WO1992010496A1 - NUCLEOSIDES DE β-L-(-)-1,3-OXATHIOLANE ENANTIOMERIQUEMENT PURS - Google Patents

NUCLEOSIDES DE β-L-(-)-1,3-OXATHIOLANE ENANTIOMERIQUEMENT PURS Download PDF

Info

Publication number
WO1992010496A1
WO1992010496A1 PCT/US1991/009123 US9109123W WO9210496A1 WO 1992010496 A1 WO1992010496 A1 WO 1992010496A1 US 9109123 W US9109123 W US 9109123W WO 9210496 A1 WO9210496 A1 WO 9210496A1
Authority
WO
WIPO (PCT)
Prior art keywords
protected
oxathiolane
gulose
thioanhydro
dideoxy
Prior art date
Application number
PCT/US1991/009123
Other languages
English (en)
Inventor
Chung K. Chu
J. Warren Beach
Lak-Shin Jeong
Original Assignee
University Of Georgia Research Foundation, 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
Priority claimed from US07/622,762 external-priority patent/US5179104A/en
Application filed by University Of Georgia Research Foundation, Inc. filed Critical University Of Georgia Research Foundation, Inc.
Publication of WO1992010496A1 publication Critical patent/WO1992010496A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/08—Bridged systems

Definitions

  • This invention is in the area of the organic synthesis of nucleosides, and in particular relates to a process for the preparation of enantiomerically pure ⁇ -L-1,3-oxathiolane nucleosides.
  • a nucleoside is a molecule consisting of a 5-carbon sugar and a purine or pyrimidine base.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • HIV is believed to be the etiological cause of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • CS-87 3'-azido-2',3'-dideoxyuridine
  • CS-91 3'-azido-2',3'-dideoxycytidine
  • CS-92 3'-azido-5-methyl-2',3'-dideoxycytidine
  • FDT 3'-fluoro-3'-deoxythymidine
  • these nucleosides are known to inhibit HIV reverse transcriptase as well as cause chain-termination of the growing viral DNA chain.
  • AZT has been approved by the U.S. Food and Drug Administration for administration to patients with AIDS and AIDS-related complex.
  • Several of the other synthetic nucleoside derivatives are undergoing various stages of clinical trials, including 2',3'- dideoxyuridine, 2'.3'-dideoxyinosine, 2',3'- dideoxycytidine, 3'-deoxy-2',3'-didehydrothymidine, and 2'-fluoro-arabinofuranosyl-2'-3'-dideoxycytidine.
  • nucleoside derivatives play an important role in their biological activity.
  • the C1' position of the ribose in the nucleoside (the carbon bound to the nitrogen of the heterocyclic base, see Figure 1) is a chiral center because the carbon is attached to four different moieties.
  • there is an optically active center at C4' of the nucleoside (the ring carbon bound to the hydroxymethyl group that is phosphorylated in nucleotides).
  • both the base attached to the C1' atom and the hydroxymethyl group attached to the C4' atom are on the same side of the carbohydrate ring.
  • a nucleoside is designated a D-nucleoside if the non-hydrogen substituent attached to the C4'-atom is above the plane of the carbohydrate ring.
  • the nucleoside is designated an L-nucleoside if the non-hydrogen substituent attached to the C4'-atom is below the plane of the carbohydrate ring.
  • nucleosides in which the Cl' or C4' substituents are on opposite sides of the carbohydrate plane are rarely biologically active, and are typically toxic.
  • the C3'-exo and C3'-endo conformations place the C5' atom in axial and equatorial positions, respectively.
  • the position of the C5' atom affects the location of the 5'-hydroxyl group in relation to the base. Since the 5'-hydroxyl group is the site of phosphorylation of the nucleoside, its location with respect to the rest of the nucleoside is important.
  • nucleosides have been shown to be potent antiviral agents.
  • BCH-189 (a 1,3-oxathiolane nucleoside) and dioxolane-T are particularly interesting in that the 3'-CH 2 groups of the ribose moieties of these nucleosides are replaced by sulfur and oxygen atoms, respectively, as shown in Figure 1.
  • nucleoside is also less toxic than the racemic
  • Belleau et al., in the Fifth International Conf. on AIDS, Montreal, Canada June 4-9, 1990, paper No. T.C.O.I., reported a method of synthesis of cytidine nucleosides that contain oxygen or sulfur in the 3'-position.
  • the dioxolane ring was prepared by the condensation of RCO 2 CH 2 CHO with glycerine.
  • the Belleau synthesis results in a racemic mixture about the C4'-carbon of the
  • ( ⁇ )-BCH-189 is currently undergoing preclinical toxicology.
  • nucleoside derivatives and to provide new anti-HIV agents.
  • Lewis acid or trimethylsilyl triflate in an organic solvent such as dichloroethane, acetonitrile, or methylene chloride, to provide the stereochemically pure ⁇ -L-(-)-1,3-oxathiolane-nucleoside.
  • Products made according to this process can be used as a research tool to study the inhibition of HIV in vitro or can be administered in a pharmaceutical composition to inhibit the growth of HIV in vivo.
  • Figure 1 is an illustration of a 1,3-oxathiolane nucleoside with the C1' and C4' chiral carbon atoms indicated by asterisk.
