WO1988005438A1 - Antiviral agents - Google Patents

Antiviral agents Download PDF

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Publication number
WO1988005438A1
WO1988005438A1 PCT/US1987/003446 US8703446W WO8805438A1 WO 1988005438 A1 WO1988005438 A1 WO 1988005438A1 US 8703446 W US8703446 W US 8703446W WO 8805438 A1 WO8805438 A1 WO 8805438A1
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Prior art keywords
guanine
compound
propyloxymethyl
formula
ethylphosphono
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PCT/US1987/003446
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English (en)
French (fr)
Inventor
Elmer J. Reist
Priscilla A. Sturm
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Sri International
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Publication date
Application filed by Sri International filed Critical Sri International
Publication of WO1988005438A1 publication Critical patent/WO1988005438A1/en
Priority to GB8821380A priority Critical patent/GB2209338A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to nucleotide analogs which are antiviral agents. Specifically, it relates to acyclic purine phosphonate nucleotide analogs which are effective against both herpes-type virus and against RNA retroviruses such as HTLV-III (HIV).
  • acyclic purine phosphonate nucleotide analogs which are effective against both herpes-type virus and against RNA retroviruses such as HTLV-III (HIV).
  • herpes zoster chicken pox
  • herpes simplex virus I & II cold sores and genital herpes
  • cytomegalovi rus cytomegalic inclusion disease
  • Epstein-Barr virus (mononucleosis).
  • the herpes viruses are medium-sized viruses containing double-stranded DNA.
  • the nucleocapsid is about 100 nm in diameter and is surrounded by a lipid containing envelope.
  • the virion is 150-200 nm in diameter, and permits latent infections which last for the life span of the host even when antibodies are present.
  • RNA virus group A very different group of virus particles is the RNA virus group.
  • retroviruses which include most tumor virions, including human T-cell leukemia virus (HTLV III), now designated human immunodeficiency virus (HIV). HIV or its close relatives are believed to be the cause of Acquired Immune Deficiency Syndrome (AIDS).
  • AIDS Acquired Immune Deficiency Syndrome
  • nucleoside analogs such as iododeoxyuridine and 5-E-bromovinyldeoxyuridine, are believed to act only after conversion by viral thymidine kinase (but not by host TK) to the nucleotide form, which is then converted to the triphosphate and incorporated into the viral DNA, thus inhibiting its replication.
  • the antiviral agents of the present invention are acyclic nucleotide analogs which are phosphonates rather than phosphates.
  • a large number of phosphonate analogs of nucleotides are described by Engel, R., Chem Reviews (1977) 11: (3)349-367.
  • Phosphonate compounds which are direct cyclic nucleotide analogs are also disclosed in U.S. 3,560,478; German Patent Application DE3,045,375VA1, published 1 July 1982; U.S. 3,446,793; British Patent 1,243,213; German Patent Application 2,009,834 published 17 September 1970 and in Holman, J., et al, Liebiqs Annalen Chem (1984) 98-107; Hampton, A., et al.
  • acyclovir is effective in vitro against Varicella-Zoster, Epstein-Barr virus, cytomegalovirus, and "B" virus, and postulate that it provides its antiviral activity by being a substrate for" phosphorylation by a viral thymidine kinase, such as that specified by the herpes virus, and, in the resulting triphosphate form, inhibits herpes virus DNA polymerase.
  • the invention provides a class of open chain alkoxymethyl nucleoside analog phosphonates which are potent antiviral agents against both herpes-type, such as cytomegalovirus, and RNA retrovirus type infections. These compounds are apparently able to penetrate the infected cell and successfully inactivate the virus. Accordingly, in one aspect, the invention is directed to compounds of the formula:
  • B represents a substituted or unsubstituted purine base, especially adenine or guanine and their halogenated derivatives
  • R1 is selected from H, methyl, hydroxymethyl, halomethyl, azidomethyl, and cyano
  • n is an integer of 0-5.
  • the compounds of the invention further include the pharmaceutically acceptable monoand dibasic salts and the mono- and diesters of the phosphonate moiety and the acid addition salts of the amino-substituted purines.
  • R1 or R2 is -CH 2 OH, or when R2 is OH, the acyl (1-6C) esters of these alcohols are included in the invention.
