TW201713342A - Pharmaceutical composition containing pyrazinecarboxamide compound as active ingredient - Google Patents

Abstract

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. 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

Medicinal composition using pyrazine carboxamide compound as an active ingredient

The present invention relates to a pharmaceutical composition for the treatment of BMX-related cancers having a pyrazine carboxamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.

BMX (bone marrow tyrosine kinase in chromosome X) is a non-receptor type tyrosine kinase belonging to the Tec family kinase, which has a PH (Pleckstrin homology) domain and a Src homology 3 domain. , Src homology 2 domain, and protein of the kinase domain. In normal tissues, BMX is reported to be expressed in epithelial cells and endothelial cells (Proc. Natl. Acad. Sci. USA 1998; 95: 3644-3649). In cancer tissues, it is confirmed that it is expressed in prostate cancer, bladder cancer, and renal cell carcinoma, suggesting that there is a possibility of BMX involvement in the pathological state of these cancers (Cancer Res. 2006; 66(16): 8058-8064, PLoS ONE 2011; 6(3): e17778, J. Exp. Clin. Cancer Res. 2014; 33: 25).

So far, in the prostate cancer cell line with a defect in the PTEN gene, if the siRNA is used to reduce the performance of BMX, the cell is increased. Colonization is hindered (J. Biol. Chem. 2007; 282: 32689-32698). Further, it is known that in the hormone-resistant human prostate cancer tissues, if BMX is hyperactive, the expression of BMX is associated with phosphorylation of the androgen receptor. In addition, in a hormone-resistant prostate cancer cell line, if BMX is excessively expressed, the tumor proliferates, and in contrast, in a hormone-resistant prostate cancer cell line, if shRNA is used to reduce the expression of BMX, tumor proliferation Obstructed (Cancer Res. 2010; 70 (13): 5587-5596). These results suggest that BMX is associated with hormone resistance in prostate cancer.

Further, it has been reported that in bladder cancer cell lines and renal cell carcinoma cell lines, survival, migration, and infiltration are hindered if BMX performance is lowered (PLoS ONE 2011; 6(3): e177778, J. Exp .Clin.Cancer Res.2014;33:25).

These results show that BMX is associated with the proliferation of these cancers in BMX-related cancers including prostate cancer, bladder cancer, and renal cell carcinoma, for example, BMX high-performance or activated cancer.

5-{[(3R)-1-propenylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-) Peptidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (hereinafter sometimes referred to as "Compound A") or a pharmaceutically acceptable salt thereof, as a cancer having the EGFR T790M mutation The active ingredient of the therapeutic pharmaceutical composition is useful (Patent Document 1).

Compound A or a pharmaceutically acceptable salt thereof is disclosed in Patent Document 1 as a free form as Example 54 and its monomethanesulfonate is disclosed as Example 261, and its inhibitory effect on EGFR mutant kinase was confirmed.

Further, in Patent Document 2 published after the priority date of the present application, Compound A or a pharmaceutically acceptable salt thereof is disclosed as BTK (Bruton's tyrosine kinase), JAK3 (Janus kinase 3), and ITK (IL2 inducible T cell kinase). An active ingredient of a therapeutic pharmaceutical composition for cancer in which one or a plurality of kinases are involved is useful.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2013/108754

[Patent Document 2] International Publication No. 2015/182628

Provided is a pharmaceutical composition for treating a cancer associated with BMX, particularly a therapeutic pharmaceutical composition for prostate cancer, bladder cancer, and/or renal cell carcinoma.

The inventors of the present invention have intensively studied for the purpose of creating a pharmaceutical composition for the treatment of cancer associated with BMX, and found that 5-{[(3R)-1-propenylpyridyl-3-yl]oxy} -6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide or its Pharmaceutically approved salts impede BMX activity and have an inhibitory effect The present invention has been accomplished by the action of tumor proliferation.

That is, the present invention relates to the presence of 5-{[(3R)-1-propenylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methyl) Pharmaceutical composition for the treatment of BMX-related cancers of piperazine-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof, particularly It is a therapeutic pharmaceutical composition for prostate cancer, bladder cancer, and/or renal cell carcinoma.

