WO2019146129A1 - Pharmaceutical composition for tumor having isocitrate dehydrogenase mutation, antitumor agent and use thereof - Google Patents
Pharmaceutical composition for tumor having isocitrate dehydrogenase mutation, antitumor agent and use thereof Download PDFInfo
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- WO2019146129A1 WO2019146129A1 PCT/JP2018/007771 JP2018007771W WO2019146129A1 WO 2019146129 A1 WO2019146129 A1 WO 2019146129A1 JP 2018007771 W JP2018007771 W JP 2018007771W WO 2019146129 A1 WO2019146129 A1 WO 2019146129A1
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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
- A61K31/33—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
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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
- A61K31/70—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
Definitions
- the present invention relates to a pharmaceutical composition for a tumor having an isocitrate dehydrogenase mutation, and an antitumor agent.
- Compound A (2-Deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known that it is useful as an antitumor agent (patent document 1). Compound A is also known to have strong antitumor activity even when orally administered to mice (Non-patent Documents 1 to 3). In addition, salts, prodrugs, injections and methods of production of Compound A are also known (Patent Documents 2 to 6).
- Isocitrate dehydrogenase is an intermediate of the citric acid cycle (TCA cycle) with NADP + as a coenzyme to isocitric acid which is an intermediate of 2-oxoglutaric acid ( ⁇ -ketoglutarate, ⁇ -ketoglutarate, ⁇ KG)
- TCA cycle citric acid cycle
- NADP + NADP + as a coenzyme to isocitric acid which is an intermediate of 2-oxoglutaric acid ( ⁇ -ketoglutarate, ⁇ -ketoglutarate, ⁇ KG)
- An enzyme that catalyzes the conversion of IDH1 is localized in the cytoplasm and IDH2 in the mitochondria, and it is known that mutations are observed in these two genes.
- IDH mutations are gene mutations found in various malignancies such as acute myeloid leukemia, glioma, chondrosarcoma and cholangiocarcinoma.
- IDH mutations in the IDH gene encoding IDH form heterodimers with wild type, it is characterized by the presence of hot spots in the amino acids causing mutations, and the mutation sites are amino acids important for enzyme reaction It concentrates on the amino acid near or that (patent document 7).
- the mutation in which the 132nd arginine of the IDH1 protein (hereinafter referred to as R132) is substituted with another amino acid is the majority.
- a mutation in which arginine at position 132 is converted to histidine, or a cysteine (R132C), leucine (R132L), serine (R132S) glycine (R132G), valine (R132V), etc. It is known that there are many mutations. There are other known examples where mutations occur in G97, R100, H133, A134 and the like.
- the IDH2 gene mutation is mostly a mutation in which R140 or R172 is converted to another amino acid. For example, R140Q mutation, R172K, R172S mutation etc. are known.
- IDH mutations are gain-of-function mutations that produce the oncometabolite 2-hydroxyglutarate (2-hydroxyglutarate, 2HG) and competitively inhibit ⁇ KG to produce epigenetic changes. Are known to contribute to the malignant transformation of tumors (Non-patent Document 4).
- An object of the present invention is to provide a pharmaceutical composition and an antitumor agent which show an effect on a tumor having an IDH mutation, and a method for preventing or treating a tumor having an IDH mutation.
- the present invention provides the following. (1) including 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof A pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation. (2) The pharmaceutical composition according to (1), wherein the isocitrate dehydrogenase mutation is at least one gene mutation selected from isocitrate dehydrogenase 1 mutation or isocitrate dehydrogenase 2 mutation. (3) The pharmaceutical composition according to (1) or (2), which is used for a patient having an isocitrate dehydrogenase 1 mutation in a tumor.
- the isocitrate dehydrogenase 1 mutation is selected from histidine (R132H), cysteine (R132C), serine (R132S), glycine (R132G), leucine (R132L), valine (R132 ⁇ ) or glutamine (R132Q) from arginine at position 132
- the pharmaceutical composition according to (4) or (5), wherein the isocitrate dehydrogenase 1 mutation is substitution of arginine at position 132 with cysteine, serine, glycine or leucine.
- the tumor is a brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, liver cancer, Biliary cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid cancer (1
- the pharmaceutical composition according to (8), wherein the tumor is biliary cancer.
- An anti-titer for treating a tumor having an isocitrate dehydrogenase mutation which comprises 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof Tumor agent.
- (11) 1- (2-Deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof for producing a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation Or use of prodrugs.
- An isocitrate dehydrogenase mutation comprising administering an effective amount of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof to a subject
- Methods of treating a tumor having: (14) A method comprising administering to a subject an effective amount of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof, prior to the administration
- a method for treating a tumor having an isocitrate dehydrogenase mutation comprising the step of confirming the presence or absence of the isocitrate dehydrogenase mutation of interest.
- Compound A exerts a therapeutic effect on tumors having an isocitrate dehydrogenase (IDH) mutation. That is, according to the present invention, there are provided a pharmaceutical composition and an antitumor agent showing an effect on a tumor having an IDH mutation, and a method of treating a tumor having an IDH mutation.
- IDH isocitrate dehydrogenase
- FIG. 1 shows the results of diagnostic imaging for cholangiocarcinoma patient 1 with an IDH mutation.
- FIG. 2 shows the results of diagnostic imaging for cholangiocarcinoma patients 2 with IDH mutations.
- FIG. 3 is a graph showing the Cmax value of the plasma concentration of a patient who receives Compound A in a clinical test.
- the range represented by “to” includes the values at both ends, unless otherwise specified.
- a “subject” is a human, mouse, monkey, domestic animal or other mammal in need of the prevention or treatment, preferably a human in need of the prevention or treatment.
- prevention refers to inhibition of onset, reduction in risk of onset or delay in onset, and the like.
- Treatment refers to amelioration or suppression (maintenance or delay) of the disease or condition to be treated.
- Treatment refers to prevention or treatment for various diseases.
- tumor is meant a benign or malignant tumor.
- cancer tumor is meant a tumor that is close to the normal cells from which the tumor cells and their sequences are derived and is not invasive or metastatic.
- malignant tumor refers to a tumor which is invasive or metastatic, in which the morphology of the tumor cells and their sequences are different from those of the normal cells from which they are derived.
- the present invention treats tumors with IDH mutations, including 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (compound A) or a salt or prodrug thereof And a pharmaceutical composition.
- Salts include pharmaceutically acceptable salts, and in particular, mineral acid salts, organic carboxylates and sulfonates.
- Preferred salts include mineral and sulfonate salts.
- Mineral acid salts include, for example, hydrochlorides, hydrobromides, hydroiodides, nitrates, phosphates and sulfates, with hydrochlorides, hydroiodides, nitrates or sulfates being preferred.
- Hydrochloride is more preferred.
- organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and the like Trifluoroacetic acid salt is mentioned.
- sulfonate examples include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate and naphthalenesulfonate, with methanesulfonate being preferred.
- the salt of compound A may be an anhydride, a hydrate or a solvate. As referred to herein simply as “salts”, the form may be an anhydride, hydrate or solvate.
- the term “anhydride” as used herein refers to the case where it is in neither hydrate nor solvate state, unless otherwise stated. Water of crystallization, water of hydration, and a salt of Compound A having no interacting solvent, which are substances which do not form hydrates or solvates originally, are included in the “anhydride” in the present invention. .
- Anhydride is also referred to as "anhydrate.”
- the salt of compound A is a hydrate
- the number of hydration water is not particularly limited, and may be a monohydrate, a dihydrate or the like.
- solvates include methanolate, ethanolate, propanolate and 2-propanolate.
- Particular preferred salts of Compound A are: Methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine; Hydrochloride salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine; As well as the anhydride of any of the above mentioned salts.
- prodrug refers to a compound or a salt thereof in which a functional group functioning as a prodrug is cleaved by a reaction in the body with enzymes such as gastric juice after administration to be converted into a compound exhibiting a desired pharmacological activity.
- Groups forming a prodrug include, for example, groups described in Stella VJ et al., Prodrugs: Challenges and Rewards. Parts 1 and 2, 2007, American Association of Pharmaceutical Principles.
- the prodrug of Compound A refers to a compound or a salt thereof which is converted to Compound A or its phosphate compound by a reaction with an enzyme or gastric juice under physiological conditions in vivo.
- a prodrug of Compound A the description of WO 2016/068341 can be incorporated and referred to, and the contents thereof are incorporated herein. More specifically, for example, the thionucleoside derivative represented by the general formula [1] described in WO 2016/068341 or a salt thereof is incorporated in the present specification, and the preferred range thereof is also WO 2016 It is the same as that described in Japanese Patent Publication No. 06/06841.
- the compound A or a salt or prodrug thereof may be used alone or in combination of two or more.
- Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, vol. 64, p7912-7920.
- the salt of Compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4.
- the prodrug of compound A can be produced, for example, by the method described in WO 2016/068341.
- the compound A or a salt or prodrug thereof according to the present invention can be used as an antitumor agent and as an active ingredient of a pharmaceutical composition.
- composition for treating a tumor having an IDH mutation, comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof .
- a pharmaceutical composition is provided.
- the pharmaceutical composition of the present invention generally comprises an emulsifier, surfactant, solubilizer, suspending agent, tonicity agent, buffer, preservative, antioxidant, stabilizer, absorption enhancer and the like. It may contain an agent.
- the route of administration of the pharmaceutical composition of the present invention may be intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository Can be mentioned.
- Methods of administration include administration by syringe or infusion.
- the dose and number of doses of Compound A or a salt or prodrug thereof can be administered in 1 to 2000 mg / m 2 per day in divided doses.
- the daily dose is preferably 20 mg / m 2 or more, more preferably 40 mg / m 2 to 200 mg / m 2 , still more preferably 80 mg / m 2 to 150 mg / m 2 , and still more preferably Is 80 mg / m 2 to 120 mg / m 2 .
- one dose can be 20 mg / m 2 or more, and after one week administration for 3 weeks, the course of withdrawal can be repeated multiple times for the fourth week.
- the single dose is preferably 40 mg / m 2 to 200 mg / m 2 , more preferably 80 mg / m 2 to 150 mg / m 2 . It is preferable to confirm the presence or absence of the target isocitrate dehydrogenase mutation (the IDH mutation confirmation step) before the administration.
- Examples of dosage forms of the pharmaceutical composition of the present invention include liquid pharmaceutical preparations such as injections.
- the dosage forms can each be prepared by conventional formulation methods known to those skilled in the art.
- the liquid pharmaceutical preparation preferably contains compound A or a salt thereof, a polyhydric alcohol having a molecular weight of 100 or less, and water.
- the content of Compound A or a salt thereof is preferably 1 to 50 mg / mL, more preferably 5 to 50 mg / mL, and particularly preferably 10 to 30 mg / mL.
- the polyhydric alcohol having a molecular weight of 100 or less is preferably a polyhydric alcohol having 3 or 4 carbon atoms, more preferably glycerin, propylene glycol or butanediol, and particularly preferably glycerin.
- examples of butanediol include 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2,3-butanediol, and 1,3-butanediol is particularly preferable.
- the lower limit of the molecular weight of polyhydric alcohol is not particularly limited, it is generally 50 or more.
- the content of polyhydric alcohol having a molecular weight of 100 or less is preferably 0.5 to 10% by mass, more preferably 0.5 to 5% by mass, and more preferably 1.0 to 2.5. More preferably, it is mass%.
- the pH of the liquid pharmaceutical preparation is preferably 1.5 to 6.9, more preferably 1.5 to 6.5, still more preferably 2.0 to 6.5, Is more preferably from 0 to 5.0, still more preferably from 2.0 to 4.0, particularly preferably from 2.6 to 3.2, 2.8 to 3.0 Most preferably.
- the liquid pharmaceutical preparation the description of WO 2017/150511 can be incorporated and referred to, and the contents thereof are incorporated herein.
