JP6542799B2 - 新規peg誘導体 - Google Patents
新規peg誘導体 Download PDFInfo
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- JP6542799B2 JP6542799B2 JP2016562685A JP2016562685A JP6542799B2 JP 6542799 B2 JP6542799 B2 JP 6542799B2 JP 2016562685 A JP2016562685 A JP 2016562685A JP 2016562685 A JP2016562685 A JP 2016562685A JP 6542799 B2 JP6542799 B2 JP 6542799B2
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Description
近年、以上の問題を克服する目的で、幾つかのドラッグデリバリーシステムが開発されている。例えば、生体許容性の素材成分から成るリン脂質リポソーム、高分子ミセル或いは水溶性高分子に低分子の抗がん剤を物理的に包埋したり化学的に共有結合したりする方法でのドラッグデリバリーシステム(以下、DDSと言う)がその代表例である。
高分子ミセル製剤の場合では、50nmに粒子径が制御されており、また、該粒子の膜表面がPEGで被覆されているので、生体内の貪食細胞への取り込みが概ね避けられており、腫瘍の近傍の新生血管を通過でき易いとの報告がある。
しかしながら、以上のナノ微粒子を用いた製剤の血中半減期は比較的短く、腫瘍へのターゲッティングも不十分であり、本来の目的が十分には達成できていないのが現状である。
また、最近、酸やアルカリで分解され難いカルバメート結合により、4本鎖のPEGと抗がん剤(CPT−11)の活性成分であるSN−38を共有結合させた報告があるが、カルバメート結合の弱点をある程度克服したに過ぎない。又、カルバメート結合体を合成する場合の化学反応の条件が過酷(強アルカリ条件)であり、分子内にエステル結合やアルカリに敏感な抗がん剤の結合には不適である。
従って、本発明の課題は、重篤な消化管毒性や骨髄毒性等の副作用が少なく、抗腫瘍効果が持続し、投与手段、投与回数を改善できる新たな悪性腫瘍治療薬を提供することにある。
さらに検討を重ねた結果、シトシン誘導体やマイトマイシンCやパクリタキセル等の抗腫瘍剤やゲフィチニブ、エルロチニブ、ラパチニブ、スニチニブ等のがんの分子標的薬の一級又は二級アミノ基に、末端にメチルカルボキシル基を導入した4本鎖のポリエチレングリコールを直接、又はβ−アラニン等のアミノ酸系スペーサーを介してアミド結合させた式(1)で表される化合物が、抗腫瘍効果の持続性に優れ、かつ安全性も高く、従来の抗腫瘍剤に比べて少ない投与量と少ない投与回数でより優れた悪性腫瘍治療効果を奏することを見出し、本発明を完成した。
R2は、式(a)、(b)、(c)、(d)、(e)又は(f)
mは10〜1000の数を示し;
矢印は結合部位を示す。〕
で表される化合物又はその塩。
〔2〕R2が式(a)又は(b)で示される基である〔1〕記載の化合物又はその塩。
〔3〕R2が式(a)で示される基である〔1〕又は〔2〕記載の化合物又はその塩。
〔4〕R2が式(a)で示される基であり、R6がヒドロキシ基、シアノ基又はハロゲン原子であり、R7が水素原子又はハロゲン原子であり、R8が水素原子又はエチニル基であり、R9及びR10が水素原子である〔1〕〜〔3〕のいずれか1項記載の化合物又はその塩。
〔5〕R1が、単結合、−NH(CH2)n1CO−、−NH(CH2)n2NHCO(CH2)n3CO−、又は
である〔1〕〜〔4〕のいずれか1項記載の化合物又はその塩。
〔6〕〔1〕〜〔5〕のいずれか1項記載の化合物又はその塩を含有する医薬。
〔7〕悪性腫瘍治療薬である〔6〕記載の医薬。
〔8〕〔1〕〜〔5〕のいずれか1項記載の化合物又はその塩、及び薬学的に許容される塩を含有する医薬組成物。
〔9〕悪性腫瘍治療薬製造のための、〔1〕〜〔5〕のいずれか1項記載の化合物又はその塩の使用。
〔10〕悪性腫瘍治療に用いるための、〔1〕〜〔5〕のいずれか1項記載の化合物又はその塩。
〔11〕〔1〕〜〔5〕のいずれか1項記載の化合物又はその塩の有効量を投与することを特徴とする悪性腫瘍の治療方法。
また、R4及びR5が一緒になって形成する炭素数1〜4のアルキレン基としては、メチレン基、エチレン基、トリメチレン基又はテトラメチレン基が挙げられ、エチレン基がより好ましい。
で表される基が好ましい。
この反応は、カルボン酸アミド形成反応であり、塩基の存在下、HBTU、DCC等の縮合剤を用いて行うことができる。
経口用固形製剤を調製する場合は、本発明化合物(1)に賦形剤、必要に応じて賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味・矯臭剤等を加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。
注射剤を調製する場合は、本発明化合物(1)にpH調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法により皮下、筋肉内及び静脈内用注射剤を製造することができる。