  • Figure 2 is an illustration of the ⁇ -D-(+) and ⁇ -L-(-) isomers of 1-[(2 ⁇ ,4 ⁇ )-2-(hydroxymethyl)-4- (1,3-oxathiolane)]cytosine (BCH-189).
  • Figure 3 is an illustration of the process for the preparation of 1,6-dideoxy-1,6-thioanhydro-L-gulose.
  • Figure 4 is an illustration of the process for the preparation of ⁇ -L-(-)-1-[(2 ⁇ ,4 ⁇ )-2-(hydroxymethyl)- 4-(1,3-oxathiolane)]cytosine.
  • protected refers to a moiety that has been placed on a functional group of a molecule to prevent further reaction of the moiety during derivatization of another portion of the molecule.
  • Protecting groups particularly for oxygen and nitrogen, are well known to those skilled in the art of organic chemistry.
  • 1,3-oxathiolane nucleoside refers to a nucleoside derivative as depicted in Figures 1 and 2, wherein a 1,3-oxathiolane is attached to a heterocyclic base, typically a purine or pyrimidine base, through the oxathiolane C5 carbon (that becomes the C1'-carbon in the nucleoside).
  • a heterocyclic base typically a purine or pyrimidine base
  • nucleosides proceeds in two stages.
  • a 1,3-oxathiolane derivative is prepared that includes a hydroxymethyl group in the chiral 2- position (that will become the hydroxymethyl group in the C4' position of the nucleoside) with the proper stereochemistry for the final enantiomerically pure ⁇ -L-(-)-nucleoside.
  • the 1,3-oxathiolane is condensed with a heterocyclic base at the C5 position to produce a 1,3-oxathiolane
  • nucleoside that has both the C1' (heterocyclic base) and the C4' (hydroxymethyl) substituents in the desired position.
  • the starting material for this process for the preparation of enantiomerically pure ⁇ -L-(-)-1,3-oxathiolane nucleosides is 1,6-thioanhydro-L-gulose ( Figure 3, compound 9), that has the appropriate chiral center at C2 for the preparation of the desired ⁇ -L-(-)-(1,3)-oxathiolane nucleosides.
  • 1,6-Thioanhydro-L-gulose can be prepared from L-gulose ( Figure 3, compound 6) in 3 steps ( Figure 3).
  • L-Gulose can be prepared from L-gulonolactone, that in turn can be prepared from D-glucurono-6,3-lactone that is readily available and inexpensive.
  • the hydroxyl groups in gulose are protected. Taking advantage of the principle that reactivity in tosylation, and in esterification generally, decreases in the order primary alcohol > secondary alcohol > tertiary alcohol, the primary hydroxyl group at C 6 is initially selectively
  • the temperature used for this initial protecting step should be the lowest that allows for C 6 esterification without reaction of the other four hydroxyl groups in the molecule, preferably between 18 and 20 degrees C.
  • Tosylation can be performed with p- toluenesulfonyl chloride and pyridine, or under other conditions known to those in the art.
  • the other four hydroxyl groups are protected, preferably with an acetyl moiety, to provide 1,2,3,4-tetra-O-(protected)-6-O- (protected)-L-gulopyranoside 2.
  • Other suitable oxygen protecting groups are known to those skilled in the art, and include benzoate. This reaction should be performed at the lowest temperature under which reaction occurs, preferably between 18 and 20 degrees C.
  • the 1-position of 1,2,3,4-tetra-O-(protected)-L-gulopyrannoside 2 is converted to 2,3,4-tri-O- (protected)-1-halo-6-O-(protected) - ⁇ -L-gulopyranoside 3. by reaction with HX, wherein X is bromo or chloro.
  • the reaction is performed in acetic acid at a temperature range of between 0 and 25 degrees C, for a time period of between six and eight hours.
  • the gulopyranoside 8. is easily converted to 2,3,4-tri-O-(protected)-1,6-dideoxy-1,6-thioanhydro-L-gulose by reaction with potassium O-ethyl xanthate, which can be purchased commercially from Aldrich Chemical Company, or prepared from KOH and carbon disulfide in ethanol. Alternatively, NaSH or (Na) 2 S can be used. The reaction is easily carried out in refluxing acetone. Typically, between 3.0 and 3.5 equivalents of xanthate reagent are used.
  • 2,3,4-tri-O-(protected)-1,6-dideoxy-1,6-thioanhydro-L-gulose is then deprotected under basic conditions at ambient temperature to provide l,6-thioanhydro-L-gulose 9.
  • Any base is suitable in this deprotection step, including ammonium hydroxide, sodium hydroxide, potassium hydroxide, and sodium methoxide. It is preferred that the pH be maintained at less than 9.
  • 1,6-thioanhydro-L-gulose 9 is easily converted to a 1,3-oxathiolane derivative via direct cleavage of the unprotected thioanhydro-L-gulose followed by reduction to the corresponding diol, isopropylidenation of the diol, silylation of the 2-hydroxymethyl group, and
  • 1,6- thioanhydro-L-gulose 9. is initially oxidized with NaIO 4 or other oxidizing agent, including KIO 4 or
  • Pb(OAc) 4 at low temperature (usually 0 to -20°C, and typically approximately -10°C), in a suitable solvent such as methanol/water, to cleave the 2,3-cis diol.
  • the resulting dialdehyde is then reduced with NaBIfy or any borohydride to provide the corresponding vicinal diol.
