TW201932120A - Pharmaceutical composition for tumor having isocitrate dehydrogenase mutation, antitumor agent and use thereof - Google Patents

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-[beta]-D-arabinofuranosyl)cytosine or a salt or a prodrug thereof.

Description

Pharmaceutical composition and antitumor agent for tumor with isocitrate dehydrogenase mutation and application thereof

The present invention relates to a pharmaceutical composition and an antitumor agent for a tumor having an isocitrate dehydrogenase mutation.

1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine) (hereinafter may be simply referred to as "compound A") has excellent antitumor activity and is useful as an antitumor agent (Patent Document 1). In addition, it is known that Compound A also has strong antitumor activity in oral administration to mice (Non-Patent Document 1 to Non-Patent Document 3). In addition, a salt of a compound A, a prodrug, an injection, and a production method are also known (Patent Documents 2 to 6).

Isocitrate dehydrogenase (IDH) is a compound that uses NADP + as a coenzyme and catalyzes isocitrate to 2-oxoglutarate (α-ketoglutarate) as an intermediate in the citric acid circuit (TCA circuit). , Α-ketoglutarate, αKG). It is known that IDH1 is localized in the cytoplasm, and IDH2 is localized in mitochondria, and mutations have been confirmed in these two genes. IDH mutations are genetic mutations found in a variety of malignant tumors such as acute myeloid leukemia or glioma, chondrosarcoma, and bile duct cancer. IDH gene mutations (IDH mutations) that encode IDH form wild-type and heterodimers, which are characterized by the presence of hotspots in the mutated amino acid, and the mutation sites are focused on enzymes. Among the amino acids important for the reaction or in the vicinity of the amino acids (Patent Document 7). In the case of IDH1, mutations in which the 132nd arginine (hereinafter referred to as R132) of the IDH1 protein is substituted with another amino acid account for the majority. For example, it is known that the mutation of the 132nd arginine is converted to histidine (expressed as R132H) or cysteine (R132C), leucine (R132L), serine (R132S) Mutations of Glycine (R132G), Valine (R132V), etc. In addition, examples of mutations in G97, R100, H133, A134 and the like are also known. Most of the IDH2 gene mutations are mutations in which R140 or R172 is converted to other amino acids. For example, R140Q mutation, R172K, R172S mutation and the like are known. Such IDH mutations are known to be gain-of-function mutations and produce 2-hydroxyglutarate (2HG) as a cancer metabolite (oncometabolite), which competitively blocks αKG and brings epigenetic The change contributes to the malignancy of the tumor (Non-Patent Document 4). [Prior Art Literature] [Patent Literature]

[Patent Literature 1] International Publication No. 1997/038001 [Patent Literature 2] International Publication No. 2013/146833 [Patent Literature 3] International Publication No. 2011/074484 [Patent Literature 4] International Publication No. 2014/027658 Manual [Patent Literature 5] International Publication No. 2016/068341 [Patent Literature 6] International Publication No. 2017/150511 [Patent Literature 7] International Publication No. 2016/052697 [Non-Patent Literature]

[Non-Patent Document 1] "Cancer Letters", 1998, Vol. 129, p103-110 [Non-Patent Document 2] "Cancer Letters", 1999, Vol. 144, p177-182 [Non-Patent Literature 3] "Oncology Reports", 2002, Volume 9, p1319-1322 [Non-Patent Literature 4] "Experimental Medicine", 2017, Volume 10 (Supplement), p165-170

[Problems to be Solved by the Invention] So far, there have been no reports of a compound A specifically exhibiting a therapeutic effect on a tumor having an IDH mutation. An object of the present invention is to provide a pharmaceutical composition and an antitumor agent exhibiting an effect on a tumor having an IDH mutation, and a method for preventing or treating a tumor having an IDH mutation. [Means for solving problems]

The present inventors made intensive studies in order to solve the above problems, and as a result, they found that Compound A exerts a therapeutic effect on a tumor having an IDH mutation, and completed the present invention.

