JP6557253B2 - 抗腫瘍化合物としてのシグマ−2受容体リガンド薬物結合体、その合成法及び使用 - Google Patents
抗腫瘍化合物としてのシグマ−2受容体リガンド薬物結合体、その合成法及び使用 Download PDFInfo
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- JP6557253B2 JP6557253B2 JP2016560467A JP2016560467A JP6557253B2 JP 6557253 B2 JP6557253 B2 JP 6557253B2 JP 2016560467 A JP2016560467 A JP 2016560467A JP 2016560467 A JP2016560467 A JP 2016560467A JP 6557253 B2 JP6557253 B2 JP 6557253B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Description
本出願は、2014年4月1日出願の米国仮出願第61/973,366号の優先権を主張し、その内容は本明細書により参照として援用される。
本研究は、国立衛生研究所(NIH)助成金5R01CA163764−03の支援を受けた。連邦政府は、本発明に一定の権利を有することができる。
本開示は、シグマ−2受容体結合化合物及び組成物、ならびに疾患治療用医薬としてのそれらの用途に関する。より詳細には、実施形態は、シグマ−2受容体リガンド薬物結合体、それらの合成、及び癌などの過剰増殖性疾患を治療するためのそれらの使用に関する。
開示を理解しやすくするため、多くの用語及び略語について、本明細書中使用される場合の定義を、以下のとおりに定める:
本開示は、構造式Iの化合物
本教示の化合物は、そのままの化学物質として投与することができるものの、それらを医薬配合物とすることも可能である。したがって、本明細書中提供されるのは、1種または複数の本教示の化合物、またはその1種または複数の薬学上許容される塩、エステル、プロドラッグ、アミド、もしくは溶媒和物を、その1種または複数の薬学上許容されるキャリア及び随意に1種または複数の他の治療成分と一緒に含む医薬配合物である。キャリアは、配合物のその他の成分と適合性があり、配合物のレシピエントに対して有害ではないという意味で、「許容される」ものでなければならない。適切な配合物は、選択した投与経路に依存する。周知の技法、キャリア、及び賦形剤のどれであっても、当該分野で、例えば、Remington’s Pharmaceutical Sciencesにおいて適切であるとおり、また理解されるとおりに使用することができる。本明細書中開示される医薬組成物は、当該分野で既知の任意の様式で、例えば、従来の混合、溶解、造粒、ドラジェ作製、湿式摩砕(levigating)、乳化、カプセル化、封入、または圧縮プロセスにより、製造することができる。
本教示の化合物は、嚥下をはじめとして経口で投与することができ、そうすることで化合物は、胃腸管に入るか、あるいは舌下または頬側投与をはじめとして口から直接血流へと吸収される。
本教示の化合物は、注射により、例えば、ボーラス注射または持続点滴により、血流、筋肉、または内臓へと直接投与することができる。非経口投与に適した手段として、静脈内、筋肉内、皮下、動脈内、腹腔内、くも膜下腔内、頭蓋内などが挙げられる。非経口投与に適した装置として、注射器(針型及び針を使用しない注射器を含む)及び輸液法が挙げられる。配合物は、単位用量または複数用量容器、例えば密閉アンプルまたはバイアルに入って存在することができる。
いくつかの形態において、本教示の化合物は、外用で(例えば、皮膚、粘膜、耳、鼻、または目に対して)または経皮投与することができる。外用投与用配合物として、ローション剤、液剤、クリーム剤、ゲル剤、ヒドロゲル剤、軟膏、フォーム剤、留置剤、パッチ剤などが挙げられるが、これらに限定されない。外用投与配合物用の薬学上許容されるキャリアとして、水、アルコール、鉱物油、グリセリン、ポリエチレングリコールなどが挙げられる。外用投与はまた、例えば、電気穿孔法、イオン導入法、フォノフォレーシスなどによっても行うことができる。
本教示の化合物の直腸内投与用坐剤は、活性作用剤を適切な非刺激性賦形剤、例えば、カカオバター、合成モノ、ジ、もしくはトリグリセリド、脂肪酸、またはポリエチレングリコールなどと混合することにより製造することができ、これらの賦形剤は、常温では固体であるが直腸温度では液体であり、したがって直腸で溶解して薬物を放出する。
