JP5676020B2 - ニトロイミダゾールを用いたプロドラッグ - Google Patents
ニトロイミダゾールを用いたプロドラッグ Download PDFInfo
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- JP5676020B2 JP5676020B2 JP2013558712A JP2013558712A JP5676020B2 JP 5676020 B2 JP5676020 B2 JP 5676020B2 JP 2013558712 A JP2013558712 A JP 2013558712A JP 2013558712 A JP2013558712 A JP 2013558712A JP 5676020 B2 JP5676020 B2 JP 5676020B2
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- 239000011541 reaction mixture Substances 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical group C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
Images
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Description
意外にも、当該カルボニル基を介して形成されたアミド結合、イミド結合またはエステル結合は還元環境下、特に、生体内の低酸素部位において開裂することを本発明者等は見出した。
このような開裂は、理論に拘束されるものではないが、還元環境下でイミダゾール環上のニトロ基がヒドロキシアミンまたはアミノ基に変換され、当該アミノ基が分子内で求核攻撃を行う次の反応スキームに従う分子内環化反応を伴って起こるものと理解できる。
したがって、本発明は、広く、2−ニトロ−1−イミダゾールプロピオン酸を、多種多様な薬物、特に、治療的活性有機化合物のプロドラッグを提供するために使用できることを見出したことに基づく。
本発明の一態様としては、一般式(I)
−O−R3 (b)を表し、
式中、R1は、アミノ基を持つ治療的活性有機化合物から当該アミノ基を除去した残基であり、かつ、R2が水素原子であるか、または、
R1とR2が隣接するN原子と一緒になって、環状アミノ基を持つ治療的活性有機化合物の残基を表す、
R3は、ヒドロキシル基を持つ治療的活性有機化合物から当該ヒドロキシ基を除去した残基である。
分子中にアミノ基、環状アミノ基またはヒドロキシル基を分子中に持つ治療的活性有機化合物のプロドラッグを製造するための反応体としての式(II)で表される化合物の使用、
についても提供される。
このような一般式(I)の化合物は、2−ニトロ−1−イミダゾールプロピオニル(以下、Izpと略称することがある。)が治療的活性有機化合物に結合していることにより、当該有機化合物が本来持っている生物活性(例えば、細胞毒性、その他の活性)を低下またはマスクする一方で、還元環境下、特に、哺乳動物の低酸素部位でIzp部分とZに相当する部分が選択的に開裂する。かような開裂によりもたらされる当該有機化合物はそれら本来の活性を低酸素部位またはその周辺で示すようになる。
したがって、一般式(I)で表される化合物は、それに含まれる治療的有機化合物を哺乳動物の特定部位で放出できるので、より安全かつ、効果的に使用できる。
こうして、「プロドラッグ」とは、それ自体当該技術分野で用いられている意味を有し、例えば、生理活性物質または治療的活性有機化合物を化学的に修飾し、生体内で酵素的またはその他の条件下で親化合物を遊離もしくは放出するように設計された化合物を意味する。
「コンジュゲート」とは、2種以上の異なる化合物が共有結合して形成された結合体を意味し、プロドラッグを包合する概念として用いている。
「治療的活性有機化合物」は、哺乳動物、特にヒトの疾患、障害、等を治療または予防する活性を持つ有機化合物を意味する。かような疾患、障害としては、腫瘍、特に悪性腫瘍、及び炎症であって、これらの病巣またはその周辺領域が正常な組織または細胞領域に比べて低酸素状態を伴うものを挙げることができる。
「抗腫瘍剤または物質」及び「抗癌剤」は互換可能な用語として使用している。
アミノ基を持つ治療的活性有機化合物の代表的な化合物としては、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、ゲムシタビン、シタラビン、メトトレキサート、ペメトレキセド、メルファラン、メサラジンを挙げることができ、
