WO2016175252A1 - Pharmaceutical composition containing pyrazinecarboxamide compound as active ingredient - Google Patents

Pharmaceutical composition containing pyrazinecarboxamide compound as active ingredient Download PDF

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WO2016175252A1
WO2016175252A1 PCT/JP2016/063246 JP2016063246W WO2016175252A1 WO 2016175252 A1 WO2016175252 A1 WO 2016175252A1 JP 2016063246 W JP2016063246 W JP 2016063246W WO 2016175252 A1 WO2016175252 A1 WO 2016175252A1
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bmx
cancer
compound
pharmaceutical composition
pharmaceutically acceptable
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PCT/JP2016/063246
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French (fr)
Japanese (ja)
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智史 小長井
博子 山本
秀樹 坂上
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アステラス製薬株式会社
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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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings

Definitions

  • the present invention relates to a pharmaceutical composition for treating cancer related to BMX, comprising a pyrazinecarboxamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • BMX bone marrow tyrosine kinase in chromosome X
  • BMX is a non-receptor tyrosine kinase belonging to the Tec family kinase, a protein having a PH (pleckstrin homology) domain, an Src homology 3 domain, an Src homology 2 domain, and a kinase domain . It has been reported that BMX is expressed in epithelial cells and endothelial cells in normal tissues (Proc. Natl. Acad. Sci. USA 1998; 95: 3644-3649).
  • BMX is involved in the growth of BMX-related cancers, including prostate cancer, bladder cancer, and renal cell carcinoma, such as those with high expression or activation of BMX. ing.
  • Compound A 5- ⁇ [(3R) -1-acryloylpyrrolidin-3-yl] oxy ⁇ -6-ethyl-3-( ⁇ 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl ⁇ Amino) pyrazine-2-carboxamide (hereinafter sometimes referred to as “Compound A”) or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for treating cancer having an EGFR T790M mutation. It is known that there is (Patent Document 1).
  • Compound A or a pharmaceutically acceptable salt thereof is disclosed in Patent Document 1 as its free form as Example 54 and its monomethanesulfonate as Example 261, and has an inhibitory action on EGFR mutant kinases. Has been confirmed. Further, in Patent Document 2 published after the priority date of the present application, Compound A or a pharmaceutically acceptable salt thereof is BTK (Bruton's tyrosine kinase), JAK3 (Janus kinase 3), ITK (IL2 inducible T cell kinase). Among them, it is disclosed that it is useful as an active ingredient of a pharmaceutical composition for treating cancer involving one or more kinases.
  • BTK Brun's tyrosine kinase
  • JAK3 Janus kinase 3
  • ITK IL2 inducible T cell kinase
  • a pharmaceutical composition for treating cancer related to BMX particularly a pharmaceutical composition for treating prostate cancer, bladder cancer and / or renal cell cancer.
  • the present invention relates to 5- ⁇ [(3R) -1-acryloylpyrrolidin-3-yl] oxy ⁇ -6-ethyl-3-( ⁇ 4- [4- (4-methylpiperazin-1-yl) piperidine.
  • 1-yl] phenyl ⁇ amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof a pharmaceutical composition for the treatment of cancer associated with BMX, in particular prostate cancer, bladder cancer, and / or
  • the present invention relates to a pharmaceutical composition for the treatment of renal cell carcinoma.
  • the present invention also relates to a therapeutic agent for cancer related to BMX containing Compound A or a pharmaceutically acceptable salt thereof, particularly a therapeutic agent for prostate cancer, bladder cancer, and / or renal cell carcinoma.
  • the present invention also relates to the use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer associated with BMX, in one embodiment, prostate cancer, bladder cancer, and / or Use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of renal cell carcinoma; Compound A or a pharmaceutically acceptable thereof for the treatment of cancer associated with BMX Use of salt, in certain embodiments, use of compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma; for the treatment of cancer associated with BMX Compound A or a pharmaceutically acceptable salt thereof, in certain embodiments, Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma; and Administer an effective amount of A or a pharmaceutically acceptable salt thereof to a subject A method for treating cancer related to BMX, comprising, as an aspect, administering to a subject an effective amount of Compound A or a pharmaceutically acceptable
  • Compound A or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has a BMX inhibitory action, and is a pharmaceutical composition for treating cancer related to BMX, particularly prostate cancer, bladder It can be used as an active ingredient of a pharmaceutical composition for treating cancer and / or renal cell carcinoma.
  • the chemical name of Compound A is 5- ⁇ [(3R) -1-acryloylpyrrolidin-3-yl] oxy ⁇ -6-ethyl-3-( ⁇ 4- [4- (4-methylpiperazine-1 -Yl) piperidin-1-yl] phenyl ⁇ amino) pyrazine-2-carboxamide, the chemical structure of which is shown below.
  • the cancer related to BMX means a cancer in which one of the causes of cancer is BMX, for example, a cancer in which BMX is highly expressed and / or activated.
  • prostate cancer, bladder cancer, and / or renal cell cancer An aspect is prostate cancer, an aspect is bladder cancer, an aspect is renal cell cancer, an aspect is prostate cancer that has acquired resistance to hormone therapy, and an aspect And prostate cancer in which androgen receptor is activated.
  • prostate cancer has acquired resistance to an androgen receptor antagonist.
  • a pharmaceutical composition for treating cancer related to BMX comprising Compound A or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating prostate cancer, bladder cancer, and / or renal cell cancer comprising Compound A or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for the treatment of cancer associated with BMX comprising Compound A monomethanesulfonate.
  • a pharmaceutical composition for treating prostate cancer, bladder cancer, and / or renal cell cancer comprising Compound A monomethanesulfonate.
  • Use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating cancer related to BMX Use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating cancer related to BMX.
  • use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating prostate cancer, bladder cancer, and / or renal cell cancer In one embodiment, the use of Compound A monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of cancer associated with BMX. In one embodiment, the use of Compound A monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma. (3) Use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of cancer associated with BMX. In one embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
  • the use of Compound A monomethanesulfonate for the treatment of cancer associated with BMX In one embodiment, the use of Compound A monomethanesulfonate for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
  • Compound A or a pharmaceutically acceptable salt thereof for the treatment of cancer related to BMX In one embodiment, Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
  • Compound A monomethanesulfonate for the treatment of cancer associated with BMX In certain embodiments, Compound A monomethanesulfonate for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
  • a method for treating cancer related to BMX comprising administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject.
  • a method for treating prostate cancer, bladder cancer, and / or renal cell cancer comprising administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject.
  • a method of treating cancer associated with BMX comprising administering to a subject an effective amount of Compound A monomethanesulfonate.
  • a method for treating prostate cancer, bladder cancer, and / or renal cell cancer comprising administering an effective amount of Compound A monomethanesulfonate to a subject.
  • Compound A or a pharmaceutically acceptable salt thereof can be obtained according to the method described in Patent Document 1 (International Publication No. 2013/108754) or a modified method thereof.