Further, the present invention relates to a therapeutic agent for a BMX-related cancer containing Compound A or a pharmaceutically acceptable salt thereof, particularly a therapeutic agent for prostate cancer, bladder cancer, and/or renal cell carcinoma.

Further, the present invention relates to the use of the compound A for producing a pharmaceutical composition for treating cancer associated with BMX or a pharmaceutically acceptable salt thereof, and as a certain aspect, for producing prostate cancer, bladder cancer, And/or use of the pharmaceutical composition for therapeutic use of renal cell carcinoma, or a pharmaceutically acceptable salt thereof; use of the compound A for treating BMX-related cancer or a pharmaceutically acceptable salt thereof, as a certain a substance for use in the treatment of a compound A of prostate cancer, bladder cancer, and/or renal cell carcinoma or a pharmaceutically acceptable salt thereof; a compound A for treating a cancer associated with BMX or a pharmaceutically acceptable drug thereof a salt, as a certain aspect, for the treatment of prostate cancer, bladder cancer, and/or renal cell carcinoma, Compound A or a pharmaceutically acceptable salt thereof; and, by using Compound A or a pharmaceutically acceptable salt thereof An effective amount of a BMX-related cancer treatment method, which is administered to a subject, is a prostate cancer obtained by administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject. Treatment of bladder cancer and/or renal cell carcinoma Method. In addition, the term "object" means that the treatment is needed. Humans or other animals, as a certain aspect, are humans in need of such treatment.

The compound A of the active ingredient of the pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof has a BMX inhibitory action and can be used as a therapeutic pharmaceutical composition for cancer associated with BMX, particularly prostate cancer, bladder cancer, and/or Or the active ingredient of the pharmaceutical composition for the treatment of renal cell carcinoma.

The invention is described in detail below.

As described above, the chemical name of the compound A is 5-{[(3R)-1-propenylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4- Methyl piperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide The chemical structure is shown below.

The so-called BMX-related cancer means that one of the causes of cancer is BMX cancer, for example, BMX high-performance and/or activated cancer. As a certain aspect, it is prostate cancer, bladder cancer, and/or renal cell carcinoma. As a certain aspect, it is a kind of prostate cancer. As a certain aspect, it is a bladder cancer, as a certain state. In the case of renal cell carcinoma, as a certain aspect, it is a prostate cancer that is resistant to hormonal therapy. As a certain aspect, the male hormone receptor is activated by prostate cancer, and as a certain aspect, it is a male hormone receptor. Antagonists acquire resistant prostate cancer.

Some aspects of the invention are as follows.

(1) A therapeutic pharmaceutical composition for cancer associated with BMX, which comprises Compound A or a pharmaceutically acceptable salt thereof. In one aspect, it is a therapeutic pharmaceutical composition for prostate cancer, bladder cancer, and/or renal cell carcinoma, which comprises Compound A or a pharmaceutically acceptable salt thereof. As a certain aspect, it is a therapeutic pharmaceutical composition for cancer associated with BMX, which contains Compound A monomethanesulfonate. In one aspect, it is a therapeutic pharmaceutical composition for prostate cancer, bladder cancer, and/or renal cell carcinoma, which comprises Compound A monomethanesulfonate.

(2) Use of a compound A or a pharmaceutically acceptable salt thereof for the production of a therapeutic pharmaceutical composition for cancer associated with BMX. In one aspect, it is a use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of prostate cancer, bladder cancer, and/or renal cell carcinoma. As a certain aspect, it is a use of a compound A monomethanesulfonate for the production of a therapeutic pharmaceutical composition for cancer associated with BMX. As a certain aspect, it is a use of a compound A monomethanesulfonate, which is used for the manufacture of a therapeutic pharmaceutical composition for prostate cancer, bladder cancer, and/or renal cell carcinoma.

(3) Use of a compound A or a pharmaceutically acceptable salt thereof for the treatment of a BMX-related cancer. As a certain aspect, it is a kind The use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of prostate cancer, bladder cancer, and/or renal cell carcinoma. As a certain aspect, it is a use of a compound A monomethanesulfonate for the treatment of cancer associated with BMX. As a certain aspect, it is a use of a compound A monomethanesulfonate for the treatment of prostate cancer, bladder cancer, and/or renal cell carcinoma.

