EP0428623A1 - PRODUCTION DU 1-($g(b)-D-ARABINOFURANOSYL)-5(E)-(2-IODOVINYL)URACIL ET SES UTILISATIONS, AINSI QUE DES ANALOGUES ASSOCIES RENFERMANT D'AUTRES RADIONUCLIDES HALOGENES, LES PRECURSEURS GENERAUX DE RADIOHALOGENATION, 1-(2,3,5-TRI-O-ACETYL-$g(b)-D-ARABINOFURANOSYL)-5(Z ET E)-(2-TRIMETHYLSILYLVINYL)URACI - Google Patents

PRODUCTION DU 1-($g(b)-D-ARABINOFURANOSYL)-5(E)-(2-IODOVINYL)URACIL ET SES UTILISATIONS, AINSI QUE DES ANALOGUES ASSOCIES RENFERMANT D'AUTRES RADIONUCLIDES HALOGENES, LES PRECURSEURS GENERAUX DE RADIOHALOGENATION, 1-(2,3,5-TRI-O-ACETYL-$g(b)-D-ARABINOFURANOSYL)-5(Z ET E)-(2-TRIMETHYLSILYLVINYL)URACI

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Publication number
EP0428623A1
EP0428623A1 EP89910499A EP89910499A EP0428623A1 EP 0428623 A1 EP0428623 A1 EP 0428623A1 EP 89910499 A EP89910499 A EP 89910499A EP 89910499 A EP89910499 A EP 89910499A EP 0428623 A1 EP0428623 A1 EP 0428623A1
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EP
European Patent Office
Prior art keywords
arabinofuranosyl
ivarau
uracil
acetyl
radiohalogen
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP89910499A
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German (de)
English (en)
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EP0428623A4 (en
Inventor
Stephen Leslie Sacks
Morris J. Robins
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Individual
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Publication of EP0428623A1 publication Critical patent/EP0428623A1/fr
Publication of EP0428623A4 publication Critical patent/EP0428623A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention pertains to novel radioactive antiviral compounds, with 1-(ß-D-arabinofuranosyl)-5(E)-(2-[*I]-iodovinyl) uracil, hereinafter referred to as w[*I]-IVaraU", as the prototype compound for the class of compounds designated as 1-(ß-D-arabinofuranosyl)-5(E)-(2-[*X]-halogenovinyl) uracil, hereinafter referred to as "[*X]-XVaraU”, and novel precursors thereof, 1-(2,3,5-tri-O-acetyl-ß-D-arabinofuranosyl)-5( Z and E) - (2-trimethylsilylvinyl) uracil, hereinafter referred to as "TMSVaraU", and processes for the preparation thereof, and uses thereof, wherein "*I” stands for a
  • radionuclide of iodine and *X stands for any other appropriate halogen radionuclide.
  • positron emitting iodine, or other appropriate halogen radionuclide into the structure of [*I] -IVaraU, makes this agent useful as a diagnostic tool for detection of herpes virus infections in vitro and in vivo .
  • BACKGROUND OF THE INVENTION Yamasa Shoyu Company Ltd. has developed a group of nonradioactive antiviral compounds known as 1- (ß-D-arabinofuranosyl)-5(E)-(2-halogenovinyl) uracils (XVara ⁇ 's) and methods of preparation of same.
  • halogeno hereinafter designated as "X” in the abbreviated form, includes bromo, chloro, and iodo.
  • the bromo derivative known as 1- (ß-D- arabinofuranosyl)-5(E)-(2-bromovinyl) uracil, or
  • BVaraU BV-araU
  • BVAU BV-araU
  • BVaraU is easy to synthesize, owing to the high reactivity of the halogen, bromine.
  • BVaraU is effective against herpes virus infections of man and animals which are associated with viral-induced (deoxy) thymidine kinases.
  • radiolabeled analogues of the XVaraU' s or related substances as targeted radiotherapeutic antiviral agents which derive their antiviral activity by precise targeting of the lethal effects of alpha and/or beta radiation and/or Auger electron decay effects to the site of viral infection.
  • Herpes simplex virus, herpes (varicella) zoster virus, cytomegalovirus, and Epstein Barr virus hereinafter referred to as "HSV”, “VZV”, “CMV”, and “EBV”, respectively, are common human herpesviruses, which significantly contribute to a number of important ailments which afflict centuries. Most often, HSV and VZV are associated with skin or mucous membrane lesions which readily lend themselves to rapid and accurate viral diagnosis, generally using standard swab/culture techniques. By contrast, target organ and life-threatening infections with these viruses often evade diagnosis, because of the difficulty in achieving access to infected tissues on which to apply the culture techniques.
  • invasive testing is often presented with the choice of either guessing what the patient has contracted based on symptoms and signs or obtaining a piece of deep tissue for analysis by surgical or endoscopic procedures (invasive testing).
  • invasive testing is not practical, e.g., with retinal or other deep ophthalmic infections, and for
  • CSF cerebrospinal fluid
  • deoxythymidine kinases a group of herpesviral-specific enzymes, hereinafter designated as "dTK's".
  • dTK's herpesviral-specific enzymes
