JP2020514292A - 癌の治療に対する併用療法 - Google Patents
癌の治療に対する併用療法 Download PDFInfo
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- JP2020514292A JP2020514292A JP2019536274A JP2019536274A JP2020514292A JP 2020514292 A JP2020514292 A JP 2020514292A JP 2019536274 A JP2019536274 A JP 2019536274A JP 2019536274 A JP2019536274 A JP 2019536274A JP 2020514292 A JP2020514292 A JP 2020514292A
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
Description
本出願は、2017年1月6日付けで出願された米国仮特許出願第62/443,588号の利益を主張するものである。この出願の全体が全ての目的で引用することにより本明細書の一部をなす。
本発明は、米国国立衛生研究所によって授与された助成金番号1R01CA188017−01A1による政府の支援を一部受けてなされたものである。合衆国政府は本発明における一定の権利を有する。
本発明は、下記の共同研究契約者によって又は代理人によって行われた。共同研究契約は、本出願の出願日において又はその出願日前に効力があり、特許請求の範囲に記載の発明は、共同研究契約の範囲で行われた活動の結果なされたものである。共同研究契約者は、G1 Therapeutics, Inc.及びイリノイ大学の評議員会である。
mは、0、1、2、3、又は4であり、
nは、0、1、2、3、又は4であり、
XAは、−O−、−CH2−、−S−、−NH−、−NMe−、−CF2−及びC3シクロアルキルから選択され、
環Bは、フェニル、ナフチル、キノリニル、5員若しくは6員の単環式ヘテロアリール、又は7員、8員、9員若しくは10員の二環式ヘテロシクリルであり、
環Cは、フェニル、チオフェニル(すなわち、チエニル)、5員若しくは6員の単環式ヘテロアリール、又は7員、8員、9員若しくは10員の二環式ヘテロシクリルであり、
R1は、ヒドロキシル、水素、ハロゲン、−O(C1〜C6アルキル)、−OC(O)(C1〜C6アルキル)、−OC(O)C6H5、−OC(O)O(C1〜C6アルキル)、−OC(O)OC6H5、及び−OSO2(C2〜C6アルキル)から選択され、
R2は、−CH=CHCOOH、−NH(CO)COOH、−COOH、−C2〜C6アルケニレン−COOH、及び−C2〜C6アルキニレン−COOHから選択され、
R3はそれぞれ独立して、水素、ハロゲン、−CN、−NO2、−C1〜C6アルキル、及び−C1〜C6フルオロアルキルから選択され、
R4はそれぞれ独立して、水素、ハロゲン、ヒドロキシル、−C1〜C6アルキル、−C1〜C6フルオロアルキル、−CN、−O(C1〜C6アルキル)、及び−O(C1〜C6フルオロアルキル)から選択される)である。
(a)任意に、薬学的に許容可能な担体において、式A、式B及び式Cから選択される少なくとも1つのSERD化合物又はその薬学的に許容可能な塩と、式Dの少なくとも1つのCDK4/6阻害化合物又はその薬学的に許容可能な塩とを治療的有効量、それを必要とする被験体に投与することを含む、本明細書に記載されるエストロゲン感受性の腫瘍又は癌等のホルモン感受性の腫瘍又は癌を治療する方法、
(b)任意に1以上の薬学的に許容可能な担体において、式A、式B及び式Cから選択される少なくとも1つのSERD化合物又はその薬学的に許容可能な塩と、式Dの少なくとも1つのCDK4/6阻害化合物又はその薬学的に許容可能な塩との組み合わせを治療的有効量、それを必要とする被験体に投与することを含む、本明細書に記載される腎臓癌、前立腺癌又は肺癌を治療する方法、