  • the compounds of Formula 1 include the cyclic forms wherein formal dehydration between R1 and one of the -OH groups on the phosphonate results in compounds of the formula:
  • the invention relates to pharmaceutical compositions containing the compounds of Formula 1 or 1a and to methods of treating or preventing herpes-type and RNA retrovirus infections by use of the compounds of Formula 1 (or 1a) or these compositions.
  • the compounds of the invention may be in the form of phosphonic acids, esters, or pharmaceutically acceptable salts.
  • the compounds may be used as the acid addition salts of the purine base.
  • the salts of the phosphonic acid moiety are salts with inorganic or organic bases and may be the mono- or dibasic salts.
  • Salts derived from inorganic bases include the sodium, potassium, lithium, alkaline metal, such as magnesium and calcium salts, and salts of the transition metals or of aluminum. Salts derived from ammonium, potassium, sodium, calcium and magnesium are preferred.
  • Suitable organic bases which are nontoxic and are capable of forming salts with the phosphonic acid moiety include various amines such as ethanolamine, triethylamine, isopropylamine, and amino acids such as lysine and arginine.
  • the phosphonic acid moiety of the compounds of the invention may also be in the form of the mono- or diester.
  • the esters will be formed from alkyl, aryl-alkyl, and aryl alcohols containing 1-8 C.
  • Alkyl alcohols include saturated or unsaturated straight chain, branch chain, or cyclic hydrocarbyl alcohols which may be substituted with one or two additional hydroxyl substituents or contain heterocyclic rings which include N, O and/or S atoms.
  • Such moieties include, for example, methyl, isobutyl, n-octyl, 2-butenyl, 4-hydroxy-n-pentyl and so forth.
  • the ester contains a phenyl substituent optionally substituted by one or two halo, alkoxy or hydroxy residues and representative groups of this class include the phenyl ester, the 3-hydroxyphenyl ester, the benzyl ester, and the 2-phenylethyl ester.
  • the alkyl (1-6C) esters are especially preferred.
  • the compounds of the invention may also be supplied as the acid addition salts which retain the biological effectiveness and properties of the free bases and which are not otherwise undesirable.
  • These salts may be formed from inorganic acids such as hydrochloric, hydrobromic acid or sulfuric acid, or from organic acids such as acetic, propionic, glycolic, oxalic, malonic, succinic, tartaric, cinnamic, methane sulfonic, p-toluene sulfonic, salicylic, and so forth.
  • R1 is selected from hydrogen, methyl, substituted methyl and cyano.
  • Substituted methyl groups include CH 2 OH, CH 2 N 3 , CH 2 CI, CH 2 Br, CH 2 F, and CH 2 I.
  • the acyl esters (1-6C) such as the esters of acetic, proprionic, butyric, and hexanoic acids, are also included.
  • the purine moieties of the invention are derived either from adenine or guanine each of which has a nucleus of the formula:
  • guanine the substituent at position 6 is hydroxyl (in the tautomer shown) and in adenine, -NH 2 .
  • Guanine has -NH 2 at position 2, adenine is unsubstituted.
  • guanine or adenine analogs having halo groups in place of the hydroxyl or amino at position 6, such as chloro or bromo in particular are preferred.
  • suitable substituents at positions 2, 6 and 8 include hydroxyl, amino and halo wherein halo is defined as fluoro, chloro, bromo, and iodo.
  • Preferred values for n in the compound of Formula 1 are 0-2.
  • Reaction Scheme 1 shows the general method to prepare the compounds of Formula 1.
  • the resulting diester is, of course, a compound of the invention, that can be converted to the free acid by a modification of the method of McKenna, et al, Tet Letts (1977) 155.
  • the monoester is prepared by treatment of the diester with aqueous 1 N sodium hydroxide, as described by Jones and Moffatt, J Am Chem Soc (1968) 90:5337. Any 6-chloro group on the purine will simultaneously be replaced by -OH.
  • the intermediate alcohol is obtained by methods which depend on the nature of R1 and R2.
  • R1 and R2 are either both methyl or both H, this alcohol is made according to Reaction Scheme 2. '
  • Reaction Scheme 2 describes the condensation of a trialkyl phosphite, wherein R' represents alkyl, with a symmetric dibromoalkane, according to the procedure of Eberhard and Westheimer, J Am Chem Soc (1965) 87:253.
  • Reaction Scheme 4 is employed to form the intermediate alcohol, derivatized to the silyl ether.
