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WO2020090698A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2020090698A1
WO2020090698A1 PCT/JP2019/042080 JP2019042080W WO2020090698A1 WO 2020090698 A1 WO2020090698 A1 WO 2020090698A1 JP 2019042080 W JP2019042080 W JP 2019042080W WO 2020090698 A1 WO2020090698 A1 WO 2020090698A1
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Prior art keywords
pharmaceutical composition
composition according
group
cancer
formula
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PCT/JP2019/042080
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English (en)
Japanese (ja)
Inventor
孫市 酒向
晋平 杉山
祐樹 倉橋
弘臣 脇田
晋也 木村
達郎 渡邉
博志 嬉野
Original Assignee
大原薬品工業株式会社
国立大学法人佐賀大学
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Application filed by 大原薬品工業株式会社, 国立大学法人佐賀大学 filed Critical 大原薬品工業株式会社
Priority to JP2020553868A priority Critical patent/JP7228169B2/ja
Priority to CN201980057284.9A priority patent/CN112638422B/zh
Publication of WO2020090698A1 publication Critical patent/WO2020090698A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • 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
    • A61K31/7064—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 containing condensed or non-condensed pyrimidines
    • A61K31/7068—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 containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—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 containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K31/7064—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 containing condensed or non-condensed pyrimidines
    • A61K31/7076—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 containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a preventive or therapeutic drug for cancer.
  • Blood cancer refers to a type of cancer that attacks the blood, bone marrow, and / or lymphatic system. This type of cancer includes leukemia and multiple myeloma, all of which can be deadly diseases that require new, more effective treatments.
  • ATL (Adult T-cell Leukemia / Lymphoma: Adult T-cell leukemia / lymphoma) is a disease discovered and named by Takatsuki et al. (Non-patent Documents 1 and 2) in 1976, and the oncogenic virus HTLV-1.
  • Human T-cell Leukemia / Lymphotropic Virus type-1 is a leukemia or malignant lymphoma caused by infection.
  • the number of HTLV-1 infected people is high in the southern part of Japan (particularly Kyushu and Okinawa), and is localized in the Caribbean coastal countries, Central Africa and South America.
  • HTLV-1 infection The routes of HTLV-1 infection include breastfeeding, sexual intercourse, blood transfusion, etc., and the carriers are said to be 5 to 10 million worldwide (about 1.1 million in Japan). Six to seven percent of them, and two to three percent of women, develop ATL each year. Note that the period from HTLV-1 infection to the onset of ATL 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, but recurrence or drug resistance In many cases, standard treatment methods have not yet been established.
  • Non-Patent Document 9 a new chemokine receptor CCR4 antibody drug, Mogamulizumab (product name: poteridio) (non-patent document 7), an antiviral drug, abacavir (non-patent document 8), histone deacetylase as a new therapeutic agent for ATL (HDAC) inhibitor Vorinostat (product name: Zolinza) (Non-Patent Document 9) and the possibility of dual inhibitor DS-3201b of histone methyltransferase EZH1 / 2 have attracted attention.
  • HDAC histone deacetylase
  • Vorinostat product name: Zolinza
  • DNMTs is an abbreviation for DNA methyltransferases (DNA methyltransferases), and methylates the amino group at the 6-position of the adenine ring in a DNA chain (Adenine N 6 -specific DNA-methyltransferase: EC 2.1.1.72), cytosine ring Enzyme that catalyzes methylation of 4-amino group (Cytosine N 4 -specific DNA-methyltransferase: EC 2.1.1.113) or methylation at the 5-position of cytosine ring (Cytosine C 5 -specific DNA-methyltransferase: EC 2.1.1.37) It is a group.
  • Non-Patent Documents 10 to 11 a group of enzymes that catalyze methylation to the 5th position of the cytosine ring in a sequence portion called CpG island, which is often found in the promoter region of expressed genes (maintenance methyltransferase DNMT1 and de novo methyltransferase DNMT3 family) Plays an extremely important role in regulating the normal development and differentiation of cells (Non-Patent Documents 10 to 11).