  • “Pharmaceutically acceptable salt of Compound A” means an acid addition salt of Compound A, specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphorus Inorganic acids such as acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfone Examples thereof include acid addition salts with organic acids such as acid (mesic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid.
  • organic acids such as acid (mesic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluen
  • the “pharmaceutically acceptable salt of Compound A” includes a solvate of Compound A, specifically, for example, a hydrate or an ethanolate, and further includes an acid addition salt of Compound A. Including solvates.
  • compound A free body
  • compound A monomethanesulfonate
  • a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof is usually used with excipients usually used in the art, that is, pharmaceutical excipients, pharmaceutical carriers, etc. It can be prepared by the method that has been described. Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or injection such as intraarticular, intravenous, intramuscular, suppository, transdermal solution, ointment, transdermal Any form of parenteral administration using a patch, a transmucosal liquid, a transmucosal patch, an inhalant or the like may be used.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are mixed with at least one inert excipient.
  • the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like.
  • the liquid composition contains generally used inert diluents such as purified water or ethanol, and further supplements such as solubilizers, wetting agents, and suspending agents, sweeteners, flavors, and fragrances. And may contain a preservative.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include alcohols such as ethanol.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • the daily dose is suitably about 0.001 to 100 mg / kg per body weight, in some embodiments 0.01 to 30 mg / kg, and in some embodiments 0.1 to 10 mg / kg. As an embodiment, 0.3 to 7 mg / kg is appropriate, and this is administered once or divided into 2 to 4 times.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the pharmaceutical composition of the present invention is 0.01 to 99% by weight, and in one embodiment 0.01 to 50% by weight of Compound A or a pharmaceutical product thereof. Containing an acceptable salt as an active ingredient.
  • the pharmaceutical composition of the present invention can be used in combination with various therapeutic agents that are effective against cancer.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • simultaneous administration it may be a combination drug or separately formulated.
  • Drugs that can be used in combination include kinase inhibitors such as sunitinib and sorafenib, mTOR inhibitors such as temsirolimus and everolimus, anti-VEGF (vascular endothelial growth factor) preparations such as bevacizumab, and interferons and interleukins Cytokine preparations, viable bacterial preparations such as BCG, alkylating agents such as cyclophosphamide and ifosfamide, mitomycin C, methotrexate, vinblastine, 5-FU, paclitaxel, mitoxantrone, etoposide, doxorubicin and cisplatin Antineoplastic agents, microtubule polymerization inhibitors such as vincris
  • a compound A monomethanesulfonate hereinafter sometimes referred to as “compound B” was used in the following Examples.
  • the concentration of Compound B was calculated in terms of the concentration of Compound A (free form).
  • BMX inhibitory activity was evaluated using the BMX QSS Assist TM Mobility Shift Assay kit (Carna Bioscience).
  • Compound B was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution having a concentration 100 times the test concentration.
  • the solution was further diluted 25 times with the attached assay buffer to obtain a test substance solution.
  • BMX attached to the kit was used. 5 ⁇ L of a 4 ⁇ concentration test substance solution prepared in the above assay buffer and 10 ⁇ L of a 2 ⁇ concentration BMX solution were mixed in the wells of a 384 well plate and left at room temperature for 30 minutes.
  • BMX activity was calculated by quantifying the conversion rate of the product obtained from the substrate peptide peak height and the product (phosphorylated substrate peptide) peak height using LabChip EZ Reader II (PerkinElmer).
  • PC-3 cells are a human prostate cancer-derived cell line, and BMX expression and BMX dependency have been confirmed (Cell Death Dis. 2014; 5: e1409).
  • PC-3 cells (American Type Culture Collection, CRL-1435) cultured using D-MEM medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 1 ⁇ 10 3 cells / well.
  • D-MEM medium Sigma
  • a DMSO solution of Compound B having a final concentration of 1 nM to 10 ⁇ M or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 .
  • the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability.
  • the cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability. As a result, Compound B suppressed the proliferation of PC-3 cells, and the IC 50 value was 800 nM.
  • DU145 Cell is a cell line derived from human prostate cancer, and BMX expression has been confirmed (Cell Death Dis. 2014; 5: e1409).
  • DU145 cells American Type Culture Collection, HTB-81) cultured using D-MEM medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 1 ⁇ 10 3 cells / well.
  • D-MEM medium Sigma
  • a DMSO solution of Compound B having a final concentration of 1 nM to 10 ⁇ M or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 .
  • the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability.
  • the cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability. As a result, Compound B suppressed the proliferation of DU145 cells, and the IC 50 value was 410 nM.
  • 22Rv1 Cell is a human prostate cancer-derived cell line, and BMX expression has been confirmed (Oncogene 2006; 25: 70-78).
  • 22Rv1 cells (American Type Culture Collection, CRL-2505) cultured using RPMI-1640 medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 1 ⁇ 10 3 cells / well.
  • a DMSO solution of Compound B having a final concentration of 1 nM to 10 ⁇ M or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 .
  • the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability.
  • the cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability. As a result, Compound B suppressed the proliferation of 22Rv1 cells, and the IC 50 value was 560 nM.
  • UM-UC-3 cell is a cell line derived from human bladder cancer, and BMX expression and BMX dependency have been confirmed (PLoS ONE 2011; 6 (3): e17778).
  • UM-UC-3 cells American Type Culture Collection, CRL-1749
  • RPMI-1640 medium Sigma
  • bovine serum 10% bovine serum were seeded in a 96-well plate at about 2 ⁇ 10 3 cells / well.
  • a DMSO solution of Compound B having a final concentration of 1 nM to 10 ⁇ M or DMSO alone (DMSO group) was added, and cultured at 37 ° C.
  • a cell number measurement reagent CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)
  • the measurement value in the DMSO group was 100% viability
  • the measurement value of the well containing only the medium was 0% viability.
  • the cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability. As a result, Compound B inhibited the growth of UM-UC-3 cells, and the IC 50 value was 560 nM.
  • OS-RC-2 cells are derived from human renal cell carcinoma, and BMX expression has been confirmed (J. Exp. Clin. Cancer Res. 2014; 33: 25).
  • OS-RC-2 cells (RIKEN, RCB0735) cultured using RPMI-1640 medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 2 ⁇ 10 3 cells / well.
  • a DMSO solution of Compound B having a final concentration of 1 nM to 10 ⁇ M or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 .
  • the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability.
  • the cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability. As a result, Compound B suppressed the proliferation of OS-RC-2 cells, and the IC 50 value was 620 nM.
  • Example 7 Antitumor Evaluation for PC-3 Subcutaneous Cancer-bearing Mouse Model Prostate cancer on the back of immunodeficient mice (CAnN.Cg-Foxn1 nu / CrlCrlj (nu / nu), male, 4 weeks old (Charles River Japan))
  • the PC-3 cell line was transplanted subcutaneously at 3 ⁇ 10 6 cells / 0.1 mL / mouse to prepare a PC-3 subcutaneous tumor-bearing mouse model.
  • the tumor volume which averaged 238 mm 3 on the day of administration, increased to an average 1162 mm 3 after 14 days.
  • the average tumor volume on the start day of administration was 242 mm 3 , but the average tumor volume after 14 days was 822 mm 3 .
