WO2019160127A1 - Utilisation d'un inhibiteur de dnmt - Google Patents
Utilisation d'un inhibiteur de dnmt Download PDFInfo
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- WO2019160127A1 WO2019160127A1 PCT/JP2019/005722 JP2019005722W WO2019160127A1 WO 2019160127 A1 WO2019160127 A1 WO 2019160127A1 JP 2019005722 W JP2019005722 W JP 2019005722W WO 2019160127 A1 WO2019160127 A1 WO 2019160127A1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Definitions
- the present invention relates to a novel use of an orally administrable DNMT inhibitor that has high stability against the hydrolytic metabolic enzyme cytidine deaminase and can be substituted for 5-azacytidine and its 2'-deoxy form.
- ATL Advanced T-cell leukemia / lymphoma
- Leukemia or malignant lymphoma caused by infection caused by Human T-cell Leukemia / Lymphotropic Virus type-1).
- HTLV-1 infections are more common in the south (especially Kyushu and Okinawa), while others are localized in the Caribbean coastal countries, Central Africa and South America.
- Infection routes of HTLV-1 include breastfeeding, sexual intercourse and blood transfusion, and there are 5 to 10 million carriers worldwide (about 1.1 million in Japan). 6-7% of women and 2-3% of women develop ATL every year.
- the period from HTLV-1 infection to ATL onset is very long, and as a result, many elderly carriers have ATL onset (non-patent document 3).
- Chemotherapy such as CHOP therapy (Non-patent document 4), modified LSG15 therapy (Non-patent document 5), EPOCH therapy (Non-patent document 6) and AZT-INF ⁇ therapy is selected for treatment of ATL. In many cases, standard treatments have not yet been established.
- chemokine receptor CCR4 antibody drug mogamulizumab (product name: Poterigio) (Non-patent document 7), antiviral drug / avacavir (Non-patent document 8), histone deacetylase as a new ATL therapeutic drug
- HDAC histone methyltransferase EZH1 / 2 dual inhibitors
- DNMTs is an abbreviation for DNA methyltransferases (Adenine N 6- specific DNA-methyltransferase: EC 2.1.1.72), cytosine. Catalyzes methylation at the 4-position amino group (Cytosine N 4 -specific DNA-methyltransferase: EC 2.1.1.113) or methylation at the 5-position of the cytosine ring (Cytosine C 5 -specific DNA-methyltransferase: EC 2.1.1.37) Enzyme group.
- Non-Patent Documents 10 to 11 a group of enzymes that catalyze methylation to the 5-position of the cytosine ring in a sequence portion called CpG island often found in the promoter region of the expressed gene (maintenance methyltransferase DNMT1 and de novo methyltransferase DNMT3 family) Plays an extremely important role in regulating normal development and differentiation of cells (Non-Patent Documents 10 to 11).
- DNMTs are also deeply involved in cancer development. That is, 60-90% of all CpGs are thought to be methylated at the 5-position of the cytosine ring, but abnormal levels of DNA methylation are closely related to silencing of the expressed gene, and the promoter region It has been clarified that transcription and expression of a gene in which (CpG island) is methylated at the 5-position cytosine ring at a high level is silenced (Non-Patent Documents 12 to 14).
- cells are equipped with a mechanism for introducing a methyl group into the 5-position of the cytosine ring at the same position in a newly created DNA strand, and it is DNMTs that enables this "DNA methylation replication". . Therefore, in cancerous cells, many of the tumor suppressor genes are transcribed and repressed, become silencing, and proliferate easily.
- the SH group of the cysteine residue in the catalytically active center of DNMT attacks the cytosine ring 6-position in the DNA sequence to activate the cytosine ring 5-position.
- a reaction mechanism has been proposed that promotes methyl group transfer from the group donor S-adenosyl-L-methionine.
- 5-azacytidine product name: “Bidaza (registered trademark)”
- its 2′-deoxy form decitabine, product name: “Dacogen (registered trademark)”
- cytosine nucleosides in chemical structure (a structure in which the carbon atom at the 5-position of the cytosine ring is substituted with a nitrogen atom), and through a nucleic acid biosynthesis route, DNA is substituted for 2′-deoxycytidine.
