WO2017104739A1 - 乳がん治療剤 - Google Patents

乳がん治療剤 Download PDF

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WO2017104739A1
WO2017104739A1 PCT/JP2016/087349 JP2016087349W WO2017104739A1 WO 2017104739 A1 WO2017104739 A1 WO 2017104739A1 JP 2016087349 W JP2016087349 W JP 2016087349W WO 2017104739 A1 WO2017104739 A1 WO 2017104739A1
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breast cancer
therapeutic agent
acid
acceptable salt
pharmacologically acceptable
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English (en)
French (fr)
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沙里 宮野
山本　裕之
学之 中川
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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Priority to ES16875716T priority Critical patent/ES2867804T3/es
Priority to CN201680068110.9A priority patent/CN108367000A/zh
Priority to US15/771,193 priority patent/US12414945B2/en
Priority to EP16875716.9A priority patent/EP3391885B1/en
Priority to MX2018006329A priority patent/MX384034B/es
Priority to RU2018119102A priority patent/RU2730503C2/ru
Priority to CN202211005176.7A priority patent/CN115177619A/zh
Priority to BR112018010103-6A priority patent/BR112018010103B1/pt
Priority to KR1020187014626A priority patent/KR102486722B1/ko
Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Priority to AU2016374441A priority patent/AU2016374441B2/en
Priority to JP2017556119A priority patent/JP6858132B2/ja
Priority to CA3001969A priority patent/CA3001969C/en
Priority to SG11201803118WA priority patent/SG11201803118WA/en
Publication of WO2017104739A1 publication Critical patent/WO2017104739A1/ja
Priority to IL258671A priority patent/IL258671A/en
Anticipated expiration legal-status Critical
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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  • the present invention relates to a therapeutic agent for breast cancer comprising a monocyclic pyridine derivative having an FGFR inhibitory action or a pharmacologically acceptable salt thereof. More particularly, 5-((2- (4- (1- (2-hydroxyethyl) piperidin-4-yl) benzamido) pyridin-4-yl) oxy) -6- (2-methoxyethoxy) -N -Methyl-1H-indole-1-carboxamide or a pharmacologically acceptable salt thereof, and relates to a therapeutic agent for breast cancer.
  • Non-patent Document 1 Breast cancer is classified according to the presence or absence of expression of estrogen receptor, progesterone receptor and HER2 receptor, and pharmacotherapy according to each type is performed along with surgery to remove the affected area. However, even if such a treatment is performed, the 5-year survival rate decreases depending on the degree of progression of breast cancer. In particular, in the case of a breast cancer called a triple negative type that does not express any of the above-mentioned receptors, even if an anticancer agent such as a taxane is administered, the effect is often insufficient (Non-patent Document 1). It has also been reported that FGFR inhibitors are effective in the treatment of breast cancer (Non-patent Document 2).
  • Foulkes et al. "Triple-Negative Breast Cancer", The New England Journal of Medicine., 363, 1938-1948, 2000.
  • Koziczak et al. "Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins", Oncogene., 23, 3501-3508, 2004.
  • An object of the present invention is to provide a new therapeutic agent for breast cancer.
  • a breast cancer therapeutic agent comprising a compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  • a method for treating breast cancer comprising administering a compound represented by formula (I) or a pharmacologically acceptable salt thereof to a patient in need thereof.
  • a composition for treating breast cancer comprising a compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  • a composition for treating breast cancer comprising a compound represented by formula (I) or a pharmacologically acceptable salt thereof and an excipient.
  • the therapeutic agent, use, compound, method or composition described above, wherein the breast cancer is locally advanced breast cancer, metastatic breast cancer or recurrent breast cancer.
  • the therapeutic agent, use, compound, method or composition described above, wherein the breast cancer expresses FGFR.
  • the compound represented by the formula (I) may have a tumor volume reducing effect on breast cancer.
  • the compound represented by formula (I) or a pharmacologically acceptable salt thereof according to the present invention can be produced by the method described in Patent Document 1.