(4) A compound A or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer associated with BMX. As a certain aspect, it is a compound A or a pharmaceutically acceptable salt thereof for use in the treatment of prostate cancer, bladder cancer, and/or renal cell carcinoma. As a certain aspect, it is a compound A monomethanesulfonate which is used for the treatment of BMX-related cancer. As a certain aspect, it is a compound A monomethanesulfonate which is used for the treatment of prostate cancer, bladder cancer, and/or renal cell carcinoma.

(5) A method for treating cancer associated with BMX, which comprises administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject. In one aspect, the present invention relates to a method for treating prostate cancer, bladder cancer, and/or renal cell carcinoma, which comprises administering an effective amount of Compound A or a pharmaceutically acceptable salt thereof to a subject. As a certain aspect, it is a method for treating cancer associated with BMX, which is obtained by administering an effective amount of Compound A monomethanesulfonate to a subject. As a certain aspect, it is a method for treating prostate cancer, bladder cancer, and/or renal cell carcinoma, which comprises administering an effective amount of the compound A monomethanesulfonate to a subject.

Compound A or a pharmaceutically acceptable salt thereof can be as described in the above Patent Document 1 (International Publication No. 2013/108754). The law, or its method of change.

In addition, the "pharmaceutically acceptable salt of the compound A" means an acid addition salt of the compound A, and specific examples thereof include inorganic substances such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, benzhydryl tartaric acid, xylene mercapto An acid addition salt of an organic acid such as tartaric acid, citric acid, methanesulfonic acid (methanesulfonic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid or the like. In addition, the "pharmaceutically acceptable salt of the compound A" includes a solvate of the compound A, and specifically includes, for example, a hydrate or an ethanolate, and further a solvate comprising an acid addition salt of the compound A. .

Further, as a certain aspect of "Compound A or a pharmaceutically acceptable salt thereof", Compound A (free form) can be exemplified, and as another aspect, Compound A monomethanesulfonate can be exemplified.

The pharmaceutical composition containing the compound A or a pharmaceutically acceptable salt thereof can be prepared by a usual method using an excipient which is generally used in the field, that is, using a pharmaceutical excipient or a pharmaceutical carrier or the like. .

The administration may be oral administration of a tablet, a pill, a capsule, a granule, a powder, a liquid, or the like, or an injection, a sitting agent, a transdermal solution, etc. in the joint, the vein, the muscle, and the like. Any form of ointment, percutaneous patch, transmucosal solution, mucosal patch, inhalant, etc., which is administered orally.

As a solid composition for oral administration, an ingot is used. Agents, powders, granules, etc. In such a solid composition, one or two or more active ingredients are mixed with at least one kind of inactive excipient. The composition may also contain an inert additive such as a lubricant or a disintegrant, a stabilizer, and a dissolution aid according to a conventional method. Tablets or pills may also be coated with a film of sugar-coated or gastric-soluble or enteric material as needed.

A liquid composition for oral administration, which comprises an opacifying agent, a solution, a suspension, a syrup or an elixir, which are permissible on a pharmaceutical agent. The liquid composition may comprise a non-reactive diluent generally used, such as purified water or ethanol, and may further contain an auxiliary agent such as a solubilizing agent, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a fragrance, and a preservative. Agent.

An injection for parenteral administration containing a sterile aqueous or nonaqueous solution, suspension or opacifier. The aqueous solvent includes, for example, distilled water for injection or physiological saline. As the nonaqueous solvent, for example, there are alcohols such as ethanol. Such a composition may further comprise an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These are sterilized, for example, by filtration through a bacteria-retaining filter, formulation or irradiation of a bactericide. Further, these can be used to produce a sterile solid composition which is dissolved or suspended in sterile water or a sterile injectable solvent before use.

Usually, in the case of oral administration, the dosage of one day is about 0.001 to 100 mg/kg per body weight, and it is 0.01 to 30 mg/kg as a certain state, and further suitable as 0.1 to 10 mg/kg as a certain aspect. As a certain aspect, 0.3 to 7 mg/kg is suitable, and this is 1 time or 2 times to 4 times. In the case of intravenous administration, the dosage on the 1st is about 0.0001~10mg/kg per body weight. It is appropriate to apply once a day to several times a day. Further, as a transmucosal agent, about 0.001 to 100 mg/kg per body weight is administered once a day to several times. The dose is appropriately determined in consideration of individual conditions such as symptoms, age, and gender.