- Drugs with such a mechanism of action can be used as a wide range of anticancer drugs, but any compound is easily hydrolyzed by the metabolic enzyme cytidine deaminase present in the blood or liver. Because of the demerit of chemical deamination, it remains in clinical use as a treatment for high-risk myelodysplastic syndromes and acute myeloid leukemia, and because of its chemical instability, It is the current situation that remains. Therefore, the emergence of orally administrable drugs that have high stability to cytidine deaminase and that can replace 5-azacytidine and its 2'-deoxy form is desired.
- Patent Documents 1 and 2 SGI-110 (guadecitabine) (Patent Documents 1 and 2) was found as a compound having high stability against the hydrolytic metabolic enzyme cytidine deaminase, and 5-aza-2′-deoxycytidine pro Although clinical development is progressing as a drug, since this compound has a dinucleotide structure, it is very polar, is not easily permeated through a membrane, and is unsuitable as an orally administered drug (Non-Patent Documents 15 to 16). .
- An object of the present invention is to create an orally administrable compound that has high stability against the hydrolytic metabolic enzyme cytidine deaminase and can be substituted for 5-azacytidine and its 2′-deoxy compound, and has a high risk. It is intended to be provided not only as a therapeutic agent for myelodysplastic syndromes and acute myeloid leukemia, but also as a novel therapeutic agent or preventive agent for ATL. In addition, the onset of ATL is an intercellular adhesion molecule ICAM-1 (Int. J. Cancer, 1995, 60 (4), 554-561.), Plays an important role in tumor progression, immune regulation and signal transduction, CD26 / DPPIV (Int. J.
- 5-azacytidine product name: “Bidaza®”
- Dacogen registered trademark
- the prophylactic / therapeutic agent of ATL containing the compound or its salt represented by this [2] Prevention of ATL containing the compound or salt thereof according to [1], wherein R 1 is a silyl group represented by the formula (II), and R 2 and R or R 3 are hydrogen atoms. Therapeutic agent. [3] Prevention of ATL containing the compound according to [1] or a salt thereof, wherein R 2 is a silyl group represented by the formula (II), and R 1 and R or R 3 are hydrogen atoms. Therapeutic agent. [4] Prevention of ATL containing the compound or salt thereof according to [1], wherein R 1 and R 2 are each a silyl group represented by the formula (II), and R or R 3 is a hydrogen atom ⁇ Therapeutic agent.
- R 4 , R 5 and R 6 are each a C 1 -C 8 alkyl group, C 6 -C 10 aryl group or C 7 -C 14 arylalkyl group which may have a substituent, [1 ] The preventive / therapeutic agent for ATL as described in the above. [8] The prophylactic / therapeutic agent for ATL according to [7], wherein the C 6 -C 10 aryl group is a phenyl group or a naphthyl group.
- a method for preventing or treating ATL comprising administering an effective amount of a compound represented by the formula: [11]
- Formula (I) for producing a pharmaceutical composition for the prevention or treatment of ATL (Wherein R is an OR 3 group or a hydrogen atom, and R 1 , R 2 and R 3 are each a hydrogen atom or formula (II): (Wherein R 4 , R 5 and R 6 are each an alkyl group, an aryl group or an arylalkyl group which may have a substituent). However, the case where R 1 , R 2 and R 3 are simultaneously hydrogen atoms is excluded. ) Or a salt thereof.
- 5-azacytidine or its 2′-deoxy saccharide ether silyl ether derivative is more lipophilic than the corresponding 5-azacytidine or its 2′-deoxy isomer, and thus can be administered orally.
- it After being absorbed in the intestine, it is activated by non-enzymatic hydrolysis in the cell membrane of ATL cells or in cells without being affected by the hydrolytic metabolic enzyme cytidine deaminase in the blood or liver. Since it is presumed to exhibit DNMT inhibitory activity when incorporated into DNA via a nucleic acid biosynthetic route, it can be expected to function as a therapeutic or prophylactic agent for ATL whose expression is induced by DNMT.
- the compound of the present invention is a compound represented by the following formula (I).
