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WO1991015498A2 - Derives nucleosidiques - Google Patents

Derives nucleosidiques Download PDF

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Publication number
WO1991015498A2
WO1991015498A2 PCT/EP1991/000639 EP9100639W WO9115498A2 WO 1991015498 A2 WO1991015498 A2 WO 1991015498A2 EP 9100639 W EP9100639 W EP 9100639W WO 9115498 A2 WO9115498 A2 WO 9115498A2
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Prior art keywords
group
formula
groups
compounds
fluoro
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Application number
PCT/EP1991/000639
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English (en)
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WO1991015498A3 (fr
Inventor
Jo Klaveness
Kjell Undheim
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Nycomed Imaging As
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Publication date
Priority claimed from GB909007650A external-priority patent/GB9007650D0/en
Priority claimed from GB909007651A external-priority patent/GB9007651D0/en
Priority claimed from GB909007566A external-priority patent/GB9007566D0/en
Application filed by Nycomed Imaging As filed Critical Nycomed Imaging As
Priority to JP91506841A priority Critical patent/JPH05505815A/ja
Priority to CA002079796A priority patent/CA2079796A1/fr
Publication of WO1991015498A2 publication Critical patent/WO1991015498A2/fr
Publication of WO1991015498A3 publication Critical patent/WO1991015498A3/fr
Priority to NO92923849A priority patent/NO923849L/no

