WO1990008147A1 - Nucleosides de purine, leur procede de production et medicaments contenant ces composes - Google Patents

Nucleosides de purine, leur procede de production et medicaments contenant ces composes Download PDF

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Publication number
WO1990008147A1
WO1990008147A1 PCT/EP1990/000059 EP9000059W WO9008147A1 WO 1990008147 A1 WO1990008147 A1 WO 1990008147A1 EP 9000059 W EP9000059 W EP 9000059W WO 9008147 A1 WO9008147 A1 WO 9008147A1
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WO
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Prior art keywords
alkyl
dideoxy
didehydro
ribofuranosylpurine
group
Prior art date
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PCT/EP1990/000059
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German (de)
English (en)
Inventor
Alfred Mertens
Harald Zilch
Bernhard Koenig
Edith Koch
Original Assignee
Boehringer Mannheim Gmbh
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 Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to KR1019900702027A priority Critical patent/KR910700256A/ko
Publication of WO1990008147A1 publication Critical patent/WO1990008147A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

Definitions

  • the invention relates to substituted 2 ', 3'-dideoxy-2', 3'-didehydropurin nucleosides, processes for their preparation and medicaments which contain these compounds.
  • the present invention relates to nucleosides and nucleotides of the general formula I
  • R 1 represents a hydrogen atom or an amino group
  • R 2 is a halogen atom; a C 1 -C 6 alkyl; C 2 -C 6 alkenyl;
  • R 5 R 6 N- in which one of the radicals R 5 or R 6 can denote a hydrogen atom, otherwise R 5 and R 6 can be the same or different and independently of one another a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxyC 1 -Cg alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl , C 3 -C 8 -cycloalkenyl-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6
  • Hetarylthio group and the "aryl” and “hetaryl” parts in all the aforementioned cases of the aryl- or hetaryl-bearing groups one or more times by hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , Trifluoromethyl, amino or halogen groups can be substituted; or a saturated, unsaturated or aromatic heterocyclic ring with one oxygen atom and / or one sulfur atom and / or one or two nitrogen atoms and 3-7 carbon atoms, this ring being substituted by one or more hydroxy, C 1 -C 6 alkyl, halogen - or C 3 -C 6 cycloalkylthio radicals can be substituted;
  • R 3 is hydrogen or the amino group
  • R 4 denotes hydrogen or a C 1 -C 6 alkylcarbonyl or a mono-, di- or triphosphate group, their optically active forms, tautomers or physiologically acceptable salts of inorganic and organic acids and bases with the exception of the compounds 6-methylamino2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-ribofuranoyl-purine, 6-dimethylamino- 2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-ribofuranoyl-purine and 6-methylthio-2 ', 3'-dideoxy-2', 3'didehydro-9-ß-ribofuranoyl-purine , as well as processes for their preparation and containing these compounds
  • the compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the onko viruses HTLV-I and II, and the lentiviruses Visna and human immunodeficiency virus HIV-1 and 2.
  • DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr virus or RNA viruses such as toga viruses or in particular retroviruses such as the onko viruses HTLV-I and II, and the lentiviruses Visna and human immunodeficiency virus HIV-1 and 2.
  • the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
  • PDL generalized lymphadenopathy
  • ARC advanced stage of the AIDS-related complex
  • compounds of the general formula I are particularly suitable for inhibiting the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription.