  • the diol is then protected, preferably with an isopropylidene group, using, for example, CH 3 C(OCH 3 ) 2 CH 3 and p-toluenesulfonic acid at room temperature.
  • the reaction can also be performed with acetone and p- toluenesulfonic acid, optionally with cupric sulfate at room temperature.
  • the hydroxymethyl group of the isopropylidene derivative 10. is then protected using methods known to those skilled in the art, typically with t-butyldiphenylsilyl chloride in DMF at room temperature, and then the diol is deprotected to form compound 11.
  • Other protecting groups known to those skilled in the art can also be used.
  • compound 9 1,6-dideoxy-1,6-thioanhydro-L-gulose can be converted to compound 18.
  • (2R,5S)-5-formyl-2-hydroxymethyl-5-1-3-oxathiolane by: (1) oxidationwith NaIO 4 at low temperature (typically dropwise addition of NaIO 4 at -10°C over 20 minutes, with additional stirring for ten minutes) followed by (2) reduction with NaBH 4 or any borohydride under similar conditions as used for 10. to provide the corresponding diol, which, without isolation, is (3) further treated with NaIO 4 .
  • the primary hydroxyl group of the aldehyde 18 is protected with a benzoyl or silyl group to give 19, which on treatment with pyridinium dichromate to afford the common intermediate 12, (2R,5S)-2- (protected-oxymethyl)-1,3-oxathiolane-5-carboxylic acid.
  • the cis-hydroxyl groups of 9 are selectively protected, preferably with an
  • isopropylidene group to provide 2,3-O-(diprotected)-1,6-thioanhydro-L-gulose 20.
  • the isopropylidene derivative can be prepared with dimethoxypropane and p-toluenesulfonic acid.
  • the 2,3-O-(diprotected)-1,6-thioanhydro-L-gulose 20 without isolation is then protected at the 4-position (see Figure 5).
  • protecting group is benzoyl, however, other protecting groups known to those skilled in the art can also be used.
  • protecting group on the 2 and 3 hydroxyl groups is then removed with catalytic amounts of an acid such as sulfuric acid, hydrochloric acid, formic acid, trifluoroacetic acid, or sulfamic acid in 60% aqueous dioxane or other suitable solvent typically at a temperature range of approximately 0 to 75°C to give 4-O-benzoyl-1,6-thioanhydro-L-gulose 22 in high yield as a solid.
  • the cis diol of 22 is oxidatively cleaved to the dialdehyde 23 using lead tetraacetate in ethyl acetate.
  • the dialdehyde 23 is reduced using sodium borohydride to give 24 which is protected at the2-hydroxymethyl by a t-butyldiphenylsilyl group to give 25 Treatment of 25 with ammonium hydroxide affords 11.
  • Compound 12 is used in a modified Hunsdiecker reaction (Dhavale, D.; et al., Tetrahedron Lett..
  • trifluoromethanesulfonate or a Lewis acid in a dry organic solvent to provide a mixture of 1'- ⁇ and 1'- ⁇ nucleosides that can be separated chromatographically or by other methods known to those in the art.
  • the choice of catalyst for condensation may affect the final product ratio of ⁇ to ⁇ nucleoside product.
  • Purine bases include adenine, hypoxanthine, guanine, N 6 -alkylpurines, N 6 -benzylpurine, 6-halopurine, 2,6-dihalopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, 6-hydroxyalkyl purine, and 6-thioalkyl purine.
  • Pyrimidine bases include thymine, cytosine,
  • Protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, and t-butyldiphenylsilyl, tritylmethyl, alkyl groups, acyl groups such as acetyl and propionyl, methylsulfonyl, and p-toluylsulfonyl.
  • Friedel-Crafts catalysts that can be used in the condensation reaction include SnCl 4 , ZnCl 4 , TiCl 4 , AICI 3 , FeCl 3 , BF 3 -diethylether, and BCI 3 . These catalysts require anhydrous conditions because the presence of water reduces their activity.
  • catalysts are also inactivated in the presence of organic solvents with active hydrogens, such as alcohols and organic acids.
  • active hydrogens such as alcohols and organic acids.
  • solvents such as carbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane, nitrobenzene, tetrachloroethane, chlorobenzene, benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile.
  • Anhydrous aluminum chloride is not soluble in carbon disulfide.
  • Niedballa et al., J. Org. Chem. 39, 25 (1974).
  • the preferred catalyst in SnCl 4 Useful solvents are 1,2-dichloroethane and methylene chloride.
  • Trimethylsilyl triflate can be used under the same conditions described above for the Friedel-Crafts catalysts. The reaction proceeds at a temperature range of from -10°C to 200°C.
  • the 5'-O-position of the nucleoside is deprotected. Desilylation can be carried out with a variety of reagents, including acetic acid,
  • the flask was fitted with a CaCl 2 tube and stirred in the ice bath for 30 min. and then at room temperature for 15 h.
  • the solvent was removed under reduced pressure and the residue partitioned between ethyl ether and cold water.
  • the organic layer was washed twice with cold water and twice with cold sat. aq NaHC0 3 solution, dried (MgSO 4 ), filtered and