(c)任意に、1以上の薬学的に許容可能な担体において、式A、式B及び式Cから選択される少なくとも1つのSERD化合物又はその薬学的に許容可能な塩と、式Dの少なくとも1つのCDK4/6阻害化合物又はその薬学的に許容可能な塩との組み合わせを治療的有効量、それを必要とする被験体に投与することを含む、本明細書に記載される乳癌、卵巣癌又は子宮内膜癌を治療する方法、
(d)任意に、1以上の薬学的に許容可能な担体において、式A、式B及び式Cから選択される少なくとも1つのSERD化合物又はその薬学的に許容可能な塩と、式Dの少なくとも1つのCDK4/6阻害化合物又はその薬学的に許容可能な塩との組み合わせを治療的有効量、それを必要とする被験体に投与することを含む、本明細書に記載されるホルモン受容体陽性転移性乳癌を治療する方法、
(e)任意に、1以上の薬学的に許容可能な担体において、式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩との組み合わせを治療的有効量、それを必要とする被験体に投与することを含む、本明細書に記載されるタモキシフェン耐性乳癌を治療する方法、
(f)任意に、1以上の薬学的に許容可能な担体において、式A、式B及び式Cから選択される少なくとも1つのSERD化合物又はその薬学的に許容可能な塩と、式Dの少なくとも1つのCDK4/6阻害化合物又はその薬学的に許容可能な塩との組み合わせを治療的有効量、それを必要とする被験体に投与することを含む、本明細書に記載される三種陰性乳癌を治療する方法、
(g)任意に、1以上の薬学的に許容可能な担体において、式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物、
(h)腫瘍又は癌を含むが、これらに限定されない、エストロゲン関連の障害の治療又は予防に有用な、式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物、
(i)腫瘍又は癌を含むが、これらに限定されない、エストロゲン関連の障害の治療又は予防のための医薬(複数の場合もある)の製造における、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物の使用、
(j)本明細書に記載される薬学的に許容可能な組成物又は組み合わせを医薬(複数の場合もある)の製造に使用することを特徴とする、腫瘍又は癌を含むが、これらに限定されない、異常な細胞増殖の障害を治療又は予防するために治療的に使用される医薬を製造する方法、
(k)乳癌、腎臓癌、子宮癌、卵巣癌又は子宮内膜癌の治療又は予防に使用される、式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物、
(l)乳癌、腎臓癌、子宮癌、卵巣癌又は子宮内膜癌の治療又は予防のための医薬の製造における、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物の使用、
(m)式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組成物又は組み合わせを、医薬(複数の場合もある)の製造において使用することを特徴とする、乳癌、腎臓癌、子宮癌、卵巣癌又は子宮内膜癌の治療又は予防において治療的に使用される医薬(複数の場合もある)を製造する方法、
(n)ホルモン受容体陽性転移性乳癌の治療又は予防に使用される、式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物、
(o)ホルモン受容体陽性転移性乳癌腫瘍の治療又は予防のための医薬の製造における、式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組み合わせ又は組成物の使用、
(p)式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、本明細書に記載される薬学的に許容可能な組成物又は組み合わせを製造に使用することを特徴とする、ホルモン受容体陽性転移性乳癌の治療又は予防のための医薬を製造する方法、
(q)式A、式B若しくは式Cの化合物又はその薬学的に許容可能な塩と、式Dの化合物又はその薬学的に許容可能な塩とを含む、有効量の本明細書に記載される薬学的に許容可能な組成物又は組み合わせを含む、治療剤製品を作製する方法。