  • the substances can influence the multiplication of retroviruses specifically by inhibiting the enzyme reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773, 1987).
  • reverse transcriptase cf. Proc. Natl. Acad. Sci. USA 83, 1911, 1986 and Nature 325, 773, 1987.
  • AIDS 3'-azido-3'-deoxythymidine
  • the compounds of the present invention and their pharmaceutical preparations can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections.
  • these further drugs include agents that can be used for the treatment and prophylaxis of HIV infections or diseases accompanying this disease, such as 3'-azido-3'-deoxythymidine, 2 ', 3'-dideoxynucleosides such as 2', 3'-dideoxycytidine , 2 ', 3'-dideoxyadenosine and 2', 3'-dideoxyinosine, acyclic nucleosides (e.g.
  • acyclovir interferons such as A-interferon
  • renal excretion inhibitors such as probenicide
  • nucleoside transport inhibitors such as dipyridamole
  • immunomodulators such as interleukin II or stimulation factors such as the granulocyte-macrophage colony factor.
  • 3,817,982 claims purine nucleosides which are substituted in the 6-position by methylamino, dimethylamino or methylamino.
  • EP-A-0,286,425 purine-9- ⁇ -D-2 ', 3'-dideoxyribofuranoside are known, which can be used for the treatment of HIV infections. Mitsuya et al. (Proc. Nat. Acad. Sci. USA 82, 7096, 1985), Baizarini et al. (Mol. Pharm. 32, 162, 1987) and DeClercq et al. (Biochem. Pharm.
  • the compounds according to the invention have an increased activity.
  • studies on pharmacological activity found that these compounds inhibit virus replication in HIV-infected human fetal lung cells at lower concentrations than the known compounds.
  • R 1 represents hydrogen or the amino group
  • R 2 halogen (eg chlorine); C 1 -C 6 alkoxy (e.g. propyloxy or isopropyloxy), which may be substituted by C 3 -C 6 cycloalkyl (e.g. cyclopropylmethoxy); C 3 -C 8 cycloalkyloxy (e.g. cyclobutyloxy or cyclopentyloxy); Aryloxy (e.g. phenyloxy), aralkyl (e.g. benzyl) or aralkyloxy (e.g.
  • benzyloxy their aryl radical can be substituted by hydroxy, C 1 -C 6 alkyl (eg methyl) or halogen; C 3 -C 6 cycloalkylthio; C 1 -C 6 alkylthio; Arylthio (for example phenylthio) or aralkylthio (for example benzylthio), the aryl radical of which can be substituted by hydroxyl, C 1 -C 6 alkyl (for example methyl) or halogen, or R 2 is a saturated, unsaturated or aromatic heterocyclic ring with a Oxygen atom and / or a sulfur atom and / or one or two nitrogen atoms and C 3 -C 7 carbon atoms (eg piperidino, pyrrolidino or furyl) and that in the ring by one or more
  • C 1 -C 6 alkyl eg methyl
  • halogen C 3 -C 6 cycloalkylthio or aralkylthio radicals (eg benzylthio), which are optionally in the aryl radical hydroxy, C 1 -C 6 alkyl (eg methyl) or halogen wear
  • R 2 is an imidazolylthio group in which the imidazole residue with C 1 -C 3 alkyl and / or C-substituted with nitro
  • R 2 is an amino group which is mono- or disubstituted is by C 1 -C 6 alkyl (e.g.
  • Methyl, ethyl or isobutyl C 1 -C 6 alkoxy (e.g.
  • hydroxy-C 1 -C 6 alkyl e.g. hydroxyethyl
  • C 3 -C 6 cycloalkyl e.g. cyclopropyl or cyclopentyl
  • Aryl e.g. phenyl
  • aralkyl e.g. benzyl
  • R 3 preferably represents a hydrogen atom.
  • alkyl in the various definitions can be straight-chain or branched and contain 1-6, preferably 1-4 carbon atoms, such as, for example, the methyl, ethyl, n-propyl, i-propyl, iso-butyl or tert-butyl group.
  • R 2 the following groups are suitable, for example, for R 2 : the methyl, methoxy, ethoxy, methylthio, dimethylamino, allylamino, gamma, gamma-dimethylallylamino, hydroxymethylamino, hydroxypropylamino, t-butylamino , i-Propylamino, i-butylamino or ethoxycarbonylmethylamino group.
  • the cycloalkyl parts of the cycloalkyl, cycloalkoxy, cycloalkylthio or cycloalkenyl groups can contain 3-8, preferably 3-6 carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • the following groups are suitable, for example: A cyclopropyl-methyl-amino or cyclopentyl-methyl-amino group.
