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D-erythropentofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D-erythropentofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D-erythropentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-D-erythropentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-D-erythropentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-D-erythropentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-D-threopentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-0-methylphosohonyl-β-D-threo pentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-methvlphosphonvl-β-D-threopentofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-0-methyl-phosphonyl-β- arabinofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-raethyl-phosphonyl-β- arabinofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methyl-phσsphonyl-β- arabinofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methyl-phosphonyl-β- arabinofuranosyl)-5-fluorouracil.
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methyl-phosphonyl-β- glycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methyl-phosphonyl-β- glycero-pentofuranosyl) thymine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methyl-phosphonyl-β-D glycero-pentofuranosyl) uracil,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-D-lyxofuranosyl cytosine,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-D-lyxofuranosyl thymine,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-D-lyxofuranosyl uracil.
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. The term "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.
The amount of the compound required will vary considerably depending upon conditions. However, these amounts are readily determinable by one skilled in the art.
Additionally, 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.
In this method, 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.
The following Experimental Detail Section and Examples are set forth to aid in an understanding of the invention. These sections are not intended to, and should not be construed to, limit in any way the invention set forth in the claims which follow thereafter.
Experimental Details
SYNTHESIS OF NUCLEOSIDE-5'-HYDROGENPHOSPHONATES. To a solution of nucleoside (0.2 mmol) in a solvent (2 mL) are added 0.6 M solution of phosphorous acid tri-n-butylammonium salt in pyridine (0.5 mL) and N,N'-dicyclohexyl-carbodiimide (0.6 mmol). The mixture is stirred at room temperature. The reaction is monitored by thin layer chromatography on a silica gel plate using isopropanol : 25% ammonium hydroxide : water (7:1:2 v/v) (system 1) as the solvent. After all the nucleoside is consumed, the mixture is centrifuged for 10 minutes. The supernatant is removed by decantation. The solid is twice washed with water. The product is isolated by preparative layer chromatography on a silica gel plates using system 1.
SYNTHESIS OF NUCLEOSIDE-5'-METHYLPHOSPHONATES. To a solution of nucleoside in a solvent mixture are added at 0 ºC successively dichloro-methylphosphoryl oxide and 1,2,4tetrazole. The mixture is stirred at 0 ºC for 1 hour and then at room temperature. After completion of the reaction as judged by thin layer chromatography on a silica gel plate in system 1, the mixture is cooled to 0 ºC, and the reaction is quenched by addition of triethylamine and water. The mixture is stirred for 2 hours at 4 ºC, and then is concentrated in vacuo. The nucleoside-5'-methylphosphonates are isolated by preparative layer chromatography on silica gel plates using system 1. The following examples are illustrated of the process and products of the present invention, but are not to be construed as limiting. Example 1
To a solution 3'-azido-3'-deoxythymidine (53 mg, 0.2 mmol) in pyridine (2 mL) are added 0.6 M solution of phosphorous acid tri-n-butylammonium salt in pyridine (0.5 mL) and N,N'-dicyclohexyl-carbodiimide (125 mg, 0.6 mmol). The mixture is stirred for 4 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 amount of pyridine and applied to a silica gel plate (20 × 20 × 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 by evaporation with ethanol (2 mL × 2) in vacuo. 1-(3-azido-3-deoxy-5-O-hydrogen-phosphonyl-β-D-erythro-pentofuranosyl)thymine (58 mg, 84% yield) is obtained as colorless foam.
By following the same procedure but using the corresponding nucleosides instead of 3' -azido-3 '-deoxythymidine, the following nucleoside-5 '-hydrogenphosphonates are prepared:
1-(2,3-Dideoxy-5'-O-hydroqenphosphonyl-β-D-glyceropentofuranosyl) cytosine,
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D-qlyceropentofuranosyl) thymine,
1-(2,3-Dideoxy-5'-O-hydroαenphosphonyl-β-D-glvceropentofuranosyl) uracil,
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl)-5- fluorouracil,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D-lyxofuranosyl)-5- fluorouracil,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosy1) thymine,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphony1-β-D-erythropentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl-β-D-erythropentofuranosyl) cytosine,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D-threopentofuranosyl) thymine,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D-threopentofuranosy1) uracil,
1- (2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β- D -threo- pentofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-hydrogenphosphonyl-β-D- arabinofuranosyl)-5-fluorouracil.