  • Compound A or a pharmaceutically acceptable salt thereof inhibits BMX activity, and it was shown to be useful as an active ingredient of a pharmaceutical composition for treating cancer related to BMX. It was. It also suppresses the proliferation of prostate cancer cell lines, PC-3 cells, DU145 cells, 22Rv1 cells, bladder cancer cell lines, UM-UC-3 cells, and renal cell carcinoma cell lines, OS-RC-2 cells. These results confirmed the therapeutic effects on these BMX-related cancers.
  • Compound A or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has a BMX inhibitory action and is a pharmaceutical composition for the treatment of cancer related to BMX, particularly prostate cancer, bladder It can be used as an active ingredient of a pharmaceutical composition for treating cancer and / or renal cell carcinoma.

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Abstract

[Problem] To provide a pharmaceutical composition for treating BMX-related cancer, particularly a pharmaceutical composition for treating prostate cancer, bladder cancer and/or renal cell carcinoma. [Solution] The present inventors have studied on compounds each having a BMX-inhibiting activity, and have confirmed that a specific pyrazinecarboxamide compound has a BMX-inhibiting activity and that a pharmaceutical composition containing the compound as an active ingredient has a therapeutic effect on BMX-related cancer, particularly prostate cancer, bladder cancer and/or renal cell carcinoma. As a result, the present invention has been accomplished.

Description

ピラジンカルボキサミド化合物を有効成分とする医薬組成物Pharmaceutical composition comprising a pyrazinecarboxamide compound as an active ingredient
　本発明は、ピラジンカルボキサミド化合物又はその製薬学的に許容される塩を有効成分とするBMXに関連する癌の治療用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for treating cancer related to BMX, comprising a pyrazinecarboxamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
　BMX（bone marrow tyrosine kinase in chromosome X）はTecファミリーキナーゼに属する非受容体型チロシンキナーゼであり、PH（プレクストリン相同）ドメイン、Src相同３ドメイン、Src相同２ドメイン、およびキナーゼドメインを有するタンパク質である。正常組織においてBMXは上皮細胞、内皮細胞に発現することが報告されている（Proc. Natl. Acad. Sci. USA 1998;95:3644-3649）。癌組織においては、前立腺癌、膀胱癌、腎細胞癌において発現が確認されており、これらの癌種では病態の進行にBMXが関与する可能性が示唆されている（Cancer Res. 2006;66(16):8058-8064、PLoS ONE 2011;6(3):e17778、J. Exp. Clin. Cancer Res. 2014;33:25）。 BMX (bone marrow tyrosine kinase in chromosome X) is a non-receptor tyrosine kinase belonging to the Tec family kinase, a protein having a PH (pleckstrin homology) domain, an Src homology 3 domain, an Src homology 2 domain, and a kinase domain . It has been reported that BMX is expressed in epithelial cells and endothelial cells in normal tissues (Proc. Natl. Acad. Sci. USA 1998; 95: 3644-3649). In cancer tissues, expression has been confirmed in prostate cancer, bladder cancer, and renal cell carcinoma, and it has been suggested that BMX may be involved in the progression of disease in these cancer types (Cancer Res. 2006; 66 ( 16): 8058-8064, PLoS ONE 2011; 6 (3): e17778, J. Exp. Clin. Cancer Res. 2014; 33: 25).
　これまでに、PTEN遺伝子が欠損した前立腺癌細胞株において、siRNAを用いてBMXの発現を低下させると、細胞増殖が阻害されることが報告されている（J. Biol. Chem. 2007;282:32689-32698）。また、ホルモン療法抵抗性ヒト前立腺癌組織において、BMXの発現が亢進すること、当該BMXの発現とアンドロゲン受容体のリン酸化とは相関することが知られている。また、ホルモン療法抵抗性前立腺癌細胞株においてBMXを過剰発現させると腫瘍の増殖が亢進し、反対にホルモン療法抵抗性前立腺癌細胞株においてshRNAを用いてBMXの発現を低下させると、腫瘍増殖が阻害される（Cancer Res. 2010;70(13):5587-5596）。これらの結果からBMXが前立腺癌におけるホルモン療法抵抗性に関与することが示唆される。
　さらに、膀胱癌細胞株および腎細胞癌細胞株において、BMXの発現を低下させると生存、遊走、浸潤が阻害されることが報告されている（PLoS ONE 2011;6(3):e177778、J. Exp. Clin. Cancer Res. 2014;33:25）。 So far, it has been reported that, in a prostate cancer cell line deficient in the PTEN gene, when BMX expression is reduced using siRNA, cell proliferation is inhibited (J. Biol. Chem. 2007; 282: 32689-32698). In addition, it is known that expression of BMX is increased in hormone therapy-resistant human prostate cancer tissue, and that the expression of BMX correlates with phosphorylation of androgen receptor. In addition, overexpression of BMX in hormone therapy-resistant prostate cancer cell lines increased tumor growth, and conversely, reduction of BMX expression using shRNA in hormone therapy-resistant prostate cancer cell lines resulted in increased tumor growth. Inhibited (Cancer Res. 2010; 70 (13): 5587-5596). These results suggest that BMX is involved in hormone therapy resistance in prostate cancer.
Furthermore, in bladder cancer cell lines and renal cell cancer cell lines, it has been reported that decreasing BMX expression inhibits survival, migration, and invasion (PLoS ONE 2011; 6 (3): e177778, J. Exp. Clin. Cancer Res. 2014; 33: 25).
　これらの結果は、前立腺癌、膀胱癌、腎細胞癌を含むBMXに関連する癌、例えば、BMXが高発現又は活性化した癌において、BMXがこれらの癌の増殖に関与していることを示している。 These results indicate that BMX is involved in the growth of BMX-related cancers, including prostate cancer, bladder cancer, and renal cell carcinoma, such as those with high expression or activation of BMX. ing.
　5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド（以下、「化合物Ａ」ということがある。）又はその製薬学的に許容される塩は、EGFR T790M変異を有する癌治療用医薬組成物の有効成分として有用であることが知られている（特許文献１）。
　化合物Ａ又はその製薬学的に許容される塩は、特許文献1において、実施例54としてそのフリー体が、実施例261としてそのモノメタンスルホン酸塩が開示されており、EGFR変異キナーゼに対する阻害作用が確認されている。
　また本願の優先日後に公開された特許文献2に、化合物Ａ又はその製薬学的に許容される塩は、BTK(Bruton's tyrosine kinase)、JAK3(Janus kinase 3)、ITK(IL2 inducible T cell kinase)のうち1種又は複数のキナーゼが関与するがんの治療用医薬組成物の有効成分として有用であることが開示されている。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } Amino) pyrazine-2-carboxamide (hereinafter sometimes referred to as “Compound A”) or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for treating cancer having an EGFR T790M mutation. It is known that there is (Patent Document 1).
Compound A or a pharmaceutically acceptable salt thereof is disclosed in Patent Document 1 as its free form as Example 54 and its monomethanesulfonate as Example 261, and has an inhibitory action on EGFR mutant kinases. Has been confirmed.
