JP2021525809A - プロドラッグおよびその医学的使用 - Google Patents
プロドラッグおよびその医学的使用 Download PDFInfo
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Abstract
Description
本発明は、置換ピペラジンカルボキサミドを有する窒素マスタード、および腫瘍を標的とする細胞毒性剤としてのそれらの対応する薬学的に許容可能な塩、ならびにそれらの単独での、または他の癌治療と組み合わせた使用方法に関する。
腫瘍選択性プロドラッグ(すなわち、細胞代謝によって、および/または腫瘍微小環境内で、治療活性化合物に選択的に変換され得る治療不活性化合物)の使用は、低酸素症などの癌に特異的な特徴を示す細胞を標的とするために癌療法において利用されてきたアプローチである。特に、低酸素腫瘍区画のみに対して細胞毒性剤となる低酸素活性化プロドラッグ(HAP)は、特に有害な予後、薬物の組み合わせ、および/または標準的な医療治療に対する耐性の場合に有望な抗腫瘍剤として示唆される(Hunter Fら、2016;Mistry INら、2017;Phillips R、2016;Silva VLおよびAl−Jamal WT、2017)。
本発明は、いくつかの態様において、抗癌剤および免疫療法を包含する併用療法およびレジメンを含む、癌治療に有用な組成物および方法を提供し、当該癌治療は、置換ピペラジンカルボキサミドを有する窒素マスタード、特に対称または非対称ハロアルカンスルホネート含有マスタード(または以下の本文に示されるような、単なるハロアルカンスルホネートマスタード)の使用を含む。特に、本発明は、それを必要とする患者において、乳癌、膵臓癌、または肺癌の治療方法において使用するための、本明細書において以下に定義される化合物、もしくはその塩、その溶媒和物、またはその立体異性体に関する。そうでなければ定式化され、本発明は、乳癌、膵臓癌、または肺癌を有する患者の治療方法に関し、当該方法は、それを必要とする患者に、有効量の本発明の化合物、もしくはその塩、その溶媒和物、またはその立体異性体を投与することを含む。
図1:本発明によって使用され得る式Iの対称または非対称ハロアルカンスルホネートマスタード。Cpd.8〜Cpd.19の構造、特定の式(I)の対称または非対称ハロアルカンスルホネート含有マスタードが提供される(A)。Cpd.11Msと命名された式Iの参照非対称ハロアルカンスルホネートマスタードの合成プロセス(B)は、WO2014031012に記載されている最初の工程を含み、3,4−ジフルオロベンズアルデヒド(化合物1)から出発して、ナトリウムスルフィネートで処理され、対応するアルキルスルホン(化合物2)を得、次いで、酸化させて、結果として対応する安息香酸(化合物3)となる。古典的ニトロ化により、化合物4が得られ、これを対応する酸塩化物(化合物5)に変換し、さらに1−エチルピペラジンと反応させて、中間体アミド(化合物6)を得る。臭化リチウムおよびアジリジンエタノールとさらに反応させ、化合物7が得られ、次いでこれをメタンスルホン無水物で官能化して、2−((2−ブロモエチル)(5−(4−エチルピペラジン−l−カルボニル)−2−(メチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネートを得、これを化合物11(Cpd.11)として同定する。メタンスルホン酸との塩形成により、化合物11Ms(Cpd.11Ms;4−(5−((2−ブロモエチル)(2−((メチルスルホニル)オキシ)エチル)アミノ)−4−(メチルスルホニル)−2−ニトロベンゾイル)−1−エチルピペラジン−1−メタンスルホネート)が得られる。式(I)のハロアルカンスルホネートマスタードは、インビボにおいてヒト酵素によって代謝され得、化合物11で例示されるような一連の細胞毒性化合物になり、これは、中間体化合物11a(Cpd.11a)に、次いで腫瘍環境内に存在する低酸素状態において化合物11b(Cpd.11b)に、次いで酸素非依存性機構によって細胞毒性化合物11c(Cpd.11c)および11d(Cpd.11d)に、修飾される(C)。これらの代謝産物は、インビボにおいて生理学的塩の存在によりさらに修飾され得、臭素および/またはOM基が塩素原子によって置換され、一または二塩化物誘導体を生成する。