Example 2 To a solution of 1-(2,3-Dideoxy-2,3-didehydro-β-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-β-D-glycero-pentofuranosyl) thymine (25 mg, 42% yield) is obtained as colorless foam.
By following the same procedure but using the corresponding nucleosides instead of 1-(2,3,-Dideoxy-2,3-didehydro-B-D-glycero-pentofuranosyl) thymine, the following nucleoside-5'-hydrogen phosphonates were prepared:
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogenphosphonyl-β-D-glycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogenphosphonvl-β-D-glycero-pentofuranosvl) thymine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogenphosphonyl-β-D-glycero-pentofuranosvl) uracil,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl) cytosine,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl) thymine, and
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl) uracil. Table 1 lists the reaction conditions, yields and chromatogaphic and UV characteristics for some representative nucleoside-5'-hydrogen-phosphonates.
Table 3 lists the 1H NMR parameters for some representative nucleoside-5'-hydrogenphosphonates.
Table 5 lists the 32P NMR data for some representative nucleoside-5'-phosphonates Example 3
To a solution of 1-(2,3 dideoxy-β-D-glycero-pentofuranosyl) cytosine (43 mg, 0.2 mmol) in trimethylphosphate (2.0 mL) are added at 0 ºC successively dichloromethylphosphoryl oxide (80 mg, 0.6 mmol) and 1,2,4-tetrazole (20 mg). The mixture is stirred at 0 ºC for 1 hour and then at room temperature for 4 hours. The mixture is cooled to 0 ºC, and the reaction is quenched by addition of triethylamine (0.2 mL) and water (0.2 mL). The mixtrue is stirred for 2 hours at 4 ºC, and then is concentrated in vacuo. 1-(2,3-dideoxy-5-O-methylphosphonyl-β-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). By following the same procedure but using the corresponding nucleosides instead of 1-(2',3'-dideoxy-B-D-glycero- pentofuranosyl) cytosine, the following nucleoside-5'-methylphosphonates are prepared:
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D-glycero- pentofuranosyl) cytosine,
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D-glycero- pentofuranosyl) thymine,
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D-glycero- pentofuranosyl) uracil,
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D- lyxofuranosyl)-5-fluorouracil,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D- erythro-pentofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D- erythro-pentofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D- erythro-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- erythro-pentofuranosyl) thymine, 1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- erythro-pentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- erythro-pentofuranosyl) cytosine, 1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- threo-pentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- threo-pentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- threo-pentofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl-β-D-arabinofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl-β-D-arabinofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl-β-D-arabinofuranosyl) cytosine, and
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl -β-D-arab ino furanosyl ) - 5 - fluorouracil .
Example 4
To a solution of 1-(2,3-anhydro-β-D-lyxopentofuranosyl) cytosine (45 mg, 0.2 mmol) in trimethylphosphate (1.0mL) are added at 0*C successively dichloromethyl phosphoryl oxide (80 mg, 0.6 mmol) and 1,2,4-tetrazole (20 mg). The mixture is stirred at 0 ºC for 1 hour and then at room temperature for 14 hours. The mixture is cooled to 0 ºC, and the reaction is quenched by addition of triethylamine (0.2 mL) and water (0.2 mL). The mixture is stirred for 2 hours at 4 ºC, and then is concentrated in vacuo. 1-(2,3-Anhydro-5-O-methylphosphonyl-β-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). By following the same procedure but using the corresponding nucleosides instead of 1-(2,3-anhydro-B-D-lyxopentofuranosyl) cytosine, the following nucleoside-5'-methylphosphonates are prepared:
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methylphosphonyl-β-D-glycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methylphosphonyl-β-D-qlγcero-pentofuranosyl) thymine,
1-(2,3-Dideoxy-2,3-didehydro-5'-0-methylphosphonvl-β-D-glycero-pentofuranosyl) uracil,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-D- lyxofuranosyl) cytosine,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-D- lyxofuranosyl) thymine, and
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-D- lyxofuranosyl) uracil. Table 2 lists the reaction conditions, yields and chromatographic and UV characteristics of some of these nucleoside-5'-methyl-phosphonates that are synthesized by the above procedure.
