JP7449913B2 - オキサチアジン様化合物を作製する方法 - Google Patents
オキサチアジン様化合物を作製する方法 Download PDFInfo
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- JP7449913B2 JP7449913B2 JP2021184435A JP2021184435A JP7449913B2 JP 7449913 B2 JP7449913 B2 JP 7449913B2 JP 2021184435 A JP2021184435 A JP 2021184435A JP 2021184435 A JP2021184435 A JP 2021184435A JP 7449913 B2 JP7449913 B2 JP 7449913B2
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- taurolidine
- compounds
- tumor
- taurultam
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- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
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Description
1.タウロリジンの腫瘍細胞に対する主な損傷は、蛍光定量的に測定される、活性酸素種(ROS)の増加である。
2.最初の工程としてのタウロリジンによる酸化ストレスの誘導は、グルタチオン又はN-アセチルシステイン等の還元剤の添加によってタウロリジンの抗腫瘍作用を妨げることができるという知見により支持される。
3.高いROSによって腫瘍細胞のミトコンドリアにもたらされた傷害は、それらの膜電位の喪失及びアポトーシス誘導因子(AIF)の放出を結果として生じる。
4.AIFは核に移動させられ、アポトーシス促進性遺伝子の発現を開始し、アポトーシスの目印として原形質膜の泡状突起(blebbing)を生じ、染色質凝縮及びDNA切断を生じる。
5.正常細胞とは対照的に、腫瘍細胞は酸化ストレスに非常に敏感である。これは、正常細胞を傷つけない、広範囲の腫瘍細胞に対するタウロリジンの作用を説明する。
イセチオン酸、
特に硫酸カルビル(Carbylsulfat)、タウリン、タウリンアミド、
システイン、イセチオン酸
I.
a.硫酸カルビルを介したイセチオン酸
システイン、タウリンを介した生合成
重亜硫酸塩を用いたエチレンオキシド
a.
a)スルファミン酸
I.出発物質2250/2255
a.
I.2244の合成
収量:1.25g、結晶化した2244により接種した(innoculated)。
融点:42℃~44℃
IR:2244に対応し、99.3%純粋。
IRは物質2244に相当する。
酢酸エチルから再結晶化した。
0.7gを得た(24%)。
融点:44℃~45℃
IRは参照物質に相当する。
収量:110mg
融点:114℃~116℃。
IRは、副生成物として99%の安息香酸を示した。
重量:110mg。油は油で汚染され、2244(イセチオン酸アミド)に対するIRピークは不明瞭であった。
110mgを酢酸エステルから再結晶化した。
収量:65mg、融点:43℃~45℃
IRは52%の2244に相当した。
収量:0.5mg
融点:114℃~116℃
IRは、対照物質としての82%の安息香酸副生成物を示した。加水分解は完了していない。
重量:0.8g。油は油で汚染され、2244(イセチオン酸アミド)に対するIRピークは不明瞭であった。
0.8gを酢酸エステルから再結晶化した。
収量:160mg、融点:43℃~45℃
IRは26%の2244に相当した。
IR:酸素中、図7に示されるように次の波数、655.82cm-1、729.12cm-1、844.85cm-1、898.86cm-1、947.08cm-1、1003.02cm-1、1060.88cm-1、1134.18cm-1、1236.41cm-1、1288.49cm-1、1317.43cm-1、1408.08cm-1、1572.04cm-1、3105.5cm-1、3209.66cm-1、3313.82cm-1、及び3427.62cm-1にピークを有する。