本発明による方法および組成物において使用される、式(I)または式(II)で定義される化合物の中で好ましい化合物は、W、X、R1、R2、R3、およびZとして定義される位置における置換基の特定の組み合わせを示す化合物、および関連するその塩、その溶媒和物、またはその立体異性体である。これらの化合物は、関連する細胞ベースの動物モデルを使用する実施例において示されるように、例示的な式(I)の化合物に曝露された場合に特に感応性および退行性である選択された癌のタイプにおいて、治療活性であると定義される。これらの証拠は、乳癌、膵臓癌、肺癌、胃腸癌、前立腺癌、卵巣癌、脳癌、頭頸部癌、もしくは軟組織肉腫、ならびに臨床および/または分子レベルで、特に低酸素領域の存在に関して定義される特定のサブタイプを有する患者の治療における、本発明の化合物、またはその塩、その溶媒和物、またはその立体異性体の使用を支持する。
以下の実施例は、例示の目的のみで提供され、本明細書中に提供される特許請求の範囲を限定するものではない。
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Dai X et al., J Cancer. 2017. 8:3131-3141.
Deer EL et al., Pancreas. 2010, 39:425-35.
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Fan G et al., J Hematol Oncol. 2015, 8:130
Hunter F et al., Mol Cancer Ther. 2014. 13:2501-14.
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Claims (31)
- R1は、C1〜6アルキルを表す、請求項1に記載の使用のための式(I)の化合物。
- R2は、C1〜6アルキルを表す、請求項1または2に記載の使用のための式(I)の化合物。
- R3は、C1〜6アルキルである、請求項2または3に記載の使用のための式(I)の化合物。
- Wは、臭素またはヨウ素であり、
Xは、OSO2Meまたは臭素である、請求項2または3に記載の使用のための式(I)の化合物。 - R2は、メチルまたはエチルであり、
R1は、メチル、エチル、プロピルまたはイソプロピルである、請求項4または5に記載の使用のための式(I)の化合物。 - 前記化合物は、
2−((2−ブロモエチル)(5−(4−メチルピペラジン−l−カルボニル)−2−(メチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物9)、
2−((2−ブロモエチル)(5−(4−エチルピペラジン−l−カルボニル)−2−(メチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物11)、
2−((2−ブロモエチル)(5−(4−イソプロピルピペラジン−l−カルボニル)−2−(メチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物13)、
2−((2−ブロモエチル)(2−(エチルスルホニル)−5−(4−メチルピペラジン−l−カルボニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物15)、
2−((2−ブロモエチル)(5−(4−エチルピペラジン−l−カルボニル)−2−(エチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物17)、および、
2−((2−ブロモエチル)(2−(エチルスルホニル)−5−(4−イソプロピルピペラジン−l−カルボニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物19)、
からなる群から選択される、請求項6に記載の使用のための式(I)の化合物。 - 前記化合物は、2−((2−ブロモエチル)(5−(4−エチルピペラジン−l−カルボニル)−2−(メチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネート(化合物11)である、請求項6に記載の使用のための式(I)の化合物。
- 前記化合物の薬学的に許容可能な塩である、請求項1〜8のいずれか1項に記載の使用のための式(I)の化合物。