吸入による投与については、いつくかの形態において、本教示の化合物は、吸入器、ネブライザー、加圧パック、またはエーロゾルスプレーもしくは粉末を送達する他の都合のよい手段から送達することができる。加圧パックは、適切な推進剤、例えばジクロロジフルオロメタン、トリクロロフルオロメタン、ジクロロテトラフルオロエタン、二酸化炭素、または他の適切なガスなどを含むことができる。加圧エーロゾルの場合、投薬単位は、計量された量を送達する弁を提供することにより、定めることができる。あるいは、吸入または吹送法による投与の場合、本開示による化合物は、乾燥粉末組成物、例えば、化合物と適切な粉末基剤、例えばラクトースまたはデンプンなどとの混合粉末の形状を取ることができる。粉末組成物は、単位剤形で、例えば、カプセル剤、カートリッジ剤、ゼラチンもしくはブリスター包装剤で存在することができ、吸入器または吹送器を用いてそのような単位剤形から粉末を投与することができる。
本開示は、シグマ−2受容体と結合する標的指向部分を特長とし、したがってシグマ−2受容体を発現する細胞に関連する障害の治療また予防に有用となり得る、化合物及び医薬組成物を提供し、そのような障害として癌が挙げられるが、これに限定されない。
いくつかの実施形態において、本開示の化合物及び医薬組成物は、癌の治療または予防に有用となり得る。
本教示の化合物は、本明細書中上記で既に記載したものなどの症状を治療するために、単独でまたは他の薬学上活性な化合物と組み合わせて使用することができる。本教示の化合物及び他の薬学上活性な化合物は、同時に(同一の剤形に含まれて、または別個の剤形に含まれてのいずれか)または順次、投与することができる。したがって、1つの実施形態において、本教示は、1種または複数の本教示の化合物を治療上有効量で、1種または複数の追加の薬学上活性な化合物とともに、対象に投与することにより、症状を治療する方法を含む。
本教示の化合物は、一般合成スキーム及び以下で詳細に記載する実験手順で示す方法を用いて調製することができる。一般合成スキーム及び実験手順は、例示の目的で提示されるのであって、制限することを意図しない。本教示の化合物を調製するための出発物質は、市販されているか、そうでなければ当該分野で既知の常法を用いて調製することができる。
aq.=水性;CDCl3=重水素化クロロホルム;DMSO−d6=重水素化ジメチルスルホキシド;DMSO=ジメチルスルホキシド;h=時間;THF=テトラヒドロフラン。
以下のスキームを用いて、本教示の合成法を実施することができる。明細書中のどこかで定義されるもの及びスキームで記載される化合物に示されていないものを含む追加の構造基を組み込んで、本明細書中開示される様々な化合物を与えることができ、または中間体化合物を、当業者に既知である技法を用いてさらに操作した後に、本教示の化合物に変換することができる。
LiAlH(o−tert−Bu)3(20.0g、78.5mmol)を無水THF(30mL)に加えた混合物を、氷浴で冷却した。化合物9−アザビシクロ[3.3.1]ノナン−3−オン(1)(5.0g、21.8mmol)を無水THF(45mL)に溶解させた溶液を滴下した。混合物を室温で一晩撹拌した。飽和NH4Cl水溶液で反応をクエンチした。固体を濾別し、THFで洗った。有機層を1つにまとめて、Na2SO4で乾燥させ、濾過し、乾固するまでエバポレートして、N−9−ベンジル−9−アザビシクロ[3.3.1]ノナン−3α−オールを、明黄色油状物として得た(4.8g、収率95%)。1H NMR (CDCl3) δ 7.20−7.35 (m, 5H), 4.22−4.32 (m, 1H), 3.79 (s, 2H), 3.02−3.06 (m, 2H), 2.33−2.43 (m, 2H), 2.12−2.26 (m, 1H), 1.85−1.99 (m, 3H), 1.30−1.54 (m, 3H),1.08−1.13 (m, 2H).
1H NMR (CDCl3) δ 7.97 (s, 1H), 7.16−7.37 (m, 6H), 6.73−6.80 (m, 2M), 5.22−5.30 (m, 1H), 3.84 (s, 3H), 3.81 (s, 2H), 3.04−3.07 (m, 2H), 2.42−2.52 (m, 2H), 2.30 (s, 3H), 1.91−2.20 (m, 3H), 1.48−1.56 (m, 3H), 1.15−1.18 (m, 2H).