12.3gを高真空下で蒸留した。
外部温度 内部温度 真空
190℃~210℃ 183℃~186℃ 0.1mm
重量:室温で固体であった9.3gの油。融点:43℃~45℃。
分析のため、0.2gの酢酸エステルを2回添加して結晶化させた。融点 43℃~44℃。
融点:42℃~44℃
IR:99.3%の2244に相当する。
重量:0.74g、融点:225℃~227℃
IR:2245は出発原料に相当する。
重量:0.38gの不純な材料を酢酸エチルで抽出した。該溶液を濃縮した。
収量:70mg、融点:95℃~98℃
IRは98%の2250に相当した。
IR:ビニルスルホンアミドと2250との混合物
2グラムを昇華させ、僅かな結晶を得た。
半固体物質の昇華:IR:98%の2250に対応する。
収量:6.3gの透明で薄い油。
IR:96%のCH2=CH-SO2-NH2(ビニルスルホンアミド)に対応する。
出発物質:
保護基:塩化ベンジル
83.9gのビニルスルホン酸ナトリウムを400mlのベンジルアルコールの溶液に添加し、0.5gのナトリウム(触媒量)を添加した。該混合物を撹拌しながら150℃まで温め、大半のビニルスルホン酸ナトリウムが溶液に溶解した。3時間後、上記混合物を一晩冷却し、厚い固体(thick solid)が結晶化した。この固体を真空濾過した後、エチルアルコール中に懸濁し、真空濾過して乾燥させた。
収量:94.0g、IR:所望の化合物(61.2%純粋)に相当する。
収量:3.1gの黒っぽい油
融点:75℃~76℃
分子式:C9H13NO3S
MW:215.2
算出値:C=50.23%、H=6.09%、N=6.51%、S=14.86%
実測値:C=50.14%、H=6.15%、N=6.35%、S=14.79%
収量:1.1gの油。
収量:1.7gの油。
CH2Cl2を添加し、撹拌して放置し、結晶化させ、真空下で吸引により分離した。
重量:0.6g、融点約40℃。
分析:
酢酸エチルから0.2gを2回再結晶化した。
融点:43℃~44℃
分子式:C2H7NO3S
MW:125
算出値:C=19.22%、H=5.65%、N=11.21%、S=25.65%
実測値:C=19.20%、H=5.67%、N=11.07%、S=25.73%
19.9グラムの1906を100mlのクロロホルムに溶解し、23グラムの純粋なベンジルアミン及び200mlの純粋なクロロホルムの溶液に添加した。直ちに、ベンジルアミン塩酸塩が沈殿し、反応混合物は温かくなった。その後、該混合物を還流し、塩酸塩化合物を吸引によって分離して、透明なCHCl3母液を乾燥のため真空に置いた。
収量:9.2g、融点:50℃~53℃
IR:前駆物質に類似するOHバンドが存在する。
化合物2250の抗腫瘍活性
緒言
タウロリジンが強力な抗腫瘍剤であるという認識に基づき、Geistlich Pharmaにより類縁体2250が合成された。
化学物質:化合物2250及びタウロリジン2%溶液は、本発明の譲受人であるウォルフーゼンのGeistlich Pharma AGにより提供された。
陽性対照:ヒト膠芽腫細胞(LN-229)を24時間に亘ってタウロリジンと共にインキュベートした後、濃度依存性細胞毒性をEC50=45μg/mlと決定し(表1、図1)、この値は、この細胞株を用いて得られた先の結果に対応する(Rodack et al. 2005)。
化合物2250は、タウロリジン型の新規な抗腫瘍剤の探索において新たな道筋を提示する。生物学的には、該化合物はタウロリジンと同じくらい強力である。化学的には、該化合物は、タウロリジンとは著しく異なる特徴を示す。エーテル-酸素によってNH基を置換することにより、タウロリジンの二環構造が回避される。化合物2250は単環構造であり、タウルルタムの近縁の構造類縁体である。
化合物2250は、ヒト膠芽腫細胞(細胞株LN-229)で決定されるように、in vitroにおいて強力な抗腫瘍活性を示す。その薬効(EC50=45μg/ml)は、同じ細胞株で試験したタウロリジン(EC50=50μg/ml)に匹敵する。