- 前記塩は、メタンスルホネート塩である、請求項8に記載の使用のための式(I)の化合物の薬学的に許容可能な塩。
- 前記化合物は、2−((2−ブロモエチル)(5−(4−エチルピペラジン−l−カルボニル)−2−(メチルスルホニル)−4−ニトロフェニル)アミノ)エチルメタンスルホネートのメタンスルホネート塩(化合物11Ms)である、請求項10に記載の使用のための式(I)の化合物。
- 式(I)の前記化合物はまた、胃腸癌細胞、前立腺癌細胞、卵巣癌細胞、脳癌細胞、頭頸部癌細胞、および軟組織肉腫細胞から選択されるヒト癌細胞において低酸素依存性細胞毒性を発揮する、請求項1〜11のいずれか1項に記載の使用のための式(I)の化合物。
- 前記化合物は、低酸素腫瘍細胞を有する対象に投与される、請求項1〜12のいずれか1項に記載の使用のための式(I)の化合物。
- 前記化合物は、5〜250の低酸素細胞毒性比(HCR)を示す、請求項12または13に記載の使用のための式(I)の化合物。
- 前記肺癌は、小細胞肺癌、非小細胞肺癌、扁平上皮細胞癌、腺癌、または大細胞癌である、請求項1〜14のいずれか1項に記載の使用のための式(I)の化合物。
- 前記乳癌は、三種陰性乳房腫瘍である、請求項1〜15のいずれか1項に記載の使用のための式(I)の化合物。
- 前記化合物は、放射線療法、化学療法、および/または免疫療法で以前に治療されたことがある対象に投与される、請求項1〜16のいずれか1項に記載の使用のための式(I)の化合物。
- 前記化合物は、前記対象における癌の薬剤耐性、免疫回避、再発、または転移を防止する、請求項17に記載の使用のための式(I)の化合物。
- 前記化合物は、非経口投与、腫瘍内投与、経動脈塞栓投与、または経口投与のために製剤化される、請求項1〜14のいずれか1項に記載の使用のための式(I)の化合物。
- 治療有効量の、請求項1〜11のいずれか1項において定義される式(I)の化合物、もしくはその塩、その溶媒和物、またはその立体異性体、あるいはそれらの組み合わせ、および薬学的に許容可能な賦形剤、アジュバント、担体、緩衝液、希釈剤、あるいは安定剤を含む、
乳癌、膵臓癌、または肺癌の治療方法において使用するための、医薬組成物。 - 前記化合物は、40〜10,000mg/m2の間に含まれる投与量で投与される、請求項1〜19のいずれか1項に記載の使用のための式(I)の化合物、または請求項20に記載の使用のための医薬組成物。
- 前記化合物または前記医薬組成物は、1ヶ月当たり2、3、4、または5日間連続して投与される、請求項21に記載の使用のための式(I)の化合物または医薬組成物。
- 前記化合物または前記医薬組成物は、1〜12ヶ月間投与される、請求項21または22に記載の使用のための式(I)の化合物または医薬組成物。
- 前記化合物は、別の治療剤または療法と同時に、または連続して、対象に投与される、請求項1〜23のいずれか1項に記載の使用のための式(I)の化合物または医薬組成物。
- 前記他の治療剤または療法は、乳癌、肺癌、および/または膵臓癌の治療に有用である、請求項24に記載の使用のための式(I)の化合物または医薬組成物。
- 式(I)の前記化合物または前記医薬組成物は、第一選択療法または第二選択療法である、請求項24または25に記載の使用のための式(I)の化合物または医薬組成物。
- 前記他の療法は、放射線療法である、請求項24または25に記載の使用のための式(I)の化合物または医薬組成物。
- 前記他の療法は、化学療法である、請求項24または25に記載の使用のための式(I)の化合物または医薬組成物。
- シスプラチン、カルボプラチン、パクリタキセル、ゲムシタビン、ドセタキセル、ドキソルビシン、ゲムシタビンおよびナブ−パクリタキセル、または、エトポシドおよびシスプラチンが投与される、請求項28に記載の使用のための式(I)の化合物または医薬組成物。
- 前記他の療法は、免疫療法である、請求項24または25に記載の使用のための式(I)の化合物または医薬組成物。
- 前記免疫療法は、PD−1およびPD−L1もしくはPD−L2を、ならびに/またはPD−1とPD−L1もしくはPD−L2との結合を、ブロック、減少および/または阻害する、請求項30に記載の使用のための式(I)の化合物または医薬組成物。
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