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    • 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
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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
    • 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
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • This invention relates to antiviral compounds and more particularly to esters, ethers and amides of nucleoside derivatives which are active against human immunodeficiency virus (HIV) , the retrovirus which causes the disease AIDS, or other viruses such as herpes simplex virus (HSV) .
  • HIV human immunodeficiency virus
  • HSV herpes simplex virus
  • Clinical symptoms are weight loss, chronic diarrhoea, persisting fever and opportunistic infections due to loss of T-cells, thus upsetting the overall balance of the immune system.
  • the patient loses his/her ability to combat otherwise insignificant infections.
  • Many substances interfering with replication have been tried, e.g.
  • 3'-azido - 3*-deoxythymidine (AZT) , 2' ,3 '-dideoxyadenosine, 3*-fluoroarabinosyladenine, 2' ,3'-dideoxycytidine, 2'-chloro-2'3'-dideoxyadenosine, 2* ,3'-dideoxyguanosine, 2' ,3'-dideoxyinosine, 2' ,3'- dideoxy - 2 • ,3'-didehydrothymidine, 3*-azido- 2',3*,- dideoxyuridine, 3'-azido - 2• ,3'-dieoxy-5-ethyl-uridine, 1-(2'-deoxy-2'-fluoro-3-D-arabinofuranosyl)-5- ethyluracil, 2,6-diamino-9-(3'-azido-2• ,3
  • European Patent Application No. 0196185A describes pharmaceutical compositions containing AZT, a known compound which has shown great promise in the treatment of AIDS and AIDS- related complex. It is believed that AZT works by inhibiting reverse transcriptase.
  • G is the residue of the glycone moiety of the nucleoside
  • Y is a hydrogen atom or a physiologically acceptable group of the formula
  • n O or 1
  • m 0 or 1
  • R is an optionally substituted alkyl or aryl group or an N-(C alkyl)-1,4-dihydropyridin- 3-yl group or, where n is 0, a hydrogen atom; R 2 and R3 are independently hydrogen atoms or lower alkyl groups or R 2 and R3 together are an alkylidene group; and X is a group selected from
  • R 4 is a hydrogen atom or a group -NY3Y4, where Y3 and Y 4 have the above meani.ngs and R5 i.s a hydrogen or halogen atom or a lower alkyl or trifluoromethyl group, with the. following provisos
  • 1(G) are hydrogen and Y 4 i.s R1CO, then Y1 i.s a group Rl(O) .CO. (OCR2R3) i.n whi.ch n and/or m is 1,
  • the glycone group - G - is not a 2 ',3'- dideoxyribosyl group or such a group having 3 *- fluorine or 3*-azido substituent nor a 2*,3'- dehydro-dideoxyribosyl group) and/or salts thereof.
  • glycone moiety G will normally be of the formula
  • glycone moieties include the 2,3-dideoxy- 2-halo-pentofuranosyl group, for example the 2-chloro- and 2-fluoro-analogues, especially when the group has the threo configuration:
  • Another preferred moiety is the 2,2-difluoro-2-deoxy- pentofuranosyl group
  • Y 5 is a hydrogen atom or an acyl or acyloxy-alkyl group as defined above for Y 1 . It is known that 2,2- difluoro-2-deoxy-nucleosides are active against herpes simplex virus (HSV) and accordingly the compounds according to the invention having this glycone moiety will find application in treatment of herpes infections.
  • HSV herpes simplex virus
  • Protected hydroxy groups will in general be groups of the formula Y 1O- where Y1 has the above meaning.
  • compositions for the treatment or prophylaxis of virus infections, in particular neurotropic viruses and especially retroviruses such as HIV.
  • compositions also form part of the invention.
  • the group R is preferably an alkyl group containing 1-20 carbon atoms which may be straight or branched, or an aryl group which may contain 6 to 20 carbon atoms and may be mono- or poly-cyclic.
  • Substituents which may be present on the alkyl groups R 1 include aryl groups preferably having 6-10 carbon atoms (as in aralkyl groupings) , hydroxy, alkoxy and carboxy groups.
  • Aryl groups include 5- or 6-membered heterocyclic aryl groups having one or more heteroato s selected from 0, N and S, such as furyl, imidazolyl, pyrrolyl, pyridinyl and thienyl groups.
  • Substituents which may be present on aryl groups include alkyl groups, e.g. having 1-6 carbon atoms, hydroxy and carboxy groups. Examples of such groups include methyl, ethyl, propyl, t-butyl, pentyl, stearyl, palmityl, carboxyethyl and benzyl groups.
  • the lower alkyl groups R 2, R3 and R5 preferably contain 1-6 carbon atoms. However, R 2 preferably
  • R 3 represents a hydrogen atom.
  • R is preferably a hydrogen atom or more preferably a methyl group.
  • R 5 i.s a halogen atom it may be a fluorine, chlorine, bromine or
  • R is preferably a hydrogen or chlorine atom or a methyl group.
  • R in any of the groups Y , Y , Y or Y 4 is an N-alkyl-l,4-dihydropyridin-3-yl group the alkyl group is preferably methyl.
  • the compounds of the invention may carry more than one of the groups Y 1, Y2, Y 3 and Y4.
  • the compounds of formula (I) D,E, I and
  • Groups Y are preferably of the formula
  • the salts of the compounds of formula (I) may be acid addition salts with organic or inorganic acids, for instance hydrochloric or phosphoric acid or methanesulphonic acid, ethane disulphonic acid, 2-naphthylsulphonic acid, pivalic acid and pamoic acid.
  • Antiviral counter-ions such as phosphonoformate or suramin may also be used.
