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WO1993002044A1 - Nucleosides acycliques de 6-phenylselenyle pyrimidine - Google Patents

Nucleosides acycliques de 6-phenylselenyle pyrimidine Download PDF

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Publication number
WO1993002044A1
WO1993002044A1 PCT/US1992/003824 US9203824W WO9302044A1 WO 1993002044 A1 WO1993002044 A1 WO 1993002044A1 US 9203824 W US9203824 W US 9203824W WO 9302044 A1 WO9302044 A1 WO 9302044A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenylselenenyl
methyl
hydroxyethoxy
compound according
hiv
Prior art date
Application number
PCT/US1992/003824
Other languages
English (en)
Inventor
Raymond F. Schinazi
Original Assignee
Baker Cummins Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Baker Cummins Pharmaceuticals, Inc. filed Critical Baker Cummins Pharmaceuticals, Inc.
Publication of WO1993002044A1 publication Critical patent/WO1993002044A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil

Definitions

  • the invention relates to analogues of acyclic pyrimidine nucleosides and antiviral compositions including the same.
  • HIV human immunodeficiency virus
  • HIV human immunodeficiency virus
  • RNA-dependent DNA polymerase is unique to, and absolutely necessary for, viral replication. It should, therefore, be possible to target this enzyme for antiviral chemotherapy.
  • 3'-azid ⁇ -3'-deoxythymidine has been approved for treatment of AIDS patients. Unfortunately most of the anti-HIV agents identified so far are only virustatic and show inhibitory
  • prophylactic compound and due to the method of viral replication which results in integration of the viral coding capacity into the host genome, drug therapy following infection is likely to be required for long periods of time; thus, more effective and non- toxic compounds are required.
  • the present invention is directed to acyclic 6- phenylselenenyl pyrimidine nucleosides.
  • the general structure of these compounds is depicted below:
  • R 1 is hydrogen, halogen, vinyl, halovinyl or C 1 -C 3 alkyl, haloalkyl or hydroxyalkyl
  • R 2 is NH or oxygen
  • R 3 is oxygen, sulfur or methyl
  • X is oxygen or sulfur
  • Y is hydroxyl or hydrogen.
  • the invention also comprehends antiviral pharmaceutical compositions comprising the novel phenylselenenyl compounds as active ingredients together with conventional pharmaceutical carriers, vehicles or excipients, and methods of antiviral treatment utilizing said compositions.
  • TBDMS tert-butyldimethylsilyl
  • non- hydroxylated analogues of the compounds 6a-f i.e., 1-ethoxy- methyl-6-(phenylselenenyl) pyrimidine nucleosides.
  • the 1-(ethoxymethyl) pyrimidine precursors of these compounds are prepared by condensing bis(trimethylsilyl) uracil derivatives with chloromethyl ether in the presence of stannic chloride in dichloromethane at room temperature overnight, pouring the reaction mixture into a mixture of cold saturated aqueous sodium bicarbonate solution and trichloromethane, and then separating the resulting emulsion by filtration, with the organic fraction dried and evaporated. Trituration of the oily residue with ether yields the 1-(ethoxymethyl) pyrimidines.
  • the synthesis of the phenylselenenyl derivatives of the 1-(ethoxymethyl) pyrimidines is accomplished by the same
  • compositions for the oral delivery of an acyclic 6-phenylselenenyl nucleoside compound, exemplified by compounds 6a-f in Scheme 1, to a patient.
  • Such compositions include an antivirally effective amount of one or more of the novel
  • Dosage forms for oral delivery may include conventional tablets, coated tablets, capsules, caplets, lozenges, liquids, elixirs or any other oral dosage form conventionally used in the pharmaceutical arts.
  • inert ingredients there are contemplated carriers, excipients, fillers, binders,
  • dideoxyinosine, azidothymidine and acyclovir dideoxyinosine, azidothymidine and acyclovir.
  • fillers such as clays or siliceous earth may be utilized if desired to adjust the size of the dosage form.
  • excipienrs and carriers may be necessary to impart the desired physical properties of the dosage form.
  • Such physical properties are, for example, release rate, texture and size.
  • excipients and carriers useful in oral dosage forms are waxes such as beeswax, castor wax, glycowax and carnauba wax, cellulose compounds such as methylcellulose, ethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose and
  • hydroxypropylmethylcellulose polyvinyl chloride, polyvinyl pyrrolidone, stearyl alcohol, glycerin monstearate, methacrylate compounds such as polymethacrylate, methyl methacrylate and ethylene glycol dimethacrylate, polyethylene glycol and
  • hydrophilic gums are hydrophilic gums.
  • a preferred embodiment of the pharmaceutical compositions of the present invention involves pharmaceutical dosage forms wherein the phenylselenenyl-substituted active ingredient is present in an amount between about 25 and about 1000 mg per dosage unit.
  • the exact dosage administered to each patient will be a function of the physical characteristics of that patient such as body weight.
  • the invention also comprehends methods of providing antiviral treatment, particularly anti-HIV-1 or HIV-2 treatment, to a patient in need of such treatment consisting of the oral administration to the patient of a pharmaceutical composition containing at least one of the novel compounds, preferably from about 25 to about 1000 mg of each such compound, from one to four times daily.
  • the melting points set forth in the Examples were determined on an Electrothermal IA 8100 digital melting point apparatus and are uncorrected. 1 H NMR spectra were recorded on a General Electric QE-300 (300 MHz) spectrometer. Experiments were monitored using TLC analysis performed on Kodak Chromatogram sheets precoated with silica gel and a fluorescent indicator, while column chromatography, employing silica gel (60-200 mesh; Fisher Scientific, Fairlawn, New Jersey) was used for the
  • Tetrahydrofuran was freshly distilled from the sodium benzophenone salt.
  • LDA (2.0 M) and diphenyl diselenide were purchased from Aldrich Chemical Company
  • Acyclic pyrimidine nucleosides 3a-f were prepared according to the procedure of Rosowsky et al.
  • TBDMS TBDMS chloride
  • halogeno derivatives (6c-e) in Vero cells This suggests that some of the selenium analogues may exhibit toxicity in other rapidly dividing cells such as human bone marrow cells.
  • compounds 6a-f When tested in human PBM cells infected with HIV-2 (strain ROD-2), compounds 6a-f were found to have activity similar to that obtained with HIV-1, with the exception of the (6-phenyl- selenenyl)-thymine derivative (6b) which was about 25-fold less active.
  • HEPT was also not active against HIV-2 in this cell culture system.
  • novel selenenyl compounds were unexpectedly found to have selective antiviral activity against both HIV-1 and HIV-2 in primary human lymphocytes, and are not inhibitors of HIV-1 RT. Taken together, the results suggest that the activity of the selenium analogues is produced by inhibition of a viral target which is different from the corresponding sulfur containing analogues, such as HEPT.
  • non-hydroxylated (i.e., 1-ethoxymethyl) analogues 7a and 7b were also evaluated for anti-HIV 1 activity and toxicity in PBM and Vero cells in accordance with the procedures outlined above. The results of these tests are set forth in Table 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nucléosides acycliques de 6-phénylsélénényle présentant une activité contre le VIH-1 et le VIH-2. L'invention concerne également des compositions antivirales comprenant les nouveaux composés et procédés de traitement utilisant ces compositions.
PCT/US1992/003824 1991-07-22 1992-05-08 Nucleosides acycliques de 6-phenylselenyle pyrimidine WO1993002044A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73334691A 1991-07-22 1991-07-22
US733,346 1991-07-22