That is, the present invention provides the following. (1) A pharmaceutical composition comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, and Treat tumors with isocitrate dehydrogenase mutations. (2) The pharmaceutical composition according to (1), wherein the isocitrate dehydrogenase mutation is at least one genetic mutation selected from the group consisting of an isocitrate dehydrogenase 1 mutation and an 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 is mutated to a 132nd amino acid mutation. (5) The pharmaceutical composition according to (4), wherein the isocitrate dehydrogenase 1 is mutated from the 132nd sperine to histidine (R132H), cysteine (R132C), and serine (R132S), glycine (R132G), leucine (R132L), valine (R132V) or glutamic acid (R132Q). (6) The pharmaceutical composition according to (4) or (5), wherein the isocitrate dehydrogenase 1 is mutated from the 132nd sperine to cysteine, serine, glycine, or white Substitution of amino acids. (7) The pharmaceutical composition according to (4) to (6), wherein the isocitrate dehydrogenase 1 is mutated from the 132nd arginine to cysteine or serine. (8) The pharmaceutical composition according to (1) to (7), wherein the tumor is a brain tumor (including glioma), acute myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative 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 , Colorectal cancer, bladder cancer, or thyroid cancer. (9) The pharmaceutical composition according to (8), wherein the tumor is a biliary tract cancer. (10) An antitumor agent for treating a tumor having an isocitrate dehydrogenase mutation, comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cell Pyrimidine, or a salt thereof, or a prodrug thereof. (11) Use of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, which is used for producing iso lemon Pharmaceutical composition for treating acid dehydrogenase-mutated tumors. (12) A 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, which is used for the treatment of Catalase mutations in tumors. (13) A method for treating a tumor having an isocitrate dehydrogenase mutation, which comprises administering a 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cell to a subject. An effective amount of pyrimidine, or a salt thereof, or a prodrug thereof. (14) A method for treating a tumor having an isocitrate dehydrogenase mutation, which comprises administering a 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cell to a subject. An effective amount of pyrimidine, a salt thereof, or a prodrug thereof includes a step of confirming the presence or absence of an isocitrate dehydrogenase mutation in the subject before the administration. [Effect of the invention]

Compound A has a therapeutic effect on tumors with an isocitrate dehydrogenase (IDH) mutation. That is, according to the present invention, there are provided a pharmaceutical composition and an antitumor agent exhibiting an effect on a tumor having an IDH mutation, and a method for treating a tumor having an IDH mutation.

In the present invention, the ranges indicated by "~" include values at both ends, except when specifically noted. The "subject" refers to mammals such as humans, mice, monkeys, and domestic animals in need of prevention or treatment, and is preferably a human in need of prevention or treatment. The term "prevention" refers to obstructing the onset, reducing the risk of onset, or delaying onset. The "treatment" refers to improvement or suppression (maintenance or delay) of a target disease or condition. The "treatment" refers to the prevention or treatment of various diseases. The so-called "tumor" refers to benign or malignant tumors. The so-called "benign tumor" refers to a tumor whose tumor cells and their arrangement have a shape similar to that of their original normal cells, and are non-invasive or metastatic. The so-called "malignant tumor" refers to a tumor whose morphology or arrangement is different from that of its original normal cells and shows invasive or metastatic tumors.

Hereinafter, the present invention will be described in detail. The present invention comprises 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (Compound A), or a salt thereof, or a prodrug thereof, and is used for treating Pharmaceutical composition of IDH mutant tumors.

(Compound A, or a salt thereof, or a prodrug thereof) First, compound A, a salt thereof, or a prodrug thereof will be described. Examples of the salt include pharmaceutically acceptable salts, and specific examples include mineral salts, organic carboxylates, and sulfonates. Preferred salts include mineral salts and sulfonates.

Examples of the mineral salt include hydrochloride, hydrobromide, hydroiodate, nitrate, phosphate, and sulfate, and the hydrochloride, hydroiodate, nitrate, or sulfate is preferred, and more Preferred is the hydrochloride. Examples of the organic carboxylate include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, and aspartic acid. Salt, trichloroacetate and trifluoroacetate. Examples of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate, and naphthalenesulfonate. Methanesulfonate is preferred.