  • examples of the pharmacologically acceptable salt include a salt with an inorganic acid, a salt with an organic acid, or a salt with an acidic amino acid.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • salts with organic acids include acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid. And the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • a preferred pharmacologically acceptable salt is succinate or maleate, and a more preferred salt is succinate. In particular, 1.5 succinate is preferred.
  • the therapeutic agent for breast cancer of the present invention can be orally administered in the form of solid preparations such as tablets, granules, fine granules, powders, capsules or liquids, jelly preparations, syrup preparations and the like.
  • the tumor therapeutic agent of the present invention may be administered parenterally in the form of injections, suppositories, ointments, cataplasms and the like.
  • the breast cancer therapeutic agent of the present invention can be formulated by the method described in the 16th revision Japanese Pharmacopoeia.
  • the dose of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, pharmaceutical preparation. Depending on the type, etc., it can be selected as appropriate.
  • the dose is 100 ⁇ g to 10 g, preferably 500 ⁇ g to 10 g, more preferably 1 mg to 5 g per day. This can be administered in 1 to 3 divided doses per day.
  • breast cancer means a benign or malignant tumor that has developed in the mammary gland (milk duct, lobule). This includes locally advanced breast cancer, metastatic breast cancer or recurrent breast cancer.
  • Example 1 Growth Inhibitory Effect of Compound A on Human Breast Cancer Cell Line Compound A was administered using 4 nude mice (BALB / cAJcl-nu / nu, female, CLEA Japan) in each group. The antitumor effect of each case was evaluated.
  • the human-derived breast cancer cell line MFM223 (ECACC) was conditioned in advance. MFM223 cells were suspended in HBSS (Wako Pure Chemical Industries, Ltd.) to a concentration of 2 ⁇ 10 8 cells / mL. The same volume of Matrigel TM matrix (Nippon Becton Dickinson Co., Ltd.) was added to the suspension and mixed thoroughly.
  • Each 0.1 mL of the mixture was transplanted into the right flank subcutaneous part of nude mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River Japan Co., Ltd.).
  • ⁇ -estradiol (Wako Pure Chemical Industries, Ltd.) prepared to a final concentration of 2.5 ⁇ g / mL was administered with drinking water.
  • the formed tumor was excised, finely cut, and added with HBSS containing a final concentration of 380 units / mL Type I collagenase (SIGMA) and a final concentration of 160 Kunit / mL Deoxyribonuclease I (SIGMA), and stirred at 37 ° C. did.
  • HBSS HBSS containing a final concentration of 380 units / mL Type I collagenase (SIGMA) and a final concentration of 160 Kunit / mL Deoxyribonuclease I (SIGMA), and stirred at 37 ° C. did.
  • SIGMA Type I collagenase
  • SIGMA 160 Kunit / mL Deoxyribonuclease I
  • the cells obtained by the above treatment were suspended in EMEM medium (Wako Pure Chemical Industries, Ltd.) containing 10% bovine serum so as to have a concentration of 1.4 ⁇ 10 8 cells / mL.
  • EMEM medium Wako Pure Chemical Industries, Ltd.
  • Matrigel TM matrix Nippon Becton Dickinson Co., Ltd.
  • the mixed solution was transplanted in an amount of 0.1 mL into the right flank subcutaneous part of each mouse and provided for evaluation of antitumor effect.
  • Twenty days after transplantation the major axis and minor axis of the tumor were measured with an electronic digital caliper (Digimatic TM caliper, Mitutoyo Corporation).
  • the mice were divided into groups so that the average values of the tumor volumes in each group were almost equal.
  • the tumor volume was calculated according to the following formula.
  • Tumor volume (mm 3 ) major axis (mm) ⁇ minor axis (mm) ⁇ minor axis (mm) / 2
  • Compound A obtained in Production Example 1 was dissolved in purified water to a concentration of 0.625 mg / mL or 2.5 mg / mL. Each group of mice was orally administered once daily for 12 days at a dose volume of 12.5 mg / kg or 50 mg / kg, 20 mL / kg. In addition, 20 mL / kg purified water was administered to the control group.
  • the tumor volume of each mouse was measured on days 3, 7, and 12 after the start of administration. The results are shown in Table 1 and FIG. The changes in body weight are shown in Table 2 and FIG.