  • X is a radiohalogen isotope selected from the group consisting of radioactive 123 I, 125 I, 127 I, 131 I, or, alternatively, from the group consisting of 75 Br, 7 ⁇ Br, 77 Br, 82 Br, 34 C1, or other appropriate radionuclides which comprises: (a) converting uridine to its arabino analogue; (b) protecting the arabino analogue by acetylation; (c) halogenating the group consisting of radioactive 123 I, 125 I, 127 I, 131 I, or, alternatively, from the group consisting of 75 Br, 7 ⁇ Br, 77 Br, 82 Br, 34 C1, or other appropriate radionuclides which comprises: (a) converting uridine to its arabino analogue; (b) protecting the arabino analogue by acetylation; (c) halogenating the group consisting of radioactive 123 I, 125 I, 127 I, 131 I, or, alternatively, from the
  • X is a radioisotope of iodine selected from the group consisting of radioactive 123 I, 125 I,- 127 I, 131 I, or alternatively, a radiohalogen selected from the group consisting of radioactive 75 Br, 76 Br, 77 Br, 82 Br, 34 Cl, or other appropriate
  • Figure 1 illustrates in graphical format the process of the invention for synthesizing a precursor compound, 1- (2, 3, 5-tri-O-acetyl-ß-D-arabinofuranosyl)-5(Z) -(2-trimethylsilylvinyl) uracil, followed by preparation of 1-(ß-D-arabinofuranosyl)-5(E) -(2-[*I]-iodovinyl) uracil, as the prototype compound for the class of compounds designated as 1-(ß-D-arabinofuranosyl)-5(E)-(2-[*X]-halogenovinyl) uracil, wherein any halogen radionuclide is used in the process.
  • Figure 5 Localization of [ 123 I] -IVaraU in HSV-1-infected areas of the New Zealand White rabbit infected onto the cribriform plate.
  • A A photograph of a positive scan from an animal scanned 7 days post-infection which is acutely infected in the nasopharynx and olfactory bulb.
  • B Scan 7 weeks post-infection of a control animal latently, but not actively infected. Olfactory bulb necrotic but no virus present. Similar appearance to an uninfected control animal.
  • KOS HSV-1
  • BVaraU is also resistant to
  • the physician can tailor the medicine according to its use by selecting the radionuclide for optimal imaging and safety characteristics for gamma scans (for example, by selecting 123 I, 131 I, or 82 Br), vs. optimal imaging and safety characteristics for positron emission scans (for example, by selecting 123 I, 127 I, 75 Br, 76 Br, 77 Br, 82 Br, 34 Cl), vs. prolonged half-life and safety for ease of use in vitro (for example, by selecting 125 I), vs.
  • radiotherapeutic antiviral effects mediated by viral dTK's for the targeting of lethal radiation for example by selecting 131 I, Br
  • the precursor compounds named above can be reacted in the penultimate synthetic step with radiolabeled iodine, using the generally available compounds, Na 125 I, Na 123 I,and Na 131 I or, in the alternative, a less-widely used iodine radionuclide, Na 127 I, or, in the alternative, other halogen
  • radionuclides e.g., Na 75 Br, Na 76 Br, Na 77 Br, Na 82 Br, Na 34 Cl, or alternative salts of these radiohalogens. Since the mechanism of localization of the nucleoside to infected sites is not dependent upon the nature of the radionuclide, per se, it is quite certain that other suitable halogen radionuclides will become available for use with this invention as future
  • the radiopharmaceutical agents of this invention can be generated quickly in a small laboratory in a hospital's nuclear medicine department.
  • the conditions are mild, standard, and easy to reproduce, and employ inexpensive and
  • Iodine monochloride is synthesized in situ as an intermediate from Na*I which is purchased in radioactive form. The overall reaction is rapid.
  • phenyliodine (III) dichloride to effect formation of iodine monochloride as a stoichiometric source of iodine radionuclides for such reactions.
  • xenon difluoride has been used to generate the mixed halogens IF, BrF, and ClF in situ, for general radiohalogenation in such reactions.
  • [*I] -IVaraU was synthesized from the precursor, TMSVaraU, with iodine monochloride (ICl) produced in situ from sodium iodide and
  • radiohalogens for synthesis of the radiobromo- and radiochloro-vinyl compounds
  • reaction This solution was neutralized with an equal volume of phosphate buffered physiological saline (pH 7.4), by adding the saline solution to the V-vial containing the radionuclide. Subsequently, 25 ⁇ l of spectral quality benzene was added, a.long with 0.5 mg of NaI and 1.0 mg of phenyliodine (III) dichloride. The reaction mixture was shaken vigorously and placed in the plastic safety container (which is supplied with the 122 I-sodium iodide), to shield it from light. The reaction was allowed to proceed for 15 minutes at room temperature, with frequent shaking. Two layers were visible; a dark red upper organic layer, and a slightly yellow-colored aqueous layer.