The salt of compound A may be an anhydrate, a hydrate, or a solvent. In the present specification, when simply referred to as "salt", the form may be an anhydrous substance, a hydrate, or a solvent. In the present specification, the term "anhydrous" refers to a state in which it is in a state of neither a hydrate nor a solvent, unless otherwise specified. Originally, even if it is a substance which does not form a hydrate or a solvent, the salt of the compound A which does not have water of crystallization, hydration, and interaction is included in the "anhydride" in this invention. Anhydrous is sometimes referred to as "anhydrate." When the salt of the compound A is a hydrate, the amount of hydrated water is not particularly limited, and may be a monohydrate, a dihydrate, or the like. Examples of the solvent compound include a methanolate, an ethanolate, a propanolate, and a 2-propanolate.

Specific examples of particularly preferred salts of the compound A are described below. 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine mesylate; 1- (2-deoxy-2-fluoro-4-thio-β -D-arabinofuranosyl) cytosine hydrochloride; and any anhydrous form of said salt.

The prodrug refers to a compound or a salt thereof that is cleaved by a functional group that functions as a prodrug after administration, and is converted into a compound showing a target pharmacological activity by a reaction such as an enzyme in the body or gastric juice. As a basis for forming a prodrug, for example, Stella VJ (Stella VJ) and others, "Prodrugs: Challenges and Rewards" (Parts 1 and 2) (Parts 1 and 2), In 2007, the base was recorded in the American Association of Pharmaceutical Scientists.

The prodrug of the compound A refers to a compound or a salt thereof converted to the compound A or its phosphate compound by a reaction such as an enzyme or gastric juice under physiological conditions in a living body. As a prodrug of Compound A, reference may be made to the description of International Publication No. 2016/068341, and these contents are incorporated into the specification of the present application. More specifically, for example, a thionucleoside derivative represented by the general formula [1] described in International Publication No. 2016/068341 or a salt thereof is incorporated into the specification of the present application. The scope is also the same as the scope described in International Publication No. 2016/068341.

In the present invention, compound A, a salt thereof, or a prodrug thereof may be used alone, or may contain two or more.

Next, the manufacturing method of the compound A, its salt, or its precursor is demonstrated. Compound A can be produced, for example, by the methods described in Patent Document 1 and "Journal of Organic Chemistry" (1999, Vol. 64, p7912-7920). The salt of the compound A or a hydrate or a solvent thereof can be produced, for example, by a method described in Patent Document 4. The precursor of the compound A can be produced, for example, by a method described in International Publication No. 2016/068341. The compound A of the present invention, a salt thereof, or a prodrug thereof can be used as an active ingredient of an antitumor agent or a pharmaceutical composition.

(Pharmaceutical composition) According to the present invention, there is provided 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, and Pharmaceutical composition for treating tumors with IDH mutations.

The pharmaceutical composition of the present invention may also generally include an emulsifier, a surfactant, a dissolution aid, a suspending agent, a tonicity adjusting agent, a buffering agent, a preservative, an antioxidant, a stabilizer, and an absorption promotion agent. Agents and other additives.

Examples of the route of administration of the pharmaceutical composition of the present invention include intravenous, intraarterial, intrarectal, intraperitoneal, intramuscular, intratumoral, or intravesical injection methods, oral administration, transdermal administration, and / or Suppositories and other methods. Examples of the administration method include administration using a syringe or drip.

The compound A, or a salt thereof, or the amount of the prodrug and the number of administrations can be divided into one or more times and administered from 1 mg / m ² to 2000 mg / m ² per day. The daily dosage 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 even more preferably 80 mg / m ² to 120 mg / m ² . However, it is not limited to these doses and times.

As a method of administration, the treatment can be repeated several times with a dose of 20 mg / m ² or more and withdrawn once a week for 3 weeks for 4 weeks. In this case, the dose once is preferably 40 mg / m ² to 200 mg / m ² , and more preferably 80 mg / m ² to 150 mg / m ² . It is preferable to confirm the presence or absence of an isocitrate dehydrogenase mutation (IDH mutation confirmation step) before the administration.