Publications (1)

Publication Number Publication Date
WO1993002044A1 true WO1993002044A1 (fr) 1993-02-04

Family

ID=24947232

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/003824 WO1993002044A1 (fr) 1991-07-22 1992-05-08 Nucleosides acycliques de 6-phenylselenyle pyrimidine

Country Status (2)

Country Link
AU (1) AU1994492A (fr)
WO (1) WO1993002044A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922727A (en) * 1996-02-22 1999-07-13 Samjin Pharmaceutical Co., Ltd Antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
US6177435B1 (en) 1992-05-13 2001-01-23 Glaxo Wellcome Inc. Therapeutic combinations
WO2005065689A1 (fr) * 2004-01-08 2005-07-21 Medivir Ab Inhibiteurs de dutpase
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989009213A1 (fr) * 1988-03-31 1989-10-05 Mitsubishi Kasei Corporation Derives de nucleoside de pyrimidine acyclique substitue en 6 et agents antiviraux contenant ces composes en tant qu'ingredients actifs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989009213A1 (fr) * 1988-03-31 1989-10-05 Mitsubishi Kasei Corporation Derives de nucleoside de pyrimidine acyclique substitue en 6 et agents antiviraux contenant ces composes en tant qu'ingredients actifs

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6177435B1 (en) 1992-05-13 2001-01-23 Glaxo Wellcome Inc. Therapeutic combinations
US5922727A (en) * 1996-02-22 1999-07-13 Samjin Pharmaceutical Co., Ltd Antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients
CN1092647C (zh) * 1996-02-22 2002-10-16 三进制药株式会社 新抗病毒的取代嘧啶二酮同素碳环核苷衍生物及其制备方法与含有其为活性成分的组合物
WO2005065689A1 (fr) * 2004-01-08 2005-07-21 Medivir Ab Inhibiteurs de dutpase
US7601702B2 (en) 2004-01-08 2009-10-13 Medivir Ab Dutpase Inhibitors
US7795270B2 (en) 2004-01-08 2010-09-14 Medivir Ab DUTPase inhibitors
US8017620B2 (en) 2004-01-08 2011-09-13 Medivir Ab Dutpase inhibitors
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors

Also Published As

Publication number Publication date
AU1994492A (en) 1993-02-23

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