本明細書で使用される以下の用語及び表現は、以下に示す意味を有する。
i.疾患又は障害を阻害すること、すなわち、その発症を抑えること、
ii.疾患又は障害を軽減すること、すなわち、その障害の退行を引き起こすこと、
iii.障害の進行を遅延させること、及び/又は、
iv.疾患又は障害の1以上の症状を阻害すること、軽減すること、又はその進行を遅らせること。
本発明は、治療的有効量の、本明細書に記載されるエストロゲン受容体ダウンレギュレーター化合物(式A、式B、及び式Cから選択される)又はその薬学的に許容可能な塩若しくはプロドラッグと、本明細書に記載されるCDK4/6阻害剤(式Dから選択される)又はその薬学的に許容可能な塩若しくはプロドラッグと、希釈剤、防腐剤、可溶化剤、乳化剤、アジュバント、賦形剤又は担体等の1以上の薬学的に許容可能なビヒクルとを含む、医薬組成物を含む。賦形剤として、限定されないが、水、生理食塩水、グリセロール、ポリエチレングリコール、ヒアルロン酸、エタノール等の液体が挙げられる。
本明細書で教示される組み合わせにおける本発明の化合物は、かかる治療に対して感受性の癌又は腫瘍を含む異常な細胞増殖の治療又は予防の方法に使用され得る。癌は、例えば、乳癌、子宮癌、卵巣癌、子宮内膜癌、前立腺癌、又は肺癌であってもよい。特に、乳癌は、タモキシフェン耐性乳癌、又は三種陰性乳癌であってもよい。
本明細書に記載された化合物を、当業者に知られている方法によって作製することができる。一つの非限定的な例では、スキームを使用して、開示される化合物を作製することができる。
スキーム6:(E)−3−(4−((2−(4−フルオロ−2−メチルベンゾイル)−6−ヒドロキシベンゾ[b]チオフェン−3−イル)オキシ)フェニル)アクリル酸(化合物1)の合成
化合物23〜化合物26は、以下に示される一般合成スキーム(一般合成経路6)に従って作製され得る。ジオキサン中のクロロトリサイクリックラクタムの撹拌溶液に適切なアミノピリジン中間体を添加した後、Pd2(dba)3、BINAP、及びナトリウム−tert−ブトキシドを添加した。内容物を加熱還流した。次いで、粗製混合物を精製して所望の化合物を得た。化合物23〜化合物26の構造を下記表7に示す。
培養プレートからこすり取った後、プロテアーゼ阻害剤とホスファターゼ阻害剤とのカクテル(1:50、いずれもSigma-Aldrich製)を含む溶解バッファー(200mmol/L Tris、1%Triton X−100、5mmol/L EDTA)に培養細胞の全細胞抽出液を作製した。タンパク質濃度を、ブラッドフォード法(Bio-Rad)を使用して計測した。タンパク質を変性条件下で分離し、湿式転写システム(Bio-Rad)を使用して、ニトロセルロース膜(Bio-Rad)上にブロットした。SuperSignal West Duraルミノール溶液(Thermo Fisher Scientific)と共にインキュベーションした後、Bio−Rad ChemiDoc Systemによりブロットの画像を取得した。データを表8に示す。
蛍光DNA定量キット(カタログ番号170−2480、カリフォルニア州ヘラクレスのBio-Rad Laboratories)を使用して、以前に記載された通りに細胞のDNA含量を特定した。簡潔には、96ウェルプレートに1ウェル当たり5000個の細胞を蒔き、指定の濃度の化合物による処理を各ウェル同時に開始した。4日目又は6日目、MCF7:WS8又はMCF7:5Cそれぞれについて、プレートの細胞を溶解し、−80℃で凍結した。各ウェルの全DNAを測定するため、プレートを室温まで温め、ヘキスト染料と共にインキュベートし、十分混合した。Synergy H4 Hybrid Multi−Mode Microplate Readerを使用して、蛍光を測定した。各分析について、6個の複製ウェルを使用し、少なくとも3回の独立した実験を行った。