新たな化合物2250(テトラヒドロ1,4,5-オキサチアジン-4-ジオキシド)を試験すると、スタフィロコッカス・アウレウス(Staphylococcus aureus)及びエシェリキア・コリ(Escherichia coli)に対する非常に高レベルの抗菌活性を有することがわかった。スタフィロコッカス・アウレウスに対する抗菌活性は、タウルルタムより約2倍高かった。
パンチプレート試験において化合物2250を試験したところ、MRSA株188、189、193、194、及び195に対して非常に活性であることがわかった。
本明細書において化合物2250、2255、2245、A1、A3、B1、B2、又はB3と識別される各化合物を本明細書で同定された癌の癌細胞株に対して試験したところ、かかる細胞株に対して活性であることがわかる。
本明細書において化合物2250、2255、2245、A1、A3、B1、B2、又はB3と識別される各化合物を、本明細書で同定された癌を有する患者に投与すると、かかる癌の治療に有効であり、患者における使用に安全であることがわかる。これらの化合物の各々をビタミンD3、その誘導体、代謝産物、又は類縁体と共に投与すると、その組み合わせが該化合物の抗腫瘍効果を増すことがわかる。
ヒト新鮮血中での化合物2250の半減期を、GC、PYE Unicam Series 204 FIDにより37℃にてin vitroで測定した。
ベースライン値:49.0ppm
1時間後:50.6ppm
2時間後:47.6ppm
20時間後:38.6ppm~39.0ppm
新たに診断された患者(54±10歳の中年)に由来するWHO悪性度IVの高悪性度の神経膠腫の組織試料を機械的に細かく刻み、酵素により消化し、解離した細胞を濾過した。単離した腫瘍細胞をバルク細胞(bulk cells)として培養した。ニューロスフェア条件下(neurobasal培地を使用する)でニューロスフェアの形成によって、ネズミのSMA560神経膠腫細胞株又は新たに単離したヒト膠芽腫細胞から癌幹細胞(CSC)を単離した。
バルク神経膠腫細胞を培養し、以前に記載されるように(Rodak et al., J. Neurosurg. 102, 1055-1068, 2005)24時間又は48時間に亘ってタウロリジン又はタウルルタムと共にインキュベートした。CSCを7日間培養した後、タウロリジン、タウルルタム、又はテモゾラミドに24時間曝露した。残った接着性細胞の数を染色し(クリスタルバイオレット又はアラマーブルー)、吸光度測定(540nm)によって定量した。未処理の対照培養物において生存する細胞の数に対する生存細胞のパーセンテージとして細胞生存を表した。結果を%死滅率、又は細胞毒性の半数効果(half-maximal cytotoxicity)に必要とされる用量であるEC50で与える。
マウスに由来する癌細胞及び癌幹細胞に対するタウロリジン及びタウルルタムの細胞毒性
マウスSMA560神経膠腫細胞株を使用して腫瘍バルク細胞及びCSCを提供した。SMA560バルク細胞と様々な濃度のタウロリジン及びタウルルタム(6.25μg/ml、12.5μg/ml、25μg/ml、50μg/ml、100μg/ml、200μg/ml)とのインキュベーションの後、24時間及び48時間のインキュベーション後に細胞毒性を判定した。タウロリジン及びタウルルタムの両方について、24時間と48時間とのインキュベーション時間の間に薬効の大きな差を伴わず、明らかな用量依存的な細胞毒性が見られた(図3A、図3B)。EC50値は、タウロリジンに対して34.6μg/ml、及びタウルルタムに対して19.3μg/mlであった(図3C)。
CSCを4名の患者から切除された膠芽腫組織から単離した。上記と同じ濃度範囲のタウロリジン及びタウルルタムを適用し、薬物とのインキュベーションの24時間後に細胞毒性を測定した。試験した4つ全ての膠芽腫CSC(GBM3番、4番、5番、及び6番)は、タウロリジン及びタウルルタムに対して同様に感受性であった(図5A、図5B)。タウロリジンの平均EC50値は13±2μg/mlであり、タウルルタムのEC50値は11±1.4μg/mlであった(表2)。これらの実験では、タウロリジン及びタウルルタムの細胞毒性能を、5μM~1000μMの濃度範囲で適用されたテモゾラミド(TIM)のものと比較した(図2C)。TMZの平均EC50値は68.5±26μg/mlであった(表2)。興味深いことに、この濃度は、患者で測定されたTMZのピーク血漿レベル(13.7μg/ml)よりもはるかに高い(Portnow et al., Clin Cancer Res 15, 7092-7098, 2009)。