  • the intermediate phosphonate is prepared as described by Gazizov, T., et al, Gen Chem USSR (1977) 47:2465, and then derivatized with alkyl chlorosilane before functionalization of the alkene to form the desired alcohol.
  • the compounds of Formulas 1 and 1a may be prepared in their salt or ester forms, and these esters or salts can be reconverted to the free acid or free purine base.
  • Phosphonic Acid Salts
  • the free phosphonic acid may be converted to the mono- or dibasic salt form by treatment with an appropriate base.
  • These salts are prepared by treating the corresponding free acids with at least one or at least two molar equivalents of a pharmaceutically acceptable base as set forth above.
  • the reaction is conducted in water, alone or in combination with an inert, water miscible organic solvent at a temperature of from 0°C-100°C, preferably room temperature.
  • Typical inert, water miscible organic solvents include methanol, ethanol and dioxane.
  • the stoichiometry of the resulting salt is dependent on the stoichiometry of the reaction components.
  • the salts can be reconverted to the phosphonic acid by standard procedures, e.g. by neutralizing with an acid resin or, less preferably, with an organic acid.
  • acid addition salts of the purine moiety may be prepared by reacting a compound of the invention with an acid such as the organic or inorganic acids exemplified above.
  • the free base is dissolved in an polar organic solvent such as methanol or ethanol and the acid is added at a temperature of 0-100°C, preferably at room temperature.
  • the resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent.
  • the acid addition salt is reconverted to the free base by treating with suitable base.
  • Desired esters of the phosphonic acid moiety may be prepared by transesterif ication of the phenyl esters using methods illustrated by Jones and Moffatt, J Am Chem Soc (1968) 90:5337. Although the examples below result in diethyl esters, the corresponding phenyl esters could be prepared by analogous methods by substituting phenyl phosphonate ester starting materials for the ethyl phosphonate ester starting materials illustrated.
  • esters can be reconverted to the free acids by hydrogenolysis of the benzyl or hydrolysis of trimethyl silyl esters. These esters may be prepared by transesterif ication as above described.
  • the compounds of this invention (including the physiologically acceptable salts and esters thereof) have antiviral activity against herpes virus forms and against RNA retroviruses.
  • the compounds are conveniently formulated into pharmaceutical preparations composed of one or more of the compounds in association with a pharmaceutically acceptable carrier.
  • Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin discloses typical carriers and methods of preparation known in the art.
  • the compounds may be administered topically, orally, parenterally (e.g., intravenously), by intramuscular injection, or by intraperitoneal injection, or the like, depending upon the nature of the viral infection being treated.
  • parenterally e.g., intravenously
  • intramuscular injection e.g., intramuscular injection
  • intraperitoneal injection e.g., intraperitoneal injection
  • the compositions are administered orally or parenterally at dose levels of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight and can be used in humans in a unit dosage form administered one to four times daily in the amount of 1-250 mg per unit dose.
  • fine powders or granules may contain diluting, dispersing, and/or surface active agents, and may be presented in water or in a syrup, in capsules or sachets in the dry state, or in a nonaqueous solution or suspension wherein suspending agents may be included, in tablets wherein binders and lubricants may be included, or in a suspension in water or a syrup. Where desirable or necessary, flavoring, preserving, suspending, thickening, or emulsifying agents may be included. Tablets and granules are preferred oral administration forms, and these may be coated.
  • compositions are preferably applied to the infected part of the body of the patient topically as an ointment, cream, aerosol, or powder, preferably as an ointment or cream.
  • the compounds may be presented in an ointment, for instance with a water soluble ointment base, or in a cream, for instance with an oil in water cream base in a concentration of from about 0.01 to 10%, preferably 0.1 to 7%, most preferably about 0.5% w/v.
  • viral infections of the eye such as Herpetic keratitis, may be treated by use of a sustained release drug delivery system as is described in the art.
  • Diethyl-3-hydroxypropylphosphonate (steps 1 and 2) is prepared from diethyl-3-bromopropyl- phosphonate.
  • Diethyl-3-bromopropylphosphonate (12.0 g, 46 mmol), prepared by the method of Eberhard, A., et al, J Am Chem Soc (1965) 87:253-260) was stirred with 12.0 g NaOAc•3H 2 O in 125 ml DMF heated in a steam bath. The reaction was evaporated to dryness in vacuo after 2 hours and partitioned between H 2 O and EtOAc, extracting the aqueous layer five times.