Further, in Patent Document 2 published after the priority date of the present application, Compound A or a pharmaceutically acceptable salt thereof is BTK (Bruton's tyrosine kinase), JAK3 (Janus kinase 3), ITK (IL2 inducible T cell kinase). Among them, it is disclosed that it is useful as an active ingredient of a pharmaceutical composition for treating cancer involving one or more kinases.
国際公開第 2013/108754号International Publication No. 2013/108754 国際公開第 2015/182628号International Publication No. 2015/182628
　BMXに関連する癌の治療用医薬組成物、特に前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物を提供する。 Provided is a pharmaceutical composition for treating cancer related to BMX, particularly a pharmaceutical composition for treating prostate cancer, bladder cancer and / or renal cell cancer.
　本発明者らは、BMXに関連する癌の治療用医薬組成物の創製を目的に鋭意検討した結果、5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩が、BMX活性を阻害し、腫瘍の増殖抑制作用を有することを知見して本発明を完成した。
　すなわち、本発明は、5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩を含有する、BMXに関連する癌の治療用医薬組成物、特に前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物に関する。 As a result of intensive studies aimed at creating a pharmaceutical composition for treating cancer related to BMX, the present inventors have found that 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl -3-({4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof has BMX activity The present invention was completed by discovering that it has an inhibitory effect on tumor growth.
That is, the present invention relates to 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine. 1-yl] phenyl} amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for the treatment of cancer associated with BMX, in particular prostate cancer, bladder cancer, and / or The present invention relates to a pharmaceutical composition for the treatment of renal cell carcinoma.
　また、本発明は、化合物Ａ又はその製薬学的に許容される塩を含有するBMXに関連する癌の治療剤、特に前立腺癌、膀胱癌、及び／又は腎細胞癌の治療剤に関する。 The present invention also relates to a therapeutic agent for cancer related to BMX containing Compound A or a pharmaceutically acceptable salt thereof, particularly a therapeutic agent for prostate cancer, bladder cancer, and / or renal cell carcinoma.
　また、本発明は、BMXに関連する癌の治療用医薬組成物の製造のための化合物Ａ又はその製薬学的に許容される塩の使用、ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物の製造のための化合物Ａ又はその製薬学的に許容される塩の使用；BMXに関連する癌の治療のための化合物Ａ又はその製薬学的に許容される塩の使用、ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療のための化合物Ａ又はその製薬学的に許容される塩の使用；BMXに関連する癌の治療のための化合物Ａ又はその製薬学的に許容される塩、ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療のための化合物Ａ又はその製薬学的に許容される塩；及び、化合物Ａ又はその製薬学的に許容される塩の有効量を対象に投与することからなるBMXに関連する癌の治療方法、ある態様として化合物Ａ又はその製薬学的に許容される塩の有効量を対象に投与することからなる前立腺癌、膀胱癌、及び／又は腎細胞癌の治療方法に関する。なお、「対象」とは、その治療を必要とするヒト又はその他の動物であり、ある態様としては、その治療を必要とするヒトである。 The present invention also relates to the use of compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer associated with BMX, in one embodiment, prostate cancer, bladder cancer, and / or Use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of renal cell carcinoma; Compound A or a pharmaceutically acceptable thereof for the treatment of cancer associated with BMX Use of salt, in certain embodiments, use of compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma; for the treatment of cancer associated with BMX Compound A or a pharmaceutically acceptable salt thereof, in certain embodiments, Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma; and Administer an effective amount of A or a pharmaceutically acceptable salt thereof to a subject A method for treating cancer related to BMX, comprising, as an aspect, administering to a subject an effective amount of Compound A or a pharmaceutically acceptable salt thereof, prostate cancer, bladder cancer, and / or renal cell cancer Relates to a method of treatment. Note that the “subject” is a human or other animal in need of the treatment, and in one embodiment, is a human in need of the treatment.
　本発明の医薬組成物の有効成分である化合物Ａ又はその製薬学的に許容される塩は、BMX阻害作用を有し、BMXに関連する癌の治療用医薬組成物、特に、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物の有効成分として使用できる。 Compound A or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has a BMX inhibitory action, and is a pharmaceutical composition for treating cancer related to BMX, particularly prostate cancer, bladder It can be used as an active ingredient of a pharmaceutical composition for treating cancer and / or renal cell carcinoma.
　以下、本発明を詳細に説明する。
　上述の通り、化合物Ａの化学名は5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミドであり、その化学構造は以下に示すとおりである。
Figure JPOXMLDOC01-appb-C000001
 Hereinafter, the present invention will be described in detail.
As described above, the chemical name of Compound A is 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazine-1 -Yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide, the chemical structure of which is shown below.
Figure JPOXMLDOC01-appb-C000001
　BMXに関連する癌とは、癌の原因の一つがBMXである癌を意味し、例えば、BMXが高発現及び／又は活性化した癌である。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌である。ある態様としては、前立腺癌であり、ある態様としては、膀胱癌であり、ある態様としては、腎細胞癌であり、ある態様としては、ホルモン療法抵抗性を獲得した前立腺癌であり、ある態様としては、アンドロゲン受容体が活性化した前立腺癌であり、ある態様としては、アンドロゲン受容体拮抗薬に抵抗性を獲得した前立腺癌である。 The cancer related to BMX means a cancer in which one of the causes of cancer is BMX, for example, a cancer in which BMX is highly expressed and / or activated. In some embodiments, prostate cancer, bladder cancer, and / or renal cell cancer. An aspect is prostate cancer, an aspect is bladder cancer, an aspect is renal cell cancer, an aspect is prostate cancer that has acquired resistance to hormone therapy, and an aspect And prostate cancer in which androgen receptor is activated. In one embodiment, prostate cancer has acquired resistance to an androgen receptor antagonist.
　本発明のある態様を以下に示す。
（１）化合物Ａ又はその製薬学的に許容される塩を含有する、BMXに関連する癌の治療用医薬組成物。ある態様として、化合物Ａ又はその製薬学的に許容される塩を含有する、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物。ある態様として、化合物Ａ モノメタンスルホン酸塩を含有する、BMXに関連する癌の治療用医薬組成物。ある態様として、化合物Ａ モノメタンスルホン酸塩を含有する、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物。
（２）BMXに関連する癌の治療用医薬組成物の製造のための、化合物Ａ又はその製薬学的に許容される塩の使用。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物の製造のための、化合物Ａ又はその製薬学的に許容される塩の使用。ある態様として、BMXに関連する癌の治療用医薬組成物の製造のための、化合物Ａ モノメタンスルホン酸塩の使用。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物の製造のための、化合物Ａ モノメタンスルホン酸塩の使用。
（３）BMXに関連する癌の治療のための、化合物Ａ又はその製薬学的に許容される塩の使用。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療のための、化合物Ａ又はその製薬学的に許容される塩の使用。ある態様として、BMXに関連する癌の治療のための、化合物Ａ モノメタンスルホン酸塩の使用。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療のための、化合物Ａ モノメタンスルホン酸塩の使用。
（４）BMXに関連する癌の治療のための、化合物Ａ又はその製薬学的に許容される塩。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療のための、化合物Ａ又はその製薬学的に許容される塩。ある態様として、BMXに関連する癌の治療のための、化合物Ａ モノメタンスルホン酸塩。ある態様として、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療のための、化合物Ａ モノメタンスルホン酸塩。
（５）化合物Ａ又はその製薬学的に許容される塩の有効量を対象に投与することからなる、BMXに関連する癌の治療方法。ある態様として、化合物Ａ又はその製薬学的に許容される塩の有効量を対象に投与することからなる、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療方法。ある態様として、化合物Ａ モノメタンスルホン酸塩の有効量を対象に投与することからなる、BMXに関連する癌の治療方法。ある態様として、化合物Ａ モノメタンスルホン酸塩の有効量を対象に投与することからなる、前立腺癌、膀胱癌、及び／又は腎細胞癌の治療方法。 Certain embodiments of the present invention are shown below.