- R is an OR 3 group or a hydrogen atom
- R 1 , R 2 and R 3 are each a hydrogen atom or formula (II):
- R 4 , R 5 and R 6 are each an alkyl group, an aryl group or an arylalkyl group which may have a substituent.
- R 1 , R 2 and R 3 are simultaneously hydrogen atoms is excluded.
- alkyl group means a saturated aliphatic hydrocarbon group, for example, a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms, for example, a methyl group, an ethyl group, and the like, unless otherwise specified.
- C 1 -C 6 alkyl groups such as propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, 2-methylhexyl group, 5-methyl Hexyl group, 2,2-dimethylpentyl group, 4,4-dimethylpentyl group, 2-ethylpentyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,3,3 -Trimethylbutyl group, 2,2,3-trimethylbutyl group, 2,3,3-trimethylbutyl group, 1-propylbutyl group, 1,1,2,2-tetramethylpropyl group, octyl group 2-methylheptyl group, 3-methylheptyl group, 6-methylheptyl group, 2-ethylhexyl group, 5,5-dimethylhexyl group,
- Preferred examples of the C 1 -C 6 alkyl group are a methyl group, an ethyl group and a propyl group.
- Preferred examples of the cyclic alkyl group are a cyclopentyl group and a cyclohexyl group.
- Aryl refers to a monocyclic or bicyclic aromatic hydrocarbon, preferably a C 6-10 aryl group such as a phenyl group or a naphthyl group, and more preferably a phenyl group.
- Arylalkyl refers to an alkyl group substituted by an aryl. Preferably, it is a C 7 to C 14 arylalkyl group. Examples of C 7 -C 14 arylalkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like.
- Alkyl group which may have a substituent, aryl group which may have a substituent or arylalkyl group which may have a substituent may have a substituent, It may be unsubstituted. When substituted, the substituent may have 1 to 5, preferably 1 to 3 substituents at the substitutable position of the alkyl group, aryl group or arylalkyl group, and the number of substituents is 2 or more. In some cases, each substituent may be the same or different. Examples of the substituent include an alkyl group, a halogen atom, a cyano group, and a nitro group. Preferred examples of the substituent are an alkyl group and a halogen.
- Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., and preferred examples are a fluorine atom and a chlorine atom.
- the salt of the compound represented by the formula (I) of the present invention may be any salt as long as it is a pharmacologically acceptable salt.
- the salt include inorganic acid salts (for example, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (for example, acetate, trifluoroacetate, succinate, And acid addition salts such as maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc. It is not limited to.
- the compound represented by the formula (I) of the present invention may be a crystal, a single crystal form, or a mixture of a plurality of crystal forms.
- the crystal can be produced by crystallization by applying a crystallization method known per se.
- the compound represented by the formula (I) of the present invention may be a solvate (for example, hydrate etc.), either a solvate or a non-solvate (eg non-hydrate etc.).
- a solvate for example, hydrate etc.
- a non-solvate eg non-hydrate etc.
- the 5-azacytidine and its 2'-deoxy sugar moiety silyl ether derivative of the present invention can be a prodrug of 5-azacytidine and its 2'-deoxy form.
- 5-azacytidine and its 2′-deoxy sugar moiety silyl ether derivative according to the present invention are expressed by DNMT. It can be a therapeutic or prophylactic agent for induced ATL.
- the desired 5-azacytidine sugar moiety silyl ether derivative (see formula (I)) can be easily obtained by reacting with the above.
- Examples of the dehydrohalogenating agent used include organic bases and inorganic bases.
- Examples of organic bases include, but are not limited to, imidazole, 1-methylimidazole, triethylamine, N, N -Diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), n-butyllithium, potassium-tert-butoxide, etc.
- inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, carbonate Sodium hydrogen, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc. are mentioned.
- As the usage-amount of a base the equivalent of a raw material compound or more is preferable.
- a range of 1.0 to 50.0 equivalents can usually be exemplified with respect to 1 mol of the raw material compound, but a range of 1.0 to 10.0 equivalents is preferable, and 1.0 to 5.0.0 is more preferable.
- the range is preferably 0 equivalent.
- the reaction of the present invention is preferably carried out in the presence of a solvent.