Table 4 lists the Η NMR parameters for some of these nucleoside-5'-methylphosphonates.
Table 1. Experimental conditions for the synthesis of 5'-hydrogenphosphonates (I, R=H)
solvent time yield chromatography UV absorption
X Y R1 R2 (mL) (hrs) (%) solvent 1 solvent 2 in H2O (nm)
Rf Rf max min pH
O Me H F pyridine (2) 4 84 0.88 0.80 266 234 7.0
O Me N5 F pyridine (2) 8 76 0.80 0.80 266 234 7.0
O Me N3 H pyridine (2) 12 64 0.68 0.55 266 234 7.0
O Me H H MeCN (2)*1 38 61 0.70 0.66 268 234 7.0
O Me F H pyridine (2) 6 78 0.62 0.56 266 234 7.0
O H H H MeCN (2)*2 8*3 36 0.54 0.48 270 247 7.0
NH2 H H H pyridine (2) 12 47 0.76 0.74 261 230 7.0
Table 1 (cont'd)
solvent time yield chromatography UV absorption
X Y R1 R2 (mL) (hrs) (%) solvent 1 solvent 2 in H2O (nm)
Rf Rf max min PH
Experimental conditions for the synthesis of 5' -hydrogenphosphonates (II, R = H)
NH2 H (MeO)3PO (2) 4*3 36 0.73 0.73 270 247 7.0
277 238 1.0
O Me (MeO)3PO (2) 8*3 40 0.63 0.60 266 234 7.0
O H MeCN (l)/(MeO)3P0(0.5) 4 52 0.54 0.53 261 230 7.0
Experimental conditions for the synthesis of 5' -hydrogenphosphonates (III , R = H)
O H (MeO)3PO (0.5) 12 52 0.43 0.54 261 230 7.0
O F (MeO)3PO (0.5) 12 58 0.45 0.45 268 234 7.0
NH2 H (MeO)3P0 (1) 14 46 0.37 0.34 270 247 7.0
277 238 1.0
*1 with 0.4 mL of N-methyllmidazole
*2 with 0.5 mL of (MeO)3PO
*3 beyond this time, side reactions take place
Table 2. Experimental conditions for the synthesis of 5'-methylphosphonates (I, R - Me)
(MeO) 3PO:MeCN time time yield chromatography Uv absorption
Y R1 R2 (mL) (mL) (hr) (hr) (%) solvent solvent iin H2O (nm)
0ºC rt* (1) (2) max nin pH
0 H H H 0.5 2 14 4 54 0.73 0.70 261 232 7.0
0 Me H H 2 0 1 4 86 0.53 0.50 266 234 7.0
NH2 H H H 1.5 0 18 0 47 0.56 0.52 270 247 7.0
277 238 1.0
0 Me F H 0.2 2 14 6 64 0.73 0.70 261 232 7.0
0 Me N3 H 0.3 1 6 2 78 0.85 0.75 266 234 7.0
0 Me H F 0.3 1 6 8 57 0.65 0.54 265 234 7.0
0 Me N3 F 0.3 2 14 0 58 0.87 0.75 265 235 7.0
Table 2 (cont'd)
(MeO)3PO:MeCN time time yield chromatography U V absorption
X Y R1 R2 (mL) (mL) (hr) (hr) (%) solvent solvent in H2O (nm)
0ºC rt* (1) (2) max nin pH
Experimental conditions for the synthesis of 5'-methylphosphonates (II, r = Me)
NH2 H 2 0 1 4 42 0.71 0.68 270 247 7.0
277 238 1.0