Examples of the dosage form of the pharmaceutical composition of the present invention include liquid pharmaceutical preparations, and examples include injections. The administration dosage form can be produced by a preparation method which is well-known to those skilled in the art. The liquid pharmaceutical preparation preferably contains Compound A or a salt thereof, a polyol 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 mg / mL to 50 mg / mL, more preferably 5 mg / mL to 50 mg / mL, and particularly preferably 10 mg / mL to 30 mg / mL. 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 glycerol, propylene glycol or butanediol, and particularly preferably glycerol. Examples of the butanediol include 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, and 2,3-butanediol. Particularly preferred is 1,3-butanediol. Diol. The lower limit of the molecular weight of the polyol is not particularly limited, but is usually 50 or more. The content of the polyhydric alcohol having a molecular weight of 100 or less in the liquid pharmaceutical preparation is preferably 0.5% by mass to 10% by mass, more preferably 0.5% by mass to 5% by mass, and even more preferably 1.0% by mass to 2.5% by 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, still more preferably 2.0 to 5.0, even more preferably 2.0 to 4.0, and particularly preferably 2.6 to 3.2. , The best is 2.8 to 3.0. As a liquid pharmaceutical preparation, the description of International Publication No. 2017/150511 can be cited and referred to, and these contents are incorporated into the specification of this application. Moreover, the preferable composition or the preferable mixing ratio of the liquid pharmaceutical preparation is also the same as the composition or the mixing ratio described in International Publication No. 2017/150511.

The pharmaceutical composition of the present invention can be effectively used in, for example, brain tumors (including gliomas), acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative tumors, peripheral T-cell lymphoma, chondrosarcoma, osteosarcoma, and thymus Tumor, liver cancer, biliary tract cancer, pheochromocytoma, paraganglioma, primitive neuroectodermal tumor, B lymphoblastic lymphoma, malignant melanoma, breast cancer, prostate cancer, colorectal cancer, bladder cancer or thyroid cancer, etc. Treatment of tumors with IDH mutations. The pharmaceutical composition of the present invention is particularly suitable for the treatment of tumors having IDH mutations such as biliary cancer. Bile duct cancer is preferably bile duct cancer, more preferably extrahepatic bile duct cancer or intrahepatic bile duct cancer.

(Isocitrate dehydrogenase mutation) Examples of the isocitrate dehydrogenase mutation (IDH mutation) in the present invention include a mutation of the 132nd arginine (hereinafter referred to as R132) of IDH1 and a mutation of G97. , R100 mutation, H133 mutation, A134 mutation, but it is not limited to these. Examples of mutations in R132 include substitution to histidine (R132H), substitution to cysteine (R132C), substitution to leucine (R132L), and substitution to serine (R132S). ), Substitution to glycine (R132G), substitution to valine (R132V), but it is not limited to these. The pharmaceutical composition of the present invention is better for treating tumors having IDH mutations that are at least one gene mutation selected from IDH1 mutations or IDH2 mutations, and more preferably for treating tumors having IDH1 mutations. The mutation with the IDH1 mutation to the 132th amino acid, that is, the 132th arginine, and the substitution from the 132nd arginine to cysteine (R132C), the substitution to serine (R132S), Glycine (R132G) or Leucine (R132L) mutant tumors are better treated, and have cysteine (R132C) or serine (R132S) ) For better treatment of substituted mutant tumors.

The present invention provides a method for administering an antitumor agent to a tumor patient having an isocitrate dehydrogenase mutation, and the antitumor agent comprises 1- (2-deoxy-2-fluoro-4-thio-β -D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof.

The invention provides a method for preventing or treating a tumor having an isocitrate dehydrogenase mutation, which comprises administering 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) to a subject. ) An effective administration amount of cytosine, or a salt thereof, or a prodrug thereof.

The present invention provides a method for using 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof. A method for the treatment of isocitrate dehydrogenase-mutated tumors, and includes the step of administering a therapeutically effective amount to a subject (a mammal including a human) in need of such treatment.

The target patient may be a patient who received gemcitabine as a pretreatment. The target patient may be a patient who has been given gemcitabine as a pre-treatment and has not confirmed the effect of partial response or more. Target patients include patients who have received gemcitabine and received chemotherapy as a pretreatment. The target patients may be patients who have received chemotherapy including gemcitabine and received pre-treatment with chemotherapy, and have not confirmed the effect of partial response or more. The target may be a patient who has undergone other chemotherapy. The target patients are those who have not anticipated improvement in other chemotherapy. According to the present invention, an improvement effect can be obtained even for such a patient who has not previously expected a therapeutic effect.

The present invention provides an antitumor agent for a tumor having an isocitrate dehydrogenase mutation, which comprises 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine , Or a salt thereof, or a prodrug thereof.