  • DNMTs are closely related to cancer development. That is, it is considered that 60 to 90% of all CpGs are methylated at the 5-position of the cytosine ring, but abnormal levels of DNA methylation are closely related to the regulation of gene expression, and the promoter region ( It has been clarified that the transcription / expression of a gene in which the CpG island) is methylated at the 5-position of the cytosine ring at a high level is silenced (Non-patent Documents 12 to 14).
  • the cell is equipped with a mechanism to introduce a methyl group into the 5-position of the cytosine ring at the same position as the parent chain in the newly created DNA chain, which enables this "replication of DNA methylation".
  • DNMTs DNMTs. Therefore, in cancerous cells, most of the tumor suppressor genes are suppressed in transcription / expression, and become in a silencing state, and are in a state in which they easily proliferate.
  • the SH group of the cysteine residue in the catalytically active center of DNMT attacks the 6-position of the cytosine ring in the DNA sequence to activate the 5-position of the cytosine ring, resulting in methylation.
  • a reaction mechanism has been proposed which promotes methyl group transfer from the group donor S-adenosyl-L-methionine.
  • 5-azacytidine product name: "Vidaza (registered trademark)”
  • its 2'-deoxy form decitabine, product name: "Dakogen (registered trademark)”
  • the chemical structure of these drugs is very similar to that of cytosine nucleosides (structure in which the carbon atom at the 5-position of the cytosine ring is replaced by a nitrogen atom), and the drug undergoes a nucleic acid biosynthetic route to produce DNA instead of 2'-deoxycytidine.
  • DNMTs suicide-mediated methylation reaction of cytosine ring position 5 is suicidally inhibited, and normal expression of the tumor suppressor gene is enabled to exert therapeutic effect. It is said to be forgotten.
  • An object of the present invention is to provide a novel preventive or therapeutic drug for cancer (especially blood cancer). ..
  • the present inventors have conducted intensive research to find out an excellent prophylactic or therapeutic drug for blood cancer, and as a result, a pharmaceutical composition comprising a DNMT inhibitor (particularly compound (I)) and another drug in combination. It was found that the product is useful for the prevention or treatment of blood cancer.
  • the present invention has been completed based on these findings.
  • a pharmaceutical composition comprising a DNMT inhibitor in combination with other agents.
  • a pharmaceutical composition comprising another drug for use in combination with a DNMT inhibitor.
  • a pharmaceutical composition comprising a DNMT inhibitor and other agents.
  • the DNMT inhibitor has the formula (I): (In the formula, R and R ′ are each an OR 3 group, a hydrogen atom, a halogen atom or an alkyl group, and R 1 , R 2 and R 3 are each a hydrogen atom or a formula (II): (In the formula, 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 4 , R 5 and R 6 are each a C 1 -C 8 alkyl group which may have a substituent, a C 6 -C 10 aryl group or a C 7 -C 14 arylalkyl group which may have a substituent.
  • the pharmaceutical composition of description [12] The pharmaceutical composition according to [11], wherein the C 6 -C 10 aryl group is a phenyl group or a naphthyl group.
  • the C 7 -C 14 arylalkyl group is a benzyl group, a phenethyl group or a naphthylmethyl group.
  • the enzyme inhibitor is selected from the group consisting of histone acetylase inhibitors, histone deacetylase inhibitors, histone methylase inhibitors, histone demethylase inhibitors and ribonucleoside diphosphate reductase inhibitors
  • the pharmaceutical composition according to [14] which is one or more kinds.
  • the enzyme inhibitor is one or more selected from the group consisting of DS-3201b, HBI-8000, trichostatin A (TSA), suramin, EPZ005687 and Adox. ..
  • [17] The pharmaceutical composition according to any one of [1] to [16], further comprising a pharmaceutically acceptable carrier.
  • a preventive or therapeutic drug for cancer which comprises the pharmaceutical composition according to any one of [1] to [21].
  • the preventive or therapeutic drug for cancer according to [26] wherein leukemia is ATL.
  • a kit for preventing or treating cancer which comprises the DNMT inhibitor described in any one of [1] to [22] and another drug.