  • Electron impact mass spectrum showed m/e 547 (M + of TMS 3 derivative); chemical ionization mass spectrum (TMS derivative) showed m/e 548 (M + +H of TMS 3 derivative); chemical ionization mass spectrum on underivatized compound gave m/e 332 (M + +H) .
  • Further characterizat ion by 1 H NMR showed ⁇ 1.17 (tr, 3H), 1.3-1.8 (m, 4H), 3.48 (tr, 2H), 3.85 (dq, 2H), 5.30 (s, 2H), 6.46 (br s, 2H) , 7.79 (s, 1H).
  • the material had a formula of (C 11 H 18 N 5 O 5 P • 1/2 H 2 O). Calc: C-38.82%, H-5.63%,
  • Diethyl7-chloromethoxyheptylphosphonate was prepared from 1 ,7-dibromoheptane and triethylphosphite in a manner analogous to that of Example 1. It was reacted with silated 2-amino-6-chloropurine, and mercuric cyanide as described for the preparation of
  • Example 5 Conversion to the Monoester: 9(7'-ethylphosphono-1'-heptyloxymethyl)guanine 6-Chloro-9(7'-diethylphosphono-1-heptyloxy methyl) guanine of Example 4 was hydrolyzed by refluxing 1 N aqueous sodium hydroxide for 4 hours and isolated in 30% yield as described for the preparation of 9-(3'- ethyl phosphono-1'-propyloxymethyl)guanine (Example 2). It had Rf 0.5 on SiGF using acetonitrile: 0.1 N aqueous ammonium chloride, (7:3) .
  • Diethyl-3,4-epoxybutanephosphonate was synthesized according to the procedure of Savignac et al., Syn Comm (1979) 7:487. In several syntheses, oxidation of the intermediate olefin compound produced a contaminating white solid which was removed by filtration of the crude, neat reaction product and rinsing the solid with ice cold CH 2 CI 2 . Evaporation of the filtrate and distillation of the residue gave the epoxide in 75% yield.
  • 6-Chloro-9(3'-diethylphosphono-1'-acetoxy methyl-1'-propyloxymethyl) guanine was prepared by coupling 112 mmol silated 6-chloroguanine with 108 mmol diethyl-3-chloromethoxy-4-acetoxybutylphosphonate ('H NMR: doublet at 5.54 ⁇ for -OCH 2 CI, prepared analogously to Example 1); according to the procedure of Example 2 for 6-chloro-9 (3'-diethyl phosphono-1'-propyloxymethyl)guanine. The reactions remained at room temperature 1 week after a 3 hour reflux period.
  • Diethyl 1-t-butyldimethylsilyloxyallyl phosphonate (76 g, 0.247 mole) was azeotroped from toluene three times and dissolved in 400 ml dry THF.
  • 1 M diborane in THF 150 ml was added dropwise at 25°C over 45 minutes and the reaction then stirred an additional 1 hour.
  • the hydroboration was terminated by addition of 65 ml H 2 O maintaining the temperature at 20°C with ice cooling.
  • 3 N NaOH (20 ml) was added followed by dropwise addition of 80 ml 30% H 2 O 2 with ice cooling to keep temperature at 40°C.
  • Example 11 Using the procedures described above, the following compounds of the invention were prepared.
  • the compounds of the invention were evaluated in vitro as antiviral agents against herpes virus and against RNA retrovirus. Various herpes strains were used. An infected B lymphoblastoid cell line was used as HIV substrate to test antiviral activity with respect to RNA retrovirus.
  • herpes virus strain employed was Strain McCrae of type 1 herpes (thymidine kinase positive virus) (HSV-1TK + ). This strain was prepared and titered in MA-104 cells and frozen at -90°C until use. Also used were strain HF (HSV-1TK-), strain E194 (HSV-2), NJB strain (MCMV), strain AD169 (HCMV).
  • MA-104 cells were used for testing of herpes-type virus, with growth medium consisting of Minimum Essential Medium (MEM) supplemented with 0.1% NaHCO 3 and 50 ⁇ l gentamicin.
  • MEM Minimum Essential Medium
  • a 96 well microtiter plate containing an established 24 hour monolayer of cells from which the medium has been decanted was added 0.1 ml of varying (one-half logio) concentrations of test compound, which incubated on the cell 15 minutes, after which 0.1 ml of virus in a concentration of 320 cell culture 50% infectious doses (CCID 50 )/0.1 ml was added.