0 H 0.5 0 14 0 67 0.50 0.46 261 232 7.0
0 Me 1.5 0 1 4 85 0.70 0.68 266 234 7.0
Experimental conditionf for the synthesis of 5'-methylphosphonates (III, R = Me)
NH2 H 1.5 0 6 12 52 0.42 0.40 270 247 7.0
277 238 1.0
0 F 0.5 0 21 18 46 0.87 0.80 269 234 7.0
Table 3. Experimental conditions for the synthesis of 5'-methylphosphonates (I, R = Me)
X Y R' R2 H1' H2' H3' H4' H5',5" H-5 H-6 5Me H-P
0 Me H F 6.11dt 5.6-5. On 4.50m 4.05n 7.68s 1.89d 6.79d
(6.1, 0.4) (0.4) (637.7)
0 Me *3 F 6.18t 5.34dt 4.58m 4.14n 7.62s 1.87d 6.29d
(6.2) (5.6, 5.1) (0.7) (639.4)
0 Me *3 H 6.2 It 2.46t 4.63t 3.88s 4.20n 7.65d 1.87d 7.11d
(6.6) (6.2) (5.45) (0.5) (0.8) (637.5)
0 Me F H 6.21t 4.56m 5.63t 5.06t 4.15t 7.62d 1.88d 6.80d
(4.7) (8.2) (8.2) (4.9) (1.1) (0.8) (639.7)
0 Me H H 6.40 2.3-2. in 4.42m 4.06m 7.78d 1.74d 6.80d
(6.6) (1.1) (1.1) (636.3)
0 H H H β.Oβdd 2.17m 3.36m 4.60m 4.02m 5.86d 7.91d 6.73d
(6.8, 6.0) (6.6) (6.6) (637.5)
NH2 H H H 6.4m 2.15m 3.52dd 4.20M 3.99n 8.04d 6.71d
(10.7, 10.7) (7.7) (629.8)
H NMR parameters for 5'-hydrogenphosphonates in D2O (II, R = J)
NH2 H 6.95t 4.98m 6.0-4.5m 4.1-4.; n 3.7-3.6n 5.45d 7.72d 6.48d
(5.0) (7.3) (7.3) (638.3)
O Me 6.1-6. On 4.5-4.3m 5.03t 4.4-4. 0m 3.62q 7.98S 6.74d
(10.7)) (6.55) (637.7)
Table 3 (cont'd)
H1 ' H2 ' H3' H4 ' H5 ' , 5" H-5 H-6 5Me H-P
IH NMR parameters for 5 ' -hydrogenphosphonates in D20 (III , R * H)
H 6.25m 4.5 4.8m 8.03d 6.78d
(6.6) (641. 1)
F 6.20s 5.9 4.0m 4.3-4.2m 7.86d 6.75d
(8.2) (645.3)
NH2 H 6.20s 4.2 2.9m 6.08d 7.85d 7. 14d
(7.7) (7.7) (641.1)
1 Chemical shifts in ppm (δ). signal description by apparent shape (e.g., t or q).
Coupling constants in Hz in ( ) right below chemical shifts first order.
For HP(0) (0H)2, 6 6.88d (672.0 Hz).
Table 4. 2H NMR parameters for 5'-methylphosphonates in D2O (I, R=Me)
X Y R1 R2 HI* H2' H3« H4' H5',5" H5 H-6 5Me Me-P
NH,H H H 6.05m 1.78m 3.58d 4.12m 4.02m 8.58d 1.31d
(10.7) (7.7) (16.5)
O Me H H 6.25m 2.03m 3.12m 5.02m 4.0-3.8m 8.13s 1.41d 1.29d
(1.1) (16.5)
O H H H 6. lit 2.13m 3.12m 5.02m 4.1-3.5m 5.86d 7.91d 1.27d
(11.2) (8.2) (8.2) (14.5)
O Me F H 6.40t 4.53 5.72d 5.16m 3.7-2m 7.75s 1.93s 1.33d
(8.8) (4. 1) (16.2)
O Me N3 H 6.53t 2.80t 4.48m 3.88d 4.4-4.3m 7.99d 2.21d 1.22d
(6.6) (6.3) (5.4) (1.1) (0.5) (16.1.