- the suitable composition of a liquid pharmaceutical preparation and a suitable compounding ratio are also the same as the thing as described in international publication 2017/150511.
- the pharmaceutical composition of the present invention is, for example, brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, Liver cancer, biliary tract cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid It can be effectively used to treat tumors with IDH mutations such as cancer.
- brain tumor including glioma
- acute myeloid leukemia myelodysplastic syndrome
- myeloproliferative tumor peripheral T cell lymphoma
- chondrosarcoma chondrosarcoma
- osteosarcoma thymoma
- Liver cancer biliary tract cancer
- the pharmaceutical composition of the present invention is particularly suitable for the treatment of tumors having an IDH mutation such as biliary cancer.
- Biliary cancer is preferably bile duct cancer, more preferably extrahepatic cholangiocarcinoma or intrahepatic cholangiocarcinoma.
- the isocitrate dehydrogenase mutation (IDH mutation) in the present invention includes, for example, mutations of arginine at position 132 of IDH1 (hereinafter referred to as R132), mutations of G97, mutations of R100, mutations of H133, and mutations of A134. These include, but are not limited to.
- R132 mutations of arginine at position 132 of IDH1
- R132C mutations of G97
- mutations of R100 mutations of H133, and mutations of A134.
- substitutions to valine (R132V) include, but are not limited to.
- the pharmaceutical composition of the present invention is suitable for the treatment of a tumor having at least one genetic mutation selected from IDH1 mutation or IDH2 mutation in IDH mutation, and more suitable for the treatment of a tumor having IDH1 mutation.
- the IDH1 mutation is a mutation at amino acid 132, that is, a mutation of arginine at position 132, and the substitution of arginine for cysteine at position 132 (R132C), substitution for serine (R132S), substitution for glycine (R132G) or It is suitable for the treatment of a tumor having a mutation for substitution to leucine (R132L), and more suitable for the treatment of a tumor having a mutation for substitution to cysteine (R132C) or serine (R132S).
- the present invention provides a method for administering an antitumor agent to a tumor patient having an isocitrate dehydrogenase mutation, wherein the antitumor agent is 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabino
- the antitumor agent is 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabino
- the present invention is an isocitrate comprising administering to a subject an effective dosage of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof.
- the present invention relates to the use of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of a tumor having an isocitrate dehydrogenase mutation.
- a method is provided which comprises the step of administering a therapeutically effective dose to a subject (a mammal, including a human) in need of such treatment.
- the subject may be a patient who has received gemcitabine as a prior treatment.
- the subject may be a patient who has been given gemcitabine as a prior treatment and a patient who has not shown an effect higher than Partial Response.
- the subject may be a patient who has been given combination chemotherapy including gemcitabine as prior treatment.
- the subject may be a patient who received combination chemotherapy including gemcitabine as a pretreatment, and a patient who did not show an effect higher than Partial Response.
- the subject may be a patient who has undergone other chemotherapy.
- the target may be a patient whose improvement is not expected by other chemotherapy. According to the present invention, the improvement effect can be obtained even for a patient who can not expect the therapeutic effect conventionally as described above.
- the present invention relates to an antitumor agent against a tumor having an isocitrate dehydrogenase mutation, which comprises 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof. provide.
- the present invention relates to 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or for the preparation of a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation.
- a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation Provide the use of salt or prodrug.
- the present invention relates to 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for use in the treatment of a tumor having an isocitrate dehydrogenase mutation.
- I will provide a.
- Example 1 ⁇ Preparation of Methanesulfonate of Compound A>
- the methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter also referred to as compound A) is described in WO 2013/146833
- the compound was synthesized according to the method of (See Example 22 described in paragraph 0487 to paragraph 0492) and used in the following tests.
- ⁇ Preparation of Liquid Pharmaceutical Composition> The methanesulfonate salt of Compound A was dissolved in an appropriate amount of water for injection, and the pH was adjusted using a 1 mol / L aqueous sodium hydroxide solution.
- Compound A was administered by intravenous injection once a week from the first week to the third week, and the dosing cycle was repeated with no dosing at the fourth week. Specifically, Compound A was administered on days 1, 8, and 15, with 28 days as one cycle, and the cycle consisting of 28 days was repeated. The dose per single dose of Compound A was 40 mg / m 2 to 90 mg / m 2 .
- CR Complete Response
- PR Partial Response
- SD Stable Disease
- PD Progressive Disease
- ECOG means Eastern Cooperative Oncology Group
- Gem-Cis means combination chemotherapy with gemcitabine and cisplatin
- Gem-Capecitabine means combination chemotherapy with gemcitabine and capecitabine.
- cholangiocarcinoma 1-2 since multiple prior treatments (treatment history) were performed, they were also described.
- the ECOG of bile duct cancer patient 1 was 0, and the ECOG of cholangiocarcinoma patients 2-3 was 1.
- FIG. 3 is a graph showing Cmax values of plasma concentrations of 38 patients receiving Compound A in a clinical test including cholangiocarcinoma patients (FIG. 3). Also in clinical trials, the most common drug-related AEs in two or more patients were fever, nausea, chills, itching, rash, dry skin, skin abrasions, and fatigue.
- Example 2 In vitro drug efficacy test using cholangiocarcinoma cell line HuCCT-1 cells
- An IDH1 mutant gene eg, IDH1R132C
- HuCCT-1 cells which are cholangiocarcinoma cell lines
- IDH1 mutation-overexpressing cell lines As a control, a cell line transfected with only pIRES puro 3 vector containing no gene is prepared (control cell line).
- Compound A is added to a control cell line and a cell line overexpressing IDH1 mutation to conduct a drug efficacy test. As a result, the efficacy of Compound A on cells having the IDH mutant gene can be confirmed.
- the pharmaceutical composition of the present invention is useful as a pharmaceutical composition having a therapeutic effect on a tumor having an IDH mutation.
Abstract
The purpose of the present invention is to provide a pharmaceutical composition which exhibits an effect against tumors having an isocitrate dehydrogenase mutation, and an antitumor agent. A pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation is provided that contains 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine or a salt or a prodrug thereof.
Description
本発明は、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍に対する医薬組成物、および抗腫瘍剤に関する。
The present invention relates to a pharmaceutical composition for a tumor having an isocitrate dehydrogenase mutation, and an antitumor agent.
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシン（以下、「化合物Ａ」と称することがある。）は、優れた抗腫瘍活性を有し、抗腫瘍剤として有用であることが知られている（特許文献１）。また化合物Ａは、マウスへの経口投与でも強い抗腫瘍活性を有することが知られている（非特許文献１～３）。また化合物Ａの塩、プロドラッグ、注射剤および製造方法についても知られている（特許文献２～６）。
1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known that it is useful as an antitumor agent (patent document 1). Compound A is also known to have strong antitumor activity even when orally administered to mice (Non-patent Documents 1 to 3). In addition, salts, prodrugs, injections and methods of production of Compound A are also known (Patent Documents 2 to 6).
イソクエン酸脱水素酵素（ｉｓｏｃｉｔｒａｔｅ ｄｅｈｙｄｒｏｇｅｎａｓｅ、ＩＤＨ）は、ＮＡＤＰ＋を補酵素としてクエン酸回路（ＴＣＡ回路）の中間体であるイソクエン酸から２－オキソグルタル酸（α－ケトグルタル酸、α－ｋｅｔｏｇｌｕｔａｒａｔｅ、αＫＧ）への変換を触媒する酵素である。ＩＤＨ１は細胞質に、ＩＤＨ２はミトコンドリアに局在しており、これら２つの遺伝子に変異が認められることが知られている。ＩＤＨ変異は急性骨髄性白血病や神経膠腫、軟骨肉腫および胆管がんなどのさまざまな悪性腫瘍においてみられる遺伝子変異である。ＩＤＨをコードするＩＤＨ遺伝子の変異（ＩＤＨ変異）は野生型とヘテロ二量体を形成するが、変異を生じるアミノ酸にホットスポットが存在するのが特徴であり、変異箇所は酵素反応に重要なアミノ酸またはその近くのアミノ酸に集中している（特許文献７）。ＩＤＨ１であれば特にＩＤＨ１タンパク質の１３２番目のアルギニン（以下Ｒ１３２のように表記する）が他のアミノ酸に置換される変異が大多数を占めている。例えば、１３２番目のアルギニンがヒスチジンに変換される変異（Ｒ１３２Ｈのように表記する）やシステイン（Ｒ１３２Ｃ）、ロイシン（Ｒ１３２Ｌ）、セリン（Ｒ１３２Ｓ）グリシン（Ｒ１３２Ｇ）、バリン（Ｒ１３２Ｖ）などに変換される変異が多いことが知られている。それ以外にもＧ９７、Ｒ１００、Ｈ１３３、Ａ１３４などに変異が生じる例が知られている。ＩＤＨ２遺伝子変異はＲ１４０、またはＲ１７２が他のアミノ酸に変換される変異が大部分である。例えばＲ１４０Ｑ変異やＲ１７２Ｋ、Ｒ１７２Ｓ変異などが知られている。このようなＩＤＨ変異は機能獲得型の変異であり、オンコメタボライトである２－ヒドロキシグルタル酸（２－ｈｙｄｒｏｘｙｇｌｕｔａｒａｔｅ、２ＨＧ）を産生し、αＫＧを競合的に阻害してエピジェネティックな変化をもたらすことで腫瘍の悪性化に寄与することが知られている（非特許文献４）。
Isocitrate dehydrogenase (isocitrate dehydrogenase, IDH) is an intermediate of the citric acid cycle (TCA cycle) with NADP + as a coenzyme to isocitric acid which is an intermediate of 2-oxoglutaric acid (α-ketoglutarate, α-ketoglutarate, αKG) An enzyme that catalyzes the conversion of IDH1 is localized in the cytoplasm and IDH2 in the mitochondria, and it is known that mutations are observed in these two genes. IDH mutations are gene mutations found in various malignancies such as acute myeloid leukemia, glioma, chondrosarcoma and cholangiocarcinoma. Although mutations (IDH mutations) in the IDH gene encoding IDH form heterodimers with wild type, it is characterized by the presence of hot spots in the amino acids causing mutations, and the mutation sites are amino acids important for enzyme reaction It concentrates on the amino acid near or that (patent document 7). In the case of IDH1, in particular, the mutation in which the 132nd arginine of the IDH1 protein (hereinafter referred to as R132) is substituted with another amino acid is the majority. For example, a mutation (denoted as R132H) in which arginine at position 132 is converted to histidine, or a cysteine (R132C), leucine (R132L), serine (R132S) glycine (R132G), valine (R132V), etc. It is known that there are many mutations. There are other known examples where mutations occur in G97, R100, H133, A134 and the like. The IDH2 gene mutation is mostly a mutation in which R140 or R172 is converted to another amino acid. For example, R140Q mutation, R172K, R172S mutation etc. are known. Such IDH mutations are gain-of-function mutations that produce the oncometabolite 2-hydroxyglutarate (2-hydroxyglutarate, 2HG) and competitively inhibit αKG to produce epigenetic changes. Are known to contribute to the malignant transformation of tumors (Non-patent Document 4).
これまでのところ、化合物ＡがＩＤＨ変異を有する腫瘍に対して具体的に治療効果を奏することは報告されていない。本発明の課題は、ＩＤＨ変異を有する腫瘍に対して効果を示す医薬組成物および抗腫瘍剤、ならびにＩＤＨ変異を有する腫瘍の予防または治療方法を提供することにある。
So far, it has not been reported that Compound A specifically exerts a therapeutic effect on tumors having an IDH mutation. An object of the present invention is to provide a pharmaceutical composition and an antitumor agent which show an effect on a tumor having an IDH mutation, and a method for preventing or treating a tumor having an IDH mutation.
本発明者らは、上記課題を解決するために鋭意検討した結果、化合物ＡがＩＤＨ変異を有する腫瘍に対して治療効果を奏することを見出し、本発明を完成するに至った。
As a result of intensive studies to solve the above problems, the present inventors have found that Compound A exerts a therapeutic effect on a tumor having an IDH mutation, and have completed the present invention.