- the solvent in the reaction of the present invention may be any solvent as long as the reaction proceeds. Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide.
- the amount of solvent used may be any amount as long as the reaction proceeds. The amount of solvent used in the reaction of the present invention can be appropriately adjusted by those skilled in the art.
- reaction temperature The reaction temperature of the present invention is not particularly limited.
- ⁇ 20 ° C. to 50 ° C. ie, minus 20 ° C. to plus 50 ° C.
- ⁇ 10 ° C. to 30 ° C. Ie, minus 10 ° C. to plus 30 ° C.
- more preferably ⁇ 10 ° C. to 20 ° C. ie minus 10 ° C. to plus 20 ° C.
- 15 ° C. particularly preferably in the range of ⁇ 5 ° C. to 10 ° C. (that is, minus 5 ° C. to plus 10 ° C.).
- reaction time The reaction time of the present invention is not particularly limited. In one embodiment, from the viewpoint of improvement in yield, suppression of by-products and economic efficiency, etc., 0.5 hours to 120 hours, preferably 1 hour to 72 hours, more preferably 1 hour to 48 hours, A range of 1 hour to 24 hours is preferable. However, the reaction time of the present invention can be appropriately adjusted by those skilled in the art.
- composition of the present invention can be used as a pharmaceutical composition by mixing it with a pharmacologically acceptable carrier as it is or by a method known per se. , Humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.).
- the pharmacologically acceptable carrier various organic or inorganic carrier substances conventionally used as a pharmaceutical material are used, and examples thereof include excipients, lubricants, binders and disintegrants in solid preparations. Examples thereof include solvents, solubilizers, suspending agents, tonicity agents and buffering agents in liquid preparations. Moreover, formulation additives such as preservatives, antioxidants, colorants and sweeteners can be used as necessary.
- Examples of the dosage form of the pharmaceutical composition include tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions, or sustained-release oral preparations. These can be safely administered orally. However, this is not the case because liquid administration is possible.
- the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
- the compounds of formula (I) of the present invention have many therapeutic and prophylactic uses.
- the compounds of the invention are used in the treatment of a wide variety of diseases sensitive to treatment with cytidines (eg, 5-azacytidine and 5-aza-2′-deoxycytidine).
- Preferred indications that can be treated using the compounds of the present invention include those with undesirable or uncontrolled cell division.
- Such indications include various cancers, but more preferably ATLs whose expression is induced by DNMT.
- Suitable pharmaceutical compositions for use in the present invention include compositions in which the active ingredient is present in an effective amount, ie, in an amount effective to achieve a therapeutic and / or prophylactic purpose in the condition being treated. Is included.
- the pharmaceutical composition used in the present invention is provided as a dosage form for oral administration.
- the pharmaceutical compositions provided herein can be provided in solid, semi-solid or liquid dosage forms for oral administration.
- oral administration also includes buccal, lingual and sublingual administration.
- Suitable oral dosage forms include tablets, capsules, pills, troches, medicinal candy, aroma preparations, cachets, pellets, drug-added chewing gum, granules, bulk powders, foamed formulations or non-foamed powders or granules , Solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups.
- the pharmaceutical composition comprises binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, pigment migration inhibitors, sweeteners and flavoring agents, One or more pharmaceutically acceptable carriers or excipients that are not limited thereto may be included.
- the amount of the compound of formula (I) of the present invention in the pharmaceutical composition or dosage form is, for example, from about 1 mg to about 2,000 mg, from about 10 mg to about 2,000 mg, from about 20 mg to about 2,000 mg, from about 50 mg to about 1,000. mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, or about 150 mg to about 250 mg may be in the range.
- the effective dose is determined according to the nature of the cancer, the degree of progression of the cancer, the treatment policy, the degree of metastasis, the amount of the tumor, the body weight, age, sex, and the patient's (although it can be appropriately selected depending on genetic or racial background, the pharmaceutically effective amount is generally determined based on factors such as clinically observed symptoms and the degree of progression of cancer.
- the daily dose is, for example, about 0.01 mg / kg to about 10 mg / kg (about 0.5 mg to about 500 mg for a 60 kg adult) when administered to a human, preferably about 0.05 mg / kg to About 5 mg / kg, more preferably about 0.1 mg / kg to about 2 mg / kg. Administration may be performed once or divided into multiple times.