O Me H F 6.12t 7.68d 1.89d 1.36d
(6.1) (1.2) (1.2) (13.2)
O Me N3 F 6.52t 5.72t 4.78m 3.54t 4.5-4.4m 7.97d 2.23d 1.69d
(4.6) (8.4) (7.40 (1.2) (1.2) (16.4)
1H NMR parameters for 5'-methylphosphonates in i D2O (II, R=Me)
NH2 H 6.93m 5.03d 5.9βm 3.96m 3.88t 6.43d 7.79d 1.16d
(5. 0) (10.4) (8.5) (8.5) (16.5)
O Me 6.94m 4.53m 4.94t 3.98m 3.61m 6.59d 1.87d 1.16d
(10 .4) (1.0) (1.0) (16.4)
0 H 6.81m 5.83m 6.50m 4.78m 4.01t 6.53d 7.30d 1.22d
(5.5) (8.0) (8.0) (16.5)
Table 4 (cont'd)
XY R1 R2 H1' H2' H3' H4' H5',5" H5 H-6 5Me Me-P
*H NMR parameters for 5*-methylphosphonates in D2O (III, R=Me)
O F 6.25t 4.3- - - - - - - - - - - - - - - - - 3.2m 8.09d 1.36d
(6.6) (16.5)
NH2 H 6.198 4.6 - - - - - - - - - - - - - - - - - 3.5m 6.15d 8.75d 1.29d
(8.5) (8.5) (16.5)
Chemical shifts in ppm ( ). Signal description by apparent shape (e.g., t or q). Coupling constants in Hz in ( ) right below chemical shifts first order.
Table 5. 32p NMR parameters for 5'-phosphonates in D2O.
Chemical shift Coupling constants
Structure R1 R2 ppm (Hz)
(δ)
I NH2 H H H H 5.65m 929.9, 422.4,207.5 I NH2 H Me H H 19.18m 541.4,302.2
I O Me H H H 6.16d 637.0
I O H Me H H 24.46m 551.7,305.0
I NH2 H H F H 6.13d 634.4
I NH2 H Me F H 5.59 619.5
I O Me Me N, H 6.29 637.2
I O Me Me H 26.72 636.6, 429.3, 214.6 I II NH, H H 6.16m 634.3, 416.6, 208.1
Example 5
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 106 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 (106 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. /
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
EXPERIMENTAL DISCUSSION
Representative compounds are tested for their inhibitory effects against human immunodeficiency virus in H-9 cells using 3'-azido-3'-deoxythymidine, 3'-deoxy-3'fluorothymidine and 2',3'-dideoxy-cytidine as standards. The results are summarized in Table 6. 1-(2,3-Dideoxy-5-O- [hydrogenphosphonyl]-β-D-erythro-pentofuranosyl)uracil and 1-(2,3-dideoxy-2,3-didehydro-5-0-[hydrogen-phosphonyl]-β-D-glycero-pentofuranosyl) thymine and inhibit replication of
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.
The inventors have found that several compounds were found to be potent and selective inhibitors of HIV-1 replication. Among all of the active compounds, AZT-HP, FLT-HP and ddT-HP exhibited the most potent anti-HIV-1 activity. AZT-HP gave EC50 (50% antiviral effective concentration) of 0.072 μM and IC50 (50% inhibitory concentration of cell growth) of 2,500 μM. A selectively index of 34,700 was achieved. FLT-HP showed EC50 of 0.135 μM and IC50 of >5,000 μM. Its selectively index was >37,000. The EC50 and IC50 of ddT-HP were 0.084 μM and 3410 μM, respectively, with a selectivity index of 40,000. As control compounds, AZT, FLT and ddT gave their ED50, IC50 and selectively index as following: AZT, 0.005 μM, 154 μM and 30,800; FLT, 0.004 μM, 190 μM and 47,500; and ddT 1.88 μM and >5,000 μM and >2,660. Although 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.