すなわち、本発明は、下記を提供する。
（１） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、
イソクエン酸デヒドロゲナーゼ変異を有する腫瘍を処置するための、医薬組成物。
（２） イソクエン酸デヒドロゲナーゼ変異が、イソクエン酸デヒドロゲナーゼ１変異またはイソクエン酸デヒドロゲナーゼ２変異より選択される少なくとも一つの遺伝子変異である、（１）に記載の医薬組成物。
（３） 腫瘍にイソクエン酸デヒドロゲナーゼ１変異を有する患者を対象として使用される、（１）または（２）に記載の医薬組成物。
（４） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアミノ酸の変異である、（３）に記載の医薬組成物。
（５） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのヒスチジン（Ｒ１３２Ｈ）、システイン（Ｒ１３２Ｃ）、セリン（Ｒ１３２Ｓ）、グリシン（Ｒ１３２Ｇ）、ロイシン（Ｒ１３２Ｌ）、バリン（Ｒ１３２∨）またはグルタミン（Ｒ１３２Ｑ）への置換である、（４）に記載の医薬組成物。
（６） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのシステイン、セリン、グリシンまたはロイシンへの置換である、（４）または（５）に記載の医薬組成物。
（７） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのシステインまたはセリンへの置換である、（４）から（６）に記載の医薬組成物。
（８） 腫瘍が、脳腫瘍（神経膠腫を含む）、急性骨髄性白血病、骨髄異形成症候群、骨髄増殖性腫瘍、末梢性Ｔ細胞性リンパ腫、軟骨肉腫、骨肉腫、胸腺腫、肝臓がん、胆道がん、褐色細胞種、傍神経節腫、原始神経外胚葉腫瘍、Ｂリンパ芽球性リンパ腫、悪性黒色腫、乳がん、前立腺がん、大腸がん、膀胱がんまたは甲状腺がんである（１）から（７）に記載の医薬組成物。
（９） 腫瘍が、胆道がんである、（８）に記載の医薬組成物。
（１０） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍を処置するための抗腫瘍剤。
（１１） イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置用医薬組成物の製造のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの使用。
（１２） イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグ。
（１３） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの有効量を対象に投与することを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置方法。
（１４） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの有効量を対象に投与することを含み、その投与の前に対象のイソクエン酸デヒドロゲナーゼ変異の有無を確認する工程を含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置方法。 That is, the present invention provides the following.
(1) including 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof
A pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation.
(2) The pharmaceutical composition according to (1), wherein the isocitrate dehydrogenase mutation is at least one gene mutation selected from isocitrate dehydrogenase 1 mutation or isocitrate dehydrogenase 2 mutation.
(3) The pharmaceutical composition according to (1) or (2), which is used for a patient having an isocitrate dehydrogenase 1 mutation in a tumor.
(4) The pharmaceutical composition according to (3), wherein the isocitrate dehydrogenase 1 mutation is a mutation at the 132nd amino acid.
(5) The isocitrate dehydrogenase 1 mutation is selected from histidine (R132H), cysteine (R132C), serine (R132S), glycine (R132G), leucine (R132L), valine (R132∨) or glutamine (R132Q) from arginine at position 132 The pharmaceutical composition according to (4), which is a substitution for
(6) The pharmaceutical composition according to (4) or (5), wherein the isocitrate dehydrogenase 1 mutation is substitution of arginine at position 132 with cysteine, serine, glycine or leucine.
(7) The pharmaceutical composition according to (4) to (6), wherein the isocitrate dehydrogenase 1 mutation is a substitution of cysteine or serine from arginine at position 132.
(8) The tumor is a brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, liver cancer, Biliary cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid cancer (1 The pharmaceutical composition according to any one of (7) to (7).
(9) The pharmaceutical composition according to (8), wherein the tumor is biliary cancer.
(10) An anti-titer for treating a tumor having an isocitrate dehydrogenase mutation, which comprises 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof Tumor agent.
(11) 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof for producing a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation Or use of prodrugs.
(12) 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of a tumor having an isocitrate dehydrogenase mutation.
(13) An isocitrate dehydrogenase mutation comprising administering an effective amount of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof to a subject Methods of treating a tumor having:
(14) A method comprising administering to a subject an effective amount of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof, prior to the administration A method for treating a tumor having an isocitrate dehydrogenase mutation, comprising the step of confirming the presence or absence of the isocitrate dehydrogenase mutation of interest.
（１） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、
イソクエン酸デヒドロゲナーゼ変異を有する腫瘍を処置するための、医薬組成物。
（２） イソクエン酸デヒドロゲナーゼ変異が、イソクエン酸デヒドロゲナーゼ１変異またはイソクエン酸デヒドロゲナーゼ２変異より選択される少なくとも一つの遺伝子変異である、（１）に記載の医薬組成物。
（３） 腫瘍にイソクエン酸デヒドロゲナーゼ１変異を有する患者を対象として使用される、（１）または（２）に記載の医薬組成物。
（４） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアミノ酸の変異である、（３）に記載の医薬組成物。
（５） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのヒスチジン（Ｒ１３２Ｈ）、システイン（Ｒ１３２Ｃ）、セリン（Ｒ１３２Ｓ）、グリシン（Ｒ１３２Ｇ）、ロイシン（Ｒ１３２Ｌ）、バリン（Ｒ１３２∨）またはグルタミン（Ｒ１３２Ｑ）への置換である、（４）に記載の医薬組成物。
（６） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのシステイン、セリン、グリシンまたはロイシンへの置換である、（４）または（５）に記載の医薬組成物。
（７） イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのシステインまたはセリンへの置換である、（４）から（６）に記載の医薬組成物。
（８） 腫瘍が、脳腫瘍（神経膠腫を含む）、急性骨髄性白血病、骨髄異形成症候群、骨髄増殖性腫瘍、末梢性Ｔ細胞性リンパ腫、軟骨肉腫、骨肉腫、胸腺腫、肝臓がん、胆道がん、褐色細胞種、傍神経節腫、原始神経外胚葉腫瘍、Ｂリンパ芽球性リンパ腫、悪性黒色腫、乳がん、前立腺がん、大腸がん、膀胱がんまたは甲状腺がんである（１）から（７）に記載の医薬組成物。
（９） 腫瘍が、胆道がんである、（８）に記載の医薬組成物。
（１０） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍を処置するための抗腫瘍剤。
（１１） イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置用医薬組成物の製造のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの使用。
（１２） イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグ。
（１３） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの有効量を対象に投与することを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置方法。
（１４） １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの有効量を対象に投与することを含み、その投与の前に対象のイソクエン酸デヒドロゲナーゼ変異の有無を確認する工程を含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置方法。 That is, the present invention provides the following.
(1) including 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof
A pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation.
(2) The pharmaceutical composition according to (1), wherein the isocitrate dehydrogenase mutation is at least one gene mutation selected from isocitrate dehydrogenase 1 mutation or isocitrate dehydrogenase 2 mutation.
(3) The pharmaceutical composition according to (1) or (2), which is used for a patient having an isocitrate dehydrogenase 1 mutation in a tumor.
(4) The pharmaceutical composition according to (3), wherein the isocitrate dehydrogenase 1 mutation is a mutation at the 132nd amino acid.
(5) The isocitrate dehydrogenase 1 mutation is selected from histidine (R132H), cysteine (R132C), serine (R132S), glycine (R132G), leucine (R132L), valine (R132∨) or glutamine (R132Q) from arginine at position 132 The pharmaceutical composition according to (4), which is a substitution for
(6) The pharmaceutical composition according to (4) or (5), wherein the isocitrate dehydrogenase 1 mutation is substitution of arginine at position 132 with cysteine, serine, glycine or leucine.
(7) The pharmaceutical composition according to (4) to (6), wherein the isocitrate dehydrogenase 1 mutation is a substitution of cysteine or serine from arginine at position 132.
(8) The tumor is a brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, liver cancer, Biliary cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid cancer (1 The pharmaceutical composition according to any one of (7) to (7).
(9) The pharmaceutical composition according to (8), wherein the tumor is biliary cancer.
(10) An anti-titer for treating a tumor having an isocitrate dehydrogenase mutation, which comprises 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof Tumor agent.
(11) 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof for producing a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation Or use of prodrugs.
(12) 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of a tumor having an isocitrate dehydrogenase mutation.
(13) An isocitrate dehydrogenase mutation comprising administering an effective amount of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof to a subject Methods of treating a tumor having:
(14) A method comprising administering to a subject an effective amount of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof, prior to the administration A method for treating a tumor having an isocitrate dehydrogenase mutation, comprising the step of confirming the presence or absence of the isocitrate dehydrogenase mutation of interest.
化合物Ａは、イソクエン酸デヒドロゲナーゼ（ＩＤＨ）変異を有する腫瘍に対して治療効果を奏する。すなわち、本発明によれば、ＩＤＨ変異を有する腫瘍に対して効果を示す医薬組成物および抗腫瘍剤、ならびにＩＤＨ変異を有する腫瘍の処置方法が提供される。
Compound A exerts a therapeutic effect on tumors having an isocitrate dehydrogenase (IDH) mutation. That is, according to the present invention, there are provided a pharmaceutical composition and an antitumor agent showing an effect on a tumor having an IDH mutation, and a method of treating a tumor having an IDH mutation.
本発明において「～」で表す範囲は、特に記載した場合を除き、両端の値を含む。
「対象」とは、その予防もしくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防もしくは治療を必要とするヒトである。
「予防」とは、発症の阻害、発症リスクの低減または発症の遅延などを意味する。
「治療」とは、対象となる疾患または状態の改善または進行の抑制（維持または遅延）などを意味する。
「処置」とは、各種疾患に対する予防または治療などを意味する。
「腫瘍」とは、良性腫瘍または悪性腫瘍を意味する。
「良性腫瘍」とは、腫瘍細胞およびその配列がその由来する正常細胞に近い形態をとり、浸潤性または転移性のない腫瘍を意味する。
「悪性腫瘍」とは、腫瘍細胞の形態やその配列がその由来する正常細胞と異なっており、浸潤性または転移性を示す腫瘍を意味する。 In the present invention, the range represented by “to” includes the values at both ends, unless otherwise specified.
A "subject" is a human, mouse, monkey, domestic animal or other mammal in need of the prevention or treatment, preferably a human in need of the prevention or treatment.
The term "prevention" refers to inhibition of onset, reduction in risk of onset or delay in onset, and the like.
"Treatment" refers to amelioration or suppression (maintenance or delay) of the disease or condition to be treated.
"Treatment" refers to prevention or treatment for various diseases.
By "tumor" is meant a benign or malignant tumor.
By "benign tumor" is meant a tumor that is close to the normal cells from which the tumor cells and their sequences are derived and is not invasive or metastatic.
The term "malignant tumor" refers to a tumor which is invasive or metastatic, in which the morphology of the tumor cells and their sequences are different from those of the normal cells from which they are derived.
「対象」とは、その予防もしくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防もしくは治療を必要とするヒトである。
「予防」とは、発症の阻害、発症リスクの低減または発症の遅延などを意味する。
「治療」とは、対象となる疾患または状態の改善または進行の抑制（維持または遅延）などを意味する。
「処置」とは、各種疾患に対する予防または治療などを意味する。
「腫瘍」とは、良性腫瘍または悪性腫瘍を意味する。
「良性腫瘍」とは、腫瘍細胞およびその配列がその由来する正常細胞に近い形態をとり、浸潤性または転移性のない腫瘍を意味する。
「悪性腫瘍」とは、腫瘍細胞の形態やその配列がその由来する正常細胞と異なっており、浸潤性または転移性を示す腫瘍を意味する。 In the present invention, the range represented by “to” includes the values at both ends, unless otherwise specified.