4−ヒドロキシベンズアルデヒド(2.4g、20.0mmol)をアセトニトリル(60mL)に溶解させた溶液に、エチル=2−ブロモアセタート(3.7g、22.0mmol))及び炭酸カリウム(8.3g、60.0mmol)を加えた。反応混合物を24時間還流させた。冷却後、反応混合物を濾過し、エバポレートして、エチル=2−(4−ホルミルフェノキシ)アセタートを明黄色液状物として得た(定量的)。1H NMR (CDCl3) δ 9.90 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4Hz, 2H), 4.71 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1Hz, 3H).
メタノール/水(2:1、90mL)中で、中間体1Eを、水酸化ナトリウム(2.2当量)を用いて、24時間加水分解し、続いて10%HCI溶液で酸性にして、2−(4−ホルミルフェノキシ)酢酸をオフホワイト色固体として得た(3.1g、収率87%)。1H NMR (DMSO−d6) δ 13.18 (br s, 1H), 9.91 (s, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 4.86 (s2, H).
2−アミノ安息香酸(5.0g、36.5mmol)をジクロロメタン(90mL)に溶解させた溶液に、トリエチルアミン(4.06g、40.1mmol)を加え、混合物を氷浴で冷却した。塩化クロロアセチル(4.5g、40.1mmol)をジクロロメタン(40mL)に溶解させた溶液を滴下し、混合物を周辺温度で一晩撹拌放置した。固体を濾別し、冷水、続いて5%ジエチルエーテル含有ヘキサンで洗い、風乾させて、2−(2−クロロアセトアミド)安息香酸を白色固体として得た(7.4g、収率95%).1H NMR (DMSO−d6) δ 11.82 (s, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 4.45 (s, 2H).
中間体1G(3.1g、14.5mmol)及び2−エトキシアニリン(2.0g、14.5mmol)をアセトニトリル(50ml)に加えた混合物に、塩化ホスホリル(6.5g、42.4mmol)を滴下した。混合物を一晩加熱還流させた。反応混合物を室温に冷却し、氷/飽和Na2CO3溶液のスラリーに注いだ。得られる固体を濾別し、水で洗い、風乾させて、2−(クロロメチル)−3−(2−エトキシフェニル)キナゾリン−4(3H)−オン(10)を褐色固体として得た(2.5g、収率53%)。1H NMR (CDCl3) δ 8.31 (d, J = 7.8 Hz, 1H), 7.78−7.82 (m, 2H), 7.47−7.55 (m, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.06−7.14 (m, 2H), 4.35 (d, J = 11.9 Hz, 1H), 4.17 (d, J = 11.9 Hz, 1H), 4.06 (q, J = 6.9 Hz, 2H), 1.23 (t, J = 6.9 Hz, 3H).
中間体1H(2.5g、8.0mmol)、K2CO3(4.4g、32.0mmol)、及びKI(1.7g、10.4mmol)をアセトニトリル(75mL)に加えた混合物に、ピペラジン(2.7g、32.0mmol)を加えた。反応混合物を、85〜90℃で一晩加熱した。冷却後、反応混合物を濾過して、固体をアセトニトリルで洗った。有機層を1つにまとめてエバポレートした。得られる残渣を水に分散させて、酢酸エチルで抽出した。有機層をブラインで洗い、Na2SO4で乾燥させ、濾過し、エバポレートした。粗残渣を、カラムクロマトグラフィー(10%メタノール、0.5%NH4OH含有ジクロロメタン)で精製して、3−(2−エトキシフェニル)−2−(ピペラジン−1−イルメチル)キナゾリン−4(3H)−オンを黄色油状物として得た(2.3g、収率79%)。1H NMR (CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H), 7.75−7.77 (m, 2H), 7.39−7.50 (m, 2H), 7.28 (d, J = 7.0 Hz, 1H), 7.01−7.08 (m, 2H), 4.05 (q, J = 6.8 Hz, 2H), 3.18−3.28 (m, 2H), 2.73 (s.4H), 2.33−2.37 (m, 2H), 2.17−2.20 (m, 2H), 1.22 (t, J = 6.8 Hz, 3H).