窒素雰囲気下、1−(2’−シアノ−2’−デオキシ−β−D−アラビノフラノシル)シトシン塩酸塩5.0モル、トリエチルアミン10.0モル及びジメチルホルムアミド8モルを反応容器に加え、さらにテトラ(スクシンイミジルカルボキシメチルポリエチレングリコール)ペンタエリスリトール1.0モルを加えた。100℃に加熱し、3時間反応撹拌した。20〜25℃に冷却後、反応混合物をメチル tert−ブチルエーテル100mL中に投入し、1時間撹拌して原料を濾別した。50〜60°でエタノールを加えて撹拌後20±5℃に冷却し16時間撹拌し、メチル tert−ブチルエーテルで洗浄する操作を繰り返し、エタノール溶液を冷却して化合物(1a)(m=平均230)を白色粉末として得た(収率88%)。融点54℃。化合物(1a)のNMRスペクトルチャートを図1に示す。
(1)窒素雰囲気下、1−(2’−シアノ−2’−デオキシ−β−D−アラビノフラノシル)シトシン塩酸塩1モル及びビリジン100mLを反応容器に投入し、テトライソプロピルジシロキサンジクロリド1.2モルを20〜25℃で滴下した。45±5℃に加熱し、2時間撹拌した。20〜25℃でヘキサンを加え、生成物を固体として単離した。20〜25℃で水中に投入し、1時間30分撹拌し、濾過後水及びヘキサンで洗浄し、蒸発乾固して化合物(3a)を得た。
窒素雰囲気下、反応容器に上記反応混合物及び酢酸エチル300mLを投入し、25±5℃でHCl/酢酸エチル 2Mを加えた。出発物質が濃HCl/酢酸エチル溶液に速やかに溶解し、5分後に目的物が固形分として分離し始める。1時間撹拌し、濾過後酢酸エチルで洗浄し化合物(3c)を得た。
(1)窒素雰囲気下、実施例2(1)で得られた化合物(3a)1モル、無水コハク酸4モル及びピリジン50mLを反応容器に投入し、40±5℃に加熱し2時間撹拌した。反応混合物を水及び酢酸エチルの混合物に添加し、1M塩酸でpHを5に調整し、30±5℃で30分撹拌した。有機相を分離し、水相から酢酸エチルで3回抽出し、有機相を合わせ、生理食塩水で洗浄した。無水Na2SO4で乾燥し、濾過後、濾液を減圧濃縮後乾燥し、化合物(3d)を得た。
(1)窒素雰囲気下、反応容器に実施例3(2)の化合物(3e)1モル、酢酸2.3モル及びジメチルホルムアミド50mLを投入し、0±5℃に冷却した。0±5℃でフッ化テトラ−n−ブチルアンモニウム(TBAF)1.6モルを加え、1時間撹拌し、化合物(3g)を製造した。
窒素雰囲気下、テトラ(カルボキシメチルポリエチレングリコール)ペンタエリスリトール1.0モル、マイトマイシンC4.8モル、HBTU5.0モル、トリエチルアミン8モル、ジメチルホルムアミド300mLを反応容器に加え、40±5℃で3時間反応させた。20〜25℃に冷却後、実施例1と同様に処理して、化合物(1e)を白色粉末として得た(m=平均230)(収率91.4%)。化合物(1e)のNMRスペクトルチャートを図5に示す。
(1)化合物(3a)に代えてマイトマイシンCを用い、実施例3(1)と同様にして、化合物(3h)を得た。
ゲムシタビン及びテトラ(スクシンイミジルカルボキシメチルポリエチレングリコール)ペンタエリスリトールを用い、実施例1と同様にして、化合物(1g)(m=平均230)を白色粉末として得た(収率82.3%)。融点57℃。1H−NMRスペクトルチャートを図7に示す。
スニチニブの脱エチル体及びテトラ(スクシンイミジルカルボキシメチルポリエチレングリコール)ペンタエリスリトールを用い、実施例1と同様にして、化合物(1h)(m=平均230)を黄色粉末として得た(収率87%)。融点55℃。1H−NMRスペクトルチャートを図8に示す。
ラパチニブ、テトラ(カルボキシメチルポリエチレングリコール)ペンタエリスリトール及びHBTUを用い、実施例4と同様にして化合物(1i)を白色粉末として得た(収率87.8%)。融点56℃。1H−NMRスペクトルチャートを図9に示す。
(1)パクリタキセルにトリフルオロ酢酸を反応させて、パクリタキセルのtert−ブトキシカルボニル基を脱離させた。
(2)パクリタキセル−t−ブトキシカルボニル脱離体及びテトラ(スクシンイミジルカルボキシメチルポリエチレングリコール)ペンタエリスリトールを用い、実施例1と同様にして化合物(1j)を得た(収率84.2%)。1H−NMRチャートを図10に示す。
BALB/cヌードマウスの右側腹部に膵臓がん細胞を5×106細胞移植し、7日後平均腫瘍が100mm3に達した時点で薬物投与を開始した。薬物投与から29日後までマウスの体重及び腫瘍体積を測定した。その結果を図11、図12及び表1に示す。1−(2’−シアノ−2’−デオキシ−β−D−アラビノフラノシル)シトシン塩酸塩(DFP−10917)は、マウスの体内に埋め込んだミクロポンプを用いて4.5mg/kg/dayを皮下への持続注入を2週間連続して行った。一方、化合物(1a)は、100mg/kg、200mg/kg又は300mg/kgを週1回静脈内投与した。この化合物(1a)の投与量は、DFP−10197に換算して2.4mg/kg、4.8mg/kg及び7.2mg/kgの週1回投与である。コントロールは、酢酸ナトリウムの緩衝液(pH=5.0)を投与した。