A "subject" is a human, mouse, monkey, domestic animal or other mammal in need of the prevention or treatment, preferably a human in need of the prevention or treatment.
The term "prevention" refers to inhibition of onset, reduction in risk of onset or delay in onset, and the like.
"Treatment" refers to amelioration or suppression (maintenance or delay) of the disease or condition to be treated.
"Treatment" refers to prevention or treatment for various diseases.
By "tumor" is meant a benign or malignant tumor.
By "benign tumor" is meant a tumor that is close to the normal cells from which the tumor cells and their sequences are derived and is not invasive or metastatic.
The term "malignant tumor" refers to a tumor which is invasive or metastatic, in which the morphology of the tumor cells and their sequences are different from those of the normal cells from which they are derived.
以下、本発明を詳細に説明する。
本発明は、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシン（化合物Ａ）またはその塩もしくはプロドラッグを含む、ＩＤＨ変異を有する腫瘍を処置するための、医薬組成物である。 Hereinafter, the present invention will be described in detail.
The present invention treats tumors with IDH mutations, including 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (compound A) or a salt or prodrug thereof And a pharmaceutical composition.
本発明は、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシン（化合物Ａ）またはその塩もしくはプロドラッグを含む、ＩＤＨ変異を有する腫瘍を処置するための、医薬組成物である。 Hereinafter, the present invention will be described in detail.
The present invention treats tumors with IDH mutations, including 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (compound A) or a salt or prodrug thereof And a pharmaceutical composition.
（化合物Ａまたはその塩もしくはプロドラッグ）
まず、化合物Ａまたはその塩もしくはプロドラッグについて説明する。
塩としては、薬学的に許容される塩が挙げられ、具体的には、鉱酸塩、有機カルボン酸塩およびスルホン酸塩が挙げられる。好ましい塩としては、鉱酸塩およびスルホン酸塩が挙げられる。 (Compound A or a salt or prodrug thereof)
First, Compound A or a salt or prodrug thereof is described.
Salts include pharmaceutically acceptable salts, and in particular, mineral acid salts, organic carboxylates and sulfonates. Preferred salts include mineral and sulfonate salts.
まず、化合物Ａまたはその塩もしくはプロドラッグについて説明する。
塩としては、薬学的に許容される塩が挙げられ、具体的には、鉱酸塩、有機カルボン酸塩およびスルホン酸塩が挙げられる。好ましい塩としては、鉱酸塩およびスルホン酸塩が挙げられる。 (Compound A or a salt or prodrug thereof)
First, Compound A or a salt or prodrug thereof is described.
Salts include pharmaceutically acceptable salts, and in particular, mineral acid salts, organic carboxylates and sulfonates. Preferred salts include mineral and sulfonate salts.
鉱酸塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩および硫酸塩が挙げられ、塩酸塩、ヨウ化水素酸塩、硝酸塩または硫酸塩が好ましく、塩酸塩がより好ましい。有機カルボン酸塩としては、例えば、ギ酸塩、酢酸塩、クエン酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、コハク酸塩、リンゴ酸塩、酒石酸塩、アスパラギン酸塩、トリクロロ酢酸塩およびトリフルオロ酢酸塩が挙げられる。スルホン酸塩としては、例えば、メタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、メシチレンスルホン酸塩およびナフタレンスルホン酸塩が挙げられ、メタンスルホン酸塩が好ましい。
Mineral acid salts include, for example, hydrochlorides, hydrobromides, hydroiodides, nitrates, phosphates and sulfates, with hydrochlorides, hydroiodides, nitrates or sulfates being preferred. , Hydrochloride is more preferred. Examples of organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and the like Trifluoroacetic acid salt is mentioned. Examples of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate and naphthalenesulfonate, with methanesulfonate being preferred.
化合物Ａの塩は、無水物、水和物または溶媒和物であってもよい。本明細書で単に「塩」というとき、その形態は、無水物、水和物または溶媒和物であり得る。本明細書で「無水物」というときは、特に記載した場合を除き、水和物でも溶媒和物でもない状態にある場合をいう。元来、水和物または溶媒和物を形成しない物質であっても、結晶水、水和水および相互作用する溶媒を持たない化合物Ａの塩は、本発明でいう「無水物」に含まれる。無水物は、「無水和物」ということもある。化合物Ａの塩が水和物であるとき、水和水の数は特に限られず、一水和物、二水和物等であり得る。溶媒和物の例としては、メタノール和物、エタノール和物、プロパノール和物および２－プロパノール和物が挙げられる。
The salt of compound A may be an anhydride, a hydrate or a solvate. As referred to herein simply as "salts", the form may be an anhydride, hydrate or solvate. The term "anhydride" as used herein refers to the case where it is in neither hydrate nor solvate state, unless otherwise stated. Water of crystallization, water of hydration, and a salt of Compound A having no interacting solvent, which are substances which do not form hydrates or solvates originally, are included in the “anhydride” in the present invention. . Anhydride is also referred to as "anhydrate." When the salt of compound A is a hydrate, the number of hydration water is not particularly limited, and may be a monohydrate, a dihydrate or the like. Examples of solvates include methanolate, ethanolate, propanolate and 2-propanolate.
特に好ましい化合物Ａの塩の具体的な例は、下記である。
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンのメタンスルホン酸塩；
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンの塩酸塩；
ならびに上記の塩のいずれかの無水物。 Specific examples of particularly preferred salts of Compound A are:
Methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine;
Hydrochloride salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine;
As well as the anhydride of any of the above mentioned salts.
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンのメタンスルホン酸塩；
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンの塩酸塩；
ならびに上記の塩のいずれかの無水物。 Specific examples of particularly preferred salts of Compound A are:
Methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine;
Hydrochloride salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine;
As well as the anhydride of any of the above mentioned salts.
プロドラッグとは、投与後、プロドラッグとして機能する官能基が体内の酵素や胃液等による反応により切断され、目的の薬理活性を示す化合物に変換される化合物またはその塩をいう。
プロドラッグを形成する基としては、例えば、Stella VJら、Prodrugs: Challenges and Rewards. Parts 1 and 2、2007年、American Association of Pharmaceutical Scientistsに記載されている基が挙げられる。 The term “prodrug” refers to a compound or a salt thereof in which a functional group functioning as a prodrug is cleaved by a reaction in the body with enzymes such as gastric juice after administration to be converted into a compound exhibiting a desired pharmacological activity.
Groups forming a prodrug include, for example, groups described in Stella VJ et al., Prodrugs: Challenges and Rewards. Parts 1 and 2, 2007, American Association of Pharmaceutical Scientists.
プロドラッグを形成する基としては、例えば、Stella VJら、Prodrugs: Challenges and Rewards. Parts 1 and 2、2007年、American Association of Pharmaceutical Scientistsに記載されている基が挙げられる。 The term “prodrug” refers to a compound or a salt thereof in which a functional group functioning as a prodrug is cleaved by a reaction in the body with enzymes such as gastric juice after administration to be converted into a compound exhibiting a desired pharmacological activity.
Groups forming a prodrug include, for example, groups described in Stella VJ et al., Prodrugs: Challenges and Rewards. Parts 1 and 2, 2007, American Association of Pharmaceutical Scientists.
化合物Ａのプロドラッグとは、生体内における生理条件下で酵素や胃液等による反応により化合物Ａまたはそのリン酸化合物に変換する化合物またはその塩をいう。
化合物Ａのプロドラッグとしては、国際公開第２０１６／０６８３４１号公報の説明を援用および参酌でき、これらの内容は本願明細書に組み込まれる。
より具体的には、例えば、国際公開第２０１６／０６８３４１号公報に記載の一般式［１］で表わされるチオヌクレオシド誘導体またはその塩が本願明細書に組み込まれ、その好適な範囲も国際公開第２０１６／０６８３４１号公報に記載のものと同一である。 The prodrug of Compound A refers to a compound or a salt thereof which is converted to Compound A or its phosphate compound by a reaction with an enzyme or gastric juice under physiological conditions in vivo.
As a prodrug of Compound A, the description of WO 2016/068341 can be incorporated and referred to, and the contents thereof are incorporated herein.
More specifically, for example, the thionucleoside derivative represented by the general formula [1] described in WO 2016/068341 or a salt thereof is incorporated in the present specification, and the preferred range thereof is also WO 2016 It is the same as that described in Japanese Patent Publication No. 06/06841.
化合物Ａのプロドラッグとしては、国際公開第２０１６／０６８３４１号公報の説明を援用および参酌でき、これらの内容は本願明細書に組み込まれる。
より具体的には、例えば、国際公開第２０１６／０６８３４１号公報に記載の一般式［１］で表わされるチオヌクレオシド誘導体またはその塩が本願明細書に組み込まれ、その好適な範囲も国際公開第２０１６／０６８３４１号公報に記載のものと同一である。 The prodrug of Compound A refers to a compound or a salt thereof which is converted to Compound A or its phosphate compound by a reaction with an enzyme or gastric juice under physiological conditions in vivo.
As a prodrug of Compound A, the description of WO 2016/068341 can be incorporated and referred to, and the contents thereof are incorporated herein.
More specifically, for example, the thionucleoside derivative represented by the general formula [1] described in WO 2016/068341 or a salt thereof is incorporated in the present specification, and the preferred range thereof is also WO 2016 It is the same as that described in Japanese Patent Publication No. 06/06841.
本発明において、化合物Ａまたはその塩もしくはプロドラッグは、一種のみを用いてもよく、または二種以上を含有してもよい。
In the present invention, the compound A or a salt or prodrug thereof may be used alone or in combination of two or more.
次に、化合物Ａまたはその塩もしくはプロドラッグの製造法について説明する。化合物Ａは、例えば、特許文献１およびジャーナル・オブ・オーガニック・ケミストリー、１９９９年、第６４巻、ｐ７９１２－７９２０に記載の方法で製造することができる。化合物Ａの塩またはその水和物もしくは溶媒和物は、例えば、特許文献４に記載の方法で製造することができる。化合物Ａのプロドラッグは、例えば、国際公開第２０１６／０６８３４１号公報に記載の方法で製造することができる。
本発明にかかる化合物Ａまたはその塩もしくはプロドラッグは、抗腫瘍剤として、また医薬組成物の有効成分として用いることができる。 Next, the process for producing Compound A or a salt or prodrug thereof is described. Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, vol. 64, p7912-7920. The salt of Compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4. The prodrug of compound A can be produced, for example, by the method described in WO 2016/068341.
The compound A or a salt or prodrug thereof according to the present invention can be used as an antitumor agent and as an active ingredient of a pharmaceutical composition.
本発明にかかる化合物Ａまたはその塩もしくはプロドラッグは、抗腫瘍剤として、また医薬組成物の有効成分として用いることができる。 Next, the process for producing Compound A or a salt or prodrug thereof is described. Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, vol. 64, p7912-7920. The salt of Compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4. The prodrug of compound A can be produced, for example, by the method described in WO 2016/068341.
The compound A or a salt or prodrug thereof according to the present invention can be used as an antitumor agent and as an active ingredient of a pharmaceutical composition.
（医薬組成物）
本発明によれば、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、ＩＤＨ変異を有する腫瘍を処置するための、医薬組成物が提供される。 (Pharmaceutical composition)
According to the present invention, for treating a tumor having an IDH mutation, comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof , A pharmaceutical composition is provided.
本発明によれば、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、ＩＤＨ変異を有する腫瘍を処置するための、医薬組成物が提供される。 (Pharmaceutical composition)
According to the present invention, for treating a tumor having an IDH mutation, comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof , A pharmaceutical composition is provided.
本発明の医薬組成物は、通常、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤および吸収促進剤などの添加剤を含んでいてもよい。
The pharmaceutical composition of the present invention generally comprises an emulsifier, surfactant, solubilizer, suspending agent, tonicity agent, buffer, preservative, antioxidant, stabilizer, absorption enhancer and the like. It may contain an agent.