Abstract

Procédé asymétrique pour la préparation de nucléosides de β-L-(-)-1,3-oxathiolane énantiomériquement purs, consistant à préparer initialement les intermédiaires chiraux-clés (2R,5R) et (2R,5S)-5-(à protection O)-2-oxyméthyle protégé)-1,3-oxathiolane à partir de 1,6-thioanhydro-L-gulose. Le 2R,5(R,S)-5-(à protection O)-2-(oxyméthyle protégé)-1,3-oxathiolane est condensé avec une base hétérocyclique désirée, en général une base purine ou pyrimidine, pour donner le produit nucléoside. La synthèse peut être utilisée pour préparer le composé pharmaceutiquement important β-L-(-)-1-[(2β,4β)-2-(hydroxyméthyle)-4-(1,3-thioxolane)]cytosine (β-L-(-)BCH-189).
PCT/US1991/009123 1990-12-05 1991-12-05 NUCLEOSIDES DE β-L-(-)-1,3-OXATHIOLANE ENANTIOMERIQUEMENT PURS WO1992010496A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US07/622,762 US5179104A (en) 1990-12-05 1990-12-05 Process for the preparation of enantiomerically pure β-D-(-)-dioxolane-nucleosides
US622,762 1990-12-05
US69919791A 1991-05-13 1991-05-13
US699,197 1991-05-13