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Abstract

本願は、５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミドまたはその薬理学的に許容される塩を含む、乳がん治療剤を開示する。

Description

乳がん治療剤
　本発明は、ＦＧＦＲ阻害作用を有する単環ピリジン誘導体またはその薬理学的に許容される塩を含む、乳がん治療剤に関する。より詳細には、５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミドまたはその薬理学的に許容される塩を含む、乳がん治療剤に関する。
Figure JPOXMLDOC01-appb-C000002
　式（Ｉ）で表される５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミドは、線維芽細胞増殖因子受容体（ＦＧＦＲ）１、２および３に対する阻害剤として知られ、胃がん、肺がん、膀胱がんおよび子宮内膜がんの細胞増殖抑制作用を有することが報告されている（特許文献１）。
　乳がんはエストロゲン受容体、プロゲステロン受容体およびＨＥＲ２受容体の発現の有無によって分類され、患部の摘出手術とともに、それぞれのタイプに応じた薬物療法が行われている。しかし、このような治療を行っても、乳がんの進行度に応じて、５年生存率は低下してしまう。特に、上記のいずれの受容体も発現しないトリプルネガティブタイプと呼ばれる乳がんの場合は、タキサン等の抗がん剤を投与しても効果が十分ではないことも多い（非特許文献１）。また、ＦＧＦＲの阻害剤が、乳がんの治療に有効であることも報告されている（非特許文献２）。
米国特許出願公開第２０１４－２３５６１４号明細書
Foulkes et al., "Triple-Negative Breast Cancer", The New England Journal of Medicine., 363, 1938-1948, 2000. Koziczak et al., "Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins", Oncogene., 23, 3501-3508, 2004.
　本発明の課題は、新しい乳がんの治療剤を提供することである。
　このような状況に鑑み、本発明者らは鋭意検討を進めた結果、上記式（Ｉ）で表される化合物が乳がんに対して、高い治療効果を示すことを見出し、本発明を完成させた。
　すなわち、本発明は以下の［１］～［９］を提供する。
［１］　式（Ｉ）で表される化合物またはその薬理学的に許容される塩を含む乳がん治療剤。
Figure JPOXMLDOC01-appb-C000003
 ［２］　式（Ｉ）で表される化合物またはその薬理学的に許容される塩の乳がん治療のための使用。
［３］　乳がん治療のための式（Ｉ）で表される化合物またはその薬理学的に許容される塩。
［４］　式（Ｉ）で表される化合物またはその薬理学的に許容される塩をそれを必要とする患者に投与する乳がんの治療方法。
［５］　式（Ｉ）で表される化合物またはその薬理学的に許容される塩を含む乳がん治療用組成物。
［６］　式（Ｉ）で表される化合物またはその薬理学的に許容される塩および賦形剤を含む乳がん治療用組成物。
［７］　乳がんが局所進行乳がん、転移乳がんまたは再発乳がんである上記治療剤、使用、化合物、方法または組成物。
［８］　乳がんがＦＧＦＲを発現しているものである上記治療剤、使用、化合物、方法または組成物。
［９］　ＦＧＦＲがＦＧＦＲ１、ＦＧＦＲ２またはＦＧＦＲ３である上記治療剤、使用、化合物、方法または組成物。
　式（Ｉ）で表される化合物は、乳がんに対して腫瘍体積の縮小効果を奏する可能性がある。
薬物投与開始後の腫瘍の体積の推移を示したグラフである。 薬物投与開始後の体重の推移を示したグラフである。
　本発明に係る式（Ｉ）で表される化合物またはその薬理学的に許容される塩は、特許文献１に記載された方法により製造することができる。
