WO2022025150A1 - 乳がん治療剤 - Google Patents
乳がん治療剤 Download PDFInfo
- Publication number
- WO2022025150A1 WO2022025150A1 PCT/JP2021/028008 JP2021028008W WO2022025150A1 WO 2022025150 A1 WO2022025150 A1 WO 2022025150A1 JP 2021028008 W JP2021028008 W JP 2021028008W WO 2022025150 A1 WO2022025150 A1 WO 2022025150A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- breast cancer
- estrogen receptor
- therapeutic agent
- acceptable salt
- aromatase inhibitor
- Prior art date
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Definitions
- the present invention is used in combination with a monocyclic pyridine derivative having a fibroblast growth factor receptor (FGFR) inhibitory action or a pharmacologically acceptable salt thereof, and an estrogen receptor antagonist or an aromatase inhibitor.
- FGFR fibroblast growth factor receptor
- an estrogen receptor antagonist or an aromatase inhibitor Regarding breast cancer therapeutic agents. More specifically, 5-((2- (4- (1- (2-hydroxyethyl) piperidin-4-yl) benzamide) pyridine-4, administered in combination with an estrogen receptor antagonist or aromatase inhibitor.
- Tamoxifen, fulvestrant, etc. which are estrogen receptor antagonists, are used for the treatment of estrogen receptor-positive breast cancer (Non-Patent Document 1).
- Exemestane, anastrozole, etc. which are aromatase inhibitors, inhibit aromatase that changes androgen secreted from the adrenal cortex into estrogen (Non-Patent Document 2). Therefore, it is used for the treatment of estrogen receptor-positive breast cancer as well as estrogen receptor antagonists.
- Estrogen receptor antagonists are commonly used in premenopausal breast cancer patients, whereas aromatase inhibitors are used in postmenopausal breast cancer patients.
- Breast cancer is classified according to the presence or absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor type 2 (Human epidermal growth factor receptor Type 2; HER2), and drug therapy according to each type along with excision surgery of the affected area. Is being done.
- An object of the present invention is to provide a therapeutic agent for breast cancer to be administered in combination of a plurality of agents.
- the present invention provides the following [1] to [18].
- [1] 5-((2- (4- (1- (2-hydroxyethyl)) represented by the formula (I), which is administered in combination with an estrogen receptor antagonist or an aromatase inhibitor. Piperidin-4-yl) benzamide) Pyridine-4-yl) Oxy) -6- (2-methoxyethoxy) -N-methyl-1H-indole-1-carboxamide or a pharmacologically acceptable salt thereof.
- Breast cancer therapeutic agent [2] 5-((2- (4- (1- (2-hydroxyethyl)) represented by the formula (I), which is administered in combination with an estrogen receptor antagonist or an aromatase inhibitor.
- a pharmaceutical composition for the treatment of breast cancer. [3] 5-((2- (4- (1- (2-hydroxyethyl) piperidin-4-yl) benzamide) pyridin-4-yl) oxy) -6- (2) represented by the formula (I) -A pharmaceutical composition for the treatment of breast cancer, which comprises N-methyl-1H-indole-1-carboxamide or a pharmacologically acceptable salt thereof and an estrogen receptor antagonist or aromatase inhibitor.
- FGFR fibroblast growth factor receptor
- Example 1 it is a graph which showed the transition of the average tumor volume of each group after the start of drug administration.
- Example 4 it is a graph which showed the transition of the average tumor volume of each group after the start of drug administration.
- the compound represented by the formula (I) according to the present invention or a pharmacologically acceptable salt thereof can be produced by the method described in Patent Document 1.
- the pharmacologically acceptable salt may be, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, or the like.
- salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
- Suitable examples of salts with organic acids include acetic acid, succinic acid, fumaric acid, maleic acid, tartrate acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like. And salt can be mentioned.
- salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
- the preferred pharmacologically acceptable salt is succinate or maleate, and the more preferred salt is succinate.