Publications (1)

Publication Number Publication Date
WO1992010496A1 true WO1992010496A1 (fr) 1992-06-25

Family

ID=27089275

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/009123 WO1992010496A1 (fr) 1990-12-05 1991-12-05 NUCLEOSIDES DE β-L-(-)-1,3-OXATHIOLANE ENANTIOMERIQUEMENT PURS

Country Status (2)

Country Link
AU (1) AU9125991A (fr)
WO (1) WO1992010496A1 (fr)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014802A1 (fr) * 1989-02-08 1994-07-07 Biochem Pharma Inc. Procedes de preparation de 1,3-oxathiolanes substituees aux proprietes antivirales
WO1994029301A1 (fr) * 1993-06-07 1994-12-22 Biochem Pharma Inc. Synthese stereoselective d'analogues de nucleosides au moyen d'un intermediaire bicyclique
US5444063A (en) * 1990-12-05 1995-08-22 Emory University Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity
US5466806A (en) * 1989-02-08 1995-11-14 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
WO1996012716A1 (fr) * 1994-10-22 1996-05-02 Chong Kun Dang Corp. Derives nucleosidiques et leur procede de preparation
US5538975A (en) * 1991-08-01 1996-07-23 Biochem Pharma, Inc. 1,3-oxathiolane nucleoside compounds and compositions
WO1996026734A1 (fr) * 1995-02-25 1996-09-06 Glaxo Group Limited Associations antivirales de bch-189 et de ritonavir
US5565438A (en) * 1994-01-28 1996-10-15 University Of Ga Research Foundation L-nucleosides for the treatment of epstein-bar virus
US5663320A (en) * 1991-05-21 1997-09-02 Biochem Pharma, Inc. Processes for the diastereoselective separation of nucleoside analogue synthetic intermediates
US5684164A (en) * 1988-04-11 1997-11-04 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
US5728575A (en) * 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5753789A (en) * 1996-07-26 1998-05-19 Yale University Oligonucleotides containing L-nucleosides
US5808040A (en) * 1995-01-30 1998-09-15 Yale University L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides
WO1998041522A1 (fr) * 1997-03-19 1998-09-24 Emory University Virus de l'immunodeficience humaine, synthese de ce virus et activites anti-virus de l'hepatite b de nucleosides de 1,3-oxaselenolane
US5852027A (en) * 1991-02-22 1998-12-22 Emory University Antiviral 1,3-dioxolane nucleoside analogues
US5914331A (en) * 1990-02-01 1999-06-22 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US5990093A (en) * 1993-09-10 1999-11-23 Emory University Treating HBV with phospholipid prodrugs of β-L-2',3'-dideoxyadenosine 5'-monophosphate
US6063787A (en) * 1994-09-06 2000-05-16 The University Of Georgia Research Foundation Center Methods for the treatment of psoriasis and genital warts
US6114343A (en) * 1990-02-01 2000-09-05 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-flurocytosin-1-yl)-1,3-oxathiolane
US6245749B1 (en) 1994-10-07 2001-06-12 Emory University Nucleosides with anti-hepatitis B virus activity
US6358963B1 (en) 1998-12-23 2002-03-19 Biochem Pharma Inc. Antiviral nucleoside analogues
US6391859B1 (en) 1995-01-27 2002-05-21 Emory University [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
US6436948B1 (en) 2000-03-03 2002-08-20 University Of Georgia Research Foundation Inc. Method for the treatment of psoriasis and genital warts
EP1081148A3 (fr) * 1992-08-25 2003-03-05 University Of Georgia Research Foundation, Inc. Nucléosides de béta-D-Dioxolane énantiomériquement Purs
US6703396B1 (en) 1990-02-01 2004-03-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers
US7439351B2 (en) 1993-09-10 2008-10-21 The Uab Research Foundation 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents
CN102234269A (zh) * 2010-04-29 2011-11-09 重庆医药工业研究院有限责任公司 拉米夫定的工业化制备方法
CN102796088A (zh) * 2012-05-21 2012-11-28 湖南千金湘江药业股份有限公司 一种拉米夫定的制备方法
JP2014132026A (ja) * 1998-08-12 2014-07-17 Gilead Sciences Inc １，３−オキサチオランヌクレオチドの製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5041449A (en) * 1988-04-11 1991-08-20 Iaf Biochem International, Inc. 4-(nucleoside base)-substituted-1,3-dioxolanes useful for treatment of retroviral infections
EP0382526B1 (fr) * 1989-02-08 1996-05-15 Biochem Pharma Inc 1,3-oxathiolanes substitués doués de propriétés antivirales