(1) A pharmaceutical composition for treating cancer related to BMX, comprising Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition for treating prostate cancer, bladder cancer, and / or renal cell cancer, comprising Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition for the treatment of cancer associated with BMX, comprising Compound A monomethanesulfonate. In one embodiment, a pharmaceutical composition for treating prostate cancer, bladder cancer, and / or renal cell cancer, comprising Compound A monomethanesulfonate.
(2) Use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating cancer related to BMX. In one embodiment, use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating prostate cancer, bladder cancer, and / or renal cell cancer. In one embodiment, the use of Compound A monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of cancer associated with BMX. In one embodiment, the use of Compound A monomethanesulfonate for the manufacture of a pharmaceutical composition for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
(3) Use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of cancer associated with BMX. In one embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma. In certain embodiments, the use of Compound A monomethanesulfonate for the treatment of cancer associated with BMX. In one embodiment, the use of Compound A monomethanesulfonate for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
(4) Compound A or a pharmaceutically acceptable salt thereof for the treatment of cancer related to BMX. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma. In certain embodiments, Compound A monomethanesulfonate for the treatment of cancer associated with BMX. In certain embodiments, Compound A monomethanesulfonate for the treatment of prostate cancer, bladder cancer, and / or renal cell carcinoma.
(5) A method for treating cancer related to BMX, comprising administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject. In one embodiment, a method for treating prostate cancer, bladder cancer, and / or renal cell cancer, comprising administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject. In one embodiment, a method of treating cancer associated with BMX, comprising administering to a subject an effective amount of Compound A monomethanesulfonate. In one embodiment, a method for treating prostate cancer, bladder cancer, and / or renal cell cancer, comprising administering an effective amount of Compound A monomethanesulfonate to a subject.
　化合物Ａ又はその製薬学的に許容される塩は、上記特許文献１（国際公開第 2013/108754号）に記載の方法に従って、あるいはその変法によって入手することができる。 Compound A or a pharmaceutically acceptable salt thereof can be obtained according to the method described in Patent Document 1 (International Publication No. 2013/108754) or a modified method thereof.
　また、「化合物Ａの製薬学的に許容される塩」とは、化合物Ａの酸付加塩を意味し、具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸（メシル酸）、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩が挙げられる。なお、「化合物Ａの製薬学的に許容される塩」には、化合物Ａの溶媒和物、具体的には、例えば水和物やエタノール和物を含み、さらに、化合物Ａの酸付加塩の溶媒和物を含む。
　なお、「化合物Ａ又はその製薬学的に許容される塩」のある態様としては、化合物Ａ（フリー体）が挙げられ、別の態様としては、化合物Ａ モノメタンスルホン酸塩が挙げられる。 “Pharmaceutically acceptable salt of Compound A” means an acid addition salt of Compound A, specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphorus Inorganic acids such as acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfone Examples thereof include acid addition salts with organic acids such as acid (mesic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid. The “pharmaceutically acceptable salt of Compound A” includes a solvate of Compound A, specifically, for example, a hydrate or an ethanolate, and further includes an acid addition salt of Compound A. Including solvates.
In addition, as a certain aspect of "Compound A or its pharmaceutically acceptable salt", compound A (free body) is mentioned, As another aspect, compound A monomethanesulfonate is mentioned.
　化合物Ａ又はその製薬学的に許容される塩を含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤用担体等を用いて、通常使用されている方法によって調製することができる。
　投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 A pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof is usually used with excipients usually used in the art, that is, pharmaceutical excipients, pharmaceutical carriers, etc. It can be prepared by the method that has been described.
Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or injection such as intraarticular, intravenous, intramuscular, suppository, transdermal solution, ointment, transdermal Any form of parenteral administration using a patch, a transmucosal liquid, a transmucosal patch, an inhalant or the like may be used.
　経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、１種又は２種以上の有効成分が、少なくとも１種の不活性な賦形剤と混合される。組成物は、常法に従って、不活性な添加剤、例えば滑沢剤や崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
　経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含む。当該液体組成物は、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含み、さらに可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like. The liquid composition contains generally used inert diluents such as purified water or ethanol, and further supplements such as solubilizers, wetting agents, and suspending agents, sweeteners, flavors, and fragrances. And may contain a preservative.
　非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水性の溶剤としては、例えばエタノールのようなアルコール類がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。 The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
　通常経口投与の場合、1日の投与量は、体重当たり約0.001～100 mg/kg、ある態様として0.01～30 mg/kg、更にある態様として0.1～10 mg/kgが適当であり、更にある態様として0.3～7mg/kgが適当であり、これを1回であるいは2回～4回に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001～10 mg/kgが適当で、1日1回～複数回に分けて投与する。また、経粘膜剤としては、体重当たり約0.001～100 mg/kgを1日1回～複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 In the case of oral administration, the daily dose is suitably about 0.001 to 100 mg / kg per body weight, in some embodiments 0.01 to 30 mg / kg, and in some embodiments 0.1 to 10 mg / kg. As an embodiment, 0.3 to 7 mg / kg is appropriate, and this is administered once or divided into 2 to 4 times. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
　投与経路、剤形、投与部位、賦形剤や添加剤の種類によって異なるが、本発明の医薬組成物は0.01～99重量%、ある態様としては0.01～50重量%の化合物Ａ又はその製薬学的に許容される塩を有効成分として含有する。 Depending on the route of administration, dosage form, administration site, type of excipient or additive, the pharmaceutical composition of the present invention is 0.01 to 99% by weight, and in one embodiment 0.01 to 50% by weight of Compound A or a pharmaceutical product thereof. Containing an acceptable salt as an active ingredient.