Claims

What is claimed is:
1. A compound having the structure:
wherein R is
Figure imgf000046_0001
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
2. A compound having the structure:
wherein R is
Figure imgf000047_0001
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
3. A compound having the structure:
wherein R is
Figure imgf000048_0001
R3 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, and
Z is a hydrogen, a hydroxy, or an amino group.
4. A compound of claim 1, 2 or 3 wherein R is:
Figure imgf000048_0002
wherein X is a hydroxy, a thiol, or an amino group,
Y is hydrogen, halogen or an alkyl group of one to four carbons.
5. A compound having the structure:
Figure imgf000049_0001
X is a hydroxy, a thiol, or an amino group,
Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
6. A compound having the structure:
Figure imgf000049_0002
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
A compound having the structure:
Figure imgf000050_0001
X is a hydroxy, a thiol, or an amino group, Y is hydrogen, a halogen or an alkyl group of one to four carbons,
R1 is hydrogen, halogen, an azido, an amino or an alkyl group of one to four carbons,
R2 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.
8. A compound of claim 4 selected from the group consisting of:
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D- glycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D- glycero-pentofuranosyl) thymine,
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D- glycero-pentofuranosyl) uracil,
1-(2,3-Dideoxy-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl)-5-fluorouracil,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl)-5-fluorouracil,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphonyl-β- D-erythro-pentofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphonyl-β- D-erythro-pentofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-5'-O-hydrogenphosphonyl-β- D-erythro-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl- β- D-ervthro-pentofuranosyl) thymine, 1-(2,3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl- β- D-erythro-pentofuranosyl) uracil, 1-(2,3-Dideoxy-3-fluoro-5'-O-hydrogenphosphonyl- β- D-erythro-pentofuranosyl) cytosine, 1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl- β- D-threo-pentofuranosyl) thymine,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl- β- D-threo-pentofuranosyl) uracil,
1-(2,3-Dideoxy-2-fluoro-5'-O-hydrogenphosphonyl- β- D-threo-pentofuranosyl) cytosine. 1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O- hydrogenphosphonyl-β-D-arabinofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O- hydrogenphosphonyl-β-D-arabinofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O- hydrogenphosphonyl-β-D-arabinofuranosyl) cytosine, and
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O- hydrogenphosphonyl-β-D-arabinofuranosyl)-5- fluorouracil.
9. A compound of claim 4 selected from the group consisting of:
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogenphosphonyl-B-D-qlycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogenphosphonyl-β-D-qlycero-pentofuranosyl) thymine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-hydrogenphosphonyl-β-D-glycero-pentofuranosyl) uracil,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl) cytosine,
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl) thymine, and
1-(2,3-Anhydro-5'-O-hydrogenphosphonyl-β-D- lyxofuranosyl) uracil.
10. A compound of claim 4 selected from the group consisting of:
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D-qlyceropentofuranosyl) cytosine,
1-(2,3-Dideoxy-5'-O-methvlphosphonvl-β-D-glyceropentofuranosyl) thymine,
1-(2,3-Dideoxy-5•-O-methvlPhosphonvl-β-D-qlyceropentofuranosyl) uracil,
1-(2,3-Dideoxy-5'-O-methylphosphonyl-β-D- lyxofuranosyl)-5-fluorouracil,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D- erythro-pentofuranosyl) thymine,
1-(3-Azido-2,3-dideoxy-5•-O-methylphosphonyl-β-D- erythro-pentofuranosyl) uracil,
1-(3-Azido-2,3-dideoxy-5'-O-methylphosphonyl-β-D- erythro-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- ervthro-pentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-
D- ervthro-pentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-
D- erythro-pentofuranosyl) cytosine, 1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-
D- ULEgs-pentofuranosyl) thymine,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β-
D- threo-pentofuranosyl) uracil,
1-(2,3-Dideoxy-3-fluoro-5'-O-methylphosphonyl-β- D- threo-pentofuranosyl) cytosine,
1-(3-Azido-2,3-dideoxy-2-fluoro-5'-0-methylphosphonyl-β-D-arabinofuranosy1) thymine, 1-(3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl-β-D-arabinofuranosyl) uracil, 1- (3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl-β-D-arabinofuranosyl) cytosine, and
1- (3-Azido-2,3-dideoxy-2-fluoro-5'-O-methylphosphonyl-β-D-arabinofuranosyl)-5fluorouracil.