　本明細書において、薬理学的に許容される塩とは、例えば無機酸との塩、有機酸との塩、または酸性アミノ酸との塩などを挙げることができる。
　無機酸との塩の好適な例としては、例えば塩酸、臭化水素酸、硫酸、硝酸、リン酸などとの塩が挙げることができる。
　有機酸との塩の好適な例としては、例えば酢酸、コハク酸、フマル酸、マレイン酸、酒石酸、クエン酸、乳酸、ステアリン酸、安息香酸、メタンスルホン酸、エタンスルホン酸、ｐ－トルエンスルホン酸などとの塩を挙げることができる。
　酸性アミノ酸との塩の好適な例としては、例えばアスパラギン酸、グルタミン酸などとの塩を挙げることができる。
　好ましい薬理学的に許容される塩は、コハク酸塩またはマレイン酸塩であり、より好ましい塩はコハク酸塩である。特に１．５コハク酸塩が好ましい。
　本発明の乳がん治療剤は、錠剤、顆粒剤、細粒剤、粉剤、カプセル剤等の固形製剤または液剤、ゼリー剤、シロップ剤等の形態で、経口投与することができる。また、本発明の腫瘍治療剤は注射剤、坐剤、軟膏剤、パップ剤等の形態で、非経口的に投与してもよい。
　本発明の乳がん治療剤は、第十六改正日本薬局方に記載された方法で製剤化することができる。
　式（Ｉ）で表される化合物またはその薬理学的に許容される塩の投与量は、症状の程度、患者の年齢、性別、体重、感受性差、投与方法、投与時期、投与間隔、医薬製剤の種類等に応じて、適宜選択することができる。通常、成人（体重６０ｋｇ）に対して経口投与する場合、１日あたり１００μｇ～１０ｇ、好ましくは５００μｇ～１０ｇ、さらに好ましくは１ｍｇ～５ｇである。これを１日１～３回に分けて投与することができる。
　本明細書において乳がんとは、乳腺（乳管、小葉）に発生した良性または悪性の腫瘍を意味する。この中には局所進行乳がん、転移乳がんまたは再発乳がんも含まれる。
　以下に実施例を挙げて、本発明をさらに詳細に説明する。
製造例１
５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミド　１．５コハク酸塩（以下、化合物Ａと表記する場合がある）の製造
Figure JPOXMLDOC01-appb-C000004
 　５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミド　２．９３ｇをナスフラスコに量り取り、６０ｍＬのエタノールを加え、攪拌しながらオイルバスで７０℃に加熱し、溶解させた。コハク酸（１．２３ｇ）を加え、オイルバスを切り、徐冷した。室温で約２時間攪拌した後、さらに５℃で１時間攪拌した。固体をろ取して、標記化合物を得た（３．７０ｇ）。
1H-NMR Spectrum (600MHz, CD3OD) δ(ppm): 1.96-2.10 (4H, m), 2.52 (6H, s), 2.93 (1H, m), 2.96 (3H, s), 3.01 (2H, m), 3.16 (2H, t, J=5.4 Hz), 3.22 (3H, s), 3.56 (2H, t, J=4.7 Hz), 3.61 (2H, m), 3.87 (2H, t, J=5.4 Hz), 4.14 (2H, t, J=4.6 Hz), 6.61 (1H, d, J=3.6 Hz), 6.68 (1H, dd, J=5.8, 2.3 Hz), 7.37 (1H, s), 7.42 (2H, d, J=8.3 Hz), 7.58 (1H, d, J=3.6 Hz), 7.73 (1H, d, J=2.2 Hz), 7.88 (2H, d, J=8.3 Hz), 8.08 (1H, s), 8.15 (1H, d, J=5.8 Hz).
13C-NMR Spectrum (100MHz, solid state) δ(ppm): 27.1, 28.3, 29.7, 34.8, 38.0, 41.3, 54.0, 57.3, 59.7, 60.9, 72.1, 72.5, 103.3, 104.2, 108.5, 116.9, 126.9, 128.6, 134.5, 136.7, 140.7, 149.4, 151.3, 155.1, 169.5, 170.1, 175.6, 179.9, 183.7.