環状アミノ基を持つ治療的活性有機化合物の代表的な化合物としては、ビンクリスチン、ビンブラスチン、ビンデシン、5−フルオロウラシル、6−メルカプトプリンを挙げることができ、
ヒドロキシル基を持つ治療的活性有機化合物の代表的な化合物としては、がドセタキセル、パクリタキセル、ビンクリスチン、ビンブラスチン、ビンデシン、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、ゲムシタビン、シタラビン、カペシタビン、ドキシフルリジン、エポチロン、ピロキシカム、メロキシカム、テノキシカム、コルチゾン、ヒドロコルチゾン、コルチゾン酢酸エステル、プレドニゾロン、メチルプレドニゾロン、ベタメタゾン、デキサメタゾン、トリアムシノロン、トリアムシノロンアセトニドを挙げることができる。
これらのうち、治療的活性有機化合物の好ましいものとしては、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ブレオマイシン、アクチノマイシン、カンプトセシン、トポテカン、イリノテカン、ドセタキセル、パクリタキセル、ビノレルビン、ビンクリスチン、ビンブラスチン、ビンデシン、ゲムシタビン、シタラビン、5−フルオロウラシル、カペシタビン、ドキシフルリジン、フルダラビン、6−メルカプトプリン、6−チオグアニン、エポチロン、ピロキシカム、メルファラン、メトトレキサート、ペメトレキセド、メサラジン、プレドニゾロン、メチルプレドニゾロン、デキサメタゾン、ベタメタゾンを挙げることができ、より好ましいものとしては、ドキソルビシン、イダルビシン、エピルビシン、ダウノルビシン、ピラルビシン、アムルビシン、アクラシノマイシン、アントラマイシン、ゾルビシン、ゲムシタビン、シタラビン、メトトレキサート、ペメトレキセド、メルファラン、メサラジン、ビンクリスチン、ビンブラスチン、ビンデシン、5−フルオロウラシル及び6−メルカプトプリン、プレドニゾロンを挙げることができる。
ESI−MS(M+H+)理論値:325.130,実測値:325.126
50mLのナスフラスコに撹拌子と化合物5(10mg)を加えた。スターラーで撹拌しながら反応容器にメタノール10mL,Pd/C 50mgを入れ、水素ガスを充填させた。水素ガスを充填させたまま24時間間撹拌し、反応後TLC(展開溶媒 酢酸エチル:ヘキサン=1:1)によって反応の進行を確認した。次にセライト濾過によってPd/Cを除去し、最後にエバポレーターによってメタノールを除去した。エレクトロスプレーイオン化質量分析により解析したところ、化合物4の生成を示す結果が得られた。すなわち、分子内環化反応を伴いアミド結合が開裂し、ナフチルメチルアミンを放出することがわかる。
化合物4の分子量理論値:138.067、実測値:138.063
この例は、化合物5が低酸素環境下の細胞で還元され、その後の分子内環化反応によりナフチルメチルアミンを放出することを確認するために行った。
ヒト膵臓がん細胞(MIA PaCa−2、理研セルバンクより入手)を細胞数が1×104cell/mLになるように調整し、96wellプレートに播種した。24時間後、化合物5を10μMの濃度で加え、通常酸素濃度インキュベーター(20%O2)と低酸素ワークステーション(0.1%O2)でそれぞれ培養した。時間経過後培地を回収し、更にトリプシンを加え細胞を回収した。回収した細胞を超音波処理により粉砕し、アセトニトリルで化合物を抽出して下記条件によりLC/MSにより解析を行った。
使用カラム : Lachrom Urtra C18(粒子径2um,2mm×50mm)カラム
測定波長 : 220nm
溶離液A :0.1%TFA含有milliQ
溶離液B :アセトニトリル
流速 :0.2mL/min
グラジエント
95:5(溶離液A:溶離液B)→95:5(5分)→30:70(15分)
この測定を行うことで低酸素環境と正常酸素環境での放出量の差を比較した。HPLCの結果を図3に示す。図より、低酸素環境下で多くのナフチルメチルアミンが放出されていることがわかる。
例2と同様に合成した化合物2(60mg)に1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(80.8mg)加え、N−ヒドロキシコハク酸イミド(48mg)を加えN,N−ジメチルホルムアミド(1mL)中、氷冷下で1時間反応させその後室温で3時間反応させた。反応後、氷冷下で酢酸を数滴滴下し30分撹拌した。酢酸エチルと飽和食塩水で分液を行い、有機層をエバポレーションにより濃縮し、2−プロパノールを加えて加熱し不純物を濾別し、濾液を氷冷することにより化合物6を得た(50mg)。
ESI−MS(M+H+)理論値:283.068,実測値:283.079
ドキソルビシン(3mg)に化合物6(2.2mg)をN,N−ジメチルホルムアミド(50μL)と水(50μL)の混合溶媒中で加え、トリエチルアミン(1.4μL)を加え24時間室温において反応させた。反応後、逆相HPLCカラム(GL Sciences Inc.Inertsil ODS−3 20X50mm、流速 5ml/min、展開液:メタノール/水=60/40(0min)〜100/0(20min)により精製した。
ESI−MS(M+Na+)理論値:733.1967,実測値:733.2013
こうして、上記反応スキームに記載の化合物7が得られた。
ヒト膵臓がん細胞(MIA PaCa−2、理研セルバンクより入手)MIA PaCa−2を5000cells/wellの濃度で撒きダルベッコ改変イーグル培地(DMEM)中で24時間培養した後に化合物7を指定濃度で加え、6時間通常酸素濃度(20%)及び低酸素濃度(0.1%)で培養した。培養後DMEM培地交換を行い、化合物を除去し、通常酸素濃度のインキュベーターにおいて48時間培養し、その後WSTアッセイにより細胞の生存率を解析した。結果を図4に示す。
図より、化合物7は、通常酸素濃度下に比べて低酸素濃度下で、ヒト膵臓がん細胞の生存率を有意に低下させることがわかる。
WO2009/018163 A1に記載されている下記化合物8を用意し、その化合物と本発明の範囲内の化合物(対応するリンカーが−CH2CH2C(=O)−であること以外、ニトロイミダゾール及び薬剤との結合様式は同じ。実施例6の化合物7)について実施例7に記載の方法に従って試験したときの細胞生存率を比較した。結果を図5に示す。
こうして精製し化合物9を得た。収率 20%
ESI−MS [M+H]+:理論値:431.11、実測値:431.20)
ヒト膵臓がん細胞(MIA PaCa−2、理研セルバンクより入手)MIA PaCa−2を5000cells/wellの濃度で撒きDMEM培地中で24時間培養した後に、化合物9を指定濃度で加え、1時間通常酸素濃度(20%)及び低酸素濃度(0.1%)で培養した。培養後培地交換を行い、化合物9を除去し、通常酸素濃度のインキュベーターにおいて48時間培養し、その後WSTアッセイにより細胞の生存率を解析した。結果を図6に示す。
ESI−MS[M−H]−:理論値296.1、実測値296.1)
ヒト膵臓がん細胞(MIA PaCa−2、理研セルバンクより入手)MIA PaCa−2を5000cells/wellの濃度で撒き、DMEM培地中で24時間培養した後に、化合物11および12の混合物を指定濃度で加え、24時間通常酸素濃度(20%)及び低酸素濃度(0.1%)で培養した。培養後培地交換を行い、化合物を除去し、通常酸素濃度のインキュベーターにおいて48時間培養し、その後WSTアッセイにより細胞の生存率を解析した。結果を図7に示す。
ESI−MS[M−H]−:理論値319.07、実測値 318.78
ESI−MS[M−H]−:理論値470.10、実測値469.63
MALDI−TOF MS[M−H]−:理論値620.19、実測値620.38
ESI−MS(M+H+)理論値:528.23,実測値:527.93
ヒト膵臓がん細胞(MIA PaCa−2、理研セルバンクより入手)を細胞数が1×104cell/mLになるように調整し、96wellプレートに播種した。24時間後、化合物13を10μMの濃度で加え、通常酸素濃度インキュベーター(20%O2)と低酸素ワークステーション(0.1%O2)でそれぞれ培養した。1時間後培地を回収し、更にトリプシンを加え細胞を回収した。回収した細胞を超音波処理により粉砕し、アセトニトリルで化合物を抽出して下記条件によりLC/MSによりプレドニゾロンの放出量解析を行った。
使用カラム : TSKgel ODS−100Z(粒子径3um,2mm×75mm)カラム
測定波長 : 250nm
溶離液A :0.1M酢酸アンモニウム
溶離液B :アセトニトリル
流速 :0.2mL/min
グラジエント
40:60(溶離液A:溶離液B)〜10:90 (20分)
この測定を行うことで低酸素環境と正常酸素環境での放出量の差を比較した。HPLCの結果を図8に示す。図より、低酸素環境下で多くのプレドニゾロンが放出されていることがわかる。
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