WO2004050666A1 - Composés de silicium utiles dans la thérapie du cancer - Google Patents

Composés de silicium utiles dans la thérapie du cancer Download PDF

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Publication number
WO2004050666A1
WO2004050666A1 PCT/GB2003/005056 GB0305056W WO2004050666A1 WO 2004050666 A1 WO2004050666 A1 WO 2004050666A1 GB 0305056 W GB0305056 W GB 0305056W WO 2004050666 A1 WO2004050666 A1 WO 2004050666A1
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WO
WIPO (PCT)
Prior art keywords
tetrahydrofuran
pyrimidin
amino
hydroxy
hydroxymethyl
Prior art date
Application number
PCT/GB2003/005056
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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
Application filed by Amedis Pharmaceuticals Ltd. filed Critical Amedis Pharmaceuticals Ltd.
Priority to AU2003302625A priority Critical patent/AU2003302625A1/en
Publication of WO2004050666A1 publication Critical patent/WO2004050666A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • 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

Definitions

  • This invention relates to silicon compounds and their use in therapy.
  • 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
  • BBB blood- brain barrier
  • This barrier is effective against many known anti-cancer agents and thus chemotherapy is of limited use.
  • Some forms of chemotherapy such as intravenous injection of high doses of cyclophosphamide, 5-fluorouracil or methotrexate, have been shown to be effective.
  • the high dosages result in numerous, often severe side-effects throughout the body.
  • these agents are generally injected into the cerebro-spinal fluid, either via intrathecal injection or by injection into an Ommaya reservoir, an access device that delivers the drugs to the brain ventricles.
  • Chemotherapy is often combined with radiation therapy and, where necessary, surgery. All three treatments may result in seizures and cognitive problems (e.g. dysphasia, memory loss or personality changes).
  • An anti-metabolite is a compound which has a similar structure to a metabolite, but which competes with or replaces the metabolite, thus preventing or reducing its normal function in cellular metabolism.
  • Anti-metabolites used in cancer therapy include methotrexate, analogues of nucleic acid bases such as mercaptopurine (Purinethol), azathioprine (Imuran), thioguanine, dacarbazine, nucleoside analogues, analogues of sugars such as mitobronitol, and analogues of steroid synthesis in the adrenals (e.g. mitotane).
  • Some anti-metabolites are also used to treat other proliferative diseases such as inflammatory conditions.
  • Cytarabine is an example of a nucleoside analogue, a specific class of anti-metabolite.
  • Other examples of launched anti-cancer drugs which are nucleoside analogues include gemcitabine, 5-fluorouracil, fludarabine and proguanil.
  • Cytarabine is metabolised inside the cell to its phosphate, which inhibits DNA elongation and repair via alpha-DNA polymerase, inhibition of DNA repair via an effect on beta-DNA polymerase, and incorporation into DNA. The last mechanism is considered to be the most important. Cytarabine is taken into the cells primarily by the nucleoside transporter and because this does not transport it across the BBB, it penetrates the brain poorly (typically having a BBB concentration of ⁇ 10% after injection). Side-effects are numerous and include cognitive dysfunction and seizures. Sufficiently high systemic doses to achieve therapeutic CNS levels cause unacceptable system myelosuppression. US-A- 5679651 describes the use of cytarabine to treat systemic lupus erythematosus (SLE; lupus), a systemic immune disease.
  • SLE systemic lupus erythematosus
  • 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 cytarabine are known, see for example WO-A-97/05154, WO- A-200211668, WO-A-98/04277 and US-A-5641758.
  • 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, 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 the same or different and are each 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; R 3 is hydrogen or -Si(R) 3 ; and each R is the same or different and is alkyl, aryl, cycloalkyl or heterocycloalkyl; with the proviso that at least one of R 1 , R 2 and R 3 comprises silicon; or a pharmaceutically acceptable salt thereof.
  • 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 the use of a compound of formula (I) for
  • Another aspect of the invention is a pharmaceutical composition
  • 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.
  • R 1 , R 2 and/or R 3 is preferably a group selected from trimethylsilyl, tert-butyldiphenysilyl, tert-butyldimethylsilyl, triethylsilyl, ethyldimethylsilyl, propyldimethylsilyl, methyldiethylsilyl, cyclopropyldimethylsilyl, cyclohexyldimethylsilyl and norbomyldimethylsilyl.
  • R is a group of formula (i)
  • X is -CH 2 CH 2 -
  • Y is -CH 2 -
  • Z is -CH 2 -.
  • the proviso concerns the stability of the group.
  • alkyl refers to an optionally substituted 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 ⁇ alkyl has the same meaning.
  • the substituents may be the same or different and selected from halogen and the like.
  • cycloalkyl refers to a saturated alicyclic moiety having from three to ten ring 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.
  • aryl refers to optionally substituted aromatic ring systems comprising six to ten ring atoms, and optionally substituted polycyclic ring systems having two or more cyclic rings at least one of which is aromatic. This term includes for example, phenyl and naphthyl.
  • the group may be optionally substituted with the substituents being the same or different in each occurrence and selected from halogen, alkyl, nitro and the like.
  • halogen refers to F, CI, Br or I.
  • a compound of the invention may be in a protected amino form.
  • protected amino refers to amino groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like groups, or in the form of a phthalimido or like group.
  • 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 cytarabine. More preferably, the stereochemistry of the compound as a whole corresponds to that of cytarabine.
  • 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, gluconic acid, 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 sulpuric
  • salts may be used in therapy.
  • Such salts may be prepared by reacting the compound with a suitable acid in a conventional manner.
  • 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 bychromatography, distillation, fractional crystallisation, or by formation of a salt if appropriate or possible under the circumstances.
  • Preferred compounds of the invention include:
  • the activity and selectivity of the compounds may be determined by any suitable assay known in the art.
  • the compounds of the invention may be used in the treatment of numerous ailments, conditions and diseases including, but not limited thereto, cancer.
  • 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.
  • the active compound may be administered orally, intravenously, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity.
  • 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.
  • Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the disease undergoing treatment.
  • 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.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • 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 corn 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.
  • 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.
  • 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,
  • 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.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. 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.
  • the 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 oleic 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.
  • 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.
  • 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.
  • Example 1 4-Amino-1-f5-(fe/ -butyldimethylsilyloxymethyl)-3.4- dihvdroxy-tetrahvdrofuran-2-vn-1r -pyrimidin-2-one
  • Example 4 4-Amino-1 -f3,4-bis(triethylsilyloxy)-5-(triethylsilyloxymethyl)- tetra vdrofuran-2-vn-1r -pyrimidin-2-one
  • Example 6 4-Amino-1-[3,4-bis(ethyldimethylsilyloxy)-5- (ethyldimethylsilyloxymethyl -tetrahvdrofuran-2-vn-1r/-pyrimidin-2-one
  • Example 9 4-amino-1-f3-hydroxy-5-hydroxymethyl-4- (dimethylpropylsilyloxy)-tetrahvdrofuran-2-vn-1f/-pyrimidin-2-one
  • 4-amino-1-[3,4-bis(dimethylpropylsilyloxy)-5- (dimethylpropyl-silyloxymethyl)-tetrahydrofuran-2-yl]-1 H-pyrimidin-2-one (Example 7, 111 mg, 0.20 mmol) in diethyl ether (5 ml) at 0 °C was added a solution of TFA (15 ⁇ l, 20 % in water).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