  • a method for preventing or treating cancer in a mammal which comprises administering an effective amount of a DNMT inhibitor and an effective amount of another drug to the mammal.
  • the pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for leukemia such as ATL whose expression is caused by DNMT.
  • the “DNA methyltransferase inhibitor” of the present invention is not particularly limited, but for example, the following formula (I): (In the formula, R and R ′ are each an OR 3 group, a hydrogen atom, a halogen atom or an alkyl group, and R 1 , R 2 and R 3 are each a hydrogen atom or a formula (II): (In the formula, 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 and R ′ in the formula (I) are preferably an OR 3 group, a hydrogen atom or a halogen atom.
  • R is an OR3 group, a hydrogen atom, a halogen atom or an alkyl group, and R'is a hydrogen atom.
  • R is an OR3 group or a hydrogen atom, and R'is a hydrogen atom.
  • R is a fluorine atom and R'is a fluorine atom.
  • alkyl group refers to a saturated aliphatic hydrocarbon group, for example, a linear or branched or cyclic alkyl group having 1 to 8 carbon atoms, unless otherwise specified, and examples thereof include a methyl group and an ethyl group.
  • C 1 -C 6 alkyl groups are methyl, ethyl and propyl groups.
  • 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 with aryl. Preferred is a C 7 -C 14 arylalkyl group. Examples of C 7 -C 14 arylalkyl groups include, but are not limited to, benzyl group, phenethyl group, naphthylmethyl group, and the like.
  • alkyl group which may have a substituent, an aryl group which may have a substituent or an arylalkyl group which may have a substituent may or may not have a substituent. Means that it may be a substitution. When it is substituted, the substituent may have 1 to 5, preferably 1 to 3 at the substitutable position of the alkyl group, aryl group or arylalkyl group, and the number of substituents is 2 or more. In this case, each substituent may be the same or different. Examples of the substituent include an alkyl group, a halogen atom, a cyano group, a nitro group, and the like, and an example of a preferable substituent is an alkyl group or a halogen.
  • Halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and preferable examples are a fluorine atom and a chlorine atom.
  • the salt of the compound represented by 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 (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate, Acid addition salts such as maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc., and the like. 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 applying a crystallization method known per se to crystallize.
  • the compound represented by the formula (I) of the present invention may be a solvate (for example, a hydrate), and a solvate and a non-solvate (for example, a non-hydrate). All of the above are included in the compound represented by the formula (I).
  • agents of the present invention include enzyme inhibitors, preferably histone deacetylase inhibitors, histone acetylase inhibitors, histone methylase inhibitors, histone demethylation.
  • enzyme inhibitors preferably histone deacetylase inhibitors, histone acetylase inhibitors, histone methylase inhibitors, histone demethylation.
  • One or more enzyme inhibitors selected from the group consisting of enzyme inhibitors and ribonucleoside diphosphate reductase inhibitors.
  • the “histone acetylase inhibitor” is not particularly limited, but examples thereof include C646, MG149, Remodelin, and Anacardic Acid.
  • histone deacetylase inhibitor is not particularly limited, and examples thereof include vorinostat (SAHA, MK0683), entinostat (MS-275), panobinostat (LBH589), trichostatin A (TSA), mosetinostat (MGCD0103).
  • AZD-9468 CG200745
  • arginine butyrate arginine butyrate
  • sulforaphane SHP-141
  • CUDC-907 YM753
  • OBP-801 sodium valproate
  • Pishijin and CI994 Tacedinaline
  • histone methyltransferase inhibitor is not particularly limited, but examples thereof include DS-3201b, EPZ-6438, GSK-126, Chaetocin, and IX01294.
  • the “histone demethylase inhibitor” is not particularly limited, and examples thereof include GSKJ4HCl, OG-L002, JIB-04, IOX1, SP2509, ORY-1001 (RG-6016), GSKJ1, ML324, GSK. -LSD1 and 2HCl and the like.
  • ribonucleoside diphosphate reductase inhibitor is not particularly limited, and examples thereof include gemcitabine, ara C, fludarabine and the like.
