JP6742982B2 - 生理活性物質結合ブロック共重合体 - Google Patents
生理活性物質結合ブロック共重合体 Download PDFInfo
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- JP6742982B2 JP6742982B2 JP2017502337A JP2017502337A JP6742982B2 JP 6742982 B2 JP6742982 B2 JP 6742982B2 JP 2017502337 A JP2017502337 A JP 2017502337A JP 2017502337 A JP2017502337 A JP 2017502337A JP 6742982 B2 JP6742982 B2 JP 6742982B2
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
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- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Description
[1] ポリエチレングリコールセグメントと、水酸基及び/又はアミノ基を有する生理活性物質を側鎖カルボキシ基に結合したアスパラギン酸誘導体及び/又はグルタミン酸誘導体を含むポリアミノ酸誘導体セグメントが連結したブロック共重合体であって、
前記ブロック共重合体の分子量が2キロダルトン以上で15キロダルトン以下であり、
測定温度25℃、散乱角度90°、波長632.8nmの測定条件で、レーザー光散乱光度計にて測定される、前記ブロック共重合体の1mg/mL水溶液の光散乱強度が、前記測定条件におけるトルエンの光散乱強度の少なくとも2倍以上である、ブロック共重合体。
前記ブロック共重合体の分子量が2キロダルトン以上で15キロダルトン以下である、ブロック共重合体。
R3が、一般式(3)
R8は置換基を有していても良い炭素環若しくは複素環アリール基、炭素数(C1〜C20)のアルキル基、炭素数(C2〜C20)のアルケニル基、炭素数(C2〜C20)のアルキニル基、炭素数(C1〜C20)のアルキルアミノ基及び炭素数(C1〜C20)のアシルアミノ基からなる群から選択される1種を示し、環Hは一般式(3−1)、(3−2)及び(3−3)
前記ブロック共重合体の分子量が2キロダルトン以上で15キロダルトン以下であり、
測定温度25℃、散乱角度90°、波長632.8nmの測定条件で、レーザー光散乱光度計にて測定される、前記ブロック共重合体の1mg/mL水溶液が、光散乱強度が、前記測定条件におけるトルエンの光散乱強度の少なくとも2倍以上であるブロック共重合体。
R8は置換基を有していても良い炭素環若しくは複素環アリール基、炭素数(C1〜C20)のアルキル基、炭素数(C2〜C20)のアルケニル基、炭素数(C2〜C20)のアルキニル基、炭素数(C1〜C20)のアルキルアミノ基及び炭素数(C1〜C20)のアシルアミノ基からなる群から選択される1種を示し、環Hは一般式(3−1)、(3−2)及び(3−3)
R8は置換基を有していても良い炭素環若しくは複素環アリール基、炭素数(C1〜C20)のアルキル基、炭素数(C2〜C20)のアルケニル基、炭素数(C2〜C20)のアルキニル基、炭素数(C1〜C20)のアルキルアミノ基及び炭素数(C1〜C20)のアシルアミノ基からなる群から選択される1種を示し、環Hは一般式(3−1)、(3−2)及び(3−3)
R8は置換基を有していても良い炭素環若しくは複素環アリール基、炭素数(C1〜C20)のアルキル基、炭素数(C2〜C20)のアルケニル基、炭素数(C2〜C20)のアルキニル基、炭素数(C1〜C20)のアルキルアミノ基及び炭素数(C1〜C20)のアシルアミノ基からなる群から選択される1種を示し、環Hは一般式(3−1)、(3−2)及び(3−3)
比較例A−4は比較例A−1の蛍光標識体として後記の分布試験に用いた。
実施例A−1及び実施例A−2、並びに比較例A−2及び比較例A−3を5%ブドウ糖注射液に溶解し、投与当日の測定体重を基に、各化合物の最大耐用量付近である7−エチル−10−ヒドロキシカンプトテシン換算50mg/kgまたは100mg/kgの用量を、雄6週齢のCrl:CD1(ICR)(ICR(IGS))マウスに尾静脈内単回投与した。対照群として、5%ブドウ糖注射液を尾静脈内単回投与した。
各化合物投与3日後に、イソフルラン麻酔下で腹大動脈から27G注射針を取り付けた1mLディスポーザブル注射筒を用いて採血した。注射筒にはあらかじめヘパリンナトリウム溶液を約10μL添加しておき、採取した血液と十分に混和した。遠心分離(4℃、1600×g、10分)して得られた血漿を測定試料とし、7180形生化学自動分析装置(株式会社日立ハイテクノロジーズ)を用いて血液化学的検査を行った。血漿中ALT(alanine aminotransferase)の測定結果を表1に示した。
実施例A−1及び実施例A−3、並びに比較例A−1及び比較例A−2の化合物を5%ブドウ糖注射液に溶解し、投与当日の測定体重を基に、7−エチル−10−ヒドロキシカンプトテシン換算40mg/kgの用量を、雄7週齢のSprague−Dawleyラット(Crl:CD;IGS、日本チャールス・リバー株式会社)に尾静脈内単回投与した。対照群として、5%ブドウ糖注射液を尾静脈内単回投与した。
各化合物投与3、5、7、11、14日後に、無麻酔下で鎖骨下静脈から26G注射針を取り付けた1mLディスポーザブル注射筒を用いて採血した。注射筒にはあらかじめEDTA−2K溶液を約3μL添加しておき、採取した血液と十分に混和して分析試料とした。血液試料を血球分析装置XT−2000iV(シスメックス株式会社)を用いて、血球分析を行った。投与7日後の網状赤血球数を表2に示した。
BALB/cヌードマウスの皮下移植で継代したヒト膵臓がんBxPC3の腫瘍塊を、約3mm角のブロックにし、套管針を用いてヌードマウスの背側部皮下に移植した。実施例B−2及び比較例B−2をそれぞれBODIPY換算量5mg/kgの濃度で5%ブドウ糖注射液で溶解し、各溶解液を同量混合し、静脈内に単回投与した。投与1時間後にヌードマウスをイソフルラン麻酔下で脱血し、取り出した腫瘍組織及び腎臓の凍結包埋切片を作製し、蛍光を観察した。結果を図3に示す。
[薬剤投与]
各化合物投与3および14日後に、無麻酔下で鎖骨下静脈から26G注射針を取り付けた1mLディスポーザブル注射筒を用いて採血した。注射筒にはあらかじめEDTA−2K溶液を約3μL添加しておき、採取した血液と十分に混和して分析試料とした。血液試料を血球分析装置XT−2000iV(シスメックス株式会社)を用いて、血球分析を行った。投与3日後の血小板数を表4に示した。
比較例B−1は分子量が18キロダルトンの化合物である。一方、実施例B−1は、分子量が4キロダルトンと小さい。以上の結果から、レゾルシノール誘導体結合高分子誘導体の血液毒性の遷延化は、分子量と相関することが考えられる。したがって、分子量が15キロダルトン以下のレゾルシノール類結合高分子誘導体とすることで、血液毒性の遷延化を回避した抗腫瘍剤を提供することができることが示された。
BALB/cヌードマウスの皮下移植で継代したヒト膵臓がんBxPC3の腫瘍塊を約3mm角のブロックにし、套管針を用いてヌードマウスの背側部皮下に移植した。実施例C−3、比較例C−2及び比較例C−3をそれぞれ5%ブドウ糖注射液で溶解し、2−(2−アミノエトキシ)−9−(ジエチルアミノ)−5H−ベンゾ[a]フェノキサジン−5−オン換算量5mg/kgで、それぞれ静脈内に単回投与した。投与1時間後にマウスをイソフルラン麻酔下で脱血し、取り出した腫瘍及び腎臓の凍結包埋切片を作製し、蛍光を観察した。結果を図7に示す。
実施例C−1及び比較例C−1を5%ブドウ糖注射液に溶解し、投与当日の測定体重を基に、各化合物の最大耐用量付近であるカバジタキセル換算60mg/kgの用量を、雄5週齢のICRマウス(Crl:CD1(ICR)、日本チャールス・リバー株式会社)に尾静脈内単回投与した。対照群として、5%ブドウ糖注射液を尾静脈内単回投与した。
各化合物投与3、5、7、11、14日後に、無麻酔下で鎖骨下静脈から26G注射針を取り付けた1
mLディスポーザブル注射筒を用いて採血した。注射筒にはあらかじめEDTA−2K溶液を約3μL添加しておき、採取した血液と十分に混和して分析試料とした。血液試料を血球分析装置XT−2000iV(シスメックス株式会社)を用いて、血球分析を行った。投与5日後の網状赤血球数を表5に示した。
Claims (14)
- ポリエチレングリコールセグメントと、水酸基を有する生理活性物質を結合又はカルボキシ基を有する結合基を介して側鎖カルボキシ基に結合したアスパラギン酸誘導体及び/又はグルタミン酸誘導体を含むポリアミノ酸誘導体セグメントが連結したブロック共重合体であって、
前記生理活性物質の水酸基は、前記アスパラギン酸誘導体及び/若しくはグルタミン酸誘導体の側鎖カルボキシ基又は前記結合基が有するカルボキシ基とエステル結合を形成しており、
前記ブロック共重合体の分子量が2キロダルトン以上で15キロダルトン以下であり、
測定温度25℃、散乱角度90°、波長632.8nmの測定条件で、レーザー光散乱光度計にて測定される、前記ブロック共重合体の1mg/mL水溶液の光散乱強度が、前記測定条件におけるトルエンの光散乱強度の少なくとも2倍以上であり、
前記ブロック共重合体が、一般式(1)
R 1 は、水素原子又は置換基を有していてもよい炭素数(C1〜C6)アルキル基を示し、
tは、20〜270の整数を示し、
Aは、置換基を有していてもよい炭素数(C1〜C6)アルキレン基を示し、
R 2 は、水素原子、炭素数(C1〜C6)アシル基及び炭素数(C1〜C6)アルコキシカルボニル基からなる群から選択される置換基を示し、
Bは、結合又はカルボキシ基を有する結合基を示し、
R 3 は、水酸基を有する生理活性物質の結合残基であって、前記水酸基がBに結合している、結合残基を示し、
R 4 は、置換基を有していてもよい炭素数(C1〜C30)の直鎖状、分岐鎖状または環状のアルコキシ基、置換基を有していてもよい炭素数(C1〜C30)の直鎖状、分岐鎖状または環状のアルキルアミノ基、置換基を有していてもよい炭素数(C1〜C30)の直鎖状、分岐鎖状または環状のジアルキルアミノ基、置換基を有していても良い炭素数(C1〜C8)アルキルアミノカルボニル(C1〜C8)アルキルアミノ基、蛍光物質の結合残基及び水酸基からなる群から選択される1種以上の置換基を示し、
nは、1又は2を示し、
x 1 、x 2 、y 1 、y 2 及びzは、それぞれ独立して0〜25の整数を示し、
(x 1 +x 2 )は、1〜25の整数を示し、
(x 1 +x 2 +y 1 +y 2 +z)は、3〜25の整数を示し、
前記R 3 及びR 4 が結合している各構成ユニット並びに側鎖カルボニル基が分子内環化した構成ユニットは、それぞれ独立してランダムに配列した構造である。]
で示される、ブロック共重合体。 - 前記ブロック共重合体における前記ポリエチレングリコールセグメントの質量含有率が10質量%以上で80質量%以下である、請求項1に記載のブロック共重合体。
- 前記ブロック共重合体における前記ポリエチレングリコールセグメントの質量含有率が30質量%以上で65質量%以下である、請求項2に記載のブロック共重合体。
- 前記ポリエチレングリコールセグメントの分子量が、1キロダルトン〜10キロダルトンである、請求項1〜3の何れか一項に記載のブロック共重合体。
- 前記ブロック共重合体における前記水酸基を有する生理活性物質の質量含有率が10質量%以上で60質量%以下である、請求項1〜4の何れか一項に記載のブロック共重合体。
- 水酸基を有する生理活性物質が、カンプトテシン誘導体、タキサン誘導体、レゾルシノール誘導体、アントラサイクリン誘導体、ラパマイシン誘導体、シチジン系代謝拮抗剤、葉酸代謝拮抗剤、プリン系代謝拮抗剤、フッ化ピリミジン系代謝拮抗剤、白金誘導体、マイトマイシン誘導体、ブレオマイシン誘導体、ビンカアルカロイド誘導体、ポドフィロトキシン誘導体、ハリコンドリン誘導体、スタウロスポリン誘導体、サリドマイド誘導体、ビタミンA誘導体、コンブレタスタチン誘導体、抗アンドロゲン剤、抗エストロゲン剤、ホルモン剤、タクロリムス誘導体、ステロイド誘導体、ポリエン系抗生物質、アゾール系誘導体、キャンディン系誘導体、ピリミジン誘導体からなる群から選択される1種以上の生理活性物質である、請求項1〜5の何れか一項に記載のブロック共重合体。
- 水酸基を有する生理活性物質が、カンプトテシン誘導体、タキサン誘導体、レゾルシノール誘導体、アントラサイクリン誘導体、ラパマイシン誘導体、シチジン系代謝拮抗剤、葉酸代謝拮抗剤、プリン系代謝拮抗剤、フッ化ピリミジン系代謝拮抗剤、白金誘導体、マイトマイシン誘導体、ブレオマイシン誘導体、ビンカアルカロイド誘導体、ポドフィロトキシン誘導体、ハリコンドリン誘導体、スタウロスポリン誘導体、サリドマイド誘導体、ビタミンA誘導体、コンブレタスタチン誘導体、抗アンドロゲン剤、抗エストロゲン剤、ホルモン剤からなる群から選択される1種以上の抗腫瘍剤である、請求項6に記載のブロック共重合体。
- R3が、一般式(3)
