WO2004050665A1 - Composes de silicium - Google Patents

Composes de silicium Download PDF

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Publication number
WO2004050665A1
WO2004050665A1 PCT/GB2003/005053 GB0305053W WO2004050665A1 WO 2004050665 A1 WO2004050665 A1 WO 2004050665A1 GB 0305053 W GB0305053 W GB 0305053W WO 2004050665 A1 WO2004050665 A1 WO 2004050665A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidin
tetrahydrofuran
amino
difluoro
hydroxy
Prior art date
Application number
PCT/GB2003/005053
Other languages
English (en)
Inventor
John Gary Montana
William Bains
Original Assignee
Amedis Pharmaceuticals Ltd.
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 GB0227905A external-priority patent/GB0227905D0/en
Priority claimed from GB0322011A external-priority patent/GB0322011D0/en
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Priority to AU2003302624A priority Critical patent/AU2003302624A1/en
Publication of WO2004050665A1 publication Critical patent/WO2004050665A1/fr

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Classifications

    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0838—Compounds with one or more Si-O-Si sequences

Definitions

  • Brain tumours are found in approximately 2% of routine autopsies and, in more than half these cases, they are metastases of tumours that originate from other sites. Although about a third of patients with central nervous system (CNS) metastases have not been previously diagnosed as having cancer, their CNS symptoms are generally the first indication of cancer.
  • CNS central nervous system
  • Gemcitabine is an example of a nucleoside analogue, a specific class of anti-metabolite.
  • Other examples of anti-cancer drugs which are nucleoside analogues include cytarabine, 5-fluorouracil, fludarabine and proguanil.
  • Gemcitabine is a DNA elongation blocker, primarily killing cells in the S phase. Under certain circumstances, gemcitabine blocks progression through the G1/S boundary. Gemcitabine promotes apoptosis, possibly by causing DNA damage and premature arrest of the cell cycle. Gemcitabine is widely used as an anti-cancer agent, e.g. for the treatment of non-small cell lung, locally-advanced pancreatic, metastatic pancreatic, breast and ovarian cancers. Gemcitabine is activated in vivo by deoxycytidine kinase.
  • a prodrug is a generally inactive compound that is converted (e.g. by metabolism) within the body into its active form.
  • Prodrugs are useful when the active form is too toxic to administer systemically, is absorbed poorly (e.g. due to BBB) or breaks down before reaching its target.
  • the prodrug functionality must modulate the release of the active drug such that it is released rapidly enough to have a therapeutic effect before it is cleared from the body, but slow enough so that it can be formulated, delivered and distributed to the target. Selection of the prodrug functionality is not straightforward and subtly depends on the chemistry of the compound.
  • Prodrugs of gemcitabine are not activated by deoxycytidine kinase, due to blocking of the 5OH group.
  • Prodrugs of gemcitabine are known, see for example WO-A-98/32762.
  • the prodrugs typically have a modified pyrimidine ring, rather than the sugar.
  • the present invention is based on the discovery that therapeutic agents can be converted into prodrug form using one or more silicon-based protecting groups. Although such groups have been used extensively in synthetic and analytical chemistry, they have rarely before been considered as suitable for use in therapeutic compounds.
  • the invention particularly concerns a particular class of compounds having one or more silicon-based protecting groups bound at an oxygen atom of the active compound, forming an -O-Si- linkage.
  • the O-Si bond readily hydrolyses, typically in timescales of minutes to days, under physiological conditions.
  • the advantages of such protecting groups are numerous. Firstly, cleavage of the O-Si bond is entirely chemical, and thus unlike conventional prodrugs, prodrugs of the invention remain effective even if the patient's physiology is abnormal.
  • silyl groups are highly lipophilic and thus enhance the penetration of the compounds across the gut wall, cell membranes and BBB.
  • a first aspect of the invention is a compound of formula (I)
  • R 1 and R 2 are -Si(R) 3 , and the other is hydrogen or -Si(R) 3 ; or R 1 is a bond, R 2 is -Si(R) 2 - or -Si(R) 2 -O-Si(R) 2 -, and R 1 O-CH 2 -CH-CH- OR 2 taken together form a ring;
  • Compounds of the invention may be prodrugs of anti-metabolites and as a consequence may have therapeutic utility in the treatment of cancer.
  • Another aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
  • each R is preferably the same or different and is methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexyl, phenyl or a group of formula (i) as defined herein.
  • alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. "C.,- 6 alkyl” has the same meaning.
  • cycloalkyl refers to a saturated alicyclic moiety having from three to ten carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The group may be a bridged moiety.
  • heterocycloalkyl refers to a saturated heterocyclic moiety having from four to ten carbon atoms and one or more heteroatoms selected from the group N, O, S, Si and P, and includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.
  • the group may be a bridged moiety.
  • Compounds of the invention are chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