The present invention provides the use of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, which is used for producing iso lemon Pharmaceutical composition for treating acid dehydrogenase-mutated tumors.

The present invention provides a 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof for use in isocitrate removal. Used in the treatment of catalase-mutated tumors. [Example]

Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited by these examples.

Example 1 <Preparation of mesylate salt of compound A> 1- (2-deoxy-2) was synthesized according to the method described in the International Publication No. 2013/146833 (refer to Example 22 described in paragraphs 0487 to 0492). -Fluoro-4-thio-β-D-arabinofuranosyl) cytosine (hereinafter, also referred to as compound A) is a mesylate salt, and was used in the following tests. <Preparation of liquid drug composition> The mesylate salt of Compound A was dissolved in an appropriate amount of water for injection, and the pH was adjusted using a 1 mol / L sodium hydroxide aqueous solution. An appropriate amount of water for injection was added and mixed so that the concentration of Compound A became 20 mg / mL. Glycerol (Merck, molecular weight 92) was added so as to have a concentration of 1.5% by mass. The pH of the liquid pharmaceutical preparation was 2.9. This liquid was filtered using a membrane filter (0.22 μm) to obtain a liquid pharmaceutical preparation. This liquid pharmaceutical preparation is used in the following treatments. Furthermore, treatment was performed at the Texas State University MD Anderson Cancer Center (hereinafter, MDACC (MD Anderson Cancer Center)) and Sara Cannon in Denver, Colorado. Institute (hereinafter, SCRI (Sarah Cannon Research Institute)).

<Determination of Dosage and Treatment Effect> In patients with cholangiocarcinoma, the administration cycle of Compound A by intravenous injection was repeated once a week from week 1 to week 3, and the drug was not administered at week 4. Specifically, 28 days were regarded as one cycle, and Compound A was administered on the first day, the eighth day, and the fifteenth day, and the cycle including the 28 days was repeated. The dosage of Compound A per administration is set to 40 mg / m ² to 90 mg / m ² .

The effect of treatment was judged based on the following criteria. The evaluation target was confirmed by image diagnosis using MRI (magnetic resonance imaging; magnetic resonance imaging), and the determination was made based on the following criteria. CR (Complete Response): The state where the tumor has completely disappeared PR (Partial Response): The state where the size of the tumor has decreased by more than 30% SD (Stable Disease): The state where the size of the tumor has not changed PD (Progressive Disease): A condition in which the sum of tumor sizes has increased by more than 20% and the absolute value has increased by more than 5 mm, or a condition in which a new lesion has appeared

(Bile duct cancer patient 1) A patient with bile duct cancer (intrahepatic bile duct cancer) who was administered Compound A at a dose of 40 mg / m ² per dose was confirmed to have 31 after 4 cycles (16 weeks) % Tumor shrinkage effect (Figure 1). In addition, PR was confirmed even in the case where the single dose was increased by 60 mg / m ² and 90 mg / m ² . This patient had received gemcitabine and cisplatin and received chemotherapy as a pretreatment, but the result of the previous treatment was PD. In addition, it has IDH1 mutation (R132S). Table 1 shows the patient's age, sex, treatment facility, single dose, history of treatment, and treatment effect of the present invention. Hereinafter, it is the same.

(Bile duct cancer patient 2) About 1 patient with bile duct cancer (intrahepatic cholangiocarcinoma) who was administered Compound A at 60 mg / m ² per dose, 31% of the tumors were confirmed to shrink after 2 cycles Effect, 41% tumor shrinkage effect was confirmed after 4 cycles (Figure 2). This patient had received gemcitabine and cisplatin combined chemotherapy, and gemcitabine and capecitabine combined chemotherapy as pretreatment. The result of the previous treatment was SD. In addition, it has an IDH1 mutation (R132C). The details are shown in Table 1.

(Bile duct cancer patients 1 to 3) Table 1 shows the age, sex, treatment facilities, single dose, pre-treatment (treatment history), ECOG, and treatment effect of the present invention for patients with bile duct cancer 1 to 3 .