  • the other drug is particularly preferably one or more selected from the group consisting of DS-3201b, HBI-8000, trichostatin A (TSA), suramin, EPZ005687 and Adox.
  • TSA trichostatin A
  • the pharmaceutical composition can be produced by a method conventionally used in the field of pharmaceutical preparation, such as the method described in the Japanese Pharmacopoeia.
  • the dosage form for oral administration of the pharmaceutical preparation of the present invention includes solid preparations such as tablets, capsules, granules and powders.
  • examples of the dosage form for parenteral administration such as intravenous, subcutaneous and intramuscular include injections, suppositories, sublingual tablets and the like.
  • the dosage form for sublingual, subcutaneous or intramuscular administration includes, for example, sustained-release preparations such as sublingual tablets and microcapsules.
  • the pharmaceutically acceptable carrier for example, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrating agent, a thickener in a solid formulation; a liquid formulation
  • an excipient a lubricant, a binder, a disintegrating agent, a thickener in a solid formulation
  • a liquid formulation The solvent, the dispersant, the solubilizing agent, the suspending agent, the isotonicity agent, the buffering agent, the soothing agent, etc. are appropriately mixed in appropriate amounts.
  • additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used according to a conventional method.
  • excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like.
  • disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • Preferable examples of the thickener include natural gums, cellulose derivatives, acrylic acid polymers and the like.
  • Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • Preferable examples of the dispersant include Tween 80, HCO 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate and the like.
  • Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like.
  • surfactant examples include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
  • tonicity agent examples include sodium chloride, glycerin, D-mannitol and the like.
  • Preferable examples of the buffer include phosphate, acetate, carbonate, citrate and the like.
  • Preferable examples of soothing agents include benzyl alcohol and the like.
  • Preferable preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferable examples of the antioxidant include sulfite, ascorbic acid and the like.
  • the pharmaceutical composition of the present invention is used for preventing or treating cancer. Cancers of the head and neck, breast cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, astrocytoma, glioblastoma multiforme , Banayan-Zonana syndrome, Cowden disease, Lermitt-Dachros disease, inflammatory breast cancer, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, kidney cancer, liver cancer, melanoma, pancreatic cancer , Sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, ATL (Adult T-cell Leukemia / Lymphoma), chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy Cell leukemia, acute lymphoblastic leukemia, acute myelog
  • the timing of administration of the preventive or therapeutic agent for ATL and the other drug is not limited, and both of the other drugs are simultaneously administered to the administration subject.
  • the doses may be administered at staggered times.
  • the preventive or therapeutic drug for ATL and the other drug may be separately formulated, or a mixture of the two may be mixed.
  • the dose of the other drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the dose of the other drug may be, for example, 1/3 to 3 times the dose when the other drug is used as a single agent.
  • the administration form of the preventive or therapeutic agent for ATL of the present invention and the other drug is not particularly limited, and the preventive or therapeutic agent for ATL and the other drug may be combined at the time of administration.
  • Examples of such a dosage form include (1) administration of a single preparation obtained by simultaneously formulating a prophylactic or therapeutic drug for ATL and another drug, (2) prophylactic or therapeutic drug for ATL and other Simultaneous administration of two preparations obtained by separately formulating a drug with the same administration route, (3) Preparation of two preparations obtained by separately preparing a prophylactic or therapeutic drug for ATL and another drug (4) Simultaneous administration of two kinds of preparations obtained by separately formulating a prophylactic or therapeutic drug for ATL and another drug by different administration routes, (5) Administration of two kinds of preparations obtained by separately formulating a prophylactic or therapeutic drug for ATL and another drug with different administration routes (for example, prophylactic or therapeutic drug for ATL ⁇ other drugs in this order Administration, or administration in the reverse order) and the like.
  • the preventive or therapeutic agent for ATL of the present invention By combining the preventive or therapeutic agent for ATL of the present invention with another drug, the following excellent effects can be obtained.
  • the dose can be reduced as compared with the case where the preventive or therapeutic drug for ATL and another drug are administered alone, (2) Other drug types can be selected according to the patient's symptoms (mild, severe, etc.), (3)
  • the treatment period can be set longer by selecting another drug having a different mechanism of action from the preventive or therapeutic drug for ATL.