本発明の医薬組成物の投与経路としては、静脈内、動脈内、直腸内、腹腔内、筋肉内、腫瘍内または膀胱内注射する方法、経口投与、経皮投与および／または坐剤などの方法が挙げられる。投与方法としては、シリンジまたは点滴による投与が挙げられる。
The route of administration of the pharmaceutical composition of the present invention may be intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository Can be mentioned. Methods of administration include administration by syringe or infusion.
化合物Ａまたはその塩もしくはプロドラッグの投与量および投与回数は、１日あたり１～２０００ ｍｇ／ｍ２を１回から数回に分割して投与することができる。１日当たりの投与量は、好ましくは２０ｍｇ／ｍ２以上であり、より好ましくは４０ｍｇ／ｍ２～２００ｍｇ／ｍ２であり、さらに好ましくは８０ｍｇ／ｍ２～１５０ｍｇ／ｍ２であり、さらに一層好ましくは８０ｍｇ／ｍ２～１２０ｍｇ／ｍ２である。しかし、これらの投与量および投与回数に制限されるものではない。
The dose and number of doses of Compound A or a salt or prodrug thereof can be administered in 1 to 2000 mg / m 2 per day in divided doses. The daily dose is preferably 20 mg / m 2 or more, more preferably 40 mg / m 2 to 200 mg / m 2 , still more preferably 80 mg / m 2 to 150 mg / m 2 , and still more preferably Is 80 mg / m 2 to 120 mg / m 2 . However, it is not limited to these doses and frequency of administration.
投与方法としては、１回の投与量が２０ｍｇ／ｍ２以上とし、週１回の投与を３週間行った後に４週目は休薬するコースを複数回繰り返すことができる。この場合、１回の投与量は好ましくは４０ｍｇ／ｍ２～２００ｍｇ／ｍ２であり、より好ましくは８０ｍｇ／ｍ２～１５０ｍｇ／ｍ２である。
その投与の前に対象のイソクエン酸デヒドロゲナーゼ変異の有無を確認すること（ＩＤＨ変異の確認工程）が好ましい。 As a method of administration, one dose can be 20 mg / m 2 or more, and after one week administration for 3 weeks, the course of withdrawal can be repeated multiple times for the fourth week. In this case, the single dose is preferably 40 mg / m 2 to 200 mg / m 2 , more preferably 80 mg / m 2 to 150 mg / m 2 .
It is preferable to confirm the presence or absence of the target isocitrate dehydrogenase mutation (the IDH mutation confirmation step) before the administration.
その投与の前に対象のイソクエン酸デヒドロゲナーゼ変異の有無を確認すること（ＩＤＨ変異の確認工程）が好ましい。 As a method of administration, one dose can be 20 mg / m 2 or more, and after one week administration for 3 weeks, the course of withdrawal can be repeated multiple times for the fourth week. In this case, the single dose is preferably 40 mg / m 2 to 200 mg / m 2 , more preferably 80 mg / m 2 to 150 mg / m 2 .
It is preferable to confirm the presence or absence of the target isocitrate dehydrogenase mutation (the IDH mutation confirmation step) before the administration.
本発明の医薬組成物の剤形の例としては、液状医薬製剤が挙げられ、例えば注射剤が挙げられる。投与剤形は、各々当業者に公知慣用の製剤方法により製造できる。
液状医薬製剤は、化合物Ａまたはその塩と、分子量１００以下の多価アルコールと、水と、を含有することが好ましい。
液状医薬製剤において、化合物Ａまたはその塩の含有量は、１～５０ｍｇ／ｍＬであることが好ましく、５～５０ｍｇ／ｍＬであることがより好ましく、１０～３０ｍｇ／ｍＬであることが特に好ましい。
分子量１００以下の多価アルコールは、炭素数３または４の多価アルコールであることが好ましく、グリセリン、プロピレングリコールまたはブタンジオールであることがより好ましく、グリセリンであることが特に好ましい。なお、ブタンジオールとしては、１，２－ブタンジオール、１，３－ブタンジオール、１，４－ブタンジオール、２，３－ブタンジオールが挙げられるが、１，３－ブタンジオールが特に好ましい。多価アルコールの分子量の下限は特に限定されないが、一般的には５０以上である。
液状医薬製剤の分子量１００以下の多価アルコールの含有量は、０．５～１０質量％であることが好ましく、０．５～５質量％であることがより好ましく、１．０～２．５質量％であることがさらに好ましい。
液状医薬製剤は、ｐＨが１．５～６．９であることが好ましく、１．５～６．５であることがより好ましく、２．０～６．５であることがより一層好ましく、２．０～５．０であることがさらに好ましく、２．０～４．０であることがさらに一層好ましく、２．６～３．２であることが特に好ましく、２．８～３．０であることが最も好ましい。
液状医薬製剤としては、国際公開第２０１７／１５０５１１号公報の説明を援用および参酌でき、これらの内容は本願明細書に組み込まれる。なお、液状医薬製剤の好適な組成や好適な配合比も国際公開第２０１７／１５０５１１号公報に記載のものと同一である。 Examples of dosage forms of the pharmaceutical composition of the present invention include liquid pharmaceutical preparations such as injections. The dosage forms can each be prepared by conventional formulation methods known to those skilled in the art.
The liquid pharmaceutical preparation preferably contains compound A or a salt thereof, a polyhydric alcohol having a molecular weight of 100 or less, and water.
In the liquid pharmaceutical preparation, the content of Compound A or a salt thereof is preferably 1 to 50 mg / mL, more preferably 5 to 50 mg / mL, and particularly preferably 10 to 30 mg / mL.
The polyhydric alcohol having a molecular weight of 100 or less is preferably a polyhydric alcohol having 3 or 4 carbon atoms, more preferably glycerin, propylene glycol or butanediol, and particularly preferably glycerin. Examples of butanediol include 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2,3-butanediol, and 1,3-butanediol is particularly preferable. Although the lower limit of the molecular weight of polyhydric alcohol is not particularly limited, it is generally 50 or more.
The content of polyhydric alcohol having a molecular weight of 100 or less is preferably 0.5 to 10% by mass, more preferably 0.5 to 5% by mass, and more preferably 1.0 to 2.5. More preferably, it is mass%.
The pH of the liquid pharmaceutical preparation is preferably 1.5 to 6.9, more preferably 1.5 to 6.5, still more preferably 2.0 to 6.5, Is more preferably from 0 to 5.0, still more preferably from 2.0 to 4.0, particularly preferably from 2.6 to 3.2, 2.8 to 3.0 Most preferably.
As the liquid pharmaceutical preparation, the description of WO 2017/150511 can be incorporated and referred to, and the contents thereof are incorporated herein. In addition, the suitable composition of a liquid pharmaceutical preparation and a suitable compounding ratio are also the same as the thing as described in international publication 2017/150511.
液状医薬製剤は、化合物Ａまたはその塩と、分子量１００以下の多価アルコールと、水と、を含有することが好ましい。
液状医薬製剤において、化合物Ａまたはその塩の含有量は、１～５０ｍｇ／ｍＬであることが好ましく、５～５０ｍｇ／ｍＬであることがより好ましく、１０～３０ｍｇ／ｍＬであることが特に好ましい。
分子量１００以下の多価アルコールは、炭素数３または４の多価アルコールであることが好ましく、グリセリン、プロピレングリコールまたはブタンジオールであることがより好ましく、グリセリンであることが特に好ましい。なお、ブタンジオールとしては、１，２－ブタンジオール、１，３－ブタンジオール、１，４－ブタンジオール、２，３－ブタンジオールが挙げられるが、１，３－ブタンジオールが特に好ましい。多価アルコールの分子量の下限は特に限定されないが、一般的には５０以上である。
液状医薬製剤の分子量１００以下の多価アルコールの含有量は、０．５～１０質量％であることが好ましく、０．５～５質量％であることがより好ましく、１．０～２．５質量％であることがさらに好ましい。
液状医薬製剤は、ｐＨが１．５～６．９であることが好ましく、１．５～６．５であることがより好ましく、２．０～６．５であることがより一層好ましく、２．０～５．０であることがさらに好ましく、２．０～４．０であることがさらに一層好ましく、２．６～３．２であることが特に好ましく、２．８～３．０であることが最も好ましい。
液状医薬製剤としては、国際公開第２０１７／１５０５１１号公報の説明を援用および参酌でき、これらの内容は本願明細書に組み込まれる。なお、液状医薬製剤の好適な組成や好適な配合比も国際公開第２０１７／１５０５１１号公報に記載のものと同一である。 Examples of dosage forms of the pharmaceutical composition of the present invention include liquid pharmaceutical preparations such as injections. The dosage forms can each be prepared by conventional formulation methods known to those skilled in the art.
The liquid pharmaceutical preparation preferably contains compound A or a salt thereof, a polyhydric alcohol having a molecular weight of 100 or less, and water.
In the liquid pharmaceutical preparation, the content of Compound A or a salt thereof is preferably 1 to 50 mg / mL, more preferably 5 to 50 mg / mL, and particularly preferably 10 to 30 mg / mL.
The polyhydric alcohol having a molecular weight of 100 or less is preferably a polyhydric alcohol having 3 or 4 carbon atoms, more preferably glycerin, propylene glycol or butanediol, and particularly preferably glycerin. Examples of butanediol include 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2,3-butanediol, and 1,3-butanediol is particularly preferable. Although the lower limit of the molecular weight of polyhydric alcohol is not particularly limited, it is generally 50 or more.
The content of polyhydric alcohol having a molecular weight of 100 or less is preferably 0.5 to 10% by mass, more preferably 0.5 to 5% by mass, and more preferably 1.0 to 2.5. More preferably, it is mass%.
The pH of the liquid pharmaceutical preparation is preferably 1.5 to 6.9, more preferably 1.5 to 6.5, still more preferably 2.0 to 6.5, Is more preferably from 0 to 5.0, still more preferably from 2.0 to 4.0, particularly preferably from 2.6 to 3.2, 2.8 to 3.0 Most preferably.
As the liquid pharmaceutical preparation, the description of WO 2017/150511 can be incorporated and referred to, and the contents thereof are incorporated herein. In addition, the suitable composition of a liquid pharmaceutical preparation and a suitable compounding ratio are also the same as the thing as described in international publication 2017/150511.
本発明の医薬組成物は、例えば、脳腫瘍（神経膠腫を含む）、急性骨髄性白血病、骨髄異形成症候群、骨髄増殖性腫瘍、末梢性Ｔ細胞性リンパ腫、軟骨肉腫、骨肉腫、胸腺腫、肝臓がん、胆道がん、褐色細胞種、傍神経節腫、原始神経外胚葉腫瘍、Ｂリンパ芽球性リンパ腫、悪性黒色腫、乳がん、前立腺がん、大腸がん、膀胱がんまたは甲状腺がんなどのＩＤＨ変異を有する腫瘍の処置に有効に使用できる。本発明の医薬組成物は、特に、胆道がんなどのＩＤＨ変異を有する腫瘍の処置に好適である。
胆道がんは、好ましくは胆管がんであり、より好ましくは肝外胆管がんまたは肝内胆管がんである。 The pharmaceutical composition of the present invention is, for example, brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, Liver cancer, biliary tract cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid It can be effectively used to treat tumors with IDH mutations such as cancer. The pharmaceutical composition of the present invention is particularly suitable for the treatment of tumors having an IDH mutation such as biliary cancer.
Biliary cancer is preferably bile duct cancer, more preferably extrahepatic cholangiocarcinoma or intrahepatic cholangiocarcinoma.
胆道がんは、好ましくは胆管がんであり、より好ましくは肝外胆管がんまたは肝内胆管がんである。 The pharmaceutical composition of the present invention is, for example, brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, Liver cancer, biliary tract cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid It can be effectively used to treat tumors with IDH mutations such as cancer. The pharmaceutical composition of the present invention is particularly suitable for the treatment of tumors having an IDH mutation such as biliary cancer.