0.1nMエストラジオール(E2)及び様々な濃度の化合物の存在下での細胞死をビヒクル対照に対して補正される相対関数単位(relative functional units)で計測した。試験した化合物は、化合物20、GW−5638、GW−7604、GDC−0810、AZD9496、ラソフォキシフェン、フルベストラント、RU 58668、タモキシフェン、4−ヒドロキシタモキシフェン、ラロキシフェン、及びバゼドキシフェンであった。上記アッセイでは、DNA含有量を計測するため、ヘキスト染料を使用する7日の増殖アッセイを行った。GW5638のIC50は946nMであり、GW−7604のIC50は1.81nMであり、GDC−0810のIC50は1.84nMであり、AZD949のIC50は0.04nMであり、ラソフォキシフェンのIC50は0.17nMであり、化合物20のIC50は0.26nMであり、フルベストラントのIC50は0.86nMであり、RU 58668のIC50は0.052nMであり、タモキシフェンのIC50は985nMであり、4−ヒドロキシタモキシフェンのIC50は3.46nMであり、ラロキシフェンのIC50は0.77nMであり、バゼドキシフェンのIC50は72nMであった。このアッセイで計測されるように、化合物20はフルベストラントよりも4倍近く強力である。このデータを図1に示す。
20nMインスリン及び様々な濃度の化合物の存在下での細胞死をビヒクル対照に対して補正される相対関数単位で計測した。試験した化合物は、化合物20、GW−5638、GW−7604、GDC−0810、AZD9496、ラソフォキシフェン、フルベストラント、RU 58668、タモキシフェン、4−ヒドロキシタモキシフェン、ラロキシフェン、及びバゼドキシフェンであった。上記アッセイでは、DNA含有量を計測するため、ヘキスト染料を使用する7日の増殖アッセイを行った。データは、化合物20が、バゼドキシフェン、ラロキシフェン、タモキシフェン、4−ヒドロキシタモキシフェン、及びラソフォキシフェンよりも効果的にインスリンで駆動される増殖を阻害することを示す。GDC−0810のIC50は55pMであり、AZD9496のIC50は2pMであり、化合物20のIC50は28pMであり、フルベストラントのIC50は149pMであり、RU 58668のIC50は13pMであった。このデータを図2A、図2B及び図2Cに示す。
エストロゲン受容体の分解を、ウェスタンブロット分析によって2XCFS細胞中で成長させたMCF7細胞において計測した。試験した化合物は、化合物20、GW−5638、GW−7604、GDC−0810、AZD9496、ラソフォキシフェン、フルベストラント、RU 58668、タモキシフェン、4−ヒドロキシタモキシフェン、ラロキシフェン、及びバゼドキシフェンであった。化合物20のIC50は33pMであり、GDC−0810のIC50は94pMであり、AZD9496のIC50は11pMであり、GW5638のIC50は310nMであり、GW−7604のIC50は420pMであった。このデータを図3A、図3B及び図3Cに示す。
様々な化合物濃度でのSKBR3(WT ER)細胞死を、ビヒクル対照に対して補正される光単位で計測した。試験した化合物は、化合物20、GW−5638、GW−7604、GDC−0810、AZD9496、ラソフォキシフェン、フルベストラント、RU 58668、タモキシフェン、4−ヒドロキシタモキシフェン、ラロキシフェン、及びバゼドキシフェンであった。アッセイではフルベストラントのIC50は4.48nMであり、RU 58668のIC50は0.29nMであり、タモキシフェンのIC50は267nMであり、4−ヒドロキシタモキシフェンのIC50は3.25nMであり、GW−7604のIC50は17.9nMであり、ラロキシフェンのIC50は0.27nMであり、バゼドキシフェンのIC50は0.71nMであり、GDC−0810のIC50は11.3nMであり、AZD9496のIC50は.0.45nMであり、化合物20のIC50は2.14nMであり、ラソフォキシフェンのIC50は0.38nMであった。このデータを図5A、図5B及び図5Cに示す。SKBR3細胞は野生型エストロゲン受容体を有した。