  • the stereochemistry of a chiral ring atom is preferably the same as that of the corresponding atom in gemcitabine. More preferably, the stereochemistry of the compound as a whole corresponds to that of gemiciabine.
  • the compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art.
  • the compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallisation and regeneration of the free base.
  • the enantiomers of the novel compounds may be separated by HPLC using a chiral column.
  • Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.
  • Compounds of the invention may be in the form of pharmaceutically acceptable salts, for example, addition salts of inorganic or organic acids.
  • inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid.
  • Organic acid addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2- methylpropionic acid, 1 ,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, gluconicacid, glutamicacid, N-glycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4-hydroxybenzoyl)benzoicacid, 1-hydroxy-2-naphthoicacid, 3-hydroxy- 2-naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, n-dodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric
  • a compound of the invention may be prepared by any suitable method known in the art. Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by formation of a salt if appropriate or possible under the circumstances.
  • Preferred compounds of the invention include:
  • cancer refers to any disease or condition characterised by uncontrolled, abnormal growth of cells and includes all known types of cancer, for example cancer of the bladder, breast, colon, brain, bone, head, blood, eye, neck, skin, lungs, ovaries, prostate and rectum; digestive, gastrointestinal, endometrial, hematological, AIDS-related, muscoskeletal, neurological and gynecological cancers; lymphomas, melanomas and leukaemia.
  • cancer refers to both solid and liquid tumours.
  • the active compound may be administered orally, intravenously, rectal ly, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity.
  • Intravenous administration is preferred.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art.
  • the compositions of the invention may contain 0.1-99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1-500 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the art.
  • compositions for oral administration include known pharmaceutical forms for such administration, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl or n-propyl p- hydroxybenzoate
  • colouring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Suitable sweetening, flavouring and colouring agents may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3- butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1 ,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as ol . eic acid, find use in the preparation of injectables.
  • the compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions for topical administration are also suitable for use in the invention.
  • the pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel.
  • a suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants.
  • An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil or wax.
  • a gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent.
  • Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. The following Examples illustrate the invention.
  • Mass spectrometry involved the use of an electrospray source operating in positive and negative ion mode.
  • the system ran at 1.5 ml/min, detection mode is through a Hexa-pole Mass Spectrometry detector and a Diode-Array detector for UV.
  • Trimethylsilyl chloride (TMSCI, 2.96 ml, 23.4 mmol) was added and the resulting mixture was stirred at room temperature for 24 h before being washed with water (200 ml) and extracted into ethyl acetate (3 x 200 ml). The combined organic extracts were then washed with saturated sodium chloride solution (200 ml), dried (magnesium sulfate, MgSO 4 ) and concentrated in vacuo. The crude material was then purified by column chromatography (silica, 1 :19-methyl alcohol-ethyl acetate) to afford the title compound in a homogeneous form (1.2 g, 24 %).
  • Example 2 4-Amino-1 -f5-f tert-butyldimethylsilyloxymethyl)-3.3-difluoro-4- hydroxy-tetrahydrofuran-2-yll-1 -pyrimidin-2-one
  • Example 3 4-Amino-1 -r5-(te/t-butyldiphenylsilyloxymethyl)-3,3-difluoro-4- hydroxy-tetrahvdrofuran-2-yl1-1f/-pyrimidin-2-one
  • 4-amino-1-[3,3-difluoro-4-hydr ⁇ xy-5- hydroxymethyl-tetrahydrofuran-2-yl]-1/-/-pyrimidin-2-one hydrochloride (2.00 g, 5.0 mmol) and imidazole (1.36 g, 20 mmol) in anhydrous DMF (29 ml) under nitrogen at 0 °C was added fe/f-butyldiphenylsilyl chloride (TBDPS-CI, 1.84 ml, 8.0 mmol).
  • Example 5 4-Amino-1 -f3,3-difluoro-5-hvdroxymethyl-4-(triethylsilyloxy)- tetrahvdrofuran-2-v ⁇ -1 -pyrimidin-2-one To a solution of 4-amino-1 -[3,3-difluoro-4-(triethylsilyloxy)-5-
  • Example 7 4-amino-1 -r3.3-difluoro-5-(ethyldimethylsilyloxymethyl)-4- hydroxy-tetrahvdrofuran-2-yl1-1 -pyrimidin-2-one This material was formed as a minor product in the synthesis of 4-amino- 1 -[4-(ethyldimethylsilyloxy)-5-(ethyldimethylsilyloxymethyl)-3,3-difluoro- tetrahydrofuran-2-yl]-1H-pyrimidin-2-one (Example 6).
  • Example 9 4-Amino-1 -r(4-diethylmethylsilyloxy)-5-(diethylmethyl- silyloxymethyl)-3,3-difluoro-tetrahvdro-furan-2-yl1-1 -pyrimidm-2-one
  • Example 11 4-Amino-1 -r4-(diethylmethylsilyloxy)-3.3-difluoro-5-hvdroxy- methyltetrahvdrofuran-2-yll-1tf-pyrimidin-2-one