　本発明の医薬組成物は、癌に有効性を示す種々の治療剤と併用することができる。当該併用は、同時投与、あるいは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与の場合には、配合剤であっても別個に製剤化されていてもよい。特に併用することができる薬剤として、スニチニブやソラフェニブのようなキナーゼ阻害剤、テムシロリムスやエベロリムスのようなmTOR阻害剤、ベバシズマブのような抗VEGF（血管内皮細胞増殖因子）製剤、インターフェロンやインターロイキンのようなサイトカイン製剤、BCGのような生菌製剤、シクロホスファミドやイホスファミドのようなアルキル化剤、マイトマイシンC、メトトレキサート、ビンブラスチン、5-FU、パクリタキセル、ミトキサントロン、エトポシド、ドキソルビシンやシスプラチンのような抗悪性腫瘍剤、ビンクリスチンのような微小管重合阻害剤、プレドニゾン、プレドニゾロンやデキサメタゾンのような副腎皮質ホルモン剤、ゲムシタビンやペメトレキセドのような代謝拮抗剤、ビカルタミドやエンザルタミドのような抗アンドロゲン剤、クロドロネートのようなビスフォスフォネート、ゴセレリンやリュープロレリンのようなGnRH（性腺刺激ホルモン放出ホルモン）アゴニスト、デガレリクスのようなGnRHアンタゴニスト、アビラテロンのようなCYP17阻害剤、プロゲステロンのような黄体ホルモン製剤、デノスマブのような抗RANKL製剤が挙げられる。 The pharmaceutical composition of the present invention can be used in combination with various therapeutic agents that are effective against cancer. The combination may be administered simultaneously, separately separately, or at desired time intervals. In the case of simultaneous administration, it may be a combination drug or separately formulated. Drugs that can be used in combination include kinase inhibitors such as sunitinib and sorafenib, mTOR inhibitors such as temsirolimus and everolimus, anti-VEGF (vascular endothelial growth factor) preparations such as bevacizumab, and interferons and interleukins Cytokine preparations, viable bacterial preparations such as BCG, alkylating agents such as cyclophosphamide and ifosfamide, mitomycin C, methotrexate, vinblastine, 5-FU, paclitaxel, mitoxantrone, etoposide, doxorubicin and cisplatin Antineoplastic agents, microtubule polymerization inhibitors such as vincristine, prednisone, corticosteroids such as prednisolone and dexamethasone, antimetabolites such as gemcitabine and pemetrexed, and bicalutamide and enzalutamide Antiandrogens, bisphosphonates such as clodronate, GnRH (gonadotropin releasing hormone) agonists such as goserelin and leuprorelin, GnRH antagonists such as degarelix, CYP17 inhibitors such as abiraterone, and progesterone Progesterone preparations, anti-RANKL preparations such as denosumab.
　本発明の医薬組成物の薬理的効果は、以下の実施例により確認した。なお、化合物Ａ又はその製薬学的に許容される塩として、以下の実施例では化合物Ａ モノメタンスルホン酸塩（以下、「化合物Ｂ」ということがある。）を使用した。それぞれの実施例において、化合物Ｂの濃度は、化合物Ａ（フリー体）の濃度に換算して算出した。 The pharmacological effect of the pharmaceutical composition of the present invention was confirmed by the following examples. In addition, as a compound A or a pharmaceutically acceptable salt thereof, a compound A monomethanesulfonate (hereinafter sometimes referred to as “compound B”) was used in the following Examples. In each Example, the concentration of Compound B was calculated in terms of the concentration of Compound A (free form).
実施例１　BMX阻害活性評価
　BMX阻害活性についてはBMX QSS AssistTM Mobility Shift Assayキット（カルナバイオサイエンス）を用いて評価した。
　化合物Ｂをジメチルスルホキシド（DMSO）に溶解し、試験濃度の100倍濃度の溶液を調製した。その溶液をさらに付属のアッセイバッファーにて25倍希釈して被験物質溶液とした。なお、反応にはキットに付属しているBMXを用いた。
　上記のアッセイバッファーにて調製した5μLの4倍濃度被験物質溶液及び10μLの2倍濃度BMX溶液を384ウェルプレートのウェル内で混合し、室温にて30分間放置した。続いて、5μLの4倍濃度基質ペプチド/ATP/MgCl2溶液を添加し、室温にて1時間反応させた。基質ペプチドは終濃度1μM、ATPは終濃度1mM、MgCl2は終濃度5mMにて使用した。その後、付属のターミネーションバッファー60μLを添加して反応を停止させた。BMX活性は、基質ペプチドピーク高さと生産物（リン酸化基質ペプチド）ピーク高さから求められる生成物の変換率をLabChip EZ Reader ＩＩ（PerkinElmer）で定量して算出した。
　データ解析は、全ての反応コンポーネントを含むコントロールウェルの平均変換率を0%阻害、BMX以外の全ての反応コンポーネントを含むバックグランドウェルの平均変換率を100%阻害とし、化合物Ｂの各試験ウェルの平均変換率から阻害率を計算した。IC50値は被験物質濃度と阻害率によるプロットを基に非線形回帰から求めた。
　その結果、化合物ＢはBMX活性を阻害し、IC50値は0.46nMであった。 Example 1 Evaluation of BMX Inhibitory Activity BMX inhibitory activity was evaluated using the BMX QSS Assist ™ Mobility Shift Assay kit (Carna Bioscience).
Compound B was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution having a concentration 100 times the test concentration. The solution was further diluted 25 times with the attached assay buffer to obtain a test substance solution. For the reaction, BMX attached to the kit was used.
5 μL of a 4 × concentration test substance solution prepared in the above assay buffer and 10 μL of a 2 × concentration BMX solution were mixed in the wells of a 384 well plate and left at room temperature for 30 minutes. Subsequently, 5 μL of 4-fold concentration substrate peptide / ATP / MgCl 2 solution was added and reacted at room temperature for 1 hour. The substrate peptide was used at a final concentration of 1 μM, ATP at a final concentration of 1 mM, and MgCl 2 at a final concentration of 5 mM. Thereafter, 60 μL of the supplied termination buffer was added to stop the reaction. The BMX activity was calculated by quantifying the conversion rate of the product obtained from the substrate peptide peak height and the product (phosphorylated substrate peptide) peak height using LabChip EZ Reader II (PerkinElmer).
In the data analysis, the average conversion rate of control wells containing all reaction components was inhibited by 0%, the average conversion rate of background wells containing all reaction components other than BMX was 100% inhibition, and each test well of Compound B was tested. The inhibition rate was calculated from the average conversion rate. IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and inhibition rate.
As a result, Compound B inhibited BMX activity, and the IC 50 value was 0.46 nM.
実施例２　前立腺癌細胞株PC-3細胞における増殖抑制評価
　PC-3細胞は、ヒト前立腺癌由来の細胞株であり、BMXの発現およびBMX依存性が確認されている（Cell Death Dis. 2014;5:e1409）。10%牛血清を含有するD-MEM培地（シグマ）を用いて培養したPC-3細胞（American Type Culture Collection、CRL-1435）を約1x103個/ウェルで96ウェルプレートに播種した。翌日に終濃度1nMから10μMとなる化合物ＢのDMSO溶液、又はDMSOのみ（DMSO群）を添加し、5%CO2存在下、37℃にて5日間培養した。その後、細胞数測定試薬（CellTiter-Glo（登録商標）Luminescent Cell Viability Assay（Promega））を用いて、DMSO群での測定値を生存率100%、培地のみのウェルの測定値を生存率0%として細胞生存率を算出した。IC50値は被験物質濃度と細胞生存率によるプロットを基に非線形回帰から求めた。
　その結果、化合物ＢはPC-3細胞の増殖を抑制し、IC50値は800nMであった。 Example 2 Growth Inhibition Evaluation in Prostate Cancer Cell Line PC-3 Cells PC-3 cells are a human prostate cancer-derived cell line, and BMX expression and BMX dependency have been confirmed (Cell Death Dis. 2014; 5: e1409). PC-3 cells (American Type Culture Collection, CRL-1435) cultured using D-MEM medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 1 × 10 3 cells / well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 . Then, using a cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)), the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability. The cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability.