試験例1と同様にして、マイトマイシンC及び化合物(1e)の抗腫瘍作用を検討した。マイトマイシンC(MMC)は、3mg/kg/dayを週一回静脈内投与した。一方、化合物(1e)は、25mg/kg、50mg/kg、100mg/kg及び200mg/kgを週1回静脈内投与した。この化合物(1e)の投与量は、MMCに換算して0.8mg/kg、1.7mg/kg、3.3mg/kg及び6.7mg/kgの週1回投与である。
BALB/cヌードマウスの右側腹部にヒト肺がん細胞A549を5×106細胞移植し、14日後平均腫瘍が127mm3に達した時点で薬物投与を開始した。化合物(1a)は、200mg/kg(DFP−10917換算量は4.8mg/kg)を1週間に1回静脈内投与し、肺がんの標準薬であるペメトレキセドは300mg/kgを1週間に1回腹腔内投与した。コントロールは、生理食塩水を1週間に1回静脈内投与した。観察は2週間(合計2回投与)とした。
その結果、化合物(1a)は、DFP−10917換算量4.8mg/kgの投与で、ペメトレキセド300mg/kg投与群と同等の腫瘍治療効果を示した。
BALB/cヌードマウスの右側腹部にヒト乳がん細胞BT474を1×107細胞移植し、試験例3と同様にして薬物投与したDFP−10917及び化合物(1a)は、1週間に1回計2回静脈内投与した。コントロールは、生理食塩水を1週間に1回投与した。
BALB/cヌードマウスの右側腹部にヒト膵臓がん細胞Panc−1を5×106細胞移植し、試験例3と同様にして薬物投与した。化合物(1g)は、1週間に1回計2回又は1週間に2回静脈内投与した。ゲムシタビンは100mg/kgを3日間で4回に分けて投与し、これを計4回静脈内投与した。コントロールは、生理食塩水を1週間に1回投与した。
BALB/cヌードマウスの右側腹部にヒト肺がん細胞A549細胞を移植し、11日後平均腫瘍が200mm3に達した時点で薬投与を開始した。投与スケジュールは表5、表6に示す。
また、化合物(1h)及び化合物(1i)は、上記の投与量で何ら体重減少が認められず、安全性も高いことが確認された(図16)。
BALB/cヌードマウスの右側腹部にヒト乳がん細胞BT474を1×107細胞移植し、腫瘍体積が100〜150mm3になったときに薬物投与した。投与は、1週間に1回、2週間投与した。
Claims (6)
- 一般式(1)
R2は、2’−シアノ−2’−デオキシ−β−D−アラビノフラノシルシトシン、3’−エチニル−β−D−アラビノフラノシルシトシン、式(b)、(c)、(d)、(e)又は(f)
mは10〜1000の数を示し;
矢印は結合部位を示す。〕
で表される化合物又はその塩。 - 請求項1又は2記載の化合物又はその塩を含有する医薬。
- 悪性腫瘍治療薬である請求項3記載の医薬。
- 請求項1又は2記載の化合物又はその塩、及び薬学的に許容される塩を含有する医薬組成物。
- R2が、2’−シアノ−2’−デオキシ−β−D−アラビノフラノシルシトシンである、請求項1記載の化合物又はその塩。
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KR102314558B1 (ko) * | 2020-05-14 | 2021-10-18 | 데루타-후라이 화마 가부시키가이샤 | 베네토클락스의 수용성 고분자 유도체 |
US11524078B2 (en) | 2020-05-14 | 2022-12-13 | Delta-Fly Pharma, Inc. | Water-soluble macromolecular derivative of Venetoclax |
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CN107001617B (zh) | 2019-08-27 |
RU2017122971A3 (ja) | 2019-02-11 |
EP3228650A1 (en) | 2017-10-11 |
US10111955B2 (en) | 2018-10-30 |
AU2015355965A1 (en) | 2017-04-27 |
AU2015355965B2 (en) | 2019-07-04 |
KR102138415B1 (ko) | 2020-07-27 |
CN107001617A (zh) | 2017-08-01 |
RU2697551C2 (ru) | 2019-08-15 |
US20170368177A1 (en) | 2017-12-28 |
WO2016088858A1 (ja) | 2016-06-09 |
ES2910659T3 (es) | 2022-05-13 |
EP3228650B1 (en) | 2022-03-09 |
JPWO2016088858A1 (ja) | 2017-09-07 |
RU2017122971A (ru) | 2019-01-09 |
EP3228650A4 (en) | 2018-10-17 |
KR20170091610A (ko) | 2017-08-09 |
PL3228650T3 (pl) | 2022-06-27 |
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