- 1.5 succinate is preferable (hereinafter, 1.5 succinate of the compound represented by the formula (I) is referred to as compound A).
- the breast cancer therapeutic agent of the present invention can be orally administered in the form of solid preparations such as tablets, granules, fine granules, powders and capsules, liquid preparations, jellies and syrups.
- the breast cancer therapeutic agent of the present invention may be administered parenterally in the form of an injection, a suppository, an ointment, a pap, or the like.
- the breast cancer therapeutic agent of the present invention can be formulated by the method described in the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (EP), or the United States Pharmacopeia (USP).
- JP Japanese Pharmacopoeia
- EP European Pharmacopoeia
- USP United States Pharmacopeia
- the dose of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is determined by the degree of symptom, patient's age, gender, body weight, sensitivity difference, administration method, administration time, administration interval, and dosage form. It can be appropriately selected according to the type and the like.
- the daily dose is 0.5 mg to 5 g, preferably 1 mg to 1 g, and more preferably 1 mg to 500 mg. This can be administered in 1 to 3 divided doses a day.
- the estrogen receptor antagonist means a drug that binds to the estrogen receptor expressed in breast cancer cells. By such a mechanism, the binding between the estrogen receptor and estrogen can be inhibited, and the growth of breast cancer cells can be suppressed.
- the estrogen receptor antagonist include fulvestrant, tamoxifen or a pharmacologically acceptable salt thereof (citrate, etc.), mepitiostane and the like. It is preferably fulvestrant.
- estrogen receptor antagonist examples include erasestrant, H3B-6545, toremifene citrate, SAR439859, AZD9833, lintdestorant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, brilanestrant, and the like. It may be a Giledestrant.
- the dose and method of administration of the estrogen receptor antagonist is, for example, in the case of fulvestrant, 500 mg is intramuscularly administered once for the first time, 2 weeks, 4 weeks, and then every 4 weeks.
- estrogen receptor antagonist is tamoxifen or a pharmacologically acceptable salt thereof, 20 to 40 mg (as tamoxifen) is orally administered in 1 to 2 divided doses per day.
- estrogen receptor antagonist is mepitiostane, administer 20 mg orally in 2 divided doses per day.
- an aromatase inhibitor that inhibits estrogen synthesis may be used instead of the estrogen receptor antagonist.
- the aromatase inhibitor include exemestane, anastrozole, letrozole and the like. Exemestane is preferred.
- the dose and method of administration of the aromatase inhibitor is, for example, in the case of exemestane, 25 mg is orally administered once a day after meals.
- the aromatase inhibitor is anastrozole, administer 1 mg orally once daily.
- the aromatase inhibitor is letrozole, administer 2.5 mg orally once daily.
- a preparation containing a compound represented by the formula (I) or a pharmacologically acceptable salt thereof and a preparation containing an estrogen receptor antagonist or an aromatase inhibitor are simultaneously administered. Or it means to administer to the patient separately. Further, a composition containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof and an estrogen receptor antagonist or an aromatase inhibitor in one formulation may be administered.
- breast cancer means a benign or malignant tumor that develops in the mammary gland (duct, lobules). This includes locally advanced breast cancer, metastatic breast cancer, recurrent breast cancer or unresectable breast cancer.
- Example 1 Growth inhibitory effect of compound A and fulvestrant (trade name: Fesolodex intramuscular injection 250 mg AstraZeneca Co., Ltd.) on a tumor derived from a human breast cancer patient (OD-BRE-0438) in 5 cases in each group NOD- SCID mice (NOD.CB17-Prkdcscid / J, female, Charles River Japan, Inc.) were used to evaluate the antitumor effect when compound A and fulvestrant were administered.
- NOD-BRE-0438 is a hormone receptor-positive breast cancer patient-derived tumor established by Oncodesign. Subcutaneous transplantation of tumor pieces was performed in NOD-SCID mice.