  • the amino group is mono- or disubstituted, but preferably simply by C 2 -C 6 alkyl, C 2 -C 6 alkenyl, alkoxy, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, alkoxyalkyl, Di-alkoxyalkyl, alkoxycarbonyl-alkyl, arylalkyl or
  • Hetarylalkyl groups it being possible for the alkyl parts of the groups mentioned in each case to contain 1-6, preferably 1-4, carbon atoms.
  • R 5 R 6 N- preference is given to compounds in which R 5 and R 6 are simultaneously a C 1 -C 6 alkyl group, or R5 is a hydrogen atom and R 6 is a C 2 -C 6 alkyl group. , C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, hydroxyalkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkenyl-alkyl, alkoxyalkyl, di-alkoxy-alkyl, alkoxycarbonyl-alkyl, Arylalkyl or hetarylalkyl group, such as a furanylmethyl, thienylmethyl or pyridylmethyl group.
  • Aryl is to be understood as meaning aromatic residues with 6-14 carbon atoms, such as phenyl or naphthyl.
  • “Hetaryl” parts in all of the aforementioned hetaryl-bearing groups are understood to mean heteroaromatic radicals having one or two nitrogen atoms and a ring size of 5-7 atoms, such as pyridinyl, pyrimidinyl, furanyl or thienyl.
  • the saturated, unsaturated or heterocyclic rings with an oxygen atom and / or a sulfur atom and / or one or two nitrogen atoms are, for example, the morpholine, piperidine or piperazine ring.
  • aryl, hetaryl or heterocyclic rings are substituted, they can be substituted once, twice or even three times, but preferably once.
  • Alkyl parts represent preferred embodiments.
  • Halogen is to be understood as fluorine, chlorine or bromine, but especially chlorine.
  • alkyl group as a bridge member, such as in the case of cycloalkyl "alkyl”, alkoxy "alkyl”, alkoxycarbonyl “alkyl”, aryl “alkyl” or hetaryl “alkyl” group, here is a C 1 -C 3 alkyl group, especially the
  • the alkyl parts contain additional substituents, such as in the case of the hydroxy-C 1 -C 6 -alkyl group, cycloalkyl-C 1 -C 6 -alkoxy, cycloalkyl-C 1 -C 6 -alkyl, etc., these substituents (in the the above examples, the hydroxy and cycloalkyl group) are at any position on the alkyl part, that is in the 1-, 2-, 3-, 4-, 5- or 6-position. Often, however, they are in each case at the terminal position of the respective alkyl part.
  • R2 represents a heterocyclic ring
  • this can have a hetero atom or a
  • the imidazole group can thus be bonded to the 6-position of the purine ring, for example, via a nitrogen atom or via a carbon atom, for example in the 1-, 2- or 4-position.
  • R 1 represents a hydrogen atom or the amino group
  • R 2 is a C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, one is simply a C 2 -C 6 alkyl, C 2 -C 6 alkenyl, hydroxy C 1 - C 4 -alkyl-, C 3 -C 6 -cycloalkyl-, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl-, C 1 -C 4 -alkoxy-carbonyl-C 1 -C 4 -alkyl-, aryl - Aryl-C 1 -C 4 alkyl or hetaryl-C 1 -C 4 alkyl group substituted amino group; an amino group substituted twice by C 1 -C 4 alkyl groups; or a heterocyclic five or six ring with one
  • Means nitrogen and oxygen atom such as the ethoxy; n-propylamino, i-propylamino, iso-butylamino, t-butylamino, 2-hydroxypropylamino, cyclopropylamino, cyclopentylamino, cyclopropylmethylamino, cyclopentylmethylamino, Ethoxycarbonyl-methylamino, phenylamino, benzylamino, phenyl-ethylamino, 1-phenyl-2-propylamino group, where the phenyl parts can be substituted by methyl, methoxy or chlorine, or the thienylmethylamino, pyridylmethylamino, furylmethylamino or morpholino group,
  • R 3 is a hydrogen atom
  • R4 represents a hydrogen atom, a triphosphate group or an acetyl group.
  • Possible salts of the compounds of the general formula I are, in particular, alkali, alkaline earth and ammonium salts of the phosphate groups.