  • the therapeutic effect can be sustained by selecting another drug having a different mechanism of action from the preventive or therapeutic drug for ATL.
  • a synergistic effect can be obtained by using a prophylactic or therapeutic drug for ATL in combination with another drug.
  • a DNMT inhibitor for example, compound (I)
  • a DNMT inhibitor for example, compound (I)
  • the content ratio of the DNMT inhibitor (for example, compound (I)) in the pharmaceutical preparation is usually 0.1 to 100% (w / w).
  • the content ratio of the DNMT inhibitor for example, compound (I)
  • the content ratio of the DNMT inhibitor is usually 0.1 to 99.9% (w / w).
  • the amount of the DNMT inhibitor of the present invention (eg, compound (I)) and the other drug in the pharmaceutical composition or dosage form is, for example, about 1 mg to about 2,000 mg, about 10 mg to about 2,000 mg, about 20 mg. It may range from mg to about 2,000 mg, 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.
  • the cell growth inhibitory effect when the ATL cell line (HTLV-1 infected cell line) was treated with decitabine and EPZ-6438 was evaluated.
  • ATL cell line HTLV-1 infected cell line
  • MT-1 strain and MT-2 strain were purchased from JCRB cell bank and used. Seed each cell into a 24-well plate at 40,000 cells / 1 ml / well in culture medium (RPMI-1640 containing 10% FBS and 1% Penn-Strep), and culture at 37 ° C, 5% CO 2 for approx. 2 Incubated for hours.
  • For MT-1 adjust the concentration of decitabine to 0.1, 0.2, 0.5, 1 ⁇ M and the concentration of EPZ-6438 to 0.5, 1, 2.5, 5 ⁇ M with the culture medium, and then use a 24-well plate.
  • the MT-1 strain and MT-2 strain which are ATL cell lines (HTLV-1 infected cell line), were purchased from JCRB cell bank. Seed each cell in a culture medium (RPMI-1640 containing 10% FBS and 1% Penn-Strep) at 0.5 x 10 5 cells / 0.9 ml / well on a 24-well plate and incubate at 37 ° C, 5% CO 2 Incubated for about 3 hours.
  • OR-21 single agent, DS-3201b single agent, and OR-21 / DS-3201b mixed solution which were diluted with the culture solution to 5 ⁇ M -1.6 ⁇ M, were added to a 24-well plate by 100 ⁇ l and cultured for 8 days ( Compound final concentration 500-16 nM).
  • OR-21 is a compound in which R, R ′ and R 2 are hydrogen atoms in the formula (I) and R 1 is a triethylsilyl group, and the name of OR-21 is 5′-O-Triethylsilyl-2. It is'-deoxy-5-azacytidine.
  • the morphological changes were observed with a phase contrast microscope 4 days after the compound treatment. The result is shown in FIG. From FIG. 1, the combined treatment of OR-21 (DNMT inhibitor) and DS-3201b (histone methyltransferase inhibitor) for 6 days synergistically suppresses MT-1 cell proliferation (IC 50 ; OR-21. : 58 nM, DS-3201b:> 500 nM, combined treatment: 36 nM).
  • a DNMT inhibitor can be combined with another drug and provided to the medical field as a preventive or therapeutic drug for cancer.

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Abstract

L'invention concerne, en tant que médicament prophylactique contre le cancer ou médicament thérapeutique contre le cancer, un composé possédant l'effet d'inhiber l'ADN méthyltransférase (DNMT), ainsi qu'un autre médicament.
PCT/JP2019/042080 2018-10-30 2019-10-28 Composition pharmaceutique WO2020090698A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
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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
WO2019160127A1 (fr) * 2018-02-19 2019-08-22 大原薬品工業株式会社 Utilisation d'un inhibiteur de dnmt

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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
WO2019160127A1 (fr) * 2018-02-19 2019-08-22 大原薬品工業株式会社 Utilisation d'un inhibiteur de dnmt

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