- the tumor excised from the mice was shredded into pieces of about 5 mm square and transplanted to the subcutaneous part of the right flank of each mouse using Tracal ( ⁇ 3.5 mm), which was donated to the evaluation of antitumor effect.
- Tracal ⁇ 3.5 mm
- ⁇ -estradiol Fluji Film Wako Pure Chemical Industries, Ltd.
- ethanol Ferji Film Wako Pure Chemical Industries, Ltd.
- the final concentration is 2.5 ⁇ g / with sterile water for water supply.
- the solution was administered to mice by drinking water from the day of tumor transplantation to the day of the end of the test.
- Tumor volume (mm 3 ) major axis (mm) x minor axis (mm) x minor axis (mm) / 2
- Compound A was dissolved in purified water to a concentration of 2.5 mg / mL.
- a commercially available preparation 50 mg / mL was used as it was. Mice were assigned to each group 30 days after tumor transplantation so that the average tumor volume was the same.
- the administration start date was set to the 0th day, and the drug was administered under the following conditions.
- Mice in each group were orally administered compound A at a dose of 25 mg / kg (10 mL / kg) once daily for 14 consecutive days.
- Fulvestrant was also injected subcutaneously on days 0 and 7 at a dose of 250 mg / kg (5 mL / kg).
- the control group was untreated.
- the tumor volume of each mouse was measured on the 0th, 4th, 7th, 11th and 14th days.
- the results (mean values) are shown in Table 1 and FIG.
- Dunnett's multiplex test was performed on the tumor volumes of the control group and each administration group on the 14th day.
- Liquid A was prepared by mixing Lipofectamine TM 3000 reagent (Thermo Fisher Scientific) (3.75 ⁇ L) and Opti-MEM TM (Thermo Fisher Scientific) (125 ⁇ L). Further, the prepared PB510B2_hCYP19A1 vector (2 ⁇ g), pC3-PBase (0.5 ⁇ g), P3000 reagent (Thermo Fisher Scientific) (5 ⁇ L), and Opti-MEM TM (125 ⁇ L) were mixed to prepare a liquid B. .. After mixing these solutions A and B and allowing them to stand at room temperature for 5 minutes, they are added to the ZR-75-1 cells obtained by the above culture, and under the conditions of 5% CO 2 , 37 ° C. Evening culture was performed. Then, the cells were cultured in a medium supplemented with 1 ⁇ g / mL puromycin.
- Liquid A was prepared by mixing Lipofectamine TM 3000 reagent (3.75 ⁇ L) and Opti-MEM TM (125 ⁇ L). Further, the prepared PB510B2_hCYP19A1 vector (2 ⁇ g), pC3-PBase (0.5 ⁇ g), P3000 reagent (5 ⁇ L), and Opti-MEM TM (125 ⁇ L) were mixed to prepare a liquid B. These solutions A and B are mixed, allowed to stand at room temperature for 5 minutes, then added to the MCF-7 cells obtained by the above culture, and cultured for 3 days under the conditions of 5% CO 2 and 37 ° C. Was done. After that, the cells were cultured in a medium supplemented with 1 ⁇ g / mL puromycin for 7 days, and then cultured in a medium supplemented with 1.5 ⁇ g / mL puromycin.
- Example 2 Growth inhibitory effect of compound A and exemestane on subcutaneously transplanted tumors of human-derived breast cancer cell line ZR-75-1-hCYP19A1 in 5 cases in each group of BALB / c nude mice (CANN.Cg-Foxn1 / CrlCrlj, female) , Japan Charles River) was used to evaluate the antitumor effect of administration of compound A and exemestane.
- mice were subcutaneously injected with a mixed anesthetic solution of 0.3 mg / kg medetomidine hydrochloride, 4 mg / kg midazolam and 5 mg / kg butorphanol tartrate.
- the skin and peritoneum on the back of the mouse were incised, the left and right ovaries were excised, and the incision was sutured.
- mice were assigned to each group so that the average tumor volume was the same.
