JP2022543832A - 変異体を治療するためのエストロゲン受容体調節剤 - Google Patents
変異体を治療するためのエストロゲン受容体調節剤 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
例えば、本出願と共に提出される出願データシート又は請求において、2019年8月6日に出願された米国仮出願第62/883,395号、及び2020年4月14日に出願された同第63/009,746号を含む、外国又は国内の優先権の主張が確認される任意の、そして、全ての出願が、37CFR1.57並びに規則4.18及び20.6に基づき、参照により本明細書に組み込まれる。
本出願は、エストロゲン受容体アルファ調節剤である化合物で乳癌を治療するための方法に関し、乳癌は、エストロゲン受容体1(ESR1)内に少なくとも1つの点変異を有する。
別段の定めがない限り、本明細書で使用される全ての技術及び科学用語は、当業者によって一般的に理解されるものと同じ意味を有する。本明細書で参照される全ての特許、出願、公開出願、及び他の出版物は、特に明記しない限り、参照によりそれらの全体が組み込まれる。本明細書のある用語に対して複数の定義が存在する場合、特に明記しない限り、この節にある定義が優先される。
関して、当業者は、窒素ベースの基(例えば、NH2)のプロトン化によって塩が形成される場合、窒素ベースの基が正電荷と会合し得(例えば、NH2がNH3 +になり得る)、正電荷が負の電荷を持つ対イオン(Cl-など)によってバランスがとられ得ることを理解する。
物の同じ元素組成の異なる結晶充填配置を含む)、非晶相、塩、溶媒和物、及び水和物を含むことが理解される。いくつかの実施形態では、本明細書に記載の化合物は、水、エタノールなどの薬学的に許容される溶媒を有する溶媒和形態で存在する。他の実施形態では、本明細書に記載の化合物は、非溶媒和形態で存在する。溶媒和物は、化学量論量又は非化学量論量のいずれかの溶媒を含有し、水、エタノールなどの薬学的に許容される溶媒での結晶化プロセス中に形成されてもよい。溶媒が水である場合に水和物が形成されるか、又は溶媒がアルコールである場合にアルコラートが形成される。加えて、本明細書に提供される化合物は、非溶媒和並びに溶媒和形態で存在することができる。概して、溶媒和形態は、本明細書に提供される化合物及び方法の目的で、非溶媒和形態と同等であると見なされる。
化合物Aは、以下
sulfoxide、DMSO)は、対象の細胞又は組織への多くの有機化合物の取り込みを促進する、一般的に利用される担体である。
本明細書に開示されるいくつかの実施形態は、それを必要とする対象における乳癌を治療するための薬剤のための製造における有効量の化合物の使用に関し、乳癌は、エストロゲン受容体α(ERα)をコードするエストロゲン受容体1(ESR1)内に少なくとも1つの点変異を有する。本明細書に開示される他の実施形態は、有効量の化合物(A)の化合物又はその薬学的に許容される塩で、それを必要とする対象の乳癌を治療する方法に関し、乳癌は、エストロゲン受容体α(ERα)をコードするエストロゲン受容体1(ESR1)内に少なくとも1つの点変異を有する。
は、リガンド結合ドメイン(LBD)中に存在し得る。別の例として、2つ、3つ、又は4つ以上の変異が、リガンド結合ドメイン(LBD)中に存在し得る。いくつかの実施形態では、変異はY537Sであり得る。いくつかの実施形態では、変異はL536Pであり得る。
療後に再発している。例えば、対象は、本明細書に記載されるものなどのSERM、SERD及び/又はアロマターゼ阻害剤で1つ以上の治療を受けた後に再発している。
特許請求の範囲を決して限定するものではない、更なる実施形態が、以下の実施例において更に詳細に開示される。
細胞を、ホルモン枯渇培地中の96細胞プレートに3000細胞/ウェルで播種した。一晩インキュベートした後、細胞を、エストラジオール(0.1nM)の存在下で6日間、示された濃度で化合物で処理した。CellTiter-Glo発光細胞生存率アッセイ(Promega)を使用して、細胞増殖の阻害を測定した。
結果が図3及び図4に示される研究では、乳癌患者由来異種移植片(PDX)モデルの腫瘍断片をNSGマウスの乳腺脂肪パッドに移植した。腫瘍が約100mm3に達したときマウスを以下の5つの治療群のうちの1つにランダム化した。ビヒクル対照、フルベストラント(200mg/kg、皮下注射、週に1回)、化合物(A)(60mg/kg、経口投与)。結果が図5に示される研究では、雌の無胸腺ヌードマウスを、1.5×106の解離した乳癌患者由来異種移植片(PDX)細胞を100μlのPBS:マトリゲル(1:1)で脇腹に皮下移植した。腫瘍が150~350mm3に達すると、(平均約200mm3)、動物をそれぞれ10匹の動物の処置群にランダムに分布させ、1週間に1回皮下注射することによってビヒクル、フルベストラント5mg/マウスを投与し、化合物(A)40mg/kgを毎日経口投与した。腫瘍体積を週に2回評価して、腫瘍体積を経時的に計算し、マウスを毒性の兆候の代理として週に2回秤量した。