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5041449A (en) * 1988-04-11 1991-08-20 Iaf Biochem International, Inc. 4-(nucleoside base)-substituted-1,3-dioxolanes useful for treatment of retroviral infections
EP0382526B1 (fr) * 1989-02-08 1996-05-15 Biochem Pharma Inc 1,3-oxathiolanes substitués doués de propriétés antivirales

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHUNG K. CHU et al., J. MED. CHEM. 1989, Vol. 32, No. 3, pp. 612-617. "Structure - activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells". & XP000577198 *
DANIEL W. NORBECK et al., TETRAHEDRON LETTERS, Vol. 30, No. 46, pp. 6263-6266, 1989, "A New 2', 3'-dideoxynucleoside Prototype with in vitro activity against HIV". & XP002069972 *
JAN BALZARINI et al., BIOCHEM AND BIOPHY. RES. COMM., Vol. 140, No. 2, 1986, pp. 735-742. "Potent and Selective anti-HTLV-III/LAV Activity of 2', 3' - dideoxy - cytidivene, the 2', 3' - unsaturated derivative of 2', 3' - dideoxycytidine". *
MARTIN et al., J. MED. CHEM. 1990, 33, 2137-2145. "Synthesis and antiviral activity of Monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human Immunodeficiency virus (HIV-1)". & XP002970743 *
PATRICK VAN ROEY et al., J.A.C.S. 1988, Vol. 110, pp. 2277-2282. "Solid - State Conformation of anti-human immunodeficiency virus type - 1 agents: crystal structures of three 3' -azido-3' deoxythymidine Analogues". & XP002995142 *
PHILLIP A. FURMAN et al., PROC. NATL. ACAD. SCIENCE U.S.A., Vol. 83, pp. 8333-8337, 1986, "Phosphorylation of 3' - azido - 3' - deoxy - thymidine and selective interaction of the 5' - triphosphate with human immunodeficiency virus reverse transcriptase". & XP001147195 *