  • TMSVaraU TMSVaraU was dissolved in 25 ⁇ l of benzene, and added to the V-vial using a glass capillary pipette. The vial was returned to the safety container and shaken every 15 minutes for 1.5 hours. At the end of this reaction, 0.5 ml of 5% aqueous bisulfite was added to the reaction vial.
  • Solvent was removed by passing a stream of N 2 gas over the vial.
  • a small piece of elemental sodium was added to 1 ml of HPLC grade methanol to form a sodium methoxide solution.
  • 0.5 ml of this solution was added to the dried compound.
  • the running solvent was chloroform: methanol, (8:2).
  • the deprotected compound has an R f of ⁇ 0.75.
  • the solution was not neutralized, and the methanol was allowed to evaporate overnight.
  • the dried residue was dissolved in 0.5 ml PBS, pH 7.4, for biological studies.
  • Isolate #615 is quite resistant in vitro to acyclovir.
  • Three resistant plaque-purified substrains of 615 have been characterized for another purpose. Two are pure DNA polymerase mutants (615.5, 615.8) which express normal amounts of dTK and yet show in vitro and in vivo resistance to acyclovir.
  • the third isolate (615.3) is a dTK deficient strain which does not phosphorylate acyclovir and phosphorylates
  • deoxythymidine very poorly.
  • the pretreatment "wildtype" isolate (sensitive to drugs as for any other HSV-1 isolate) was also plaque-purified (294.1) and used as a sensitive control.
  • a laboratory-induced acyclovirresistant mutant of strain KOS, known as ACG r 4 was also used [an HSV-1 reference strain which was artificially induced to lack the dTK enzyme (viral dTK's are
  • PRK Primary Rabbit Kidney Cells
  • tissue culture grade roller tubes kept rolling at 1 rpm at 37°C.
  • Tubes contained approximately 1.4 ⁇ 10 6 cells/tube.
  • Each tube was infected with an moi of 10 in 1.0 ml of media and incubated for 6 hours at 37°C.
  • cpm Approximately 4.8 ⁇ 10 6 counts per minute, hereinafter referred to as "cpm", of [ 125 I] -IVaraU (100 ⁇ l) were then added to each tube and incubation continued for 0.75 hours at 37°C.
  • the medium was then removed from the tubes and replaced with 2.0 ml of 0.25% trypsin in EDTA, and incubated at 37°C until cells were separated from the plastic, transferred into 12 ⁇ 75 mm plastic tubes, and centrifuged to a pellet at 800 ⁇ 9 and washed 3 times in PBS, pH 7.4, 4°C, and counted in a gamma counter (Beckman).
  • roller tubes were again seeded with PRK cells as described in example 4, and infected with 10 moi of the wild-type isolate, 294.1 and ACG r 4 (dTK negative) in parallel. After 6 hours of incubation at 37°C, 4 ⁇ 10 4 cpm of [ 125 I] -IVaraU were added and the incubation continued for a further 0.75 hours. The media were then removed, the monolayers washed with PBS, pH 7.4, 37°C, and the media were replaced with no nucleoside added. Incubation was restarted in the roller
  • PRK cells were grown to confluence at the bottom of tissue culture grade plastic roller tubes. For this experiment, the number of cells were 1.29 ⁇ 10 6 . Inocula per cell, of 1, 0.1, 0.01, 0.001, and 0.0001 plaque-forming units, hereinafter referred to as "PFU", of HSV-1 strain 294.1 (Wild type) were used. The media were removed and replaced with Hank's "199", containing 2% inactivated fetc.1 calf serum and the various viral inocula.
  • PFU plaque-forming units
  • the tubes were spun at room temperature for 1800 revolutions per minute for 30 minutes, and incubated at 37°C. for 2,3,4,5,6,7,8,10,12,20,22,24 hours. Forty-five minutes prior to completion of the incubation period, 4.0 ⁇ 10 6 cpm of [ 125 I] -IVaraU were added to the viral growth media in 100 ⁇ l of PBS. Cells were then trypsinized with 2.0 ml of 0.25% trypsin and
  • VERO cells were obtained from the American Type Culture Collection. The cells were grown to confluence and infected with HSV-1, strain F; or HSV-2, strain G, used as reference; strains. These strains were obtained from Dr. Bernard Roizman,
  • CPE cytopathic effects
  • virus stocks were diluted (one at a time) to a final concentrations of 1 DUo and added to each of the wells (except for the cell control which contains drug dilutions without virus infection) in 50 ⁇ l volumes. The plates were then incubated at 37°C, in an atmosphere of 5% CO 2 for 1 hour.
  • Antiviral drug dilutions were made during this period, beginning at the highest concentration of IVaraU 0.065 ⁇ g/ml which was equal to a radiation dose in wells treated with [ 125 I] -IVaraU, of 0.50 ⁇ Ci/ml and then serially 2-fold diluted 16 times, and added to the wells at the end of the 1 h adsorption period in a volume of 50 ⁇ l. All experiments were performed in quadruplicate, and results are expressed as the average of those four wells at each drug dilution. The unlabeled IVaraU and the [ 125 I] -IVaraU were compared at equal concentrations and dilutions in parallel. Two types of controls are run on each 96 well plate. One column receives mock virus inoculation [50 ⁇ l of Medium 199 (with