  • the plate was covered with plastic wrap and incubated at 37°C. Included with the test were toxicity controls (each concentration of compound + test medium in place of virus), virus controls (virus + test medium in place of compound) and cell controls (test medium in place of compound and virus).
  • the cells were examined microscopically after 72 hours for evidence of cytotoxicity and for viral cytopathic effect (CPE).
  • Vidarabine was run on the same plate in parallel.
  • the test compounds were added to the medium at a concentration of 2000 ⁇ g/ml for use as a positive control.
  • Antiviral activity was determined by observation of inhibition of viral CPE. This activity was expressed by ED 50 , defined as that dose range of compound causing 50% CPE inhibition.
  • VR Virus Rating
  • Compound 5 (9-(3'-phosphono-1'-hydroxy- methylpropoxymethyl) guanine, monoethyl ester, showed an ED 50 of 0.1-3.2 ⁇ g/ml against human CMV. It was mildly effective against HSV1TK + and HSV-2.
  • Compound 2 also was tested in vivo in guinea pigs as an agent against HSV-1TK + .
  • the animals were inoculated with the virus; 18 hours later Compound 2 at two concentrations (0.4% and 1-2% (saturated) solution in water) was administered, and five days later blister diameters at the point of inoculation were measured.
  • a 5% solution of acyclovir or a 1.4% solution of poly(vinylalcohol) was used as control. Satellite lesions were measured, as well.
  • Table 5 shows the results of two experiments showing the antiviral activity of compounds 2 and 5 against human cytomegalovirus.
  • bMaximum tolerated dose That dose causing approximately 50% cytotoxic effects in cells, determined by the microscopic examination of cells for sloughing, shape alteration, and granularity in separately run control tests in 96-well mieroplates,
  • RT reverse transcriptase assay
  • MMLV Moloney murine leukemia virus
  • AMV avian myeloblastosis virus
  • Boehringer Mannheim was used to direct DNA synthesis from a polyribonucleotide template and a oligodeoxynucleotide primer under reaction conditions (Houts, G.E., et al, J Virol (1979) 29:517.) Reaction mixtures (100 ⁇ l) for the assay of
  • MMLV RT consisted of 50 mM Tris-hydrochloride, pH 8.0, 6 mM MgCl 2 , 40 mM KCl, 100 ⁇ g bovine serum albumin per ml, 1 mM dithiothreitol, 0.1 mM polyadenylic acid (Pharmacia, Inc.), 01 mM oligo(dT)12-18 (Pharmacia, Inc.), 0.4 mM deoxythymidine triphosphate (dTTP), and 0.1 mM tritiated (93.5 Cl/mmol) dTTP (New England Nuclear). The compounds assayed were added in various concentrations and dilutions at a volume of 10 ⁇ l.
  • Results were confirmed by duplicate assays. Dilutions were made using 10% aqueous DMSO. The total activity was measured by spotting on dry Whatman 3 mm filter disks and radioactivity was determined by liquid scintillation techniques. The assay time course was begun by adding 10 units of RT from MMLV or AMV and incubating the reaction at 37°C. Aliquots (10 ⁇ l) were removed as a function of time and quenched in 20 ⁇ l of stop mix [0.25 mM EDTA, 0.5 mg/ml yeast tRNA (BDH Biochemicals, England), 10 mM sodium pyrophosphate].
  • HIV infectious HIV was assayed in cell culture as described originally by Barre-Sinoussi et al for isolation of LAV, except that persistently infected lymphoblastoid cells were used instead of mononuclear cells from anti-LAV negative donors.
  • HIV obtained from cell culture was stored in liquid nitrogen in aliquots of RPMI 1640 culture medium with 20% of total calf serum and 20% glycerol and containing 1,000 TCID-50 HIV.
  • the lymphoblastoid cells (10 6 ) were incubated with 1,000 TCID-50 of HIV obtained from cell cultures, and cells were then cultured in RPMI-1640 medium.
  • Culture medium was changed every 3 days for 3 weeks and the medium for each 3-day period from Day 6 through Day 21 was assayed for viral reverse transcriptase activity by concentrating (pelleting) virus by ultracentrifugation in the 100 place Spinco 25 rotor and assaying pellets for reverse transcriptase (RT) using a 32 P-dTTP in the presence of dimer-template poly rA-oligo dT.