- Compound A was dissolved in purified water to a concentration of 2.5 mg / mL.
- Tween (registered trademark) 80 was mixed with a 0.5% methylcellulose solution so as to have a concentration of 0.4%.
- Exemestane was dissolved in this mixture to a concentration of 5 mg / mL.
- the administration start date was set to the 0th day, and the drug was administered under the following conditions.
- compound A was 50 mg / kg (20 mL / kg)
- exemestane was 1 mg / mouse (200 ⁇ L / mouse)
- compound A and exemestane were given once daily.
- the control group was untreated.
- Example 3 Concomitant effect of compound A and letrozole, anastrozole or exemethan using human-derived breast cancer cell line MCF-7-hCYP19A1 expressing human aromatase Human breast cancer cell line MCF-7 prepared in Reference Example 4.
- E-MEM medium L-glutamine, phenol red, sodium pyruvate, non-essential
- FBS FBS
- penicillin / streptomycin Fuji Film Wako Pure Chemical Industries, Ltd.
- Culture was maintained in a 5% CO 2 incubator with amino acids 1500 mg / L sodium hydrogen carbonate, Fuji Film Wako Pure Medicine) (hereinafter referred to as culture medium).
- each cell suspension prepared at 0.25 ⁇ 104 cells / mL in a culture medium containing 10% FBS was added, and the cells were cultured overnight in an incubator.
- a phenol red-free RPMI-1640 medium containing 10% FBS (Charcoal-Stripped FBS, GIBCO), penicillin / streptomycin, and 1.5 ⁇ g / mL puromycin (Fuji Film Wako Pure Chemical Industries, Ltd.) (hereinafter , Septic medium) was added in 100 ⁇ L increments and cultured in an incubator.
- the medium was removed, 100 ⁇ L of assay medium was added, the medium was exchanged, and the cells were cultured in an incubator for another 2 days. Then, the medium was removed, and 25 ⁇ L of androstendione prepared to a final concentration of 10 nmol / L in the assay medium, FGF2 (GIBCO) prepared to a final concentration of 25 ng / mL in the assay medium, and FGF10 adjusted to a final concentration of 100 ng / mL ( After adding 25 ⁇ L of R & D assays), 25 ⁇ L of each of the solutions described below was added, and the mixture was cultured in an incubator for 7 days.
- GEBCO FGF2
- FGF10 adjusted to a final concentration of 100 ng / mL
- Retrozole prepared to a final concentration of 2000 nmol / L in the assay medium
- anastrozole prepared to a final concentration of 10000 or 2000 nmol / L
- exemestane prepared to a final concentration of 2000 nmol / L or 400 nmol / L.
- the number of cells in each well after culturing was measured by using CellTiter Glo TM 2.0 (Promega), and the emission intensity was measured to calculate the amount of intracellular ATP contained.
- Example 4 Growth inhibitory effect of compound A and letrozole on subcutaneously transplanted tumors of human-derived breast cancer cell line MCF-7-hCYP19A1 5 cases of BALB / c nude mice in each group (CAnN.Cg-Foxn1 / CrlCrlj, female, Nippon Charles River) was used to evaluate the antitumor effect of administration of compound A and letrozole.
- mice were subcutaneously injected with a mixed anesthetic solution of 0.3 mg / kg medetomidine hydrochloride, 4 mg / kg midazolam and 5 mg / kg butorphanol tartrate.
- the skin and peritoneum on the back of the mouse were incised, the left and right ovaries were excised, and the incision was sutured.
- Antisedan (Nippon Zenyaku Kogyo) diluted with physiological saline (Otsuka Pharmaceutical Factory) so as to have a final concentration of 0.2 mg / mL was subcutaneously administered at a dose equivalent to 1 mg / kg (100 ⁇ L / mouse).