Cette invention se rapporte à un composé représenté par la formule (I), où R1 et R2, qui sont identiques ou différents, représentent chacun hydrogène ou -Si(R)3; ou 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 représente hydrogène ou -Si(R)3; et chaque R, qui est identique ou différent, représente alkyle, aryle, cycloalkyle ou hétérocycloalkyle; à condition qu'au moins l'un des éléments R1, R2 et R3 comprenne du silicium ; ou à un sel de ce composé, acceptable sur le plan pharmaceutique.
PCT/GB2003/005056 2002-11-29 2003-11-20 Composés de silicium utiles dans la thérapie du cancer WO2004050666A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003302625A AU2003302625A1 (en) 2002-11-29 2003-11-20 Silicon compounds useful in cancer therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0227906.5A GB0227906D0 (en) 2002-11-29 2002-11-29 Compounds and their use
GB0227906.5 2002-11-29

Publications (1)

Publication Number Publication Date
WO2004050666A1 true WO2004050666A1 (fr) 2004-06-17

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PCT/GB2003/005056 WO2004050666A1 (fr) 2002-11-29 2003-11-20 Composés de silicium utiles dans la thérapie du cancer

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AU (1) AU2003302625A1 (fr)
GB (1) GB0227906D0 (fr)
WO (1) WO2004050666A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007019221A3 (fr) * 2005-08-03 2007-06-28 Rnd Pharmaceuticals Inc Compositions pharmaceutiques d'analogues d'amide nucleoside adenosine substitue contenant du silicium
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
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
US10479807B2 (en) 2014-10-08 2019-11-19 Epigenetics Phrama LLC Silylated pyrimidine prodrugs and methods of their use

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
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CHIU F-T ET AL: "SYNTHESIS HYDROLYTIC REACTIVITY AND ANTI CANCER EVALUATION OF N TRI ORGANO SILYLATED AND O TRI ORGANO SILYLATED COMPOUNDS AS NEW TYPES OF POTENTIAL PRO DRUGS", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 71, no. 5, 1982, pages 542 - 551, XP009027194, ISSN: 0022-3549 *
MILLERSHIP J S ET AL: "Prodrugs utilizing a reversible silyl linkage", INTERNATIONAL JOURNAL OF PHARMACEUTICS 1986 NETHERLANDS, vol. 28, no. 1, 1986, pages 1 - 9, XP009027180 *
PICHAT, LOUIS ET AL: "Lithiation of silyl derivatives of cytosine nucleosides. Preparation of 6-methylcytidine 6-carboxycytidine, and 6-iodocytidine", COMPTES RENDUS DES SEANCES DE L'ACADEMIE DES SCIENCES, SERIE C: SCIENCES CHIMIQUES (1973), 277(21), 1157-8, XP009027195 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007019221A3 (fr) * 2005-08-03 2007-06-28 Rnd Pharmaceuticals Inc Compositions pharmaceutiques d'analogues d'amide nucleoside adenosine substitue contenant du silicium
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
CN108368148A (zh) * 2016-04-21 2018-08-03 大原药品工业株式会社 5-氮杂胞苷的糖部分甲硅烷基醚衍生物
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
CN108368148B (zh) * 2016-04-21 2021-11-05 大原药品工业株式会社 5-氮杂胞苷的糖部分甲硅烷基醚衍生物
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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GB0227906D0 (en) 2003-01-08

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