  • [ 125 I] -IVaraU (136 ⁇ Ci; 37 Ci/mmol) were given to 3 infected rabbits 1 hour prior to in situ perfusion and sacrifice. 5-7 ⁇ m sections were stained with HSV-1 monoclonal antibodies, labeled by immunoperoxidase, counted by 0.0058 mm 2 grids, and assessed for peroxidase positive hits per total number of grids. Maximal infection was seen in the right olfactory bulb with 32.9% peroxidase positive. [ 125 I] -IVaraU uptake was also maximal in this region, with a mean of 13,872 cpm per gram of tissue.
  • Figure 6 displays in radiographic print form, a series of nuclear scans over time from an animal with HSV-1 (KOS) encephalitis infected via the cribriform plate 9 days prior to the scans. After infusion with [ 123 I] -IVaraU three scans in different head views were obtained.
  • KOS HSV-1
  • the agent useful as a unique radiotherapeutic tool for herpes virus infections by precise targeting of the lethal effects of alpha and/or beta radiation and/or Auger electron decay effects to the site of viral infection.
  • the uses for the agent include, but are not restricted to, the following:
  • the compound is useful as a marker of viral growth in vitro .
  • This allows for the following: (a) Automation of viral cultures;
  • Deep seated infections will be detectable with this agent.
  • viral diagnosis is often missed.
  • the physician may not consider the diagnosis, or considers it, but is afraid of the risk of the test.
  • biopsy is clinically impossible.
  • intravenous injections of isotopes in the range of 1 to 20 mCi, total body dose may be administered at one time by intravenous bolus
  • the amount of the agent in molar quantities required will be determined by the specific activity of the synthesized material. Regardless, the actual quantity of the agent in its nucleoside form
  • the administered will be less than 1 mg per day. In certain clinical situations, it may be preferable to apply the diagnostic agent either topically or
  • ointments or dermatological salves or ointments may be preferred with such doses as would otherwise be
  • Herpes virus-related clinical syndromes which present diagnostic problems and which might benefit from the enhanced diagnostic capabilities described herein, include, but are not limited to, the following:
  • HSV and VZV infections of the eye including: retinitis, keratitis, ulceris, uveitis, retinal necrosis and zoster ophthalmicus.
  • HSV meningitis often associated with genital herpes infections.
  • HSV and VZV sensory nerve, root and ganglionic infections are also included, since the agent could enhance understanding of HSV infection enough to clarify their relationship to HSV, if any.
  • a partial list of possibly-related syndromes includes multiple sclerosis, schizophrenia, migraine and other severe headache, Alzheimer's disease, and others. It is expected that new knowledge to be gained through the use of this agent will expand the knowledge of
  • herpes virus-induced diseases there are also a variety of herpes virus-induced diseases in the veterinary setting, each specific to a certain type of animal. Many of these viruses express the herpes virus enzyme, dTK, which specifically phosphorylates [*I] -IVaraU, and/or [*X]-XVaraU. In such situations, the veterinarian may elect to diagnose a herpes viral disease after intravenous, or intraperitoneal administration to the animal of from 0.01 to 0.50 ⁇ Ci per kg of total body weight.
  • dTK herpes virus enzyme
  • halogen radionuclides including 131 I, 82 Br, and others with suitable cytotoxic alpha and/or beta emission characteristics, and/or 125 I, or 77 Br, or other halogen radionuclides which display suitable Auger electron decay phenomena, localized, and thereby targeted destruction of cells actively or latently infected with HSV, VZV, or EBV will be
  • Such therapy may be used in conjunction with any antiherpesviral antiviral agent, since the
  • administration and dosage of this agent as an antiviral drug will be determined by the physician in ccordance with the specific clinical condition. Based on the potent in vitro antiviral effects observed, it is possible, however, to predict a dosage range of from 5 to 150 mCi total dose as the isotope, administered by intravenous injection, or 5 to 150 mCi total dose as the isotope, administered orally. Either mode of administration may be possible, depending on whether long-term administration of the agent is required. The amount of the agent in molar quantities required will be determined by the specific activity of the