ネズミの神経膠腫細胞株に由来する癌幹細胞及びヒト癌幹細胞に対し、タウロリジン及びタウルルタムを試験した。タウロリジン及びタウルルタムは、4名の膠芽腫患者から新たに単離されたヒト癌幹細胞(タウロリジンについてEC50=13±2μg/ml、タウルルタムについてEC50=11±1.4μg/ml)に対するのと同じく、ネズミの神経膠腫細胞株に由来する癌幹細胞に対して強力な抗腫瘍活性(タウロリジンについてEC50=12.5μg/ml、タウルルタムについてEC50=10μg/ml)を付与することが分かった。
膵臓幹細胞様多細胞性スフェロイド培養物に対する抗腫瘍効果
多細胞性スフェロイドは、成長を刺激する3次元構造で成長する腫瘍細胞、微小環境条件、及び実際の腫瘍の幹細胞様特性で構成される。多細胞性腫瘍スフェロイド(MCTS)モデルは、単層培養物で見られる多くの欠陥を補うものである。200μm~500μmの大きさのスフェロイドは、腫瘍に類似する形態学的及び機能的な特徴を有しつつ、酸素、栄養素、及び分解産物の化学勾配を発生させる。したがって、MCTSモデルを利用するアッセイは、薬物浸透の評価を可能とし、単層培養物と比較してin vivoでの成功をより予測しやすい。MCTSアッセイは、標準的な単層とin vivoの腫瘍との間の中間の複雑さの腫瘍モデル系である。
悪性膵癌におけるタウロリジン及び化合物2250の抗腫瘍剤としてのin vivo研究
タウロリジン及び化合物2250の効果をヌードマウス(NMRI-Foxn1 nu/nu)で分析した。1×107腫瘍細胞(PancTu-I及びMiaPaca 2)を脇腹に皮下注入した。動物を3つの群、すなわち対照群、タウロリジンによる腹腔内注射治療(TRD)群、及び化合物2250による腹腔内注射治療(NDTRLT)群に無作為化した。
Claims (3)
- 以下の反応工程:
前記反応d)が、化合物2264を濃HClと共に沸騰させ、還流させて反応混合物を形成させることと、前記反応混合物を冷却して前記反応混合物の水相から油相を分離することと、前記水相を濃縮することと、油性残渣を冷却して2244の結晶を形成させることとを更に含む、又は
前記反応d)が、化合物2264を濃HClと共に沸騰させ、還流させて反応混合物を形成させることと、前記反応混合物を冷却して前記反応混合物の水相から油相を分離することと、前記水相を塩化メチレンと共に溶解させることと、前記塩化メチレンを分離することと、前記水相を濃縮することと、冷却して油を形成させることとを更に含む、又は 前記反応d)が、化合物2264を濃HClと共に沸騰させ、還流させて反応混合物を形成させることと、前記反応混合物を冷却することと、ジクロロメタンを添加して水相及び油相を形成させることと、前記水相を蒸発させることと、前記水相から得られた油を2244結晶により接種することと、2244の結晶を得ることとを更に含む、方法。 - 以下の反応工程:
前記反応d)が、化合物2264を濃HClと共に沸騰させ、還流させて反応混合物を形成させることと、前記反応混合物を冷却して前記反応混合物の水相から油相を分離することと、前記水相を濃縮することと、油性残渣を冷却して2244の結晶を形成させることとを更に含む、又は
前記反応d)が、化合物2264を濃HClと共に沸騰させ、還流させて反応混合物を形成させることと、前記反応混合物を冷却して前記反応混合物の水相から油相を分離することと、前記水相を塩化メチレンと共に溶解させることと、前記塩化メチレンを分離することと、前記水相を濃縮することと、冷却して油を形成させることとを更に含む、又は 前記反応d)が、化合物2264を濃HClと共に沸騰させ、還流させて反応混合物を形成させることと、前記反応混合物を冷却することと、ジクロロメタンを添加して水相及び油相を形成させることと、前記水相を蒸発させることと、前記水相から得られた油を2244結晶により接種することと、2244の結晶を得ることとを更に含む、方法。
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