  • Organic or inorganic base salts may be formed with acidic groups present in the molecule; suitable counter-ions include alkali metal ions such as sodium and potassium ions, divalent ions such as calcium and zinc ions and organic ions such as tetraalkylammonium and choline or ions derived from meglumine or ethylenediamine. Salts according to the invention may be formed by reaction of the compound of formula (I) with an appropriate acid or base.
  • compositions according to the invention may be used in the treatment and/or prophylaxis of virus infections, in particular HIV infections, and such a method forms a further feature of the invention. They may be formulated in conventional manner by admixture of one or more compounds of formula (I) as defined above with excipients and/or carriers.
  • the compounds of formula (I) may themselves be inhibitors of reverse transcriptase when the 5'- hydroxy group is free, it is possible that they are converted jln vivo to the desacyl or desalkyl nucleosides. Nevertheless the substitution at the respective O- and N- atoms gives surprising advantages in terms of uptake and sustained activity.
  • the compounds of formula (I) are more lipophilic than the parent compounds and this permits rapid and efficient absorption from the gastro-intestinal tract; the absorption rate may be optimised by careful choice of the substituent group to give the desired balance of lipophilicity and hydrophilicity.
  • the lipophilic nature of the compunds of formula (I) also gives the molecules the ability to penetrate the cell membranes more easily and leads to higher intracellular concentrations, giving an improved dose/effect ratio.
  • the steady hydrolysis of the compounds ensures a sustained concentration of the active compound in the cell and thereby permits longer intervals between doses, overcoming a significant drawback of the prior art compounds.
  • the compounds according to the invention can penetrate the blood-brain barrier and thus permit treatment of the neurological disorders which have been observed to be related to the presence of neurotropic viruses, e.g. retroviruses such as HIV, and lentiviruses (Yarchoan et al. The Lancet, January 17, 1987, page 132). This is a significant advantage compared to the corresponding unsubstituted compounds or other antiviral compounds and is not referred to anywhere in the prior art. Attempts have been made to treat these neurological disorders with AZT but with limited success.
  • the invention thus further provides a method of treatment of neurological disorders caused by neurotropic viruses wherein an effective dose of a compound of formula (I) or a salt thereof is administered to a patient suffering from such a disorder.
  • Compounds of formula (I) may be prepared in any convenient way, for example, by reaction of a compound of formula (II)
  • Y 1 is as hereinbefore defined and XB is as hereinbefore defined for X except that any of the groups Y 1, Y2, Y3 and Y4 may each additionally represent a protecting group, with the proviso that at least one of Y 1, Y2, Y3 and Y4 i.s a hydrogen atom] with a reagent serving to introduce a group R 1(0) CO. (OCR2R3) as defined above followed where required by removal of any protecting groups and/or unwanted substituents so introduced.
  • OCR2R3 group R 1(0) CO.
  • acylation or alkylation is effected while one or more groups Y 1, Y2, Y 3 and Y4 remain as hydrogen atoms
  • Such protecting groups may, in fact, be conventional N- or O-protecting groups including groups R OCO- which may be selectively removed in the presence of the group(s) intended to remain.
  • an N-benzyloxycarbonyl may be used to protect an exocylic amino group and if the group which is intended to remain is not one which is removable by reduction, for example a straight chain alkoxycarbonyl group, the
  • N-benzyloxycarbonyl group can readily be removed selectively using hydrogen and a noble metal catalyst such as palladium.
  • Trisubstituted silyl groups may also be used as protecting groups, especially for the 5'-oxygen atom, and include trialkylsilyl e.g. trimethylsilyl, dimethyl- t-butylsilyl, and thexyldimethyl silyl groups.
  • the reagent introduces a group R 1(O) .CO. (OCR2R3) - only into the purine or pyrimidine base then it will be convenient to protect all of the hydroxyl groups present in the glycone, if any; adjacent hydroxyl groups can be protected with a bidentate protecting group such as the
  • 1,1,3,3-tetraisopropyldisilox-l,3-diyl group In general, where more than one of Y 1, Y2, Y3 and Y 4 are hydrogen, and a mixture of compounds is produced, the individual components may readily be separated, for example by chromatography.
  • 2' ,3•-dideoxy derivatives i.e. introduction of a group Y 1 i.n whi.ch m i.s 1
  • i.t is especially effective to form a dianion of the nucleoside (e.g. by reacting with sodium hydride) and to react this with one equivalent of the alkylating agent.
  • Monoalkylation of a hydroxy group other than the 5'-hydroxy group in the sugar moiety is carried in a similar fashion using a 5'-protected nucleoside. It is of course, still possible to use protected forms of the nucleoside, for example by acylation of a nucleophilic nitrogen atom before salt formation with sodium hydride.
  • Suitable acylating agents for use in the reaction have the formula Ac-L where L is a leaving group.
  • suitable acylating agents include the acid halides and acid anhydrides advantageously in the presence of a base;
  • acylating agents include the haloformate esters and reactive carbonic acid diesters.
  • the halogen may, for example, be chlorine or bromine.
  • the base for use in the reaction with the acid halide or anhydride may, for example, be a heterocyclic base such as pyridine or 4-dimethylamino- pyridine.