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Abstract

Composés radioactifs antiviraux renfermant le 1-(beta-D-arabino-furanosyl)-5(E)-(2-[*I]-iodovinyl)uracil, indiqué ci-après par "[*I]-IVaraU", comme composé prototype pour la classe de composés désignés sous le nom de 1-(beta-D-arabinofuranosyl)-5(E)-(2-[*X]- halogénovinyl)uracil, indiqués ci-après par "[*X]-XVaraU", et les nouveaux précurseurs de ceux-ci, 1-(2,3,5-tri-O-acétyl-beta-D-arabinofuranosyl)-5(Z et E)-(2-triméthylsilylvinyl)uracil, indiqués ci-après par "TMSVaraU", procédés de préparation de ces composés et utilisation de ceux-ci, formules dans lesquelles "*I" désigne un radionuclide de l'iode, et "*X" désigne toute autre radionuclide halogéné approprié. L'inclusion de l'iode émetteur gamma ou de positron approprié, ou d'un autre radioncuclide halogéné approprié, dans la structure de [*I]-IVaraU, rend cet agent utile comme outil de diagnostic pour la détection des infections in vitro et in vivo dues au virus de l'herpès. L'inclusion d'isotopes de l'iode apropriés émetteurs alpha et/ou béta et/ou gamma, et/ou associés à une décroissance électronique Auger (spécifiquement nucléaires-toxiques), ou d'autres radionuclides halogénés appropriés, dans la structure de cet agent rend ledit agent utile comme outil unique radiothérapeutique pour des infections dues au virus de l'herpès, par ciblage précis des effets létaux des radiations alpha et/ou béta et/ou des effets de décroissance électronique Auger sur le site de l'infection virale.
EP19890910499 1988-08-10 1989-08-08 Production of radioiodinated 1--g(b)-d-arabinofuranosyl)-5(e)-(2-iodovinyl)uracil, and uses thereof, and related analogues incorporating alternative halogen radionuclides, the general radiohalogenation precursors, 1-(2,3,5-tri-o-acetyl--g(b)-d-arabinofuranosyl)-5(z and e)-(2-trimethylsilylvinyl)urac Withdrawn EP0428623A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US23113788A 1988-08-10 1988-08-10
US231137 2002-08-30
2003-07-18