- intramuscular testosterone enanthate (Fuji Pharmaceutical Co., Ltd.) was diluted with sesame oil to make a solution with a concentration of 15.6 mg / mL under the conditions of 0.1 mL / mouse (1.56 mg / mouse). was administered intramuscularly. Then, the mice were intramuscularly administered once a week until the end date of the test.
- Compound A was dissolved in purified water to a concentration of 2.5 mg / mL.
- letrozole was dissolved in 0.3% hydroxypropyl cellulose / sterile water to a concentration of 0.05 mg / mL.
- the administration start date was set to the 0th day, and the drug was administered under the following conditions.
- compound A was 25 mg / kg (10 mL / kg)
- letrozole was 0.01 mg / mouse (200 ⁇ L / mouse)
- compound A and letrozole were given. It was orally administered once a day for 14 consecutive days.
- the control group was untreated.
- Tumor volumes of each mouse were measured on days 0, 4, 7, 11, and 14. The results (mean values) are shown in Table 8 and FIG.
- the major axis and the minor axis of the tumor were measured with an electronic digital caliper (Digimatic TM caliper, Mitutoyo Co., Ltd.).
- the tumor volume was calculated according to the following formula.
- Tumor volume (mm 3 ) major axis (mm) x minor axis (mm) x minor axis (mm) / 2 Dunnett's multiplex test was performed on the tumor volumes of the control group and each administration group on the 14th day.
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Abstract
Description
[1]エストロゲン受容体拮抗剤またはアロマターゼ阻害剤と組み合わせて投与されることを特徴とする、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-カルボキサミドまたはその薬理学的に許容される塩を含有する乳がん治療剤。
[3]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-カルボキサミドまたはその薬理学的に許容される塩およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を含有する、乳がん治療用医薬組成物。
[4]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-カルボキサミドまたはその薬理学的に許容される塩を含有する製剤とエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を含有する製剤を含む、乳がん治療用キット。
[5]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-カルボキサミドまたはその薬理学的に許容される塩およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を、それらを必要とする患者に投与する、乳がんの治療方法。
[6]エストロゲン受容体拮抗剤またはアロマターゼ阻害剤と組み合わせて投与されることを特徴とする、乳がん治療の使用のための式(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-カルボキサミドまたはその薬理学的に許容される塩。
[7]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-カルボキサミドまたはその薬理学的に許容される塩およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を含む、乳がん治療のための組み合わせ。
[8]エストロゲン受容体拮抗剤またはアロマターゼ阻害剤と組み合わせて投与されることを特徴とする、乳がん治療剤の製造のための式(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-カルボキサミドまたはその薬理学的に許容される塩の使用。