  • a heterocyclic base such as pyridine or 4-dimethylamino- pyridine.
  • the latter increases the speed of the reaction and may be used advantageously with pyridine.
  • the reaction will normally be carried out in the presence of an inert solvent e.g. a substituted amide solvent such as dimethylformamide, dimethyl- acetamide or a halogenated hydrocarbon such as dichloromethane.
  • N-acyl groups R CO- may be removed selectively, for example by reaction with a phenol such as p-methyl-phenol. Where multiple substitution is to be effected, a stronger base such as sodium hydride may be advantageous.
  • Suitable acyloxyalkylating agents for use in the invention will in general be of the formula R 1 C0.0.CR R 3 L or R O.CO.O.CR 2 R L, where L is a leaving group.
  • the group L may for example, be a halogen atom such as a chlorine or bromine atom or a hydrocarbon-sulphonyloxy group such as a tosyloxy or mesyloxy group.
  • alkylation reaction will normally be effected in the presence of a base, conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
  • a base conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
  • Bases as used for acylation may also be useful.
  • Perbenzoylated l-(2-fluoro-2-deoxy-3-D-arabino- furanosyl)cytosine C. H. Tann, P. H. Brodfeuhrer, S. P. Brundidge, C. Sapino. H. G. Howell J. Or ⁇ . Chem. 50 (1985)3644.
  • compositions according to the invention may be formulated conventionally by means well known in the art, and may be administered by any convenient route, for instance orally, rectally, vaginally, intraveneously or intramuscularly.
  • suitable formulations include tablets and capsules, aqueous formulations for intravenous injection and oil-based formulations for intramuscular injection. Suitable dosages will lie in the range 0.1 to lOOmg per kilogram of bodyweight per 24 hour period.
  • the compositions according to the invention may also contain other active antivirals for instance acyclovir. phosphonoformate, suramin, Evans Blue, interferons or AZT.
  • N-Benzyloxycarbonyl-l-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy-?-D-threo-pentofuranosyl)cytosine (1.0 mmol) is added to a suspension of 5% palladium on charcoal (8mg) in ethanol (4ml) .
  • the hydrogenolysis is run at atmospheric presure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium hydride in a separate compartment.
  • the reaction is run at ambient temperature and is monitored by TLC in order to ensure that overreduction in the heterocyclic ring does not occur.
  • the reaction time is about 1 hour.
  • the mixture is then filtered through a thin bed of Celite, the filtrate evaporated and the product purified by chromatography on silica gel using chloroform-ethanol (9:1).
  • N 6 -B ⁇ nzyloxycarbonyl-9-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy- ⁇ -D-threo-pentofuranosyl)adenine (0.1 mmol) is added to a suspension of 5% palladium on charcoal (8mg) in ethanol (4ml) .
  • the hydrogenolysis is run at atmospheric pressure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium hydride in a separate compartment.
  • the reaction is run at ambient temperature and is monitored by TLC in order to ensure that overreduction in the heterocyclic ring does not occur.
  • the reaction time is about 1 hour.
  • the mixture is then filtered through a thin bed of Celite, the . filtrate evaporated and the product purified by chromatography on silica gel using chloroform-ethanol (9:1).
  • 1,1,3,3-tetraisopropyldisiloxane (0.2mmol) are added to pyridine (2ml) , the reaction mixture stirred at ambient temperature for 8 hours, the solvent removed at reduced pressure, chloroform (15 ml) added to the residue, washed with aqueous bicarbonate and with water, and the dried (MgS0 4 ) solution evaporated. The residue is chromatographed on silica gel using ethyl acetate-hexane to furnish 2' .2 '-difluoro-3' .5'-O-(1.1,3,3- tetraisopropyldisilox-1.3-diyl)thymidine.
  • the silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) .
  • the silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) .
  • the mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10ml) , washed with water (2ml) , dried (MgSO ) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol 95:5.
  • 1-(2-Fluoro-2-deoxy-, ⁇ -D-arabinofuranosyl)-5-iodocytosine (0.2mmol) is dissolved in a mixture of pyridine (0.5ml) and DMF (0.5ml), the solution cooled to 0 ⁇ C, isobutyl chloroformate (0.5mmol) and 4-N,N-dimethylaminopyridine (0.2mmol) added, the mixture stirred at ambient temperature for 12 hours, water (4ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica gel. The product is eluted with chloroform:ethanol (98:2).
  • Potassium carbonate (7 mmol) was added to a solution of 3',5'-bis-O- (thexyldimethylsilyl)-2',2'-difluorothymidine (6 mmol) in dry DMF (20 ml), the mixture stirred at 60°C for 1 h, cooled to 0°C, chloromethyl pivalate (10 mmol) added and the mixture stirred at 60°C for 2 h. Water was added and the mixture freeze-dried and the residue subjected to flash chromatography on silica gel using EtOAc:hexane (5:7).
  • Potassium carbonate (0.25 mmol) was added to a solution of 3',5'-bis-O- (thexyldimethylsilyI)-2 ' ,2'-difluorothymidine (0.2 mmol) in DMF (4 ml), the mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, 1-chloroethyl ethyl carbonate (0.25 mmol) added and the mixture stirred at 40°C for 2 days before the solvent was removed at reduced pressure. The residue was dissolved in hexane: EtOAc (7:5) and the filtrate subjected to flash cromatography using the above eluant.