式(I)の化合物の生物学的有効性を評価するのに使用可能なアッセイは以下のとおりである。
6匹の成年メスマウスで死体解剖を行った。マウスの系統名は、C57BL/6であった。事前の処置として、2週間の課程にわたって、フェロトーシス誘導薬物またはビヒクル対照の腹腔内投与を毎日行った。マウスには、あらかじめ皮下にKCKO異種移植も行っておいた(Besmer, D.M., et al., Cancer Res.17:4432−4442, 2011)。
CFPAC−1、BxPC−3、AsPC−1、PANC−1、及びMia PaCa−2細胞株を、アメリカ培養細胞系統保存機関(ATCC、Manassas、VA)から入手した。SYO−1細胞株、すなわち滑膜肉腫細胞株(Kawai, A., et al., Cancer Lett. 204: 105−113, 2004)は、Dr. Brian Van Tine(Washington University School of Medicine、St.Louis、MO)により提供された。KCKO細胞株は、遺伝子導入マウスのヒトMUC1発現膵臓腫瘍から単離した(Besmer et al. Cancer ResearCH 2011; 71:4432−4442, Tinder et al J Immunol 2008; 181: 3116−3125)。KCKO細胞株は、Dr. Pinku Mukherjee (University of North Carolina、Charlotte、NC)により提供された。PANC−1細胞は、ダルベッコ変法イーグル培地に4mMのL−グルタミン、1.5g/Lの重炭酸ナトリウム、及び10%ウシ胎児血清(FBS)を添加したもので培養した。Mia PaCa−2細胞株は、ダルベッコ変法イーグル培地に10%FBS及び2.5%ウマ血清を添加したもので培養した。BxPC−3、AsPC−1、及びKCKO細胞株は、RPM1−1640培地に10%FBSを添加したもので培養した。SYO−1滑膜肉腫細胞は、ダルベッコ変法イーグル培地に10%FBSを添加したもので培養した。抗生物質のペニシリン(100mg/ml)及びストレプトマイシン(100mg/ml)を培地に添加し、細胞を、加湿インキュベーター中、37℃で5%CO2下に維持した。
統計分析及びデータプロットは、GraphPad Prismソフトウェアバージョン6(San Diego、CA)を用いて行った。結果は、少なくとも3つの生物学的複製物の平均±SEMで表した。IC50値は、正規化した生存率対薬物濃度で曲線当てはめを行うことにより計算した。一元配置ANOVAを用いて、NAC及びZVADを用いた試験でのIC50値及びSW V−49s阻害における差異を分析した。対応のない両側t検定を用いて、CBC及び生化学分析における差異を評価し、シスチン取り込み、カスパーゼ、及びROS検出アッセイのサブグループにおける差異を確認した。二元配置ANOVAを用いて、腫瘍体積における差異を分析した。カプラン・マイヤー生存分析法を用い、群間の差異をログランク検定で比較した。全ての分析について、p値<0.05を、有意であると見なした。
マウスA(ID:732)は、ビヒクル対照であった。被毛を右側腹部にわたって剪毛したが、一部再生してきた。右側腹部に非常に小さな皮下肥厚が触知できた。鼻または眼からの分泌物または下痢はなかった。体水分及び体脂肪は正常であった。体重は21グラムであった。
マウスAについて、剖検前の検査で認められた皮下肥厚は、大きさ0.5×0.1cmの堅い腫瘤であった。0.4×0.1cmの肥厚範囲が遠位結腸近くの腸間膜に認められ、理屈に拘らなければ、これは恐らく肥大リンパ節の結果と思われる。直径2mmの発赤病巣が左肺に認められた。心臓及び肝臓は軽度に褪色していた。腸管、筋骨格系、泌尿器系、生殖器系、脳、胸腺、脾臓、副腎、甲状腺、下垂体、中耳、または眼に、肉眼病変はなかった。
マウスAについて、軽度の多発性炎症浸潤物が、マクロファージ、好中球、リンパ球、及び形質細胞を含む腸間膜脂肪中に認められた。リンパ過形成、組織球増殖、及び髄洞の拡大を伴う反応性腸間膜リンパ節が認められた。肺では、1葉に中度の限局性出血が認められ、理屈に拘らなければ、CO2安楽死に関連しているようであった。脳、心臓、肝臓、腎臓、脾臓、膵臓、または胃腸管に顕著な病変はなかった。