Although the type of the administration route, the dosage form, the administration site, the excipient or the additive is different, the pharmaceutical composition of the present invention contains 0.01 to 99% by weight, and as a certain aspect, 0.01 to 50% by weight of the compound A is contained. Or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition of the present invention can be used in combination with various therapeutic agents which are effective for cancer. The combined use can be administered simultaneously, or individually or continuously at desired intervals. In the case of simultaneous administration, the compounding agent may be formulated separately. In particular, as a concomitant agent, for example, a kinase inhibitor of sunitinib or sorafenib, a mTOR such as temsirolimus or everolimus may be mentioned. Inhibitors, such as bevacizumab anti-VEGF (vascular endothelial cell proliferation factor) preparations, interferon or interleukin interleukin preparations, such as BCG probiotic preparations, such as cyclophosphamide or isocyclic phosphorus Alkylamine alkylating agents such as mitomycin C, methotrexate, vinblastine, 5-FU, paclitaxel, mitoxantrone, etoposide , an anti-neoplastic agent of doxorubicin or cisplatin, such as a microtubule polymerization inhibitor of vincristine, such as prednisone, prednisolone or ground. Dexamethasone adrenocortical hormone agent, such as gemcitabine (gemcitabine) or a pemetrexed metabolic antagonist, such as bicalutamide or enzalutamide, an anti-androgen agent, such as a clodronate bisphosphonate Salt, GnRH (gonadotropin-releasing hormone) agonist such as goserelin or leuprorelin, GnRH anti-antagonism such as degarelix, such as abiraterone a CYP17 inhibitor, such as a progesterone progesterone preparation, an anti-RANKL preparation such as denosumab.

[Examples]

The pharmacological effects of the pharmaceutical composition of the present invention are confirmed by the following examples. Further, as the compound A or a pharmaceutically acceptable salt thereof, the compound A monomethanesulfonate (hereinafter sometimes referred to as "compound B") is used in the following examples. In each of the examples, the concentration of the compound B was calculated in terms of the concentration of the compound A (free body).

Example 1 BMX inhibition activity evaluation

About inhibitory activity using BMX BMX QSS Assist ^TM Mobility Shift Assay kit (Carna Biosciences) were evaluated.

Compound B was dissolved in dimethyl hydrazine (DMSO) to prepare a solution having a concentration of 100 times the test concentration. This solution was further diluted 25-fold into the test substance solution in an auxiliary analysis buffer. In addition, the kit-attached BMX is used in the reaction.

5 μL of the 4-fold concentration test substance solution prepared in the above analysis buffer and 10 μL of the 2-fold concentration BMX solution were mixed in the wells of the 384-well plate, and left at room temperature for 30 minutes. Then, 5 μL of a 4-fold concentration of the matrix peptide/ATP/MgCl ₂ solution was added, and the reaction was allowed to proceed at room temperature for 1 hour. The matrix peptide was used at a final concentration of 1 μM, ATP was a final concentration of 1 mM, and MgCl ₂ was a final concentration of 5 mM. Thereafter, 60 μL of the attached stop buffer was added to stop the reaction. The BMX activity was calculated by quantitatively calculating the ratio of the peak height of the matrix peptide to the peak height of the product (phosphorylated matrix peptide) peak by LabChip EZ Reader II (PerkinElmer).

In the data analysis, the average conversion ratio of the control wells including all the reaction components was 0%, and the average conversion ratio of the background value pores including all the reaction components except BMX was 100%, and each of the compounds B was blocked. The average conversion rate of the test wells was used to calculate the inhibition rate. The IC ₅₀ value is determined by a non-linear regression based on the graph of the concentration of the test substance and the inhibition rate.

As a result, Compound B inhibited BMX activity with an IC ₅₀ value of 0.46 nM.