Biliary cancer is preferably bile duct cancer, more preferably extrahepatic cholangiocarcinoma or intrahepatic cholangiocarcinoma.
（イソクエン酸デヒドロゲナーゼ変異）
本発明におけるイソクエン酸デヒドロゲナーゼ変異（ＩＤＨ変異）としては、例えば、ＩＤＨ１の１３２番目のアルギニン（以下Ｒ１３２のように表記する）の変異、Ｇ９７の変異、Ｒ１００の変異、Ｈ１３３の変異、Ａ１３４の変異が挙げられるが、これらに制限されない。また、Ｒ１３２の変異としては、例えば、ヒスチジンへの置換（Ｒ１３２Ｈ）、システインへの置換（Ｒ１３２Ｃ）、ロイシンへの置換（Ｒ１３２Ｌ）、セリンへの置換（Ｒ１３２Ｓ）、グリシンへの置換（Ｒ１３２Ｇ）、バリンへの置換（Ｒ１３２Ｖ）が挙げられるが、これらに制限されない。
本発明の医薬組成物は、ＩＤＨ変異が、ＩＤＨ１変異またはＩＤＨ２変異より選択される少なくとも一つの遺伝子変異を有する腫瘍の処置に好適であり、ＩＤＨ１変異を有する腫瘍の処置により好適である。ＩＤＨ１変異が、１３２番目のアミノ酸の変異、すなわち１３２番目のアルギニンの変異であり、１３２番目のアルギニンからシステインへの置換（Ｒ１３２Ｃ）、セリンへの置換（Ｒ１３２Ｓ）、グリシンへの置換（Ｒ１３２Ｇ）またはロイシンへの置換（Ｒ１３２Ｌ）の変異を有する腫瘍の処置に好適であり、システイン（Ｒ１３２Ｃ）またはセリン（Ｒ１３２Ｓ）への置換の変異を有する腫瘍の処置により好適である。 (Isocitrate dehydrogenase mutation)
The isocitrate dehydrogenase mutation (IDH mutation) in the present invention includes, for example, mutations of arginine at position 132 of IDH1 (hereinafter referred to as R132), mutations of G97, mutations of R100, mutations of H133, and mutations of A134. These include, but are not limited to. Moreover, as a mutation of R132, for example, substitution to histidine (R132H), substitution to cysteine (R132C), substitution to leucine (R132L), substitution to serine (R132S), substitution to glycine (R132G), Substitutions to valine (R132V) include, but are not limited to.
The pharmaceutical composition of the present invention is suitable for the treatment of a tumor having at least one genetic mutation selected from IDH1 mutation or IDH2 mutation in IDH mutation, and more suitable for the treatment of a tumor having IDH1 mutation. The IDH1 mutation is a mutation at amino acid 132, that is, a mutation of arginine at position 132, and the substitution of arginine for cysteine at position 132 (R132C), substitution for serine (R132S), substitution for glycine (R132G) or It is suitable for the treatment of a tumor having a mutation for substitution to leucine (R132L), and more suitable for the treatment of a tumor having a mutation for substitution to cysteine (R132C) or serine (R132S).
本発明におけるイソクエン酸デヒドロゲナーゼ変異（ＩＤＨ変異）としては、例えば、ＩＤＨ１の１３２番目のアルギニン（以下Ｒ１３２のように表記する）の変異、Ｇ９７の変異、Ｒ１００の変異、Ｈ１３３の変異、Ａ１３４の変異が挙げられるが、これらに制限されない。また、Ｒ１３２の変異としては、例えば、ヒスチジンへの置換（Ｒ１３２Ｈ）、システインへの置換（Ｒ１３２Ｃ）、ロイシンへの置換（Ｒ１３２Ｌ）、セリンへの置換（Ｒ１３２Ｓ）、グリシンへの置換（Ｒ１３２Ｇ）、バリンへの置換（Ｒ１３２Ｖ）が挙げられるが、これらに制限されない。
本発明の医薬組成物は、ＩＤＨ変異が、ＩＤＨ１変異またはＩＤＨ２変異より選択される少なくとも一つの遺伝子変異を有する腫瘍の処置に好適であり、ＩＤＨ１変異を有する腫瘍の処置により好適である。ＩＤＨ１変異が、１３２番目のアミノ酸の変異、すなわち１３２番目のアルギニンの変異であり、１３２番目のアルギニンからシステインへの置換（Ｒ１３２Ｃ）、セリンへの置換（Ｒ１３２Ｓ）、グリシンへの置換（Ｒ１３２Ｇ）またはロイシンへの置換（Ｒ１３２Ｌ）の変異を有する腫瘍の処置に好適であり、システイン（Ｒ１３２Ｃ）またはセリン（Ｒ１３２Ｓ）への置換の変異を有する腫瘍の処置により好適である。 (Isocitrate dehydrogenase mutation)
The isocitrate dehydrogenase mutation (IDH mutation) in the present invention includes, for example, mutations of arginine at position 132 of IDH1 (hereinafter referred to as R132), mutations of G97, mutations of R100, mutations of H133, and mutations of A134. These include, but are not limited to. Moreover, as a mutation of R132, for example, substitution to histidine (R132H), substitution to cysteine (R132C), substitution to leucine (R132L), substitution to serine (R132S), substitution to glycine (R132G), Substitutions to valine (R132V) include, but are not limited to.
The pharmaceutical composition of the present invention is suitable for the treatment of a tumor having at least one genetic mutation selected from IDH1 mutation or IDH2 mutation in IDH mutation, and more suitable for the treatment of a tumor having IDH1 mutation. The IDH1 mutation is a mutation at amino acid 132, that is, a mutation of arginine at position 132, and the substitution of arginine for cysteine at position 132 (R132C), substitution for serine (R132S), substitution for glycine (R132G) or It is suitable for the treatment of a tumor having a mutation for substitution to leucine (R132L), and more suitable for the treatment of a tumor having a mutation for substitution to cysteine (R132C) or serine (R132S).
本発明は、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍患者に抗腫瘍剤を投与する方法であって、抗腫瘍剤が、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、方法を提供する。
The present invention provides a method for administering an antitumor agent to a tumor patient having an isocitrate dehydrogenase mutation, wherein the antitumor agent is 1- (2-deoxy-2-fluoro-4-thio-β-D-arabino Provided are methods comprising furanosyl) cytosine or a salt or prodrug thereof.
本発明は、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの有効投与量を対象に投与することを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の予防または治療方法を提供する。
The present invention is an isocitrate comprising administering to a subject an effective dosage of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof. Provided are methods for preventing or treating a tumor having a dehydrogenase mutation.
本発明は、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置に用いるための方法であって、治療有効用量をそのような処置が必要な対象（ヒトを含む哺乳動物）に投与する工程を含む方法を提供する。
The present invention relates to the use of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of a tumor having an isocitrate dehydrogenase mutation. A method is provided which comprises the step of administering a therapeutically effective dose to a subject (a mammal, including a human) in need of such treatment.
対象としては、前治療としてゲムシタビンを投与された患者でもよい。
対象としては、前治療としてゲムシタビンを投与された患者であり、Ｐａｒｔｉａｌ Ｒｅｓｐｏｎｓｅ以上の効果が認められなかった患者でもよい。
対象としては、前治療としてゲムシタビンを含む併用化学療法が実施された患者でもよい。
対象としては、前治療としてゲムシタビンを含む併用化学療法が実施された患者であり、Ｐａｒｔｉａｌ Ｒｅｓｐｏｎｓｅ以上の効果が認められなかった患者でもよい。
対象としては、他の化学療法が実施された患者でもよい。
対象としては、他の化学療法では改善が見込めない患者でもよい。
本発明によれば、上記のような従来は治療効果が見込めない患者に対しても、改善効果が得られる。 The subject may be a patient who has received gemcitabine as a prior treatment.
The subject may be a patient who has been given gemcitabine as a prior treatment and a patient who has not shown an effect higher than Partial Response.
The subject may be a patient who has been given combination chemotherapy including gemcitabine as prior treatment.
The subject may be a patient who received combination chemotherapy including gemcitabine as a pretreatment, and a patient who did not show an effect higher than Partial Response.
The subject may be a patient who has undergone other chemotherapy.
The target may be a patient whose improvement is not expected by other chemotherapy.
According to the present invention, the improvement effect can be obtained even for a patient who can not expect the therapeutic effect conventionally as described above.
対象としては、前治療としてゲムシタビンを投与された患者であり、Ｐａｒｔｉａｌ Ｒｅｓｐｏｎｓｅ以上の効果が認められなかった患者でもよい。
対象としては、前治療としてゲムシタビンを含む併用化学療法が実施された患者でもよい。
対象としては、前治療としてゲムシタビンを含む併用化学療法が実施された患者であり、Ｐａｒｔｉａｌ Ｒｅｓｐｏｎｓｅ以上の効果が認められなかった患者でもよい。
対象としては、他の化学療法が実施された患者でもよい。
対象としては、他の化学療法では改善が見込めない患者でもよい。
本発明によれば、上記のような従来は治療効果が見込めない患者に対しても、改善効果が得られる。 The subject may be a patient who has received gemcitabine as a prior treatment.
The subject may be a patient who has been given gemcitabine as a prior treatment and a patient who has not shown an effect higher than Partial Response.
The subject may be a patient who has been given combination chemotherapy including gemcitabine as prior treatment.
The subject may be a patient who received combination chemotherapy including gemcitabine as a pretreatment, and a patient who did not show an effect higher than Partial Response.
The subject may be a patient who has undergone other chemotherapy.
The target may be a patient whose improvement is not expected by other chemotherapy.
According to the present invention, the improvement effect can be obtained even for a patient who can not expect the therapeutic effect conventionally as described above.
本発明は、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍に対する抗腫瘍剤を提供する。
The present invention relates to an antitumor agent against a tumor having an isocitrate dehydrogenase mutation, which comprises 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof. provide.
本発明は、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置用医薬組成物の製造のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの使用を提供する。
The present invention relates to 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or for the preparation of a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation. Provide the use of salt or prodrug.
本発明は、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置において使用するための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを提供する。
The present invention relates to 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof for use in the treatment of a tumor having an isocitrate dehydrogenase mutation. I will provide a.
以下に実施例により本発明をさらに詳しく説明するが、本発明はこれら実施例に制限されるものではない。
EXAMPLES The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.
実施例１
＜化合物Ａのメタンスルホン酸塩の調製＞
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンのメタンスルホン酸塩（以下、化合物Ａとも言う）を、国際公開第２０１３／１４６８３３号パンフレットに記載の方法（段落０４８７～段落０４９２に記載の実施例２２を参照）に準じて合成し、以下の試験で用いた。
＜液状医薬組成物の調製＞
化合物Ａのメタンスルホン酸塩を適量の注射用水に溶かし、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いてｐＨを調整した。化合物Ａの濃度が２０ｍｇ／ｍＬとなるように適量の注射用水を加えて混合した。
また１．５質量％の濃度になるようにグリセリン（メルク社製、分子量９２）を添加した。この液状医薬製剤のｐＨは、２．９であった。この液をメンブランフィルター（０．２２μｍ）を用いてろ過し、液状医薬製剤を得た。
この液状医薬製剤を、以下の治療で用いた。なお、治療は、米国テキサス州立大学ＭＤアンダーソンがんセンター（以下、ＭＤＡＣＣ）および米国コロラド州デンバー市にあるサラ・キャノン研究所（以下、ＳＣＲＩ）で行った。 Example 1
<Preparation of Methanesulfonate of Compound A>
The methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (hereinafter also referred to as compound A) is described in WO 2013/146833 The compound was synthesized according to the method of (See Example 22 described in paragraph 0487 to paragraph 0492) and used in the following tests.
<Preparation of Liquid Pharmaceutical Composition>
The methanesulfonate salt of Compound A was dissolved in an appropriate amount of water for injection, and the pH was adjusted using a 1 mol / L aqueous sodium hydroxide solution. An appropriate amount of water for injection was added and mixed such that the concentration of Compound A was 20 mg / mL.