実施例１　ヒト乳がん細胞株（ＭＦＭ２２３）に対する化合物Ａによる増殖抑制作用
　各群４例のヌードマウス（ＢＡＬＢ／ｃＡＪｃｌ－ｎｕ／ｎｕ、雌、日本クレア株式会社）を使用して、化合物Ａを投与した場合の抗腫瘍効果を評価した。
　ヒト由来乳癌細胞株ＭＦＭ２２３（ＥＣＡＣＣ）について、予め馴化処理を行った。ＭＦＭ２２３細胞を、ＨＢＳＳ（和光純薬工業株式会社）に、２×１０８個／ｍＬの濃度となるように懸濁した。当該懸濁液に、同容量のマトリゲルＴＭマトリックス（日本ベクトン・ディッキンソン株式会社）を添加し、十分に混和した。その混和液をヌードマウス（ＣＡｎＮ．Ｃｇ－Ｆｏｘｎ１ｎｕ／ＣｒｌＣｒｌｊ、雌、日本チャールズリバー株式会社）の右脇腹皮下部に、０．１ｍＬずつ移植した。飼育中は終濃度２．５μｇ／ｍＬに調製したβ―エストラジオール（和光純薬工業株式会社）を飲水投与させた。移植後４６日に、形成した腫瘍を摘出し、細かく裁断し、終濃度３８０ｕｎｉｔ／ｍＬ　Ｔｙｐｅ　Ｉ　ｃｏｌｌａｇｅｎａｓｅ（ＳＩＧＭＡ）および終濃度１６０Ｋｕｎｉｔ／ｍＬ　Ｄｅｏｘｙｒｉｂｏｎｕｃｌｅａｓｅ　Ｉ（ＳＩＧＭＡ）を含むＨＢＳＳを加え、３７℃にて攪拌した。１００μｍ　セルストレイナー（Ｆａｌｃｏｎ（登録商標））を通した後、遠心し細胞を回収し、１０％ウシ血清を含んだＥＭＥＭ培地（和光純薬工業株式会社）にて培養した。
　上記処理により得られた細胞を、１０％ウシ血清を含んだＥＭＥＭ培地（和光純薬工業株式会社）に、１．４×１０８個／ｍＬの濃度となるように懸濁した。当該懸濁液に、同容量のマトリゲルＴＭマトリックス（日本ベクトン・ディッキンソン株式会社）を添加し、十分に混和した。その混和液を各マウスの右脇腹皮下部に、０．１ｍＬずつ移植し、抗腫瘍効果評価に供与した。
　移植から２０日後に、腫瘍の長径および短径を電子デジタルノギス（デジマチックＴＭキャリパ、株式会社ミツトヨ）で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスの群分けを行った。なお、腫瘍の体積は、以下の式に従って算出した。
　腫瘍体積（ｍｍ３）＝長径（ｍｍ）×短径（ｍｍ）×短径（ｍｍ）／２
　製造例１で得た化合物Ａを０．６２５ｍｇ／ｍＬまたは２．５ｍｇ／ｍＬの濃度となるように、精製水に溶解した。
　各群のマウスに、１２．５ｍｇ／ｋｇまたは５０ｍｇ／ｋｇ、２０ｍＬ／ｋｇの投与容量で１日１回、１２日間、経口投与した。なお、対照群には、２０ｍＬ／ｋｇの精製水を投与した。
　投与開始後３、７、および１２日目に、各マウスの腫瘍体積を測定した。その結果を表１および図１に示した。また、体重の推移を表２および図２に示した。
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
  

Claims (6)

  1. 　５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミドまたはその薬理学的に許容される塩を含む、乳がん治療剤。
    Figure JPOXMLDOC01-appb-C000001
  2. 　塩が１．５コハク酸塩である、請求項１に記載の治療剤。
  3. 　５－（（２－（４－（１－（２－ヒドロキシエチル）ピペリジン－４－イル）ベンズアミド）ピリジン－４－イル）オキシ）－６－（２－メトキシエトキシ）－Ｎ－メチル－１Ｈ－インドール－１－カルボキサミドまたはその薬理学的に許容される塩を含む、乳がん治療用医薬組成物。
  4. 　塩が１．５コハク酸塩である、請求項３に記載の医薬組成物。
  5. 　乳がんが局所進行乳がん、転移乳がんまたは再発乳がんである、請求項１または２に記載の治療剤。
  6. 　乳がんが局所進行乳がん、転移乳がんまたは再発乳がんである、請求項３または４に記載の医薬組成物。
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