様々な化合物濃度でのSKBR3(D538G ER)細胞死を、ビヒクル対照に対して補正される光単位で計測した。試験した化合物は、化合物20、GW−5638、GW−7604、GDC−0810、AZD9496、ラソフォキシフェン、フルベストラント、RU 58668、タモキシフェン、4−ヒドロキシタモキシフェン、ラロキシフェン、及びバゼドキシフェンであった。アッセイでは、フルベストラントのIC50は10.5nMであり、RU 58668のIC50は1.56nMであり、タモキシフェンのIC50は2.99nMであり、4−ヒドロキシタモキシフェンのIC50は3.11nMであり、GW−5638のIC50は0.17nMであり、GW−7604のIC50は22.6nMであり、ラロキシフェンのIC50は3.73nMであり、バゼドキシフェンのIC50は4.27nMであり、GDC−0810のIC50は24.5nMであり、AZD9496のIC50は1.20nMであり、化合物20のIC50は14.7nMであり、ラソフォキシフェンのIC50は1.39nMであった。このデータを、図6A、図6B及び図6Cに示す。SKBR3細胞は、D538G突然変異エストロゲン受容体を有した。
様々な化合物濃度でのSKBR3(Y537S ER)細胞死を、ビヒクル対照に対して補正される光単位で計測した。試験した化合物は、化合物20、GW−5638、GW−7604、GDC−0810、AZD9496、ラソフォキシフェン、フルベストラント、RU 58668、タモキシフェン、4−ヒドロキシタモキシフェン、ラロキシフェン、及びバゼドキシフェンであった。アッセイではフルベストラントのIC50は20.2nMであり、RU 58668のIC50は2.87nMであり、4−ヒドロキシタモキシフェンのIC50は11.0nMであり、GW−5638のIC50は4.91μMであり、GW−7604のIC50は2.56nMであり、ラロキシフェンのIC50は4.79nMであり、バゼドキシフェンのIC50は29.0nMであり、GDC−0810のIC50は1.30μMであり、AZD9496のIC50は2.57nMであり、化合物20のIC50は56.0nMであり、ラソフォキシフェンのIC50は1.07nMであった。このデータを、図7A、図7B及び図7Cに示す。SKBR3細胞は、Y537S突然変異エストロゲン受容体を有した。
MCF7:TamR腫瘍細胞を、タモキシフェン治療したマウスに移植した。Tam刺激腫瘍が約0.1cm3の腫瘍体積に達したら、動物を無作為化し(1群当たり7匹〜9匹のマウス)、継続的なタモキシフェン治療を行いながら、ビヒクル又はSERDフルベストラント(5mg/マウスの毎週1回の筋肉内注射)、SERD化合物20(30mg/kg/日又は100mg/kg/日、経口投与)及び/又は、CDK4/6阻害剤化合物23(50mg/kg/日又は100mg/kg/日、経口投与)を与えた。各群の腫瘍増殖を、試験群ごとに平均腫瘍体積±SEMとして示す。図8に示されるように、連続的な治療がおよそ30日間に亘って与えられた場合、50mg/kgの化合物23と30mg/kgの化合物20との組み合わせは、50mg/kgのCDK4/6阻害剤である化合物23単独、及び30mg/kgの化合物20単独よりも、腫瘍体積を減少させるのに有効であった。図9は連続的な投薬の最初の14日間の治療の描写であり、ここで、同じ効果、すなわち、化合物23(50mg/kg)と化合物20(30mg/kg)との組み合わせは、単独で投与される同じ投薬量の化合物23及び化合物20のいずれよりも、効果的に腫瘍を減少させることが観察された。
下記表10に示されるように、化合物20は、より良好な効力、選択性、DMPK特性、安全性、in vivo有効性、及び/又は薬物様特性を有しながら、GDC−810、フルベストラント、及びAZD9496と同程度に活性又はそれらより活性である。実施例10、実施例11及び実施例12で収集されたIC50を表10で比較する。