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6175008B1 (en) 1988-04-11 2001-01-16 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US6831174B2 (en) 1988-04-11 2004-12-14 Shire Biochem Inc. Processes for preparing substituted 1, 3-oxathiolanes with antiviral properties
US5684164A (en) * 1988-04-11 1997-11-04 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
WO1994014802A1 (fr) * 1989-02-08 1994-07-07 Biochem Pharma Inc. Procedes de preparation de 1,3-oxathiolanes substituees aux proprietes antivirales
US5466806A (en) * 1989-02-08 1995-11-14 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US6114343A (en) * 1990-02-01 2000-09-05 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-flurocytosin-1-yl)-1,3-oxathiolane
US5827727A (en) * 1990-02-01 1998-10-27 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5892025A (en) * 1990-02-01 1999-04-06 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US6703396B1 (en) 1990-02-01 2004-03-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers
US6642245B1 (en) 1990-02-01 2003-11-04 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US6069252A (en) * 1990-02-01 2000-05-30 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US6346627B1 (en) 1990-02-01 2002-02-12 Emory University Intermediates in the synthesis of 1,3-oxathiolane nucleoside enantiomers
US7468436B2 (en) 1990-02-01 2008-12-23 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US7160999B2 (en) 1990-02-01 2007-01-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers
US5914331A (en) * 1990-02-01 1999-06-22 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US5728575A (en) * 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5830898A (en) * 1990-12-05 1998-11-03 Emory University Enantiomerically pure β-di-dioxolane-nucleosides with selective anti-hepatitis B virus activity
US5444063A (en) * 1990-12-05 1995-08-22 Emory University Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity
US5684010A (en) * 1990-12-05 1997-11-04 Emory University Enantiomerically pure β-D-dioxolane nucleosides with selective anti-hepatitis B virus activity
US5834474A (en) * 1990-12-05 1998-11-10 Emory University Enantiomerically pure B--D--dioxolane nucleosides with selective anti-hepatitus B virus activity
US5852027A (en) * 1991-02-22 1998-12-22 Emory University Antiviral 1,3-dioxolane nucleoside analogues
US5744596A (en) * 1991-05-21 1998-04-28 Biochem Pharma Inc. Nucleoside analogues and synthetic intermediates
US5696254A (en) * 1991-05-21 1997-12-09 Biochem Pharma Inc. Processes for the diastereoselective synthesis of nucleoside analogues
US5756706A (en) * 1991-05-21 1998-05-26 Biochem Pharma Inc. Processes for the diastereoselective synthesis of nucleoside analogues
US5663320A (en) * 1991-05-21 1997-09-02 Biochem Pharma, Inc. Processes for the diastereoselective separation of nucleoside analogue synthetic intermediates
US5693787A (en) * 1991-05-21 1997-12-02 Biochem Pharma Inc. Intermediates in the synthesis of 1,3-oxathiolanyl cytosine nucleoside analogues
US5618820A (en) * 1991-08-01 1997-04-08 Biochem Pharma, Inc. 1,3-oxathiolane nucleoside analogues and methods for using same
US5538975A (en) * 1991-08-01 1996-07-23 Biochem Pharma, Inc. 1,3-oxathiolane nucleoside compounds and compositions
US7262213B2 (en) 1992-04-16 2007-08-28 University Of Georgia Research Foundation, Inc. Compounds and methods for the treatment of cancer
EP1081148A3 (fr) * 1992-08-25 2003-03-05 University Of Georgia Research Foundation, Inc. Nucléosides de béta-D-Dioxolane énantiomériquement Purs
CN1046720C (zh) * 1993-06-07 1999-11-24 生物化学及药物有限公司 用二环中间体的核苷类似物立体选择合成
WO1994029301A1 (fr) * 1993-06-07 1994-12-22 Biochem Pharma Inc. Synthese stereoselective d'analogues de nucleosides au moyen d'un intermediaire bicyclique
US5763606A (en) * 1993-06-07 1998-06-09 Biochem Pharma, Inc. Stereoselective synthesis of nucleoside analogues using bicyclic intermediate
US6525033B1 (en) 1993-09-10 2003-02-25 Emory University Nucleosides with anti-hepatitis B virus activity
US7439351B2 (en) 1993-09-10 2008-10-21 The Uab Research Foundation 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents
US5990093A (en) * 1993-09-10 1999-11-23 Emory University Treating HBV with phospholipid prodrugs of β-L-2',3'-dideoxyadenosine 5'-monophosphate
US5565438A (en) * 1994-01-28 1996-10-15 University Of Ga Research Foundation L-nucleosides for the treatment of epstein-bar virus
US5567688A (en) * 1994-01-28 1996-10-22 Univ. Of Ga Research Foundation L-nucleosides for the treatment of hepatitis B-virus
US5587362A (en) * 1994-01-28 1996-12-24 Univ. Of Ga Research Foundation L-nucleosides
US8076347B2 (en) 1994-09-06 2011-12-13 University Of Georgia Research Foundation, Inc. Compounds and methods for the treatment of cancer
US6063787A (en) * 1994-09-06 2000-05-16 The University Of Georgia Research Foundation Center Methods for the treatment of psoriasis and genital warts
US6245749B1 (en) 1994-10-07 2001-06-12 Emory University Nucleosides with anti-hepatitis B virus activity
US7468357B2 (en) 1994-10-07 2008-12-23 Emory University Nucleosides with anti-hepatitis B virus activity
US6034087A (en) * 1994-10-22 2000-03-07 Chong Kun Dang Corp. Nucleoside derivatives and process for preparing thereof
WO1996012716A1 (fr) * 1994-10-22 1996-05-02 Chong Kun Dang Corp. Derives nucleosidiques et leur procede de preparation
US5703058A (en) * 1995-01-27 1997-12-30 Emory University Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent
US7419966B2 (en) 1995-01-27 2008-09-02 Emory University [5-carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides
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
US5808040A (en) * 1995-01-30 1998-09-15 Yale University L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides
WO1996026734A1 (fr) * 1995-02-25 1996-09-06 Glaxo Group Limited Associations antivirales de bch-189 et de ritonavir
US5753789A (en) * 1996-07-26 1998-05-19 Yale University Oligonucleotides containing L-nucleosides
US6197777B1 (en) 1997-03-19 2001-03-06 Emory University Synthesis, anti-human immunodeficiency virus, and anti-hepatitis B virus activities of 1,3-oxaselenolane nucleosides
US6590107B1 (en) 1997-03-19 2003-07-08 Emory University Synthesis, anti-human immunodeficiency virus, and anti-hepatitis B virus activities of 1,3-oxaselenolane nucleosides
US6071922A (en) * 1997-03-19 2000-06-06 Emory University Synthesis, anti-human immunodeficiency virus, and anti-hepatitis B virus activities of 1,3-oxaselenolane nucleosides
WO1998041522A1 (fr) * 1997-03-19 1998-09-24 Emory University Virus de l'immunodeficience humaine, synthese de ce virus et activites anti-virus de l'hepatite b de nucleosides de 1,3-oxaselenolane
JP2014132026A (ja) * 1998-08-12 2014-07-17 Gilead Sciences Inc １，３−オキサチオランヌクレオチドの製造方法
US6545001B2 (en) 1998-12-23 2003-04-08 Biochem Pharma, Inc. Antiviral nucleoside analogues
US6358963B1 (en) 1998-12-23 2002-03-19 Biochem Pharma Inc. Antiviral nucleoside analogues
US6436948B1 (en) 2000-03-03 2002-08-20 University Of Georgia Research Foundation Inc. Method for the treatment of psoriasis and genital warts
CN102234269A (zh) * 2010-04-29 2011-11-09 重庆医药工业研究院有限责任公司 拉米夫定的工业化制备方法
CN102234269B (zh) * 2010-04-29 2015-09-16 重庆医药工业研究院有限责任公司 拉米夫定的工业化制备方法
CN102796088A (zh) * 2012-05-21 2012-11-28 湖南千金湘江药业股份有限公司 一种拉米夫定的制备方法