  • Lithium, sodium and potassium salts are preferred as alkali salts.
  • Magnesium and calcium salts are particularly suitable as alkaline earth metal salts.
  • ammonium salts are understood to be salts which contain the ammonium ion, which can be substituted up to four times by alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals.
  • the substituents can be the same or different.
  • the compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable acids.
  • suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
  • the compounds of general formula I are new compounds. They can be prepared in analogy to known, related compounds (Robins, Hansske THL 25, 367, 1984 and the literature cited therein). For the preparation of the compounds of the general formula I, a process has proven to be particularly expedient in which a compound of the general formula II
  • X is halogen such as fluorine, chlorine, bromine or iodine, to a mixture of the isomers IV a, b and V a, b
  • the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as, for. B. olive oil, suspended or dissolved.
  • suitable pharmaceutical carriers such as, for. B. olive oil, suspended or dissolved.
  • the new substances of general formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers.
  • additives are e.g. B. tartrate and citrate buffers, ethanol, Complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high-molecular polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), gelatin, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 tablets with an active ingredient content of 0.5-1000 mg being administered with each application.
  • the tablets can also be delayed, which reduces the number of applications per day to 1-3.
  • the active substance content of the retarded tablets can be 20 - 2000 mg.
  • the active ingredient can also be given by injection one to eight times a day or by continuous infusion, with amounts of 5-4000 mg per day usually being sufficient.
  • 6-Propylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-D-ribofuranosylpurine a) 100 ml chloroform, 2.1 ml dist. Dimethylformamide and 5.5 ml (76 mmol) of thionyl chloride were placed under nitrogen and stirred for 15 minutes at room temperature. 10 g (25 mmol) of 2 ', 3', 5'-triacetylinosine were added and the clear solution was stirred under reflux for 5 hours.
  • Example 1 ad The following end compounds are obtained analogously to Example 1 ad: a) 6- (2-methylphenylmethylamino) -2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-D-ribofuranosylpurine in 58% yield from the mp. 141-142 ° C. b) 6-Dimethylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-D-ribofuranosylpurine in 78% yield, mp. 134-137 ° C.
  • 2-Amino-6-methylamino-2 ', 3'-dideoxy-2', 3'-didehvdro-9-ß-D-ribofuranosylpurine a) 3.5g (11.8mmol) 2-amino-6-methylamino-9 -ß-D-ribofuranosylpurin were absolute in 70. DMF dissolved and 1.93 g (28.3 mmol) imidazole added. 2.14 g (14.2 mmol) was then tert while stirring. Butyldimethysilyl chloride was added dropwise and stirring was continued for 20 hours.
  • Example 5 ad The following end compounds are obtained analogously to Example 5 ad: a) 2-hydroxy-6-methylamino-2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-D-ribofuranosylpurine, mp b) 2- Amino-6-ethoxy-2 ', 3'-dideoxy-2', 3'-didehydro-9-ß-D-ribofuranosylpurine, mp. C) 6- (2-thienylmethylamino) -2 ', 3'-dideoxy- 2 ', 3'-didehydro-9-ß-D-ribofuranosylpurine, mp.
  • Example 2a 250 mg (0.75 mmol) of the compound obtained in Example 2a were mixed with 5 mg of dimethylaminopyridine and 113 mg (1.11 mmol) of acetic anhydride in 15 ml of dichloromethane and stirred at 25 ° C. for 4 hours. The solvent was then distilled off and the residue was chromatographed on silica gel 60 (mobile phase: CH 2 Cl 2 / CH 3 OH, 99: 1). 200 mg of the title compound of mp 125 ° C. are obtained.