- the stability of the thus obtained 5-azacytidine saccharide ether silyl ether derivative (see formula (I)) in the presence of cytidine deaminase was found to have the saccharide silyl ether group according to the present invention.
- the 5-azacytidine sugar moiety silyl ether derivative (formula (I) having high stability to the above hydrolytic metabolic enzyme and having appropriate hydrolysis reactivity under physiological conditions.
- the 5-azacytidine sugar moiety silyl ether derivative according to the present invention was very stable against cytidine deaminase.
- 5-azacytidine and 5-aza-2'-deoxycytidine disappeared completely under the reaction conditions described above.
- Non-enzymatic hydrolysis of 5-azacytidine sugar moiety silyl ether derivatives for example, 5'-O- (Triethylsilyl) -5-azacytidine (compound J )
- 5'-O- (Triethylsilyl) -5-azacytidine compound J
- the formation of 5-azacytidine in formula (I), R 1 , R 2 and R 3 are hydrogen atoms
- ATL cell lines (HTLV-1-infected cell lines) in the table below were cultured in a culture solution (RPMI-1640 containing 10% FBS and 1% Penn-Strep (* ATN- 1 strain is further seeded with 1% NEAA, and the ILT-Mat strain is further seeded into a 96-well plate at 3,000-7,000 cells / 50 ml / well in 50 ng / ml h IL-2). Incubate for about 3 hours at 37 ° C in a carbon dioxide stream.
- ATL cell line (HTLV-1 infected cell line): ATN-1, ILT-Mat, TL-Mor strains are purchased from RIKEN BioResource Center (RIKEN BRC), MJ strains are purchased from American Type Culture Collection (ATCC), MT- 2, MT-4 strain was purchased from JCRB cell bank. From the results of Table 3, it was found that the sugar moiety silyl ether derivative of 5-aza-2′-deoxycytidine has very high anti-ATL activity.
- the DNMT inhibitor which has high stability with respect to the metabolic enzyme cytidine deaminase can be provided to a medical field as a novel ATL therapeutic agent or a preventive agent.
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Abstract
Le problème décrit par la présente invention est de fournir, en tant qu'agent thérapeutique ou prophylactique pour ATL, un composé qui remplace les injections (« Vidaza » (marque déposée) ou « Dacogen » (marque déposée)) cliniquement utilisées en tant qu'agent thérapeutique pour des syndromes myélodysplasiques à haut risque ou une leucémie myéloïde aiguë, présente une stabilité élevée contre la cytidine désaminase, une hydrolase métabolique, est absorbé dans l'organisme même par administration orale, et a pour effet d'inhiber l'ADN méthyltransférase (DNMT) en étant incorporé dans une voie de biosynthèse d'acide nucléique. La solution selon l'invention porte sur un agent prophylactique/thérapeutique pour ATL, l'agent contenant un composé représenté par la formule (I) ou un sel de celui-ci (dans la formule, R est un groupe OR3 ou un atome d'hydrogène, R1, R2 et R3 représentent chacun un atome d'hydrogène ou un groupe silyle représenté par la formule (II) (dans la formule, R4, R5 et R6 représentent chacun un groupe alkyle, un groupe aryle ou un groupe arylalkyle qui peut comporter un substituant) ; cependant, le cas où R1, R2 et R3 sont tous un atome d'hydrogène est exclu).
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WO2020090698A1 (fr) * | 2018-10-30 | 2020-05-07 | 大原薬品工業株式会社 | Composition pharmaceutique |
JPWO2021060341A1 (fr) * | 2019-09-26 | 2021-04-01 |
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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 |
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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 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2020090698A1 (fr) * | 2018-10-30 | 2020-05-07 | 大原薬品工業株式会社 | Composition pharmaceutique |
JPWO2021060341A1 (fr) * | 2019-09-26 | 2021-04-01 | ||
WO2021060341A1 (fr) * | 2019-09-26 | 2021-04-01 | 大原薬品工業株式会社 | Utilisation d'un inhibiteur de dnmt |
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