Example 2 Evaluation of Proliferation Inhibition in Prostate Cancer Cell Line PC-3 Cells

PC-3 cells are cell lines derived from human prostate cancer, and BMX expression and BMX dependence were confirmed (Cell Death Dis. 2014; 5: e1409). PC-3 cells (American Type Culture Collection, CRL-1435) cultured in D-MEM medium (Sigma) containing 10% bovine serum were sown to a 96-well plate at about 1 × 10 ³ /well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO (DMSO group) was added, followed by incubation at 37 ° C for 5 days in the presence of 5% CO ₂ . Thereafter, the cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)) was used, and the measured value of the DMSO group was taken as a survival rate of 100%, and only the measured value of the well of the medium was used as a survival rate of 0%. Calculate the cell survival rate. The IC ₅₀ value is determined from a non-linear regression based on the graph of the concentration of the test substance and the cell survival rate.

As a result, Compound B inhibited proliferation of PC-3 cells with an IC ₅₀ value of 800 nM.

Example 3 Evaluation of proliferation inhibition in prostate cancer cell line DU145 cells

DU145 cells are cell lines derived from human prostate cancer, and the expression of BMX was confirmed (Cell Death Dis. 2014; 5: e1409). DU145 cells (American Type Culture Collection, HTB-81) cultured in D-MEM medium (Sigma) containing 10% bovine serum were sown to a 96-well plate at about 1 × 10 ³ /well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO (DMSO group) was added, followed by incubation at 37 ° C for 5 days in the presence of 5% CO ₂ . Thereafter, the cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)) was used, and the measured value of the DMSO group was taken as a survival rate of 100%, and only the measured value of the well of the medium was used as a survival rate of 0%. Calculate the cell survival rate. The IC ₅₀ value is determined from a non-linear regression based on the graph of the concentration of the test substance and the cell survival rate.

As a result, Compound B inhibited the proliferation of DU145 cells with an IC ₅₀ value of 410 nM.

Example 4 Evaluation of proliferation inhibition in prostate cancer cell line 22Rv1 cells

The 22Rv1 cell is a cell line derived from human prostate cancer, and the performance of BMX was confirmed (Oncogene 2006; 25: 70-78). 22Rv1 cells (American Type Culture Collection, CRL-2505) cultured in RPMI-1640 medium (Sigma) containing 10% bovine serum were sown to a 96-well plate at about 1 × 10 ³ /well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO (DMSO group) was added, followed by incubation at 37 ° C for 5 days in the presence of 5% CO ₂ . Thereafter, the cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)) was used, and the measured value of the DMSO group was taken as a survival rate of 100%, and only the measured value of the well of the medium was used as a survival rate of 0%. Calculate the cell survival rate. The IC ₅₀ value is determined from a non-linear regression based on the graph of the concentration of the test substance and the cell survival rate.

As a result, Compound B inhibited the proliferation of 22Rv1 cells with an IC ₅₀ value of 560 nM.

Example 5 Evaluation of proliferation inhibition in bladder cancer cell line UM-UC-3

UM-UC-3 cells are cell lines derived from human bladder cancer, and BMX expression and BMX dependence were confirmed (PLoS ONE 2011; 6(3): e17778). UM-UC-3 cells (American Type Culture Collection, CRL-1749) cultured in RPMI-1640 medium (Sigma) containing 10% bovine serum were sown to a 96-well plate at about 2 × 10 ³ /well. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or DMSO (DMSO group) was added, followed by incubation at 37 ° C for 5 days in the presence of 5% CO ₂ . Thereafter, the cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)) was used, and the measured value of the DMSO group was taken as a survival rate of 100%, and only the measured value of the well of the medium was used as a survival rate of 0%. Calculate the cell survival rate. The IC ₅₀ value is determined from a non-linear regression based on the graph of the concentration of the test substance and the cell survival rate.

As a result, Compound B inhibited proliferation of UM-UC-3 cells with an IC ₅₀ value of 560 nM.

Example 6 Evaluation of proliferation inhibition in renal cell carcinoma cell line OS-RC-2

The OS-RC-2 cell is a cell line derived from human renal cell carcinoma, and it is confirmed that BMX is expressed (J. Exp. Clin. Cancer Res. 2014; 33: 25). OS-RC-2 cells (Ryoken, RCB0735) cultured in RPMI-1640 medium (Sigma) containing 10% bovine serum were seeded at about 2 × 10 ³ /well into a 96-well plate. On the next day, a DMSO solution of Compound B having a final concentration of 1 nM to 10 μM or a DMSO (DMSO group) was added, followed by incubation at 37 ° C for 5 days in the presence of 5% CO ₂ . Thereafter, the cell number measurement reagent (CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega)) was used, and the measured value of the DMSO group was taken as a survival rate of 100%, and only the measured value of the well of the medium was used as a survival rate of 0%. Calculate the cell survival rate. The IC ₅₀ value is determined from a non-linear regression based on the graph of the concentration of the test substance and the cell survival rate.