Also Published As

Publication number Publication date
AU9125991A (en) 1992-07-08

Similar Documents

Publication Publication Date Title
US5248776A (en) Process for enantiomerically pure β-L-1,3-oxathiolane nucleosides
WO1992010496A1 (fr) NUCLEOSIDES DE β-L-(-)-1,3-OXATHIOLANE ENANTIOMERIQUEMENT PURS
US5767122A (en) Enantiomerically pure β-d-dioxolane nucleosides
US5852027A (en) Antiviral 1,3-dioxolane nucleoside analogues
EP1164133B1 (fr) Procédé pour la Préparation de Nucléosides de béta-D-Dioxolane énantiomériquement Purs
EP0382526B1 (fr) 1,3-oxathiolanes substitués doués de propriétés antivirales
US6121431A (en) Nucleoside derivatives
AU658136C (en) Method and compositions for the synthesis of BCH-189 and related compounds
RU2439069C2 (ru) Способ получения 1,3-оксатиолановых нуклеозидов
JP2960164B2 (ja) 抗ウイルス特性を有する置換１，３−オキサチオラン類および置換１，３−ジチオラン類
WO1994004154A9 (fr) NUCLEOSIDES ENANTIOMERIQUEMENT PURS DE β-D-DIOXOLANE
US5175267A (en) Stereoselective glycosylation of hetercyclic bases
Beach et al. Stereocontrolled Routes for the Synthesis of Anti-HIV and Anti-HBV Nucleosides

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA