JP2021178792A - ベネトクラクスの水溶性高分子誘導体 - Google Patents
ベネトクラクスの水溶性高分子誘導体 Download PDFInfo
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- JP2021178792A JP2021178792A JP2020084919A JP2020084919A JP2021178792A JP 2021178792 A JP2021178792 A JP 2021178792A JP 2020084919 A JP2020084919 A JP 2020084919A JP 2020084919 A JP2020084919 A JP 2020084919A JP 2021178792 A JP2021178792 A JP 2021178792A
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- venetoclax
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Abstract
Description
すなわち、本発明は、以下の発明を包含する。
[2] マルチアーム型水溶性ポリマーの末端カルボキシル基と複数のベネトクラクスのピロール環の二級アミノ基とがそれぞれアミド縮合してなる、[1]の化合物又はその薬理学的に許容される塩。
[3] マルチアーム型水溶性ポリマーが、末端カルボキシル化マルチアーム型ポリエチレングルコールである、[1]又は[2]の化合物又はその薬理学的に許容される塩。
[4] 下記式(II):
で表される[3]の化合物又はその薬理学的に許容される塩。
[5] [1]〜[4]のいずれかの化合物又はその薬理学的に許容される塩を含む、がんを治療又は寛解するための医薬組成物。
[6] がんが血液がんである、[5]の医薬組成物。
[7] 血液がんが急性骨髄性白血病又は慢性リンパ性白血病である、[6]の医薬組成物。
[9] がんが血液がんである、[8]の化合物又はその薬理学的に許容される塩。
[10] 血液がんが急性骨髄性白血病又は慢性リンパ性白血病である、[9]の化合物又はその薬理学的に許容される塩。
[12] がんが血液がんである、[11]の方法。
[13] 血液がんが急性骨髄性白血病又は慢性リンパ性白血病である、[12]の方法。
[15] がんが血液がんである、[14]の使用。
[16] 血液がんが急性骨髄性白血病又は慢性リンパ性白血病である、[15]の使用。
「ベネトクラクス」は下記式(I):
一実施形態において、本発明の化合物は下記式(II):
窒素雰囲気下、CTPEG(4.530g、1等量)をDMF溶媒55mLに入れて、50℃で加熱し均一溶解した。N,N−ジイソプロピルエチルアミン(以下、「DIC」という。)(0.296g、20等量)、1−ヒドロキシベンゾトリアゾール(以下、「HOBT」という。)(0.258g、6等量)、および、ベネトクラクス(0.474g、4.8等量)を順次添加した。60℃で6時間攪拌を続けてから40℃に冷却した後、攪拌しながら30℃に加温したメチルテトラ−ブチルエーテル(以下「MTBE」という。)を20分間掛けて滴下し、その後60分掛けて冷却し、30分間攪拌してから、生成した結晶をろ過して集め、20mLのMTBEで洗浄し、得られた結晶を40℃に加温した20mLの無水エタノールに溶かし、70mLのMTBEを20分掛けて滴下し、60分掛けて0℃に冷却し、30分間攪拌し、生成した沈殿物をろ過して集めた。同じ方法で再結晶精製操作を数回繰り返し、35℃の真空乾燥器の中で5時間以上乾燥し、HPLC分析で、式(II)の化合物の純度が97%以上、各々の不純物1%以下のものが得られたので、窒素ガスを充填したプラスチックのバッグの中に入れて、−20℃で保存した。得られた式(II)の化合物の化学構造、ならびに式(I)の化合物の化学構造を、H−NMRの分析(図1参照)により同定した。また、HPLCの分析によって、式(II)の化合物の高い純度を確認した(図2参照)。
式(I)の化合物と式(II)の化合物の殺細胞効果の濃度依存性を以下の通り調べた。
ヒト急性骨髄性白血病細胞株のMV4−11を用いて、式(I)の化合物及び式(II)の化合物の各IC50(50%阻害率)調べた(図3(1)参照)。その結果、式(I)の化合物のIC50(50%阻害率)は0.16pM、式(II)の化合物のIC50は0.85pMであり、何れの化合物も高い阻害率が確認された。但し、式(I)の化合物は、タンパク質結合率が高い(≧99.9%)ため、血清の含有量が少ない培地(Opti−MEM)を用いた。