Further, glycerin (manufactured by Merck, molecular weight 92) was added to a concentration of 1.5% by mass. The pH of this liquid pharmaceutical preparation was 2.9. This solution was filtered using a membrane filter (0.22 μm) to obtain a liquid pharmaceutical preparation.
This liquid pharmaceutical preparation was used in the following treatment. The treatment was conducted at the University of Texas MD Anderson Cancer Center (hereinafter MDACC) and at the Sara Cannon Research Institute (SCRI) located in Denver, Colorado.
＜化合物Ａのメタンスルホン酸塩の調製＞
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンのメタンスルホン酸塩（以下、化合物Ａとも言う）を、国際公開第２０１３／１４６８３３号パンフレットに記載の方法（段落０４８７～段落０４９２に記載の実施例２２を参照）に準じて合成し、以下の試験で用いた。
＜液状医薬組成物の調製＞
化合物Ａのメタンスルホン酸塩を適量の注射用水に溶かし、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いてｐＨを調整した。化合物Ａの濃度が２０ｍｇ／ｍＬとなるように適量の注射用水を加えて混合した。
また１．５質量％の濃度になるようにグリセリン（メルク社製、分子量９２）を添加した。この液状医薬製剤のｐＨは、２．９であった。この液をメンブランフィルター（０．２２μｍ）を用いてろ過し、液状医薬製剤を得た。
この液状医薬製剤を、以下の治療で用いた。なお、治療は、米国テキサス州立大学ＭＤアンダーソンがんセンター（以下、ＭＤＡＣＣ）および米国コロラド州デンバー市にあるサラ・キャノン研究所（以下、ＳＣＲＩ）で行った。 Example 1
<Preparation of Methanesulfonate of Compound A>
The methanesulfonic acid salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (hereinafter also referred to as compound A) is described in WO 2013/146833 The compound was synthesized according to the method of (See Example 22 described in paragraph 0487 to paragraph 0492) and used in the following tests.
<Preparation of Liquid Pharmaceutical Composition>
The methanesulfonate salt of Compound A was dissolved in an appropriate amount of water for injection, and the pH was adjusted using a 1 mol / L aqueous sodium hydroxide solution. An appropriate amount of water for injection was added and mixed such that the concentration of Compound A was 20 mg / mL.
Further, glycerin (manufactured by Merck, molecular weight 92) was added to a concentration of 1.5% by mass. The pH of this liquid pharmaceutical preparation was 2.9. This solution was filtered using a membrane filter (0.22 μm) to obtain a liquid pharmaceutical preparation.
This liquid pharmaceutical preparation was used in the following treatment. The treatment was conducted at the University of Texas MD Anderson Cancer Center (hereinafter MDACC) and at the Sara Cannon Research Institute (SCRI) located in Denver, Colorado.
＜投与および治療効果の判定＞
胆管がん患者に対して、第１週目～第３週目までは週一回、化合物Ａを静脈注射により投与し、第４週目は投薬しないという投薬サイクルを繰り返した。具体的には、２８日間を１サイクルとして、第１日目、第８日目および第１５日目に化合物Ａを投与し、この２８日間からなるサイクルを繰り返した。化合物Ａの一回の投与当たりの投与量は、４０ｍｇ／ｍ２～９０ｍｇ／ｍ２とした。 <Determination of administration and treatment effect>
For patients with cholangiocarcinoma, Compound A was administered by intravenous injection once a week from the first week to the third week, and the dosing cycle was repeated with no dosing at the fourth week. Specifically, Compound A was administered ondays 1, 8, and 15, with 28 days as one cycle, and the cycle consisting of 28 days was repeated. The dose per single dose of Compound A was 40 mg / m 2 to 90 mg / m 2 .
胆管がん患者に対して、第１週目～第３週目までは週一回、化合物Ａを静脈注射により投与し、第４週目は投薬しないという投薬サイクルを繰り返した。具体的には、２８日間を１サイクルとして、第１日目、第８日目および第１５日目に化合物Ａを投与し、この２８日間からなるサイクルを繰り返した。化合物Ａの一回の投与当たりの投与量は、４０ｍｇ／ｍ２～９０ｍｇ／ｍ２とした。 <Determination of administration and treatment effect>
For patients with cholangiocarcinoma, Compound A was administered by intravenous injection once a week from the first week to the third week, and the dosing cycle was repeated with no dosing at the fourth week. Specifically, Compound A was administered on
治療の効果は、以下の基準で判定した。
ＭＲＩ（核磁気共鳴画像法；ｍａｇｎｅｔｉｃ ｒｅｓｏｎａｎｃｅ ｉｍａｇｉｎｇ）による画像診断により評価対象を確認し、以下の基準で判定した。
ＣＲ（Ｃｏｍｐｌｅｔｅ Ｒｅｓｐｏｎｓｅ）：腫瘍が完全に消失した状態
ＰＲ（Ｐａｒｔｉａｌ Ｒｅｓｐｏｎｓｅ）：腫瘍の大きさの和が３０％以上減少した状態
ＳＤ（Ｓｔａｂｌｅ Ｄｉｓｅａｓｅ）：腫瘍の大きさが変化しない状態
ＰＤ（Ｐｒｏｇｒｅｓｓｉｖｅ Ｄｉｓｅａｓｅ）：腫瘍の大きさの和が２０％以上増加かつ絶対値でも５ｍｍ以上増加した状態、あるいは新病変が出現した状態 The effect of the treatment was determined based on the following criteria.
The evaluation target was confirmed by image diagnosis by MRI (magnetic resonance imaging), and was judged based on the following criteria.
CR (Complete Response): A state in which the tumor has completely disappeared PR (Partial Response): A state in which the sum of tumor sizes has decreased by 30% or more
SD (Stable Disease): A state in which the size of the tumor does not change PD (Progressive Disease): A state in which the sum of the size of the tumor has increased by 20% or more and an absolute value by 5 mm or more, or a new lesion appears
ＭＲＩ（核磁気共鳴画像法；ｍａｇｎｅｔｉｃ ｒｅｓｏｎａｎｃｅ ｉｍａｇｉｎｇ）による画像診断により評価対象を確認し、以下の基準で判定した。
ＣＲ（Ｃｏｍｐｌｅｔｅ Ｒｅｓｐｏｎｓｅ）：腫瘍が完全に消失した状態
ＰＲ（Ｐａｒｔｉａｌ Ｒｅｓｐｏｎｓｅ）：腫瘍の大きさの和が３０％以上減少した状態
ＳＤ（Ｓｔａｂｌｅ Ｄｉｓｅａｓｅ）：腫瘍の大きさが変化しない状態
ＰＤ（Ｐｒｏｇｒｅｓｓｉｖｅ Ｄｉｓｅａｓｅ）：腫瘍の大きさの和が２０％以上増加かつ絶対値でも５ｍｍ以上増加した状態、あるいは新病変が出現した状態 The effect of the treatment was determined based on the following criteria.
The evaluation target was confirmed by image diagnosis by MRI (magnetic resonance imaging), and was judged based on the following criteria.
CR (Complete Response): A state in which the tumor has completely disappeared PR (Partial Response): A state in which the sum of tumor sizes has decreased by 30% or more
SD (Stable Disease): A state in which the size of the tumor does not change PD (Progressive Disease): A state in which the sum of the size of the tumor has increased by 20% or more and an absolute value by 5 mm or more, or a new lesion appears
（胆管がん患者１）
化合物Ａを１回の投与当たり４０ｍｇ／ｍ２で投与した胆管がん（肝内胆管がん）患者１名において、４サイクル（１６週間）後に３１％の腫瘍縮小効果が確認された（図１）。
また、1回の投与量を６０ｍｇ／ｍ２及び９０ｍｇ／ｍ２と増量した場合でもＰＲが確認された。
この患者は、前治療として、ゲムシタビンおよびシスプラチンの併用化学療法を受けていたが、前治療の結果はＰＤであった。また、ＩＤＨ１変異（Ｒ１３２Ｓ）を有していた。患者の年齢、性別、治療施設、１回の投与量、治療歴、本発明の治療効果などを表１に示す。以下、同様。 (Bile duct cancer patients 1)
In 1 patient with cholangiocarcinoma (intrahepatic cholangiocarcinoma) treated with 40 mg / m 2 of Compound A per administration, 31% of tumor reduction effect was confirmed after 4 cycles (16 weeks) (FIG. 1) ).
In addition, PR was confirmed even when the single dose was increased to 60 mg / m 2 and 90 mg / m 2 .
This patient had received prior chemotherapy with gemcitabine and cisplatin in combination chemotherapy, but the outcome of the prior treatment was PD. It also had an IDH1 mutation (R132S). The patient's age, sex, treatment facility, single dose, treatment history, treatment effect of the present invention, etc. are shown in Table 1. The same applies below.
化合物Ａを１回の投与当たり４０ｍｇ／ｍ２で投与した胆管がん（肝内胆管がん）患者１名において、４サイクル（１６週間）後に３１％の腫瘍縮小効果が確認された（図１）。
また、1回の投与量を６０ｍｇ／ｍ２及び９０ｍｇ／ｍ２と増量した場合でもＰＲが確認された。
この患者は、前治療として、ゲムシタビンおよびシスプラチンの併用化学療法を受けていたが、前治療の結果はＰＤであった。また、ＩＤＨ１変異（Ｒ１３２Ｓ）を有していた。患者の年齢、性別、治療施設、１回の投与量、治療歴、本発明の治療効果などを表１に示す。以下、同様。 (Bile duct cancer patients 1)
In 1 patient with cholangiocarcinoma (intrahepatic cholangiocarcinoma) treated with 40 mg / m 2 of Compound A per administration, 31% of tumor reduction effect was confirmed after 4 cycles (16 weeks) (FIG. 1) ).
In addition, PR was confirmed even when the single dose was increased to 60 mg / m 2 and 90 mg / m 2 .
This patient had received prior chemotherapy with gemcitabine and cisplatin in combination chemotherapy, but the outcome of the prior treatment was PD. It also had an IDH1 mutation (R132S). The patient's age, sex, treatment facility, single dose, treatment history, treatment effect of the present invention, etc. are shown in Table 1. The same applies below.
（胆管がん患者２）
化合物Ａを１回の投与当たり６０ｍｇ／ｍ２で投与した胆管がん（肝内胆管がん）患者１名においては、２サイクル後に３１％の腫瘍縮小効果が確認され、４サイクル後に４１％の腫瘍縮小効果が確認された（図２）。この患者は、前治療として、ゲムシタビンおよびシスプラチンの併用化学療法、ならびにゲムシタビンおよびカペシタビンの併用化学療法を受けていた。前治療の結果はＳＤであった。また、ＩＤＨ１変異（Ｒ１３２Ｃ）を有していた。詳細は、表１に示す。 (Bile duct cancer patients 2)
In one patient with cholangiocarcinoma (intrahepatic cholangiocarcinoma) who received Compound A at 60 mg / m 2 per administration, 31% tumor reduction effect was confirmed after 2 cycles and 41% after 4 cycles The tumor reduction effect was confirmed (FIG. 2). This patient had received prior treatment with combination chemotherapy with gemcitabine and cisplatin, and combination chemotherapy with gemcitabine and capecitabine. The result of the prior treatment was SD. It also had an IDH1 mutation (R132C). Details are shown in Table 1.