[9]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-カルボキサミドまたはその薬理学的に許容される塩、およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤が、同時にまたは別々に投与される、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[10]薬理学的に許容される塩が1.5コハク酸塩である、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[11]エストロゲン受容体拮抗剤が、フルベストラント、タモキシフェンもしくはその薬理学的に許容される塩またはメピチオスタンである、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[12]エストロゲン受容体拮抗剤が、フルベストラントである、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[13]アロマターゼ阻害剤が、エキセメスタン、アナストロゾールまたはレトロゾールである上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[14]アロマターゼ阻害剤が、エキセメスタンである、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[14a]アロマターゼ阻害剤が、レトロゾールである、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[15]乳がんがエストロゲン受容体陽性である、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[16]乳がんが局所進行乳がん、転移乳がん、再発乳がんまたは切除不能な乳がんである、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[17]線維芽細胞増殖因子受容体(FGFR)を発現している乳がん治療用である、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
[18]FGFRがFGFR1、FGFR2またはFGFR3である、上記の治療剤、組成物、キット、方法、化合物、組み合わせまたは使用。
各群5例のNOD-SCIDマウス(NOD.CB17-Prkdcscid/J、雌、日本チャールズ・リバー株式会社)を使用して、化合物Aとフルベストラントを投与した場合の抗腫瘍効果を評価した。
OD-BRE-0438はOncodesign社によって樹立されたホルモン受容体陽性乳がん患者由来腫瘍である。NOD-SCIDマウス皮下に腫瘍片を移植することで継代をおこなった。マウスから摘出した上記腫瘍を約5mm角に細断しトラカール(Φ3.5mm)を用いて、各マウスの右脇腹皮下部に移植し、抗腫瘍効果評価に供与した。
βエストラジオール(富士フィルム和光純薬株式会社)を、99.5%エタノール(富士フィルム和光純薬株式会社)で1mg/mLの濃度の溶液とした後、給水用滅菌水で最終濃度2.5μg/mLに調製した。その溶液を腫瘍移植日から試験終了日まで、マウスに飲水投与した。
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。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
腫瘍移植後30日に、腫瘍体積平均値が同じとなるように、各群にマウスを割り付けた。
各群のマウスに、化合物Aを25mg/kg(10mL/kg)の用量で、1日1回、14日間連続で、経口投与した。また、フルベストラントを250mg/kg(5mL/kg)の用量で、第0日および第7日に、皮下注射した。対照群は無処置とした。
PB-CMV-MCS-EF1α-Puroベクター(システムバイオサイエンス)をXba IとNot Iで切断し、これにマルチプルクローニングサイトを挿入したPB510B2ベクターを作製した。次に、PB510B2ベクターをXba IとCla Iで切断し、ヒトCYP19A1(NM_001347249.2)のORFを挿入し、PB510B2_hCYP19A1ベクターを得た。
pcDNA3.1(-) Mammalian Expression Vector(サーモフィッシャーサイエンティフィック)のネオマイシン発現モジュール(SV40 promoter-Neomycin ORF-SV40 poly A)を除去したベクターpC3-vectorを構築した。次に、Super PiggyBac Transposase Expression Vector(システムバイオサイエンス)のSuper PiggyBac TransposaseのORFを、pC3-vectorのCMV promoterの下流に挿入することでpC3-PBaseベクターを得た。
ヒト由来乳がん細胞株ZR-75-1(ECACC)を、6ウェルのマイクロプレート(FALCON)に播種した。培地として、10% FBS(SIGMA)、およびペニシリン/ストレプトマイシン(富士フィルム和光純薬)を含むRPMI-1640培地(4,500mg/Lグルコース、L-グルタミン、フェノールレッド、HEPES、ピルビン酸ナトリウム含有、富士フィルム和光純薬)を使用した。当該播種した細胞について、インキュベーターを使用して、5%CO2、37℃の条件下で15日間培養を行った。
ヒト由来乳がん細胞株MCF-7(ECACC)を、6ウェルのマイクロプレート(ファルコン)に播種した。培地として、10% FBS(SIGMA)、およびペニシリン/ストレプトマイシン(富士フィルム和光純薬)、E-MEM培地(L-グルタミン、フェノールレッド、ピルビン酸ナトリウム、非必須アミノ酸、1500mg/Lの炭酸水素ナトリウム含有、富士フィルム和光純薬)を使用した。当該播種した細胞について、インキュベーターを使用して、5%CO2、37℃の条件下で一晩培養を行った。
各群5例のBALB/cヌードマウス(CAnN.Cg-Foxn1/CrlCrlj、雌、日本チャールズ・リバー)を使用して、化合物Aとエキセメスタンを投与した場合の抗腫瘍効果を評価した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