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EP0428623A1 true EP0428623A1 (fr) 1991-05-29
EP0428623A4 EP0428623A4 (en) 1993-12-08

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EP19890910499 Withdrawn EP0428623A4 (en) 1988-08-10 1989-08-08 Production of radioiodinated 1--g(b)-d-arabinofuranosyl)-5(e)-(2-iodovinyl)uracil, and uses thereof, and related analogues incorporating alternative halogen radionuclides, the general radiohalogenation precursors, 1-(2,3,5-tri-o-acetyl--g(b)-d-arabinofuranosyl)-5(z and e)-(2-trimethylsilylvinyl)urac

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EP (1) EP0428623A4 (fr)
WO (1) WO1990001324A1 (fr)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3755296A (en) * 1969-07-24 1973-08-28 Kohjin Co Process for preparing 1-{62 -d-arabinofuranosyl-cytosine and 2,2{40 -cyclocytidine
GB1601020A (en) * 1978-04-24 1981-10-21 Stichting Grega Vzw 2'-deoxy-5 (2-halogenovinyl)-uridines
GB2060604B (en) * 1979-10-03 1983-11-23 Univ Birmingham And Stichting E15-(2-halogenovinyl)-2'-deoxycytidines
JPS5687599A (en) * 1979-12-19 1981-07-16 Yamasa Shoyu Co Ltd E 55 22halogenovinyl arabinofuranosyluracil and its preparation
US4782142A (en) * 1982-01-05 1988-11-01 The Research Foundation Of State University Of New York Novel 5-substituted 2-pyrimidinone nucleosides and methods of use
US4624846A (en) * 1983-07-29 1986-11-25 Immunomedics, Inc. Method for enhancing target specificity of antibody localization and clearance of non-target diagnostic and therapeutic principles
US4745182A (en) * 1984-08-24 1988-05-17 University Patents, Inc. Herpes virus specific immunological materials and methods
US4851520A (en) * 1988-01-29 1989-07-25 President & Fellows Of Harvard College Method of making radioiodinated pyrimidine nucleoside or nucleotide

Non-Patent Citations (4)

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Title
ANTIVIRAL RESEARCH vol. 7, no. 2, February 1987, pages 79 - 86 S. SUZUKI ET AL 'ANTIVIRAL ACTIVITY OF VARIOUS 1-BETA-D-ARABINOFURANOSYL-E-5-HALO GENOVINYLURACILS AND E-5-BROMOVINYL-2'-DEOXYURIDINE AGAINST SALMON HERPES VIRUS, ONCORHYNCHUS MASOU VIRUS (OMV)' *
JOURNAL OF ORGANIC CHEMISTRY. vol. 48, no. 11, 1983, EASTON US pages 1854 - 1862 M. J. ROBINS ET AL 'NUCLEIC ACID RELATED COMPOUNDS. 39. EFFICIENT CONVERSION OF 5-IODO TO 5-ALKYNYL AND DERIVED 5-SUBSTITUTED URACIL BASES AND NUCLEOSIDES' *
See also references of WO9001324A1 *
TETRAHEDRON LETTERS. no. 6, 1974, OXFORD GB pages 543 - 546 R. B. MILLER ET AL 'THE STEREOSPECIFIC SYNTHESIS OF VINYL HALIDES USING A VINYLSILANE AS THE SYNTHETIC PRECURSOR' *

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EP0428623A4 (en) 1993-12-08
WO1990001324A1 (fr) 1990-02-22

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