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Abstract

Composés nucléosidiques répondant à la formule (I): Y1O-G-X dans laquelle Y1 est un atome d'hydrogène ou un groupe acyle ou acyloxyméthyle; G est le résidu de la moitié glycone du nucléoside; et X est une base de purine ou de pyrimidine ou un dérivé ester, amide ou acyloxyalkyle de cette base. Les composés présentent une activité antivirale.
PCT/EP1991/000639 1990-04-04 1991-04-04 Derives nucleosidiques WO1991015498A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP91506841A JPH05505815A (ja) 1990-04-04 1991-04-04 ヌクレオシド誘導体
CA002079796A CA2079796A1 (fr) 1990-04-04 1991-04-04 Derives de nucleosides
NO92923849A NO923849L (no) 1990-04-04 1992-10-02 Nukleosid-derivater

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9007566.4 1990-04-04
GB9007651.4 1990-04-04
GB909007650A GB9007650D0 (en) 1990-04-04 1990-04-04 Nucleoside derivatives
GB909007651A GB9007651D0 (en) 1990-04-04 1990-04-04 Nucleoside derivatives
GB9007650.6 1990-04-04
GB909007566A GB9007566D0 (en) 1990-04-04 1990-04-04 Nucleoside derivatives

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WO1991015498A2 true WO1991015498A2 (fr) 1991-10-17
WO1991015498A3 WO1991015498A3 (fr) 1992-06-11

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EP (1) EP0523110A1 (fr)
JP (1) JPH05505815A (fr)
AU (1) AU7558491A (fr)
CA (1) CA2079796A1 (fr)
OA (1) OA09677A (fr)
WO (1) WO1991015498A2 (fr)