薬物処置した動物と対照動物の間に認められた違いは、薬物処置した動物で認められた、腸管及び腹部臓器の漿膜表面に沿ったならびに膵臓を取り囲む腸間膜での最小〜中度慢性腹膜炎の存在であった。一方で、対照動物は、繊維増殖を伴わない、腸間膜での最小〜軽度多巣性炎症性浸潤物を示した。他の知見として、マウスCでALT及びASTの上昇が認められたことが挙げられる。理屈に拘らなければ、この知見についての病因は、不明であった。予想通り、肝細胞障害の組織学的証拠はなかった。理屈に拘らなければ、他に可能性のある原因として、血液試料の溶血、または腫瘍浸潤による骨損傷が挙げられた。
これらの実験では、以下の構造の蛍光標識化シグマ−2リガンドSW120を用いて、SW V−49sの競合結合アッセイを行った。
これらの実験では、ヒト及びマウスの膵臓癌細胞株ならびに滑膜肉腫細胞株を、SW V−49sまたはその親化合物であるSV119及びエラスチン単独でまたはこれらを併用しての両方で処理してから24時間後の生存度アッセイを行った。データは、SWV−49についてヒト膵臓癌細胞株Panc−1(ATCC(登録商標)CRL−1469(商標))に対して4.3μMのIC50濃度(図4A);SW V−49sについてヒト膵臓癌細胞株BxPC−3(ATCC(登録商標)CRL−1687(商標))に対して2.3μMのIC50濃度(図4B);SW V−49sについてヒト膵臓癌細胞株MIA PaCa−2(ATCC(登録商標)CRL−1420(商標))に対して2.3μMのIC50濃度(図4C);SW V−49sについてヒト膵臓の癌細胞株AsPC−1(ATCC(登録商標)CRL−1682(商標))に対して3μMのIC50濃度(図4D);及びSW V−49sについてマウス膵臓癌細胞株(KCKO細胞)に対して2.2μMのIC50濃度(図4E)を示した。比較として、エラスチン単独では、試験した全てのヒト及びマウス膵臓癌細胞株に対して>100μMのIC50を示した;SV119単独では、試験した全てのヒト及びマウス膵臓癌細胞株に対して>54μMのIC50を示した;そしてエラスチンとSV119の等モル混合物は、試験した全てのヒト及びマウス膵臓癌細胞株に対して>44μMのIC50を示した。
これらの実験では、本発明者らは、本教示の化合物が、膵臓癌細胞に対して、アポトーシス細胞死経路、フェロトーシス細胞死経路、またはそれらの組み合わせのどれを引き起こすことにより致死性であるのかを調べた。すなわち、本発明者らは、アポトーシス細胞死の指標としてカスパーゼ3/7についてのアッセイを行い、フェロトーシス細胞死の指標として活性酸素種(ROS)の生成についてアッセイを行った。図5Aに示すとおり、AsPC−1細胞を、50μMのエラスチン、SV119、またはエラスチン+SV119の等モル混合物で24時間処理すると、4μMのSW V−49sと比較してはるかに低いカスパーゼ活性がもたらされた。図5Bには、8μMのSW V−49s、8μMのエラスチン、8μMのSV119、または8μMのエラスチンとSV119の等モル混合物で7時間処理したAspc−1細胞のCaspase−Glo(登録商標)(Promega)アッセイの結果を示す。SW V−49sで処理した細胞は、全ての対照と比較して、カスパーゼ3/7の有意な増加(約3倍)を示した*p<0.0001。
これらの実験では、実施例9で記載したマウスの生存実験において、SW V−49sを与えられた群では生存率が100%であった(図8)。その他の全ての群では、平均生存率は、18日前後に集中していた。