参考例4で作製したヒト乳がん細胞株MCF-7-hCYP19A1を、10%FBS(SIGMA)、ペニシリン/ストレプトマイシン(富士フィルム和光純薬)、1.5μg/mLのピューロマイシンを含むE-MEM培地(L-グルタミン、フェノールレッド、ピルビン酸ナトリウム、非必須アミノ酸、1500mg/L炭酸水素ナトリウム含有、富士フィルム和光純薬)(以下、培養培地と表記する)で、5%CO2インキュベーター中で培養維持をおこなった。
(1)アッセイ培地で終濃度2000nmol/Lに調製したレトロゾール(SIGMA)、終濃度10000もしくは2000nmol/Lに調製したアナストロゾール(SIGMA)、終濃度2000nmol/Lもしくは400nmol/Lに調製したエキセメスタン(SIGMA)または終濃度0.05%DMSOを含むアッセイ培地(対照群または化合物A単剤の場合に使用)
(2)アッセイ培地で終濃度1000nmol/Lに調製した化合物Aまたは終濃度0.005%DMSOを含むアッセイ培地(対照群または(1)記載の薬剤単剤の場合に使用)
各群5例のBALB/cヌードマウス(CAnN.Cg-Foxn1/CrlCrlj、雌、日本チャールズ・リバー)を使用して、化合物Aとレトロゾールを投与した場合の抗腫瘍効果を評価した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
第14日の対照群と各投与群の腫瘍体積について、ダネットの多重検定を行った。
Claims (19)
- 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-カルボキサミドまたはその薬理学的に許容される塩、およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤が、同時にまたは別々に投与される、請求項1に記載の治療剤。
- 薬理学的に許容される塩が1.5コハク酸塩である、請求項1または2に記載の治療剤。
- エストロゲン受容体拮抗剤が、フルベストラント、タモキシフェンもしくはその薬理学的に許容される塩またはメピチオスタンである、請求項1~3のいずれか一項に記載の治療剤。
- エストロゲン受容体拮抗剤が、フルベストラントである、請求項1~3のいずれか一項に記載の治療剤。
- アロマターゼ阻害剤が、エキセメスタン、アナストロゾールまたはレトロゾールである請求項1~3のいずれか一項に記載の治療剤。
- アロマターゼ阻害剤が、エキセメスタンである、請求項1~3のいずれか一項に記載の治療剤。
- アロマターゼ阻害剤が、レトロゾールである、請求項1~3のいずれか一項に記載の治療剤。
- 乳がんがエストロゲン受容体陽性である、請求項1~8のいずれか一項に記載の治療剤。
- 乳がんが局所進行乳がん、転移乳がん、再発乳がんまたは切除不能な乳がんである、請求項1~9のいずれか一項に記載の治療剤。
- 線維芽細胞増殖因子受容体(FGFR)を発現している乳がん治療用である、請求項1~10のいずれか一項に記載の治療剤。
- FGFRがFGFR1、FGFR2またはFGFR3である、請求項11に記載の治療剤。
- エストロゲン受容体拮抗剤またはアロマターゼ阻害剤と組み合わせて投与されることを特徴とする、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-カルボキサミドまたはその薬理学的に許容される塩を含有する乳がん治療用医薬組成物。
- 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およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を含有する、乳がん治療用医薬組成物。
- 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有する製剤とエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を含有する製剤を含む、乳がん治療用キット。
- 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およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を、それらを必要とする患者に投与する、乳がんの治療方法。
- エストロゲン受容体拮抗剤またはアロマターゼ阻害剤と組み合わせて投与されることを特徴とする、乳がん治療の使用のための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。
- 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およびエストロゲン受容体拮抗剤またはアロマターゼ阻害剤を含む、乳がん治療のための組み合わせ。
- エストロゲン受容体拮抗剤またはアロマターゼ阻害剤と組み合わせて投与されることを特徴とする、乳がん治療剤の製造のための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の使用。
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EP4151212A1 (en) | 2023-03-22 |
AU2021315234A1 (en) | 2023-01-19 |
US20230172924A1 (en) | 2023-06-08 |
TW202220652A (zh) | 2022-06-01 |
EP4151212A4 (en) | 2024-04-10 |
BR112022027069A2 (pt) | 2023-02-07 |
KR20230047056A (ko) | 2023-04-06 |
CA3185174A1 (en) | 2022-02-03 |
CN115996722A (zh) | 2023-04-21 |
JPWO2022025150A1 (ja) | 2022-02-03 |
MX2023000060A (es) | 2023-02-01 |
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