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JPH06157570A (ja) * 1992-06-22 1994-06-03 Eli Lilly & Co 立体選択的グリコシル化法
US5430026A (en) * 1992-06-22 1995-07-04 Eli Lilly And Company 2'-deoxy-2',2'-difluoro (4-substituted pyrimidine) nucleosides, bicyclic derivatives,pharmaceutical compositions, and synthetic precursors
WO2006111058A1 (fr) * 2005-04-18 2006-10-26 Chengdu Zhengkai Biotech Co. Ltd. N4-(oxycarbonyle substitue)-2',2'-difluoro-2'-desoxycytidines et leurs utilisations
US7265096B2 (en) 2002-11-04 2007-09-04 Xenoport, Inc. Gemcitabine prodrugs, pharmaceutical compositions and uses thereof
US7678830B2 (en) 2002-01-15 2010-03-16 Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
US7714012B2 (en) 2006-11-17 2010-05-11 Trustees Of Dartmouth University Synthesis and biological activities of new tricyclic-bis-enones (TBEs)
US7795305B2 (en) 2000-11-28 2010-09-14 Board Of Regents, The University Of Texas System CDDO-compounds and combination therapies thereof
US7863327B2 (en) 1998-06-19 2011-01-04 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US7915402B2 (en) 2008-04-18 2011-03-29 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring
US7943778B2 (en) 2008-04-18 2011-05-17 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: C-17 homologated oleanolic acid derivatives
US8071632B2 (en) 2008-04-18 2011-12-06 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
US8124799B2 (en) 2008-04-18 2012-02-28 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
US8129429B2 (en) 2008-01-11 2012-03-06 Reata Pharmaceuticals, Inc. Synthetic triterpenoids and methods of use in the treatment of disease
US8258329B2 (en) 2008-04-18 2012-09-04 Reata Pharmaceuticals, Inc. Dehydroandrosterone analogs including an anti-inflammatory pharmacore and methods of use
US8299046B2 (en) 2006-11-17 2012-10-30 Trustees Of Dartmouth College Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth
WO2013151774A1 (fr) 2012-04-04 2013-10-10 Halozyme, Inc. Polythérapie par un agent anti-hyaluronane et un taxane ciblant une tumeur
US8921340B2 (en) 2006-11-17 2014-12-30 Trustees Of Dartmouth College Methods for using synthetic triterpenoids in the treatment of bone or cartilage diseases or conditions
US9205113B2 (en) 2012-05-08 2015-12-08 Trustees Of Dartmouth College Synthetic triterpenoids and methods for modulating stem/progenitor cell gene expression
WO2016078160A1 (fr) * 2014-11-17 2016-05-26 常州方圆制药有限公司 Dérivé de cytidine et application de celui-ci
WO2016078397A1 (fr) * 2014-11-17 2016-05-26 常州方圆制药有限公司 Nouveau type de dérivé de cytidine et application de celui-ci
WO2019222435A1 (fr) 2018-05-16 2019-11-21 Halozyme, Inc. Procédés de sélection de sujets pour une polythérapie anticancéreuse avec un ph20 soluble conjugué à un polymère
WO2020216646A1 (fr) * 2019-04-24 2020-10-29 Aenorasis Commercial Company of Pharmaceutical and Medical Products and Machines Societe Anonyme Dérivés de cytidine et procédés de formation de dérivés de cytidine
RU2828746C2 (ru) * 2019-04-24 2024-10-17 Энорасис Коммершл Компани Оф Фармасьютикал Энд Медикал Продактс Энд Машинз Сосьете Аноним Производные цитидина и способы получения производных цитидина

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CA2073063A1 (fr) * 1989-11-06 1991-05-07 Jo Klaveness Derives nucleosidiques
JPH11217396A (ja) * 1998-01-30 1999-08-10 Ajinomoto Co Inc ヌクレオシド誘導体の製造方法

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CA2079796A1 (fr) 1991-10-05
OA09677A (en) 1993-05-15
EP0523110A1 (fr) 1993-01-20
WO1991015498A3 (fr) 1992-06-11
JPH05505815A (ja) 1993-08-26
AU7558491A (en) 1991-10-30

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