薬物の細胞毒性を、CELLTITER−GLO(登録商標)、発光細胞生存度アッセイ(Promega、Madison、WI)により評価した。膵臓細胞株を、処理の24時間前に、白色96ウェル透明底プレートに2×104/ウェルの密度で蒔いた。薬物をDMSOに溶解させ、培養液で系列希釈して、DMSOの最終濃度を1%未満とした。次いで、細胞を24時間処理して、CELLTITER−GLO(登録商標)試薬100μlを各ウェルに添加した。プレートの内容物を、オービタルシェーカーを用いて混合し、引き続き室温で10分間インキュベートした。発光シグナルを、マルチモードマイクロプレートリーダー(BioTek instruments、Winooski、VT)を用いて測定した。異なる薬物濃度について3つ組でアッセイした。薬物の効力を評価するため、化合物のIC50を、ヒト及びマウス由来の膵臓癌細胞株パネルでin vitroで計算した。細胞を、SW V−49s、SVI19、エラスチン、及びエラスチンとSV119の等モル混合物で24時間処理し、次いで、CELLTITBR−GLO(登録商標)生存度アッセイを行った。エラスチンは、活性が最も低い化合物であり、IC50>150μMであった。SVI19は、中程度の効力を示し、その効力はエラスチンが加わることで増強された。しかしながら、SW V−49sは、エラスチンとSV119の等モル混合物での処理と比較して、IC50の17〜20倍の低下という強い細胞毒性を示した(表4及び図9)。これらの結果は、SW V49sが、膵臓癌細胞に選択的に送達されることを示す。
これらの実験では、シスチン取り込みアッセイを、既に記載されたとおりに行った(Dixon, S.J. et al Cell 2012; 149: 1060−1072)。簡単に述べると、5×105のAsPC−1細胞/ウェルを6ウェルプレートに一晩蒔いておいた。翌日、細胞を、予め温めておいたNa+フリー取り込み緩衝液(137mMの塩化コリン、3mMのKCl、1mMのCaCl2、1mMのMgCl2、5mMのD−グルコース、0.7mMのK2HPO4、及び10mMのHEPES[pH7.4])で2回洗浄した。続いて、細胞を、取り込み緩衝液1ml中、37℃で10分間インキュベートして、細胞アミノ酸を枯渇させた。次いで、緩衝液を、200μMのSW V−49s及び0.12μCi(80〜110mCi/mmol)のL−[3,3’−14C]−シスチン(American Radiolabeled Chemicals、St Louis、MO)を含有する取り込み緩衝液600μlと交換して、37℃で3分間インキュベートした。その後、細胞を、氷冷した取り込み緩衝液で3回洗浄し、0.1MのNaOH500μlで溶解させた。この溶解物にシンチレーション液1mlを加え、シンチレーションカウンターで1分あたりの放射線カウントとして測定した。
これらの実験では、カスパーゼ−3/7、8、及び9の活性を、AsPC−1細胞において、対応するCASPASE−GLO(登録商標)アッセイを用いて、使用説明書に従って(Proraega、Madison、Wi)、測定した。このアッセイは、カスパーゼ特異的基質を利用したもので、この基質は、切断されるとルシフェラーゼの基質であるアミノルシフェリンを放出し、その結果、カスパーゼ特異的な発光シグナルを生じる。細胞を、2×104の密度で、白色96ウェル透明底プレートに24時間蒔いておいてから、4μMの化合物で処理した。次いで、内容物をプレートシェーカーで30秒間混合し、その後室温で90分間インキュベートした。マルチモードマイクロプレートリーダー(BioTek)を用いて、発光シグナルを測定した。アッセイは3つ組で行い、DMSOのカスパーゼ活性をベースラインと見なした。
本発明者らは、SW V−49sがアポトーシス及びROS生成を誘導できることを実証した。細胞死の誘導におけるこれら2つの機構の役割を査定するため、SW V−49sの効力に対するパンカスパーゼ阻害剤及び抗酸化剤の効果を試験した。これらの実験では、AsPC−1細胞を、10mMの抗酸化剤N−アセチルシステイン(NAC)、20μMのパンカスパーゼ阻害剤ZVAD、及び対照としてDMSOで1時間前処理した。次いで、3つの群を、10μMのSW V−49sで5時間処理し、その後CELLTITER−GLO(登録商標)生存度アッセイを行った。結果は、NAC及びZVADで前処理した細胞の生存度が、それぞれ63%及び91%に低下したのと比較して、SW V−49sのみで処理した細胞の生存度が、39%に低下したことを示した(図13、p<0.0001)。NACは、SW V−49s活性を阻害するのにより有効であることがわかった(図13、p<0.002)。これらのデータは、SW V−49sの二重機能性を示し、SW V−49sがアポトーシス及びROS依存性細胞死の両方を誘導できることを示す。