[Table 1] In the table, ECOG refers to the Eastern Cooperative Oncology Group, Gem-Cis refers to the combined chemotherapy of gemcitabine and cisplatin, and Gem-Capecitabine refers to the combined chemotherapy of gemcitabine and capecitabine. In addition, patients with cholangiocarcinoma 1 to 2 have performed multiple previous treatments (history of treatment), so these are also described. The ECOG of patients with cholangiocarcinoma 1 is 0, and the ECOG of patients with cholangiocarcinoma 2-3 is 1.

A graph showing Cmax values of plasma concentrations of 38 patients administered Compound A in a clinical trial including patients with cholangiocarcinoma (Figure 3). In clinical trials, fever, nausea, chills, pruritus, macular rash, dry skin, skin peeling, and fatigue were found in the most common drug-related AEs in two or more patients.

The usefulness of the present invention can also be confirmed by an in vitro test described below.

Example 2 (In vitro efficacy test using bile duct cancer cell line HuCCT-1 cells) The pIRES puro 3 vector was incorporated with an IDH1 mutant gene (for example, IDH1R132C), and an expression vector for the IDH1 mutant gene was produced. ). Regarding this expression vector, HuCCT-1 cells, which are bile duct cancer cell lines, were genetically introduced to produce IDH1 mutant high-expression cell lines. As a control, a cell line (control cell line) in which only the gene pIRES puro 3 vector to which no gene was added was gene-transduced was prepared. Compound A was added to a control cell line and an IDH1 mutant high-expressing cell line, and a drug efficacy test was performed. As a result, it was confirmed that Compound A had a pharmacological effect on cells having an IDH mutant gene.

In addition to the above-mentioned cholangiocarcinoma cell lines, experiments were performed similarly on cell lines such as colorectal cancer, bladder cancer, chondrosarcoma, and acute myeloid leukemia, and the same drug effect was confirmed. [Industrial availability]

The pharmaceutical composition of the present invention is useful as a pharmaceutical composition that exhibits a therapeutic effect on a tumor having an IDH mutation.

no

FIG. 1 shows the results of image diagnosis for a cholangiocarcinoma patient 1 having an IDH mutation. FIG. 2 shows the results of image diagnosis on a bile duct cancer patient 2 having an IDH mutation. FIG. 3 is a graph showing Cmax values of plasma concentrations of patients administered Compound A in a clinical trial.

Claims (13)

A medicinal composition comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, and used for treating iso lemon Acid Dehydrogenase Mutations in Tumors. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the isocitrate dehydrogenase mutation is at least one genetic mutation selected from the group consisting of an isocitrate dehydrogenase 1 mutation and an isocitrate dehydrogenase 2 mutation. . The pharmaceutical composition according to item 1 or item 2 of the scope of patent application, wherein a patient having an isocitrate dehydrogenase 1 mutation in the tumor is used as a subject. The pharmaceutical composition according to item 3 of the scope of patent application, wherein the isocitrate dehydrogenase 1 is mutated to a 132th amino acid mutation. The pharmaceutical composition according to item 4 of the scope of patent application, wherein the isocitrate dehydrogenase 1 is mutated from the 132nd arginine to histidine, cysteine, serine, and glycine , Leucine, valine or glutamine. The pharmaceutical composition according to item 4 or item 5 of the scope of patent application, wherein the isocitrate dehydrogenase 1 is mutated from the 132nd arginine to cysteine, serine, and glycine Or leucine. The pharmaceutical composition according to any one of claims 4 to 6, in which the isocitrate dehydrogenase 1 is mutated from the 132nd arginine to cysteine or serine Replacement. The pharmaceutical composition according to any one of claims 1 to 7, in which the tumor is a brain tumor, a glioma, an acute myeloid leukemia, a bone marrow dysplasia syndrome, a bone marrow proliferative tumor, and a 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, colorectal cancer, bladder cancer or thyroid cancer. The pharmaceutical composition according to item 8 of the scope of patent application, wherein the tumor is a biliary tract cancer. An antitumor agent for a tumor having an isocitrate dehydrogenase mutation, comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or Salt, or its prodrug. Use of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, for the production of isohydrogen dehydrogenation Pharmaceutical composition for treating enzyme-mutated tumors. 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, or a salt thereof, or a prodrug thereof, which is used to treat mutations with isocitrate dehydrogenase Tumor. A method for treating a tumor having an isocitrate dehydrogenase mutation, which comprises administering 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine to a subject, or An effective amount of its salt, or its prodrug.