MCF7 ER+乳癌モデルにおいて、化合物23の投与は、経口化合物20の有効性を高めた。一日経口用量の化合物23(50mg/kg)、化合物20(30mg/kg又は100mg/kg)、又は化合物20(30mg/kg又は100mg/kg)と化合物23(50mg/kg)との組み合わせを28日間、マウスに投与した。腫瘍体積をおよそ41日間計測し、投薬を1日目に開始した。図10は、30mg/kgの化合物20を単独で投与した場合、及び30mg/kgの化合物20と化合物23(50mg/kg)とを組み合わせて投与した場合の腫瘍体積減少の比較を示す。また、図10は、100mg/kgの化合物20を単独で投与した場合、及び100mg/kgの化合物20と化合物23(50mg/kg)とを組み合わせて投与した場合の腫瘍体積減少の比較を示す。いずれの場合も、化合物23は、化合物20の有効性を高めた。図11は、41日目の各投薬の最終腫瘍体積を示す。30mg/kgの化合物20を単独で投与した場合と比較して、30mg/kgの化合物20と化合物23(50mg/kg)とを組み合わせて投与した場合、腫瘍体積はより減少した。同様に、100mg/kgの化合物20を単独で投与した場合と比較して、100mg/kgの化合物20と化合物23(50mg/kg)とを組み合わせて投与した場合、腫瘍体積はより減少した。100mg/kg及び30mg/kgのいずれの投薬量でも、化合物23は化合物20の有効性を高めた。
化合物20及び化合物23(図12A及び図12B)、並びに化合物20と化合物23との組み合わせ(図12C及び図12D)は、タモキシフェン耐性(TamR)異種移植片腫瘍の増殖を阻害した。図12Aに示されるように、治療(およそ70日)の間に腫瘍体積を計測した場合、単一用量の化合物23(50mg/kgを1日1回(qd)、及び100mg/kgを1日1回(qd)投与)が腫瘍体積を減少させた。1日1回与えられる100mg/kgの用量の化合物23は、1日1回与えられる100mg/kgの用量のパルボシクリブの投与に匹敵した。図12Bに示されるように、単一用量の化合物20(30mg/kgを1日1回投与、及び100mg/kgを1日1回投与)は、治療(およそ70日)の間に腫瘍体積を減少させるのに有効であった。化合物20の投薬量を、フルベストラントの用量(200mg/kgを1週間に1回(qw))と比較した。
OVX nu/nu(卵巣切除ヌード)マウスにおいてLTED異種移植片腫瘍は、図13に示されるように、単一用量の化合物20の投薬に反応した。マウスに5mg/kg、10mg/kg、30mg/kg、又は100mg/kgの化合物20を投与し、腫瘍体積を治療期間(30日)に亘って計測したところ、腫瘍体積の減少は投薬レベルと相関した。
単独で及び様々な組み合わせで投与された化合物20、化合物23、タモキシフェン、フルベストラント、及びパルボシクリブを、ESR1WT(エストロゲン受容体野生型)乳癌に対してin vivoで評価した。化合物20と化合物23との組み合わせ、パルボシクリブと化合物23との組み合わせ、化合物23とフルベストラントとの組み合わせ、及びフルベストラントとパルボシクリブとの組み合わせを研究で評価した。各化合物の用量、投与経路及びスケジュールを表11に示す。投薬は28日間続けて、腫瘍体積を70日以上計測した。図14Aは、研究全体に亘る腫瘍体積の減少を表すグラフであり、図14Bは、投薬が完了した時、28日目に計測された腫瘍体積を表すグラフである。図14Aに示されるように、研究期間中、化合物23の投与はフルベストラント及び化合物20の有効性を高めた。また、化合物20とパルボシクリブとの組み合わせは、化合物20又はパルボシクリブのいずれかの単独投与と比較して、研究期間中、腫瘍体積を減少させるのにより有効であった。図14Bに示されるように、腫瘍体積を28日目に計測した場合、化合物20と化合物23との組み合わせは、化合物20又は化合物23のいずれかの単独投与よりも腫瘍体積を減少させるのに有効であった。同様に、投薬が完了した日に腫瘍体積を計測した場合、化合物20はパルボシクリブの有効性を高め、化合物23はフルベストラントの有効性を高めた。
Claims (52)
- 前記被験体がヒトである、請求項1に記載の方法。
- 前記癌が、乳癌、卵巣癌、子宮内膜癌、腎臓癌、子宮癌、前立腺癌、又は肺癌である、請求項2に記載の方法。
- 前記癌がエストロゲン関連の癌である、請求項3に記載の方法。
- 前記エストロゲン関連の癌が、乳癌、卵巣癌、子宮内膜癌、腎臓癌、又は子宮癌から選択される、請求項4に記載の方法。