ワシントン大学施設内動物管理機関により認可された動物実験プロトコルに従って、動物実験を行った。マウスを用いたin vivo実験を行って、SW V−49s、SVI19、エラスチン、SV119とエラスチンの併用、及びビヒクルの効果を比較した。in vivo実験で使用したビヒクルは、25%クレモフォールと75%H2Oの混合物である。C57BL/6マウス(6週齢、国立癌研究所研究室)の右側腹部に、KCKO細胞をRPMI培養液に加えた単独細胞懸濁液200μLを注入した(マウス1匹あたり25×104/105細胞)。マウスは無作為に4つの群に分けた(n=15)。平均腫瘍径が約5mmの時点で処置を開始した。マウスには、100μL/用量中375nmolesのSW V−49s及びビヒクルを10日間、SV119、エラスチン、SV119とエラスチンの等モル混合物を、毎日、腹腔内注射して与えた。腫瘍をデジタルノギスで1日おきに測定した。病態評価のため、異なる治療群から複数のマウスを本大学の比較医学科に送った。全血球計数(CBC)及び生化学的解析(AST、ALT、BUN、全ビリルビン、及びCr)のため血液を採取した。臓器は、肉眼検査及び組織学的検査を行った。
[1]
以下の構造
である、化合物またはその塩。
[2]
n=1かつR1はHである、[1]に記載の化合物またはその塩。
[3]
n=5かつR1はHである、[1]に記載の化合物またはその塩。
[4]
前記塩は、シュウ酸塩である、[1]〜[3]いずれか1項に記載の化合物またはその塩。
[5]
癌の治療方法であって、該治療を必要としている対象に、[1]〜[3]いずれか1項に記載の化合物またはその塩を治療上有効量で投与することを含む、前記方法。
[6]
前記化合物またはその塩は、[2]に記載の化合物またはその塩である、[5]に記載の癌の治療方法。
[7]
前記化合物またはその塩は、[3]に記載の化合物またはその塩である、[5]に記載の癌の治療方法。
[8]
前記癌は、膵癌である、[5]〜[7]いずれか1項に記載の癌の治療方法。
[9]
前記癌は、滑膜肉腫である、[5]〜[7]いずれか1項に記載の癌の治療方法。
[10]
[1]に記載の化合物の合成方法であって、以下の構造
式中、nは1〜5の整数であり、R1はHまたはメチルである、
前記方法。
[11]
n=1かつR1はHである、[10]に記載の方法。
[12]
n=5かつR1はHである、[10]に記載の方法。
[13]
癌の治療に使用するための、[1]に記載の化合物またはその塩。
[14]
前記癌は、膵癌である、[13]に記載の化合物またはその塩。
[15]
前記癌は、滑膜肉腫である、[13]に記載の化合物またはその塩。
[16]
癌の治療用医薬の製造のための、[1]に記載の化合物または塩の使用。
[17]
前記癌は、膵癌である、[16]に記載の化合物またはその塩の使用。
[18]
前記癌は、滑膜肉腫である、[16]に記載の化合物またはその塩の使用。
他の実施形態
上記に記載された詳細な説明は、当業者が本開示を実施する助けとなるように提供されるものである。しかしながら、本明細書中記載され特許請求される開示は、本明細書中開示される具体的な実施形態によりその範囲が制限されないものとする。なぜなら、これらの実施形態は、本開示の複数の態様の例示を意図するからである。等価な実施形態は何でも本開示の範囲内に含まれるものとする。事実、本明細書中示され記載されるものに加えて、本発明発見の精神または範囲から逸脱しない本開示の様々な修飾が、上記の説明から当業者には明らかであるだろう。そのような修飾もまた、付随する請求項の範囲内に含まれるものとする。
Claims (22)
- 構造式IV
[式中、
nが1、2、3、4および5より選択される整数であり、R2がHまたはメチルである]
を有する、化合物またはその塩。 - n=1であり、R2がHである、請求項1に記載の化合物またはその塩。
- n=5であり、R2がHである、請求項1に記載の化合物またはその塩。
- 塩がシュウ酸塩である、請求項1〜3のいずれか1項に記載の化合物またはその塩。
- 下記構造式
より選択される化合物またはその塩。 - 請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩、および薬学上許容されるキャリア、アジュバントまたはビヒクルを含む、組成物。
