二炭酸酸とヘテロサイクリック塩基の複合体における固体酸塩相互作用:結晶学,水素結合分析,および15N NMRスペクトロスコピー

Z Jane Li¹, Yuriy Abramov, Jon Bordner

¹Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA. jane.li@pfizer.com

Journal of the American Chemical Society

|June 22, 2006

まとめ

固体酸塩複合体の形成は,がん薬候補の溶解性と生物利用性を著しく高めます. これらの複合体は,異なる陽子伝送行動とユニークな構造特性を表しています.

科学分野:

製薬化学製薬化学について
マテリアルサイエンス材料科学
化学結晶学化学結晶学とは

背景:

癌の治療薬である可能性のある化合物1は,その弱い基本的な性質のため,水溶性の低下を示し,医薬品開発を妨げています.
薬剤候補の溶解性と生物利用性を改善するための戦略の開発は,効果的な治療の提供に不可欠です.

研究の目的:

化合物1の固体酸塩複合体の形成と特徴を二カルボキシル酸で調べる.
これらの複合物の物理化学的特性,特に溶解性および生物利用性に対する影響を評価する.
これらの複合体内の陽子伝送と水素結合の構造的基礎を解明する.

主な方法:

3つの二カルボキシル酸塩複合体の合成と特徴付け:セスキスキュシネート (2),ディマロネート (3),ディマレート (4).
構造分析にはX線結晶学と15N固体核磁共振 (NMR) 光譜を用いた.
自由塩基と比較して,溶解性および生物利用性を含む物理化学的性質の評価.

主要な成果:

固体酸塩複合体は,化合物1の自由塩基と比較して,溶解性と生物利用性が著しく改善されたことを実証しました.
構造分析により,異なる陽子伝送行動が明らかになった:複合体2は中性であり,3は混合イオン/ズウィテリオンであり,4はデルタpKaと相関するイオン塩であり,複合体2は中性であった.
最大限の水素結合相互作用により,複合体内の拡張された3次元ネットワークが形成され,化合物1の機能群と柔軟なバックボーンによりユニークなパッケージングアレンジメントが形成されました.

結論:

固体酸塩複合化は,稀溶性ヘテロサイクリック塩基の医薬品活性を高めるための効果的な戦略です.
この研究は,有機複合体における水素結合と陽子の移転を理解する上で,X線結晶学と15N固体NMRの互補的な役割を強調しています.
この発見は,薬物開発のためのヘテロサイクリック塩基-炭酸酸複合体の構造-特性関係に関する貴重な洞察を提供します.

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