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à un composé représenté par la formule (I), où l'un des éléments R1 et R2 représente -Si(R)3, et l'autre représente hydrogène ou -Si(R)3; ou alors R1 représente une liaison, R2 représente -Si(R)2- ou -Si(R)2 -O-Si(R)2-, et R1O-CH2-CH-CH-OR2 forme ensemble un cycle; R3 et R4, qui sont identiques ou différents, représentent chacun halogène; et chaque R, qui est identique ou différent, représente alkyle, aryle, cycloalkyle ou hétérocycloalkyle; ou à un sel de ce composé, acceptable sur le plan pharmaceutique.
PCT/GB2003/005053 2002-11-29 2003-11-20 Composes de silicium WO2004050665A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003302624A AU2003302624A1 (en) 2002-11-29 2003-11-20 Silicon compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0227905.7 2002-11-29
GB0227905A GB0227905D0 (en) 2002-11-29 2002-11-29 Compounds and their use
GB0322011.8 2003-09-19
GB0322011A GB0322011D0 (en) 2003-09-19 2003-09-19 Compounds and their use

Publications (1)

Publication Number Publication Date
WO2004050665A1 true WO2004050665A1 (fr) 2004-06-17

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AU (1) AU2003302624A1 (fr)
WO (1) WO2004050665A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117760A3 (fr) * 2006-02-06 2007-12-06 Reddys Lab Ltd Dr Préparation de gemcitabine
WO2017183217A1 (fr) 2016-04-21 2017-10-26 大原薬品工業株式会社 Dérivé d'éther de silyle à fragment de sucre de 5-azacytidine
US9901641B2 (en) 2016-04-21 2018-02-27 Ohara Pharmaceutical Co., Ltd. Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
EP3204121A4 (fr) * 2014-10-08 2018-05-09 Epigenetics Pharma LLC Promédicaments sous forme de pyrimidine silylée et méthodes d'utilisation desdits promédicaments
WO2018230479A1 (fr) * 2017-06-13 2018-12-20 大原薬品工業株式会社 Dérivé d'éther de silyle en position 5' pour agent anticancéreux nucléosidique ou agent anti-viral
US10227374B2 (en) 2016-04-21 2019-03-12 Ohara Pharmaceutical Co., Ltd. Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOTRA, LAKSHMI P. ET AL: "Structure-Activity Relationships of 2'-Deoxy-2',2'-difluoro-L-erythro- pentofuranosyl Nucleosides", JOURNAL OF MEDICINAL CHEMISTRY (1997), 40(22), 3635-3644, 1997, XP002271339 *
XIANG, YUEJUN ET AL: "Synthesis and anti-HIV activities of 2'-deoxy-2',2''-difluoro-.beta.-L- ribofuranosyl-pyrimidine and -purine nucleosides", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (1995), 5(7), 743-8, 1995, XP002271340 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117760A3 (fr) * 2006-02-06 2007-12-06 Reddys Lab Ltd Dr Préparation de gemcitabine
EP3204121A4 (fr) * 2014-10-08 2018-05-09 Epigenetics Pharma LLC Promédicaments sous forme de pyrimidine silylée et méthodes d'utilisation desdits promédicaments
US10479807B2 (en) 2014-10-08 2019-11-19 Epigenetics Phrama LLC Silylated pyrimidine prodrugs and methods of their use
WO2017183217A1 (fr) 2016-04-21 2017-10-26 大原薬品工業株式会社 Dérivé d'éther de silyle à fragment de sucre de 5-azacytidine
WO2017183215A1 (fr) * 2016-04-21 2017-10-26 大原薬品工業株式会社 Dérivé éther de silyle à fraction sucre de 5-azacytidine
US9901641B2 (en) 2016-04-21 2018-02-27 Ohara Pharmaceutical Co., Ltd. Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
KR20180134835A (ko) * 2016-04-21 2018-12-19 오하라 야꾸힝 고교 가부시키가이샤 5-아자사이티딘류의 당 부분(糖部) 실릴에테르 유도체
US10227374B2 (en) 2016-04-21 2019-03-12 Ohara Pharmaceutical Co., Ltd. Silyl etherified derivatives of 5-azacytidines in carbohydrate moiety
EP3543249A1 (fr) 2016-04-21 2019-09-25 Ohara Pharmaceutical Co., Ltd. Dérivé d'éther de silyle de fraction de sucre de 5-azacytidine
KR102579485B1 (ko) 2016-04-21 2023-09-20 오하라 야꾸힝 고교 가부시키가이샤 5-아자사이티딘류의 당 부분(糖部) 실릴에테르 유도체
WO2018230479A1 (fr) * 2017-06-13 2018-12-20 大原薬品工業株式会社 Dérivé d'éther de silyle en position 5' pour agent anticancéreux nucléosidique ou agent anti-viral

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