- 請求項1〜5のいずれか1項に記載の化合物またはその薬学上許容される塩を含む、治療を必要とする対象において癌を治療するための医薬であって、癌が膵癌または滑膜肉腫である、医薬。
- 化合物またはその薬学上許容される塩が、請求項2に記載の化合物またはその塩である、請求項7に記載の医薬。
- 化合物またはその薬学上許容される塩が、請求項3に記載の化合物またはその塩である、請求項7に記載の医薬。
- 癌が膵癌である、請求項7に記載の医薬。
- 癌が滑膜肉腫である、請求項7に記載の医薬。
- 請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩および更なる治療薬を含む、治療を必要とする対象において膵癌または滑膜肉腫を治療するための医薬であって、請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩が、患者に更なる治療薬と順次または同時投与される、医薬。
- 更なる治療薬が、アルキル化剤、アントラサイクリン、代謝拮抗剤、架橋剤、DNA複製阻害剤、挿入剤、微小管破壊剤、PARP阻害剤、放射線類似作用剤、放射線増感剤、鎖分断剤またはトポイソメラーゼII阻害剤より選択される、請求項12に記載の医薬。
- 更なる治療薬が、アミノグルテチミド、アムサクリン、アナストロゾール、アスパラギナーゼ、バラセルチブ、bcg、ビカルタミド、ブレオマイシン、ブセレリン、ブスルファン、カンプトテシン、カペシタビン、カルボプラチン、カルムスチン、クロラムブシル、クロロキン、シスプラチン、クラドリビン、クロドロネート、コルヒチン、シクロホスファミド、シプロテロン、シタラビン、ダカルバジン、ダクチノマイシン、ダウノルビシン、デメトキシビリジン、ジクロロアセタート、ジエンエストロール、ジエチルスチルベストロール、ドセタキセル、ドキソルビシン、エピルビシン、エストラジオール、エストラムスチン、エトポシド、エベロリムス、エキセメスタン、フィルグラスチム、フルダラビン、フルドロコルチゾン、フルオロウラシル、フルオキシメステロン、フルタミド、ゲムシタビン、ゲニステイン、ゴセレリン、ヒドロキシウレア、イダルビシン、イフォスファミド、イマチニブ、インターフェロン、イリノテカン、イロノテカン、レトロゾール、ロイコボリン、ロイプロリド、レバミソール、ロムスチン、ロニダミン、メクロレタミン、メドロキシプロゲステロン、メゲストロール、メルファラン、メルカプトプリン、メスナ、メトホルミン、メトトレキセート、マイトマイシン、ミトタン、ミトキサントロン、ニルタミド、ノコダゾール、オラパリブ、オクトレオチド、オキサリプラチン、パクリタキセル、パミドロネート、ペントスタチン、ペリホシン、プリカマイシン、ポルフィマー、プロカルバジン、ラルチトレキセド、リツキシマブ、ソラフェニブ、ストレプトゾシン、スニチニブ、スラミン、タモキシフェン、テモゾロミド、テムシロリムス、テニポシド、テストステロン、チオグアニン、チオテパ、二塩化チタノセン、トポテカン、トラスツズマブ、トレチノイン、ビンブラスチン、ビンクリスチン、ビンデシンおよびビノレルビンより選択される、請求項12または13に記載の医薬。
- 請求項1に記載の化合物またはその塩の合成方法であって、構造
式中、nは1〜5の整数であり、R2はHまたはメチルである、方法。 - n=1であり、R2がHである、請求項15に記載の方法。
- n=5であり、R2がHである、請求項15に記載の方法。
- 構造式SW V-49:
で示される化合物またはその薬学上許容される塩。 - 請求項18に記載の化合物またはその薬学上許容される塩および1以上の薬学上許容される賦形剤、アジュバントまたはビヒクルを含む、医薬組成物。
- 請求項18に記載の化合物またはその薬学上許容される塩を含む、治療を必要とする患者において癌を治療するための医薬であって、癌が膵癌または滑膜肉腫である、医薬。
- 癌が膵癌である、請求項20に記載の医薬。
- 癌が滑膜肉腫である、請求項20に記載の医薬。
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