- 前記エストロゲン関連の癌が乳癌である、請求項4に記載の方法。
- 前記エストロゲン関連の癌が卵巣癌である、請求項4に記載の方法。
- 前記エストロゲン関連の癌が子宮内膜癌である、請求項4に記載の方法。
- 前記エストロゲン関連の癌が腎臓癌である、請求項4に記載の方法。
- 前記エストロゲン関連の癌が子宮癌である、請求項4に記載の方法。
- 前記エストロゲン関連の癌が、転移性の内分泌療法耐性乳癌である、請求項4に記載の方法。
- 前記内分泌療法がタモキシフェンである、請求項11に記載の方法。
- 前記癌が乳癌である、請求項3に記載の方法。
- 前記乳癌がホルモン受容体陽性転移性乳癌である、請求項13に記載の方法。
- 前記乳癌がタモキシフェン耐性乳癌である、請求項13に記載の方法。
- 前記乳癌が三種陰性乳癌である、請求項13に記載の方法。
- 前記癌が前立腺癌である、請求項3に記載の方法。
- 前記癌が肺癌である、請求項3に記載の方法。
- 前記被験体に、式A及び式Dと組み合わせて又はそれに代えて、別の化学療法剤が更に投与される、請求項1〜18のいずれか一項に記載の方法。
- 前記キットが、前記式Aの化合物及び前記式Dの化合物の投薬に関する指示書を備える、請求項47に記載のキット。
- 前記エストロゲンによって媒介される異常な細胞増殖が乳癌である、請求項47又は48に記載のキット。
- 前記エストロゲンによって媒介される異常な細胞増殖が子宮癌である、請求項47又は48に記載のキット。
- 前記エストロゲンによって媒介される異常な細胞増殖が卵巣癌である、請求項47又は48に記載のキット。
- 前記エストロゲンによって媒介される異常な細胞増殖が子宮内膜癌である、請求項47又は48に記載のキット。
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EP3565558B1 (en) | 2023-12-06 |
EA201991622A1 (ru) | 2020-01-23 |
CN110177554B (zh) | 2023-06-02 |
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IL267795A (en) | 2019-09-26 |
EP3565558A4 (en) | 2020-08-26 |
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AU2022203554B2 (en) | 2024-03-28 |
RU2019124081A3 (ja) | 2022-01-31 |
AU2022203554A1 (en) | 2022-06-16 |
NZ754865A (en) | 2023-07-28 |
KR20190103285A (ko) | 2019-09-04 |
RU2019124081A (ru) | 2021-02-08 |
TW201836600A (zh) | 2018-10-16 |
KR102576011B1 (ko) | 2023-09-06 |
TWI823845B (zh) | 2023-12-01 |
AR110728A1 (es) | 2019-04-24 |
BR112019013814A2 (pt) | 2020-01-21 |
CA3048057A1 (en) | 2018-07-12 |
ZA201904188B (en) | 2022-12-21 |
EP3565558A1 (en) | 2019-11-13 |
AU2018205262A1 (en) | 2019-07-11 |
IL267795B2 (en) | 2023-02-01 |
IL267795B (en) | 2022-10-01 |
US11364222B2 (en) | 2022-06-21 |
CN110177554A (zh) | 2019-08-27 |
JP7229162B2 (ja) | 2023-02-27 |
WO2018129387A1 (en) | 2018-07-12 |
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