R7は、メルカプト基、水酸基、ハロゲン原子、ニトロ基、シアノ基、炭素数(C1〜C20)のアルキル基、炭素数(C2〜C20)のアルケニル基、炭素数(C2〜C20)のアルキニル基、炭素環又は複素環アリール基、炭素数(C1〜C8)のアルキルチオ基、アリールチオ基、炭素数(C1〜C8)アルキルスルフィニル基、アリールスルフィニル基、炭素数(C1〜C8)アルキルスルフォニル基、アリールスルフォニル基、スルファモイル基、炭素数(C1〜C8)のアルコキシ基、アリールオキシ基、炭素数(C1〜C8)のアシルオキシ基、炭素数(C1〜C8)のアルコキシカルボニルオキシ基、カルバモイルオキシ基、アミノ基、炭素数(C1〜C8)のアシルアミノ基、炭素数(C1〜C8)のアルコキシカルボニルアミノ基、ウレイド基、スルフォニルアミノ基、スルファモイルアミノ基、ホルミル基、炭素数(C1〜C8)のアシル基、カルボキシル基、炭素数(C1〜C8)のアルコキシカルボニル基、カルバモイル基及び炭素数(C1〜C8)のアルキルシリル基からなる群から選択される1種を示し、
R8は、置換基を有していても良い炭素環若しくは複素環アリール基、炭素数(C1〜C20)のアルキル基、炭素数(C2〜C20)のアルケニル基、炭素数(C2〜C20)のアルキニル基、炭素数(C1〜C20)のアルキルアミノ基及び炭素数(C1〜C20)のアシルアミノ基からなる群から選択される1種を示し、
環Hは、一般式(3−1)、(3−2)及び(3−3)
からなる群より選ばれる複素環アリール基である。]
で表されるレゾルシノール誘導体の結合残基であって、前記レゾルシノール誘導体のいずれか一つの水酸基が、請求項1に定義される一般式(1)のBに結合している、結合残基である、請求項1〜5の何れか一項に記載のブロック共重合体。 - R3が、パクリタキセル、ドセタキセル又はカバジタキセルの結合残基であって、前記パクリタキセル、ドセタキセル又はカバジタキセルにおけるいずれか一つの水酸基が、請求項1に定義される一般式(1)のBに結合している、結合残基である、請求項1〜5の何れか一項に記載のブロック共重合体。
- 請求項1〜10の何れか一項に記載のブロック共重合体から形成されるナノ粒子。
- 前記ナノ粒子の体積平均粒径が20ナノメートル未満である、請求項11に記載のナノ粒子。
- 請求項1〜10に記載のブロック共重合体又は請求項11若しくは12に記載のナノ粒子を有効成分とする医薬品。
- 請求項1〜10に記載のブロック共重合体又は請求項11若しくは12に記載のナノ粒子を有効成分とする抗腫瘍剤。
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EP2641605B1 (en) * | 2010-11-17 | 2018-03-07 | Nippon Kayaku Kabushiki Kaisha | Polymer derivative of cytidine metabolism antagonist |
RU2014144945A (ru) * | 2012-04-10 | 2016-05-27 | Те Риджентс Оф Те Юниверсити Оф Калифорния | Бис-полимерные липид-пептидные конъюгаты и наночастицы из них |
JP2017160125A (ja) | 2014-08-04 | 2017-09-14 | 日本化薬株式会社 | 核酸代謝拮抗剤が結合したポリアミノ酸誘導体。 |
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CN107249589A (zh) | 2017-10-13 |
TWI746434B (zh) | 2021-11-21 |
KR20170120568A (ko) | 2017-10-31 |
EP3263107B1 (en) | 2020-11-11 |
WO2016136641A1 (ja) | 2016-09-01 |
US10357573B2 (en) | 2019-07-23 |
EP3263107A1 (en) | 2018-01-03 |
AU2016224760A1 (en) | 2017-07-27 |
US20180050112A1 (en) | 2018-02-22 |
AU2016224760B2 (en) | 2021-01-28 |
CN107249589B (zh) | 2021-06-08 |
JPWO2016136641A1 (ja) | 2017-11-30 |
TW201634060A (zh) | 2016-10-01 |
RU2017122808A (ru) | 2019-03-25 |
RU2017122808A3 (ja) | 2019-04-19 |
RU2732612C2 (ru) | 2020-09-21 |
CA2974936A1 (en) | 2016-09-01 |
EP3263107A4 (en) | 2018-10-17 |
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