As a result, Compound B suppressed the proliferation of PC-3 cells, and the IC 50 value was 800 nM.
実施例３　前立腺癌細胞株DU145細胞における増殖抑制評価
　DU145細胞は、ヒト前立腺癌由来の細胞株であり、BMXの発現が確認されている（Cell Death Dis. 2014;5:e1409）。10%牛血清を含有するD-MEM培地（シグマ）を用いて培養したDU145細胞（American Type Culture Collection、HTB-81）を約1x103個/ウェルで96ウェルプレートに播種した。翌日に終濃度1nMから10μMとなる化合物ＢのDMSO溶液、又はDMSOのみ（DMSO群）を添加し、5%CO2存在下、37℃にて5日間培養した。その後、細胞数測定試薬（CellTiter-Glo（登録商標）Luminescent Cell Viability Assay（Promega））を用いて、DMSO群での測定値を生存率100%、培地のみのウェルの測定値を生存率0%として細胞生存率を算出した。IC50値は被験物質濃度と細胞生存率によるプロットを基に非線形回帰から求めた。
　その結果、化合物ＢはDU145細胞の増殖を抑制し、IC50値は410nMであった。 Example 3 Evaluation of Growth Inhibition in Prostate Cancer Cell Line DU145 Cell DU145 cell is a cell line derived from human prostate cancer, and BMX expression has been confirmed (Cell Death Dis. 2014; 5: e1409). DU145 cells (American Type Culture Collection, HTB-81) cultured using D-MEM medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 1 × 10 3 cells / well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 . Then, using a cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)), the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability. The cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability.
As a result, Compound B suppressed the proliferation of DU145 cells, and the IC 50 value was 410 nM.
実施例４　前立腺癌細胞株22Rv1細胞における増殖抑制評価
　22Rv1細胞は、ヒト前立腺癌由来の細胞株であり、BMXの発現が確認されている（Oncogene 2006;25:70-78）。10%牛血清を含有するRPMI-1640培地（シグマ）を用いて培養した22Rv1細胞（American Type Culture Collection、CRL-2505）を約1x103個/ウェルで96ウェルプレートに播種した。翌日に終濃度1nMから10μMとなる化合物ＢのDMSO溶液、又はDMSOのみ（DMSO群）を添加し、5%CO2存在下、37℃にて5日間培養した。その後、細胞数測定試薬（CellTiter-Glo（登録商標）Luminescent Cell Viability Assay（Promega））を用いて、DMSO群での測定値を生存率100%、培地のみのウェルの測定値を生存率0%として細胞生存率を算出した。IC50値は被験物質濃度と細胞生存率によるプロットを基に非線形回帰から求めた。
　その結果、化合物Ｂは22Rv1細胞の増殖を抑制し、IC50値は560nMであった。 Example 4 Growth Inhibition Evaluation in Prostate Cancer Cell Line 22Rv1 Cell 22Rv1 cell is a human prostate cancer-derived cell line, and BMX expression has been confirmed (Oncogene 2006; 25: 70-78). 22Rv1 cells (American Type Culture Collection, CRL-2505) cultured using RPMI-1640 medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 1 × 10 3 cells / well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 . Then, using a cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)), the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability. The cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability.
As a result, Compound B suppressed the proliferation of 22Rv1 cells, and the IC 50 value was 560 nM.
実施例５　膀胱癌細胞株UM-UC-3細胞における増殖抑制評価
　UM-UC-3細胞は、ヒト膀胱癌由来の細胞株であり、BMXの発現およびBMX依存性が確認されている（PLoS ONE 2011;6(3):e17778）。10%牛血清を含有するRPMI-1640培地（シグマ）を用いて培養したUM-UC-3細胞（American Type Culture Collection、CRL-1749）を約2x103個/ウェルで96ウェルプレートに播種した。翌日に終濃度1nMから10μMとなる化合物ＢのDMSO溶液、又はDMSOのみ（DMSO群）を添加し、5%CO2存在下、37℃にて5日間培養した。その後、細胞数測定試薬（CellTiter-Glo（登録商標）Luminescent Cell Viability Assay（Promega））を用いて、DMSO群での測定値を生存率100%、培地のみのウェルの測定値を生存率0%として細胞生存率を算出した。IC50値は被験物質濃度と細胞生存率によるプロットを基に非線形回帰から求めた。
　その結果、化合物ＢはUM-UC-3細胞の増殖を抑制し、IC50値は560nMであった。 Example 5 Evaluation of Growth Inhibition in Bladder Cancer Cell Line UM-UC-3 Cell UM-UC-3 cell is a cell line derived from human bladder cancer, and BMX expression and BMX dependency have been confirmed (PLoS ONE 2011; 6 (3): e17778). UM-UC-3 cells (American Type Culture Collection, CRL-1749) cultured using RPMI-1640 medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 2 × 10 3 cells / well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 . Then, using a cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)), the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability. The cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability.
As a result, Compound B inhibited the growth of UM-UC-3 cells, and the IC 50 value was 560 nM.
実施例６　腎細胞癌細胞株OS-RC-2細胞における増殖抑制評価
　OS-RC-2細胞は、ヒト腎細胞癌由来の細胞株であり、BMXの発現が確認されている（J. Exp. Clin. Cancer Res. 2014;33:25）。10%牛血清を含有するRPMI-1640培地（シグマ）を用いて培養したOS-RC-2細胞（理研、RCB0735）を約2x103個/ウェルで96ウェルプレートに播種した。翌日に終濃度1nMから10μMとなる化合物ＢのDMSO溶液、又はDMSOのみ（DMSO群）を添加し、5%CO2存在下、37℃にて5日間培養した。その後、細胞数測定試薬（CellTiter-Glo（登録商標）Luminescent Cell Viability Assay（Promega））を用いて、DMSO群での測定値を生存率100%、培地のみのウェルの測定値を生存率0%として細胞生存率を算出した。IC50値は被験物質濃度と細胞生存率によるプロットを基に非線形回帰から求めた。
　その結果、化合物ＢはOS-RC-2細胞の増殖を抑制し、IC50値は620nMであった。 Example 6 Evaluation of Growth Inhibition in Renal Cell Carcinoma Cell Line OS-RC-2 Cells OS-RC-2 cells are derived from human renal cell carcinoma, and BMX expression has been confirmed (J. Exp. Clin. Cancer Res. 2014; 33: 25). OS-RC-2 cells (RIKEN, RCB0735) cultured using RPMI-1640 medium (Sigma) containing 10% bovine serum were seeded in a 96-well plate at about 2 × 10 3 cells / well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO alone (DMSO group) was added, and cultured at 37 ° C. for 5 days in the presence of 5% CO 2 . Then, using a cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)), the measurement value in the DMSO group was 100% viability, and the measurement value of the well containing only the medium was 0% viability. The cell viability was calculated as IC 50 values were obtained from nonlinear regression based on a plot of test substance concentration and cell viability.