U937(ヒト組織球性リンパ腫細胞株)、MV4−11(ヒト急性骨髄性白血病細胞株)、PANC−1(ヒト膵臓がん細胞株)及びA549(ヒト肺がん細胞株)に対する式(II)の化合物の50%阻害濃度とがん細胞株のプロテアーゼ活性との間で良い相関が認められた(図4参照)。この結果、プロテアーゼが高いがん細胞の周辺で、式(II)の化合物のアミド結合が酵素で代謝されることにより、式(I)の化合物が選択的に放出されていることが示唆された。
ヒト急性骨髄性白血病細胞株OCI−AML−2をマウスの皮下に移植したモデルを用いて、コントロール群、式(II)の化合物を100mg/kg、200mg/kg、および300mg/kgの各投与量、毎週1回、静脈内投与を2週間行なった群、ならびに、式(I)の化合物を100mg/kgの投与量を、2週間、毎日経口投与した群の間での腫瘍の増殖抑制効果を比較した(図5(1)参照)。
ヒト急性骨髄性白血病細胞株のMV4−11をマウスの皮下に移植した動物モデルを用いて、コントロール群、式(II)の化合物を300mg/kgの投与量(式(I)物質の投与量で換算すると、24mg/kg)で、週1回の頻度で静脈内への投与を3週間行なった群、式(I)の化合物を50mg/kgの投与量で、3週間連日経口投した群の3群の間で腫瘍の増殖抑制効果を比較した。
ヒトの組織球性リンパ腫細胞株のU937を、マウスの皮下に移植して作製したモデルを用い、コントロール群、式(II)の化合物を200mg/kg、および300mg/kgの投与量で、毎週1回の頻度で、2週間静脈内投与した群、式(I)の化合物を100mg/kgの投与量で、2週間、毎日経口投与した群の3群の間で腫瘍の増殖抑制効果を比較した。
ベネクレクスタ(登録商標)錠10mg、ベネクレクスタ(登録商標)錠50mg、ベネクレクスタ(登録商標)錠100mgの医薬品インタビューフォーム(日本病院薬剤師会、2019年11月作成(第2版))には、『ベネトクラクスはアポトーシス抑制タンパク質であるBCL−2を選択的に阻害する経口投与可能な低分子の物質である。BCL−2がアポトーシス促進性タンパク質(BAX/BAK,BIMなど)と相互作用することにより、してアポトーシス抑制性に機能している。ベネトクラクスは、BCL−2を直接結合することによりアポトーシス促進性タンパク質を遊離させ、腫瘍細胞を速やかなアポトーシスに誘導し、抗腫瘍作用を示すと考えられる』と記載されている。BAXは細胞質に発現するタンパク質であるが、BCL−2の阻害によってアポトーシスが誘導されると、ミトコンドリアの外膜に蓄積すると報告されている。
上記医薬品インタビューフォームには、「アポトーシス促進性タンパク質」としてミトコンドリアより細胞質に流出した「チトクロムC」が示されている。そこで、ヒト急性骨髄性白血病細胞のMV4−11を培地に播種して、一晩培養してから、式(I)の化合物を0.1μM及び1μMの濃度で、又、式(II)の化合物を0.01μM、0.1μM、及び1μMの濃度で各々添加し、5時間のインキュベーションをした後に、細胞質画分及びミトコンドリア画分を抽出し、チトクロムCの放出を調べた。
上記医薬品インタビューフォームには、ミトコンドリアより細胞質に流出したチトクロムCはカスパーゼを活性化してアポトーシスを誘導することが示されている。そこで、ヒト急性骨髄性白血病細胞のMV4−11を培地に播種して、一晩培養してから、式(I)の化合物を1pM、0.01nM、0.1nM、1nM、0.01μM、0.1μM及び1μMの濃度で、又、式(II)の化合物を1pM、0.01nM、0.1nM、1nM、0.01μM、及び0.1μMの濃度で各々添加し、24時間のインキュベーションをした後に、培地を回収し、カスパーゼ活性を従来公知の手法により調べた。
式(I)の化合物を、0.5%濃度のCMC(カルボキシメチルセルロース)を含んだ生理食塩水の中に加えて、超音波照射等の操作を加えたところ、10mg/mLの濃度で、均一の懸濁溶液が得られた(図11(1)参照)。
Claims (7)
- マルチアーム型水溶性ポリマーの末端にそれぞれアミド結合した複数のベネトクラクスを含んでなる化合物又はその薬理学的に許容される塩。
- マルチアーム型水溶性ポリマーの末端カルボキシル基と複数のベネトクラクスのピロール環の二級アミノ基とがそれぞれアミド縮合してなる、請求項1に記載の化合物又はその薬理学的に許容される塩。
- マルチアーム型水溶性ポリマーが、末端カルボキシル化マルチアーム型ポリエチレングルコールである、請求項1又は2に記載の化合物又はその薬理学的に許容される塩。
- 請求項1〜4のいずれか一項に記載の化合物又はその薬理学的に許容される塩を含む、がんを治療又は寛解するための医薬組成物。
- がんが血液がんである、請求項5に記載の医薬組成物。
- 血液がんが急性骨髄性白血病又は慢性リンパ性白血病である、請求項6に記載の医薬組成物。
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