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Abstract

Des composés ont la formule (I), dans laquelle R1 représente hydrogène ou le groupe amino, R2 représente un atome d'halogène, un groupe C1-C6-alkyle, C2-C6-alkényle, C1-C6-alkoxy, C3-C6-cycloalkyl-C1-C6-alkoxy, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C1-C6-alkylthio, un groupe amino substitué, un groupe aryle, aralkyle, aryloxy, aralkoxy, arylthio, aralkylthio ou hétarylthio, ou un noyau fermé héterocyclique, R3 représente hydrogène ou le groupe amino et R4 représente hydrogène, C1-C4-acyle aliphatique ou un groupe monophosphate, biphosphate ou triphosphate. L'invention concerne ces composés, leurs tautomères, leurs sels physiologiquement admissibles d'acides et de bases organiques et inorganiques, leur procédé de production et des médicaments antiviraux qui contiennent ces composés.
PCT/EP1990/000059 1989-01-14 1990-01-11 Nucleosides de purine, leur procede de production et medicaments contenant ces composes WO1990008147A1 (fr)

Priority Applications (1)

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KR1019900702027A KR910700256A (ko) 1989-01-14 1990-01-11 푸린 누클레오시드, 이들의 제조방법 및 이들 화합물을 포함하는 약제

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DEP3900964.5 1989-01-14
DE3900964A DE3900964A1 (de) 1989-01-14 1989-01-14 Neue nukleoside, verfahren zu deren herstellung sowie arzneimittel, die diese verbindungen enthalten

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AU (1) AU4951490A (fr)
DE (1) DE3900964A1 (fr)
IL (1) IL93001A0 (fr)
PT (1) PT92862A (fr)
WO (1) WO1990008147A1 (fr)
ZA (1) ZA90218B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0340778A2 (fr) * 1988-05-06 1989-11-08 Bristol-Myers Squibb Company Prodrogues de 2',3'-didéshydro-2',3'-didésoxynucléosides
WO1993006119A1 (fr) * 1991-09-27 1993-04-01 The Institute Of Cancer Research Derives de desoxynucleosides
US5559101A (en) * 1994-10-24 1996-09-24 Genencor International, Inc. L-ribofuranosyl nucleosides
US5885972A (en) * 1994-10-24 1999-03-23 Genencor International, Inc. L-pyranosyl nucleosides

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3817982A (en) * 1971-12-29 1974-06-18 Syntex Inc 2{40 ,3{40 -unsaturated nucleosides and method of making

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3817982A (en) * 1971-12-29 1974-06-18 Syntex Inc 2{40 ,3{40 -unsaturated nucleosides and method of making

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Band 101, Nr. 1, 2. Juli 1984, (Columbus, Ohio, US) M.J. ROBINS et al.: "Nucleic Acid-Related Compounds. 46. A Mild Conversion of Vicinal Diols to Alkenes. Efficient Transformation of Ribonucleosedes into 2'-ene and 2',3-Dideoxynucleosides", siehe seite 652* Zusammenfassung 7564z & Tetrahedron Lett. 1984, 25(4), 367-70* *
CHEMICAL ABSTRACTS, Band 88, Nr. 20, 15. Mai 1978,(Columbus, Ohio, US) R. MENGEL et al.: "Nucleoside Rearrangements. IV. A New Route to 2',3'-Unsaturated Nucleosides - a Mild Rearrangement of Vicinal Cis-Diols in Olefins", siehe seite 638, *Zusammenfassung 152898d & Tetrahedron Lett. 1977, (48), 4203-6* *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0340778A2 (fr) * 1988-05-06 1989-11-08 Bristol-Myers Squibb Company Prodrogues de 2',3'-didéshydro-2',3'-didésoxynucléosides
EP0340778A3 (fr) * 1988-05-06 1990-11-22 Bristol-Myers Squibb Company Prodrogues de 2',3'-didéshydro-2',3'-didésoxynucléosides
WO1993006119A1 (fr) * 1991-09-27 1993-04-01 The Institute Of Cancer Research Derives de desoxynucleosides
US5559101A (en) * 1994-10-24 1996-09-24 Genencor International, Inc. L-ribofuranosyl nucleosides
US5885972A (en) * 1994-10-24 1999-03-23 Genencor International, Inc. L-pyranosyl nucleosides

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ZA90218B (en) 1990-10-31
KR910700256A (ko) 1991-03-14
AU4951490A (en) 1990-08-13
IL93001A0 (en) 1990-09-17
DE3900964A1 (de) 1990-07-19
PT92862A (pt) 1990-07-31

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