WO2016175252A1 - Composition pharmaceutique contenant un composé de pyrazinecarboxamide en tant que principe actif - Google Patents

Composition pharmaceutique contenant un composé de pyrazinecarboxamide en tant que principe actif Download PDF

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Publication number
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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English (en)
Japanese (ja)
Inventor
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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Publication of WO2016175252A1 publication Critical patent/WO2016175252A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

L'invention concerne une composition pharmaceutique permettant de traiter le cancer associé au BMX, en particulier une composition pharmaceutique permettant de traiter le cancer de la prostate, le cancer de la vessie et/ou le cancer à cellules rénales. Les auteurs de l'invention ont étudié des composés ayant chacun une activité d'inhibition de BMX, et ont confirmé qu'un composé de pyrazinecarboxamide spécifique présente une activité d'inhibition de BMX, et qu'une composition pharmaceutique contenant le composé en tant que principe actif présente un effet thérapeutique sur le cancer associé au BMX, en particulier le cancer de la prostate, le cancer de la vessie et/ou le cancer à cellules rénales. La présente invention est le fruit des résultats de cette étude.
PCT/JP2016/063246 2015-04-28 2016-04-27 Composition pharmaceutique contenant un composé de pyrazinecarboxamide en tant que principe actif WO2016175252A1 (fr)

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JP2015092301A JP2018104290A (ja) 2015-04-28 2015-04-28 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
JP2015-092301 2015-04-28

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017090699A1 (fr) * 2015-11-27 2017-06-01 アステラス製薬株式会社 Composition pharmaceutique pour l'activation du système immunitaire et/ou composition pharmaceutique pour l'immunothérapie du cancer, contenant comme principe actif un pyrazine carboxamide
WO2018079570A1 (fr) 2016-10-26 2018-05-03 アステラス製薬株式会社 Composition pharmaceutique stable
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526299A (ja) * 2008-06-27 2011-10-06 アビラ セラピューティクス， インコーポレイテッド ヘテロアリール化合物およびそれらの使用
WO2013108754A1 (fr) * 2012-01-17 2013-07-25 アステラス製薬株式会社 Composé pyrazine carboxamide
WO2014025486A1 (fr) * 2012-08-06 2014-02-13 Acea Biosciences Inc. Nouveaux composés de pyrrolopyrimidine utilisés en tant qu'inhibiteurs des protéines kinases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526299A (ja) * 2008-06-27 2011-10-06 アビラ セラピューティクス， インコーポレイテッド ヘテロアリール化合物およびそれらの使用
WO2013108754A1 (fr) * 2012-01-17 2013-07-25 アステラス製薬株式会社 Composé pyrazine carboxamide
WO2014025486A1 (fr) * 2012-08-06 2014-02-13 Acea Biosciences Inc. Nouveaux composés de pyrrolopyrimidine utilisés en tant qu'inhibiteurs des protéines kinases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017090699A1 (fr) * 2015-11-27 2017-06-01 アステラス製薬株式会社 Composition pharmaceutique pour l'activation du système immunitaire et/ou composition pharmaceutique pour l'immunothérapie du cancer, contenant comme principe actif un pyrazine carboxamide
WO2018079570A1 (fr) 2016-10-26 2018-05-03 アステラス製薬株式会社 Composition pharmaceutique stable
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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