  • Compounds to be tested for neutralization of infection were incubated with HIV aliquots (10 3 TCID-50) for 30 minutes at 22°C before incubation with 10° lymphoblastoid cells.
  • a formulation suitable for injections intramuscularly or intraperitoneally is prepared by combining the first four of the following materials:
  • the material forms a clear solution which is filtered and sealed in sterile containers.
  • a simple intravenous injection formulation is formed by dissolving 1 gram of an active compound in 250 ml of injectable saline which after filtering is packaged in sterile bottles.
  • a cream for topical administration is formulated by stirring 10 g of active compound of the invention with 20 g of mineral oil, 40 g of petroleum jelly, 0.3 g of mixed methyl/propyl paraben, and 5 g of nonionic surfactant at 50°C. Then 150 ml of water are stirred into the mixture at 50°C at high speed to form a cream, and the mixture is cooled and packaged in capped tubes.
  • An oral dosage form is prepared from 10 g of a compound of the invention, 100 g of lactose, and 1 g of starch, which are mixed with 0.1 g of magnesium stearate in methanol to granulate. The methanol is removed by gentle heating with stirring. A portion of this material is retained as a granular powder for oral use while the remainder is hand formed into 250 mg tablets in a manual tableting machine.

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PCT/US1987/003446 1987-01-20 1987-12-23 Antiviral agents WO1988005438A1 (en)

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GB8821380A GB2209338A (en) 1987-01-20 1988-09-12 Antiviral agents

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU614128B2 (en) * 1988-04-01 1991-08-22 Merrell Dow Pharmaceuticals Inc. Novel fluorophosphonate nucleotide derivatives
WO1993006112A1 (en) * 1991-09-24 1993-04-01 The Wellcome Foundation Limited Therapeutic nucleosides
US5208221A (en) * 1990-11-29 1993-05-04 Bristol-Myers Squibb Company Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives
WO1994003466A1 (en) * 1992-07-31 1994-02-17 Sri International Acyclic purine phosphonate nucleotide analogs as antiviral agents, and related synthetic methods
WO1995007919A1 (en) * 1993-09-17 1995-03-23 Gilead Sciences, Inc. Method for dosing therapeutic compounds
WO1997041133A1 (en) * 1996-04-29 1997-11-06 Sri International Enantiomerically pure 2-aminopurine phosphonate nucleotide analogs as antiviral agents
US5717095A (en) * 1995-12-29 1998-02-10 Gilead Sciences, Inc. Nucleotide analogs
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
US5922695A (en) * 1996-07-26 1999-07-13 Gilead Sciences, Inc. Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability
US8592397B2 (en) 2003-01-14 2013-11-26 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8598185B2 (en) 2005-06-13 2013-12-03 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US8871271B2 (en) 2005-06-13 2014-10-28 Gilead Sciences, Inc. Method and composition for pharmaceutical product

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984004748A1 (en) * 1983-05-24 1984-12-06 Stanford Res Inst Int Novel antiviral agents
EP0173624A2 (de) * 1984-08-24 1986-03-05 Merck & Co. Inc. 4-(Guanin-9-yl)butanale und antivirale Präparate die sie enthalten

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984004748A1 (en) * 1983-05-24 1984-12-06 Stanford Res Inst Int Novel antiviral agents
EP0173624A2 (de) * 1984-08-24 1986-03-05 Merck & Co. Inc. 4-(Guanin-9-yl)butanale und antivirale Präparate die sie enthalten

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU614128B2 (en) * 1988-04-01 1991-08-22 Merrell Dow Pharmaceuticals Inc. Novel fluorophosphonate nucleotide derivatives
US5208221A (en) * 1990-11-29 1993-05-04 Bristol-Myers Squibb Company Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives
WO1993006112A1 (en) * 1991-09-24 1993-04-01 The Wellcome Foundation Limited Therapeutic nucleosides
US5532225A (en) * 1992-07-31 1996-07-02 Sri International Acyclic purine phosphonate nucleotide analogs as antiviral agents, and related synthetic methods
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SE8803309D0 (sv) 1988-09-19
DE3790883T1 (de) 1988-12-08
SE8803309L (sv) 1988-09-19
NL8720745A (nl) 1988-12-01
GB8821380D0 (en) 1988-11-02
JPH01501864A (ja) 1989-06-29
GB2209338A (en) 1989-05-10
EP0309491A1 (de) 1989-04-05

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