As a result, Compound B suppressed the proliferation of OS-RC-2 cells, and the IC 50 value was 620 nM.
実施例７　PC-3皮下担癌マウスモデルに対する抗腫瘍評価
　免疫不全マウス（CAnN.Cg-Foxn1nu/CrlCrlj(nu/nu)、雄、4週齢（日本チャ－ルスリバー））の背部に前立腺癌細胞株PC-3細胞を3x106個/0.1 mL/マウスで皮下移植し、PC-3皮下担癌マウスモデルを作製した。腫瘍体積（[短径]2 x長径/2）をもとに群分けしたPC-3皮下担癌マウスモデルに対して、0.5%メチルセルロース溶液（コントロール群：10mL/kg/day、QD、po (n=5)）、化合物Ｂ（化合物Ｂ投与群：100mg/kg/day、QD、po (n=5)、0.5%メチルセルロース懸濁液として）を14日間投与し、腫瘍体積の変化を経時的に測定した。
　その結果、コントロール群では、投与開始日に平均238mm3であった腫瘍体積が、14日後には平均1162mm3まで増加した。一方、化合物Ｂ投与群では、投与開始日の平均腫瘍体積は242mm3であったが、14日後の平均腫瘍体積は822mm3であった。 Example 7 Antitumor Evaluation for PC-3 Subcutaneous Cancer-bearing Mouse Model Prostate cancer on the back of immunodeficient mice (CAnN.Cg-Foxn1 nu / CrlCrlj (nu / nu), male, 4 weeks old (Charles River Japan)) The PC-3 cell line was transplanted subcutaneously at 3 × 10 6 cells / 0.1 mL / mouse to prepare a PC-3 subcutaneous tumor-bearing mouse model. A PC-3 subcutaneous tumor-bearing mouse model divided into groups based on tumor volume ([minor axis] 2 x major axis / 2), 0.5% methylcellulose solution (control group: 10 mL / kg / day, QD, po ( n = 5)), compound B (compound B administration group: 100 mg / kg / day, QD, po (n = 5), 0.5% methylcellulose suspension) was administered for 14 days, and changes in tumor volume over time Measured.
As a result, in the control group, the tumor volume, which averaged 238 mm 3 on the day of administration, increased to an average 1162 mm 3 after 14 days. On the other hand, in the compound B administration group, the average tumor volume on the start day of administration was 242 mm 3 , but the average tumor volume after 14 days was 822 mm 3 .
　以上の結果から、化合物Ａ又はその製薬学的に許容される塩がBMX活性を阻害することが確認され、BMXに関連する癌の治療用医薬組成物の有効成分として有用であることが示された。また、前立腺癌細胞株であるPC-3細胞、DU145細胞、22Rv1細胞、膀胱癌細胞株であるUM-UC-3細胞、腎細胞癌細胞株であるOS-RC-2細胞の増殖を抑制することが確認され、これらのBMXに関連する癌への治療効果が確認できた。さらに、前立腺癌細胞株であるPC-3細胞を皮下移植した皮下担癌マウスモデルにおいても、化合物Ａ モノメタンスルホン酸塩を投与した群において、腫瘍の増殖抑制という顕著な抗腫瘍効果が確認できた。 From the above results, it was confirmed that Compound A or a pharmaceutically acceptable salt thereof inhibits BMX activity, and it was shown to be useful as an active ingredient of a pharmaceutical composition for treating cancer related to BMX. It was. It also suppresses the proliferation of prostate cancer cell lines, PC-3 cells, DU145 cells, 22Rv1 cells, bladder cancer cell lines, UM-UC-3 cells, and renal cell carcinoma cell lines, OS-RC-2 cells. These results confirmed the therapeutic effects on these BMX-related cancers. Furthermore, even in a subcutaneous cancer-bearing mouse model in which PC-3 cells, which are prostate cancer cell lines, were subcutaneously transplanted, a remarkable antitumor effect of suppressing tumor growth could be confirmed in the group administered with Compound A monomethanesulfonate. It was.
　本発明の医薬組成物の有効成分である、化合物Ａ又はその製薬学的に許容される塩は、BMX阻害作用を有し、BMXに関連する癌の治療用医薬組成物、特に前立腺癌、膀胱癌、及び／又は腎細胞癌の治療用医薬組成物の有効成分として使用できる。 Compound A or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, has a BMX inhibitory action and is a pharmaceutical composition for the treatment of cancer related to BMX, particularly prostate cancer, bladder It can be used as an active ingredient of a pharmaceutical composition for treating cancer and / or renal cell carcinoma.

Claims (9)

  1. 　5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩を含有する、BMXに関連する癌の治療用医薬組成物。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } Amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for treating cancer associated with BMX.
  2. 　BMXに関連する癌が、前立腺癌である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the cancer associated with BMX is prostate cancer.
  3. 　BMXに関連する癌が、膀胱癌である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the cancer associated with BMX is bladder cancer.
  4. 　BMXに関連する癌が、腎細胞癌である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the cancer associated with BMX is renal cell carcinoma.
  5. 　5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩が、5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド　モノメタンスルホン酸塩である、請求項１～請求項４のいずれか１項に記載の医薬組成物。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } Amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof is 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- 5. [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate according to any one of claims 1 to 4. Pharmaceutical composition.
  6. 　BMXに関連する癌の治療用医薬組成物の製造のための、5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩の使用。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4-] for the manufacture of a pharmaceutical composition for the treatment of cancer associated with BMX Use of (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof.
  7. 　BMXに関連する癌の治療のための、5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩の使用。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazine-) for the treatment of BMX related cancers Use of 1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof.
  8. 　BMXに関連する癌の治療のための、5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazine-) for the treatment of BMX related cancers 1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof.
  9. 　5-{[(3R)-1-アクリロイルピロリジン-3-イル]オキシ}-6-エチル-3-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-カルボキサミド又はその製薬学的に許容される塩の有効量を対象に投与することからなる、BMXが関連する癌の治療方法。 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } Amino) pyrazine-2-carboxamide or a method for treating cancer associated with BMX, comprising administering to a subject an effective amount of a pharmaceutically acceptable salt thereof.
PCT/JP2016/063246 2015-04-28 2016-04-27 Pharmaceutical composition containing pyrazinecarboxamide compound as active ingredient WO2016175252A1 (en)

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WO2017090699A1 (en) * 2015-11-27 2017-06-01 アステラス製薬株式会社 Pharmaceutical composition for immunoactivation and/or pharmaceutical composition for cancer immunotherapy, containing pyrazine carboxamide as active ingredient
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US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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