Claims (27)
- 対象の乳癌を治療するための医薬品の製造における有効量の化合物の使用であって、前記化合物は化合物(A)、又はその薬学的に許容される塩であり、構造は次のとおりであり
- 前記乳癌がY537S変異を有する、請求項1に記載の使用。
- 前記乳癌がL536P変異を有する、請求項1に記載の使用。
- 前記乳癌がER陽性乳癌である、請求項1~3のいずれか一項に記載の使用。
- 前記乳癌が、ER陽性/HER2陰性乳癌である、請求項1~3のいずれか一項に記載の使用。
- 前記乳癌が局所乳癌である、請求項1~5のいずれか一項に記載の使用。
- 前記乳癌が、転移性乳癌である、請求項1~5のいずれか一項に記載の使用。
- 前記乳癌が再発性乳癌である、請求項1~7のいずれか一項に記載の使用。
- 前記対象が、内分泌療法で以前に治療されている、請求項1~8のいずれか一項に記載の使用。
- 前記治療が、選択的ER調節剤(SERM)であった、請求項9に記載の使用。
- 前記選択的ER調節剤が、タモキシフェン、ラルキシフェン、オスペミフェン、ベザジ
オキシフェン、トレミフェン及びラスオフォキシフェンからなる群から選択される、請求項10に記載の使用。 - 前記治療が、選択的ER分解剤(SERD)であった、請求項9に記載の使用。
- 前記選択的ER分解剤が、フルベストラント、エレスタント、(E)-3-[3,5-ジフルオロ-4-[(1R、3R)-2-(2-フルオロ-2-メチルプロピル)-3-メチル-1,3,4,9-テトラヒドロピリド[3,4-b]インドール-1-イル]フェニル]プロプ-2-エン酸、(R)-6-(2-(エチル(4-(2-(エチルアミノ)エチル)ベンジル)アミノ)-4-メトキシフェニル)-5,6,7,8-テトラヒドロナフタレン-2-オール、(E)-3-(4-((E)-2-(2-クロロ-4-フルオロフェニル)-1-(1H-インダゾール-5-イル)ブト-1-エン-1-イル)フェニル)アクリル酸、(E)-3-(4-((2-(2-(1,1-ジフルオロエチル)-4-フルオロフェニル)-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、(E)-3-(4-((2-(4-フルオロ-2,6-ジメチルベンゾイル)-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、(S)-8-(2,4-ジクロロフェニル)-9-(4-((1-(3-フルオロプロピル)ピロリジン-3-イル)オキシ)フェニル)-6,7-ジヒドロ-5H-ベンゾ[7]アヌレン-3-カルボン酸及び/又は3-((1R、3R)-1-(2,6-ジフルオロ-4-((1-(3-フルオロプロピル)アゼチジン-3-イル)アミノ)フェニル)-3-メチル-1,3,4,9-テトラヒドロ-2H-ピリド[3,4-b]インドール-2-イル)-2,2-ジフルオロプロパン-1-オールからなる群から選択される、請求項12の使用。
- 前記治療がアロマターゼ阻害剤であった、請求項9に記載の使用。
- 前記アロマターゼ阻害剤が、ステロイド性アロマターゼ阻害剤である、請求項14に記載の使用。
- 前記ステロイド性アロマターゼ阻害剤が、エキセメスタン及びテストラクトンからなる群から選択される、請求項15に記載の使用。
- 前記アロマターゼ阻害剤が、非ステロイド性アロマターゼ阻害剤である、請求項14に記載の使用。
- 前記非ステロイド性アロマターゼ阻害剤が、アナストゾール及びレトラゾールからなる群から選択される、請求項17に記載の使用。
- 前記対象が女性である、請求項1~18のいずれか一項に記載の使用。
- 前記対象が閉経前の女性である、請求項19に記載の使用。
- 前記対象が閉経周辺期の女性である、請求項19に記載の使用。
- 前記対象が閉経期の女性である、請求項19に記載の使用。
- 前記対象が閉経後の女性である、請求項19に記載の使用。
- 前記対象が男性である、請求項1~18のいずれか一項に記載の使用。
- 前記対象が、15pg/mL超かつ350pg/mL以下の範囲の血清エストラジオール濃度を有する、請求項1~24のいずれか一項に記載の使用。
- 前記対象が、15pg/mL以下の血清エストラジオール濃度を有する、請求項1~24のいずれか一項に記載の使用。
- 前記対象が、10pg/mL以下の血清エストラジオール濃度を有する、請求項1~24のいずれか一項に記載の使用。
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AU2020326691A1 (en) | 2022-03-03 |
TW202120084A (zh) | 2021-06-01 |
CA3148221A1 (en) | 2021-02-11 |
CN114269342A (zh) | 2022-04-01 |
EP3993787A1 (en) | 2022-05-11 |
US20210038573A1 (en) | 2021-02-11 |
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