11. A compound of claim 4 selected from group consisting of:
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methylphosphonyl-β-D-qlycero-pentofuranosyl) cytosine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methylphosphonyl-β-D-qlycero-pentofuranosyl) thymine,
1-(2,3-Dideoxy-2,3-didehydro-5'-O-methylphosphonyl-β-D-glycero-pentofuranosyl) uracil,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-Dlyxofuranosyl) cytosine,
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-Dlyxofuranosyl) thymine, and
1-(2,3-Anhydro-5'-O-methylphosphonyl-β-Dlyxofuranosyl) uracil.
12. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound of claims 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable metal salt therof and a pharmaceutically acceptable carrier.
13. A method of treating a viral infection which comprises contacting the viral infection with an amount of the compound of claims 1, 2, 3, 4, 5, 6, or 7 effective to suppress viral replication.
14. A method of claim 13, wherein the infection is caused by human immunodeficiency virus.
15. A method of claim 13, wherein the viral infection is caused by heptitis virus.
16. A method of claim 13, wherein the viral infection is caused by cytomegalo virus.
17. A method of treating a subject afflicted with a viral infection which comprises administering to the subject an amount of the composition of claim 9 to effective suppress viral replication.
18. A method of claim 17, wherein the subject is a domestic animal.
19. A method of claim 17, wherein the subject is a human being.
PCT/US1991/004362 1990-06-19 1991-06-19 5'-hydrogenphosphonates and 5'-methylphosphonates of sugar modified nucleosides, compositions and uses thereof WO1991019727A1 (en)

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US5508270A (en) * 1993-03-06 1996-04-16 Ciba-Geigy Corporation Nucleoside phosphinate compounds and compositions
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US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
WO2006062434A1 (en) * 2004-11-25 2006-06-15 Kukhanova Marina Konstantinovn Modified 5'- phosphonate azidothymidine-potential anti-viral preparations
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
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017651A3 (en) * 1992-03-04 1993-11-25 Max Delbrueck Centrum Antiviral nucleoside analogues, their production and use
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 (en) * 1995-01-27 1999-09-01 Univ Emory 5-carboxamido or 5-fluoro]- 2',3'-unsaturated or 3'-modified]-pyrimidine nucleosides
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 (en) * 2000-04-13 2009-07-22 Pharmasset, Inc. 3'-or 2'-hydroxymethyl substituted nucleoside derivatives for treatment of viral infections
WO2006062434A1 (en) * 2004-11-25 2006-06-15 Kukhanova Marina Konstantinovn Modified 5'- phosphonate azidothymidine-potential anti-viral preparations
RU2322450C2 (en) * 2004-11-25 2008-04-20 Закрытое акционерное общество "Производственно-коммерческая Ассоциация АЗТ" Modified 5'-phosphonates of 3'-azido-3'-deoxythymidine as active components for potential antiviral preparations
US7999099B2 (en) * 2004-11-25 2011-08-16 Marina Konstantinovna Kukhanova Modified 5′-phosphonate azidothymidine—potential anti-viral preparations
KR101323698B1 (en) 2004-11-25 2013-10-30 마리나 콘스탄티노브나 쿠카노바 Modified 5'-phosphonates of AZT potential antiviral drugs

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