As a result, Compound B inhibited proliferation of OS-RC-2 cells with an IC ₅₀ value of 620 nM.

Example 7 Anti-tumor evaluation of PC-3 subcutaneous cancer-bearing mouse model

Subcutaneous transplantation of prostate cancer cells at 3×10 ⁶ /0.1 mL/mouse in the back of immunocompromised mice (CAnN.Cg-Foxn1 ^nu /Cr1Cr1j (nu/nu), male, 4 weeks old (Charles River, Japan)) The PC-3 cells were cultured to produce a PC-3 subcutaneous cancer-bearing mouse model. For the PC-3 subcutaneous cancer-bearing mouse model grouped on the basis of tumor volume ([short diameter] ² × long diameter/2), a 0.5% methylcellulose solution was administered for 14 days (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), over time Changes in tumor volume were determined.

As a result, in the control group, the tumor volume on the start of the day was 238 mm ³ on average, and increased to an average of 1162 mm ³ after 14 days. On the other hand, in the compound B administration group, the average tumor volume at the start of administration was 242 mm ³ , but the average tumor volume after 14 days was 822 mm ³ .

From the above results, it was confirmed that Compound A or its pharmaceutics The above approved salt inhibits BMX activity and is useful as an active ingredient of a therapeutic pharmaceutical composition for cancer associated with BMX. Furthermore, it was confirmed that the proliferation of PC-3 cells, DU145 cells, 22Rv1 cells, UM-UC-3 cells of bladder cancer cell lines, and OS-RC-2 cells of renal cell carcinoma cell lines were inhibited in prostate cancer cell lines. These treatment effects on BMX-related cancers. Further, in the subcutaneous cancer-bearing mouse model of PC-3 cells of the subcutaneously transplanted prostate cancer cell line, a significant antitumor effect of inhibition of tumor proliferation was also confirmed in the group administered with the compound A monomethanesulfonate.

[Industrial availability]

The compound A of the active ingredient of the pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof has a BMX inhibitory action, and can be used as a therapeutic pharmaceutical composition for cancer associated with BMX, particularly prostate cancer, bladder cancer, and / or an active ingredient of a pharmaceutical composition for the treatment of renal cell carcinoma.

Claims (9)

A pharmaceutical composition for the treatment of cancer associated with BMX, which comprises 5-{[(3R)-1-propenylpyrrolidin-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. The pharmaceutical composition of claim 1, wherein the cancer associated with BMX is prostate cancer. The pharmaceutical composition of claim 1, wherein the cancer associated with BMX is bladder cancer. The pharmaceutical composition of claim 1, wherein the cancer associated with BMX is renal cell carcinoma. The pharmaceutical composition according to any one of claims 1 to 4, wherein 5-{[(3R)-1-propenylpyrrolidin-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-Propylpyridylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine) 1-yl]phenyl}amino)pyrazine-2-carboxamide monomethanesulfonate. 5-{[(3R)-1-Propylpyridylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl) Use of piperidin-1-yl]phenyl}amino)pyrazine-2-carboxyguanamine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of cancer associated with BMX. 5-{[(3R)-1-Propylpyridylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl) Piperidin-1-yl]phenyl}amine The use of pyrazine-2-carboxyguanamine or a pharmaceutically acceptable salt thereof for the treatment of BMX-associated cancer. 5-{[(3R)-1-Propylpyridylpyrrolidin-3-yl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl) Piperidin-1-yl]phenyl}amino)pyrazine-2-carboxyguanamine or a pharmaceutically acceptable salt thereof for use in the treatment of BMX-associated cancer. A method for treating cancer associated with BMX, which is composed of 5-{[(3R)-1-propenylpyridyl-3-yl]oxy}-6-ethyl-3-({4-[ An effective amount of 4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof is administered to a subject Made.