化合物Ａを１回の投与当たり６０ｍｇ／ｍ２で投与した胆管がん（肝内胆管がん）患者１名においては、２サイクル後に３１％の腫瘍縮小効果が確認され、４サイクル後に４１％の腫瘍縮小効果が確認された（図２）。この患者は、前治療として、ゲムシタビンおよびシスプラチンの併用化学療法、ならびにゲムシタビンおよびカペシタビンの併用化学療法を受けていた。前治療の結果はＳＤであった。また、ＩＤＨ１変異（Ｒ１３２Ｃ）を有していた。詳細は、表１に示す。 (Bile duct cancer patients 2)
In one patient with cholangiocarcinoma (intrahepatic cholangiocarcinoma) who received Compound A at 60 mg / m 2 per administration, 31% tumor reduction effect was confirmed after 2 cycles and 41% after 4 cycles The tumor reduction effect was confirmed (FIG. 2). This patient had received prior treatment with combination chemotherapy with gemcitabine and cisplatin, and combination chemotherapy with gemcitabine and capecitabine. The result of the prior treatment was SD. It also had an IDH1 mutation (R132C). Details are shown in Table 1.
（胆管がん患者１～３）
胆管がん患者１～３の年齢、性別、治療施設、１回の投与量、前治療（治療歴）、ECOG、本発明の治療効果などを表１に示す。 (Bile duct cancer patients 1-3)
The age, sex, treatment facility, single dose, previous treatment (treatment history), ECOG, treatment effect of the present invention, etc. of the patients with bile duct cancer 1 to 3 are shown in Table 1.
胆管がん患者１～３の年齢、性別、治療施設、１回の投与量、前治療（治療歴）、ECOG、本発明の治療効果などを表１に示す。 (Bile duct cancer patients 1-3)
The age, sex, treatment facility, single dose, previous treatment (treatment history), ECOG, treatment effect of the present invention, etc. of the patients with bile duct cancer 1 to 3 are shown in Table 1.
胆管がん患者を含む臨床試験で化合物Ａを投与された３８患者の血漿中濃度のCmax値を示したグラフである（図３）。また臨床試験では、２人以上の患者で最も一般的な薬物関連ＡＥは、発熱、吐き気、悪寒、かゆみ、かぶれ、乾燥皮膚、皮膚剥離、および疲労がみられた。
FIG. 3 is a graph showing Cmax values of plasma concentrations of 38 patients receiving Compound A in a clinical test including cholangiocarcinoma patients (FIG. 3). Also in clinical trials, the most common drug-related AEs in two or more patients were fever, nausea, chills, itching, rash, dry skin, skin abrasions, and fatigue.
また、本発明の有用性は、以下に記載するｉｎ ｖｉｔｒｏ試験でも確認することができる。
The utility of the present invention can also be confirmed by the in vitro tests described below.
実施例２
（胆管癌細胞株ＨｕＣＣＴ－１細胞を用いたｉｎ ｖｉｔｒｏ薬効試験）
ｐＩＲＥＳ ｐｕｒｏ ３ ｖｅｃｔｏｒにＩＤＨ１変異遺伝子（例えば、ＩＤＨ１Ｒ１３２Ｃ）を組み込み、ＩＤＨ１変異遺伝子の高発現ベクターを作製している。この発現ベクターを胆管癌細胞株であるＨｕＣＣＴ－１細胞に遺伝子導入を行い、ＩＤＨ１変異高発現細胞株を作製する。対照として遺伝子が入っていないｐＩＲＥＳ ｐｕｒｏ ３ ｖｅｃｔｏｒのみを遺伝子導入した細胞株を作製する（コントロール細胞株）。コントロール細胞株およびＩＤＨ１変異高発現細胞株に化合物Ａを添加し、薬効試験を行う。
この結果、ＩＤＨ変異遺伝子を有する細胞に対する化合物Ａの薬効が確認できる。 Example 2
(In vitro drug efficacy test using cholangiocarcinoma cell line HuCCT-1 cells)
An IDH1 mutant gene (eg, IDH1R132C) is incorporated into pIRES puro 3 vector to prepare a high expression vector of the IDH1 mutant gene. This expression vector is transfected into HuCCT-1 cells, which are cholangiocarcinoma cell lines, to produce IDH1 mutation-overexpressing cell lines. As a control, a cell line transfected with only pIRES puro 3 vector containing no gene is prepared (control cell line). Compound A is added to a control cell line and a cell line overexpressing IDH1 mutation to conduct a drug efficacy test.
As a result, the efficacy of Compound A on cells having the IDH mutant gene can be confirmed.
（胆管癌細胞株ＨｕＣＣＴ－１細胞を用いたｉｎ ｖｉｔｒｏ薬効試験）
ｐＩＲＥＳ ｐｕｒｏ ３ ｖｅｃｔｏｒにＩＤＨ１変異遺伝子（例えば、ＩＤＨ１Ｒ１３２Ｃ）を組み込み、ＩＤＨ１変異遺伝子の高発現ベクターを作製している。この発現ベクターを胆管癌細胞株であるＨｕＣＣＴ－１細胞に遺伝子導入を行い、ＩＤＨ１変異高発現細胞株を作製する。対照として遺伝子が入っていないｐＩＲＥＳ ｐｕｒｏ ３ ｖｅｃｔｏｒのみを遺伝子導入した細胞株を作製する（コントロール細胞株）。コントロール細胞株およびＩＤＨ１変異高発現細胞株に化合物Ａを添加し、薬効試験を行う。
この結果、ＩＤＨ変異遺伝子を有する細胞に対する化合物Ａの薬効が確認できる。 Example 2
(In vitro drug efficacy test using cholangiocarcinoma cell line HuCCT-1 cells)
An IDH1 mutant gene (eg, IDH1R132C) is incorporated into pIRES puro 3 vector to prepare a high expression vector of the IDH1 mutant gene. This expression vector is transfected into HuCCT-1 cells, which are cholangiocarcinoma cell lines, to produce IDH1 mutation-overexpressing cell lines. As a control, a cell line transfected with only pIRES puro 3 vector containing no gene is prepared (control cell line). Compound A is added to a control cell line and a cell line overexpressing IDH1 mutation to conduct a drug efficacy test.
As a result, the efficacy of Compound A on cells having the IDH mutant gene can be confirmed.
上記の胆管癌細胞株以外に、大腸癌、膀胱癌、軟骨肉腫及び急性骨髄性白血病などの細胞株でも同様に実験を行うことで、同様の薬効が確認できる。
In addition to the above-mentioned cholangiocarcinoma cell lines, similar drug effects can be confirmed by conducting experiments in the same manner with cell lines such as colon cancer, bladder cancer, chondrosarcoma and acute myeloid leukemia.
本発明の医薬組成物は、ＩＤＨ変異を有する腫瘍に対して治療効果を示す医薬組成物として有用である。
The pharmaceutical composition of the present invention is useful as a pharmaceutical composition having a therapeutic effect on a tumor having an IDH mutation.
Claims (13)
- １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、
イソクエン酸デヒドロゲナーゼ変異を有する腫瘍を処置するための、医薬組成物。 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or salts or prodrugs thereof
A pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation. - イソクエン酸デヒドロゲナーゼ変異が、イソクエン酸デヒドロゲナーゼ１変異またはイソクエン酸デヒドロゲナーゼ２変異より選択される少なくとも一つの遺伝子変異である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the isocitrate dehydrogenase mutation is at least one gene mutation selected from isocitrate dehydrogenase 1 mutation or isocitrate dehydrogenase 2 mutation.
- 腫瘍にイソクエン酸デヒドロゲナーゼ１変異を有する患者を対象として使用される、請求項１または２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, which is used for a patient having an isocitrate dehydrogenase 1 mutation in a tumor.
- イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアミノ酸の変異である、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the isocitrate dehydrogenase 1 mutation is a mutation at the 132nd amino acid.
- イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのヒスチジン、システイン、セリン、グリシン、ロイシン、バリンまたはグルタミンへの置換である、請求項４に記載の医薬組成物。 The pharmaceutical composition according to claim 4, wherein the isocitrate dehydrogenase 1 mutation is substitution of arginine at position 132 with histidine, cysteine, serine, glycine, leucine, valine or glutamine.
- イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのシステイン、セリン、グリシンまたはロイシンへの置換である、請求項４または５に記載の医薬組成物。 The pharmaceutical composition according to claim 4 or 5, wherein the isocitrate dehydrogenase 1 mutation is substitution of arginine at position 132 with cysteine, serine, glycine or leucine.
- イソクエン酸デヒドロゲナーゼ１変異が、１３２番目のアルギニンからのシステインまたはセリンへの置換である、請求項４から６に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 4 to 6, wherein the isocitrate dehydrogenase 1 mutation is a substitution from arginine at position 132 to cysteine or serine.
- 腫瘍が、脳腫瘍（神経膠腫を含む）、急性骨髄性白血病、骨髄異形成症候群、骨髄増殖性腫瘍、末梢性Ｔ細胞性リンパ腫、軟骨肉腫、骨肉腫、胸腺腫、肝臓がん、胆道がん、褐色細胞種、傍神経節腫、原始神経外胚葉腫瘍、Ｂリンパ芽球性リンパ腫、悪性黒色腫、乳がん、前立腺がん、大腸がん、膀胱がんまたは甲状腺がんである請求項１から７に記載の医薬組成物。 Tumors include brain tumor (including glioma), acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative tumor, peripheral T cell lymphoma, chondrosarcoma, osteosarcoma, thymoma, liver cancer, biliary tract cancer , Pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B-lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colon cancer, bladder cancer or thyroid cancer. Pharmaceutical composition as described in-.
- 腫瘍が、胆道がんである、請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8, wherein the tumor is biliary cancer.
- １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍に対する抗腫瘍剤。 An antitumor agent against a tumor having an isocitrate dehydrogenase mutation, which comprises 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof.
- イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置用医薬組成物の製造のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの使用。 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the preparation of a pharmaceutical composition for treating a tumor having an isocitrate dehydrogenase mutation Use of.
- イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置のための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグ。 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of a tumor having an isocitrate dehydrogenase mutation.
- １－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩もしくはプロドラッグの有効量を対象に投与することを含む、イソクエン酸デヒドロゲナーゼ変異を有する腫瘍の処置方法。 Tumor having an isocitrate dehydrogenase mutation, comprising administering to the subject an effective amount of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt or prodrug thereof Treatment method.
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| US201862623293P | 2018-01-29 | 2018-01-29 | |
| US62/623,293 | 2018-01-29 |
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| WO2023008511A1 (en) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Pharmaceutical composition and anti-tumor agent for tumors that have at least either impaired bap1 or pbrm1 function |
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| WO1997038001A1 (en) * | 1996-04-09 | 1997-10-16 | Yamasa Corporation | 1-(2-DEOXY-2-FLUORO-4-THIO-β-D-ARABINOFURANOSYL)CYTOSINES |
| WO2016052697A1 (en) * | 2014-10-01 | 2016-04-07 | 第一三共株式会社 | Isoxazole derivative as mutated isocitrate dehydrogenase 1 inhibitor |
| JP2018500360A (en) * | 2014-12-22 | 2018-01-11 | ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Mutant IDH1 inhibitor useful for cancer treatment |
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2018
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| WO1997038001A1 (en) * | 1996-04-09 | 1997-10-16 | Yamasa Corporation | 1-(2-DEOXY-2-FLUORO-4-THIO-β-D-ARABINOFURANOSYL)CYTOSINES |
| WO2016052697A1 (en) * | 2014-10-01 | 2016-04-07 | 第一三共株式会社 | Isoxazole derivative as mutated isocitrate dehydrogenase 1 inhibitor |
| JP2018500360A (en) * | 2014-12-22 | 2018-01-11 | ザ ユナイテッド ステイツ オブ アメリカ， アズ リプレゼンテッド バイ ザ セクレタリー， デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Mutant IDH1 inhibitor useful for cancer treatment |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023008511A1 (en) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Pharmaceutical composition and anti-tumor agent for tumors that have at least either impaired bap1 or pbrm1 function |
| KR20240028451A (en) | 2021-07-29 | 2024-03-05 | 후지필름 가부시키가이샤 | Pharmaceutical composition and anti-tumor agent for tumors with decreased function of at least one of BAP1 and PBRM1 |
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| TW201932120A (en) | 2019-08-16 |
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