isopropyl (S)-2-amino-6-diazo-5-oxohexanoate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: isopropyl (S)-2-amino-6-diazo-5-oxohexanoate
• 英文别名: isopropyl 2-amino-6-diazo-5-oxohexanoate；isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoate；propan-2-yl (2S)-2-amino-6-diazo-5-oxohexanoate
• 化学式: C₉H₁₅N₃O₃
• 分子量: 213.236
• InChiKey: KEYYOCJSFDOEMI-QMMMGPOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  15
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  isopropyl (S)-2-amino-6-diazo-5-oxohexanoate 以 氘代氯仿 为溶剂， 以45%的产率得到isopropyl 5-(diazomethyl)-3,4-dihydro-2H-pyrrole-2-carboxylate
  参考文献：
  名称：

  Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma

  摘要：

  The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DONs therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DONs amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.

  DOI：

  10.1021/acs.jmedchem.6b01069
• 作为产物：
  描述：

  5-氧代-L-脯氨酸异丙酯 在 正丁基锂 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 25.75h， 生成 isopropyl (S)-2-amino-6-diazo-5-oxohexanoate
  参考文献：
  名称：

  [EN] METHOD OF PREPARING A DON PRODRUG FROM L-PYROGLUTAMIC ACID
  [FR] PROCÉDÉ DE PRÉPARATION D'UN PROMÉDICAMENT DE DON À PARTIR D'ACIDE L-PYROGLUTAMIQUE

  摘要：

  本公开提供了一种制备化合物I的方法，其中R1为C1-C4烷基；R2为C1-C4烷基；R3从C1-C6烷基、(芳基)烷基和(杂环芳基)烷基组成的群体中选择，在>95%的化学纯度和>95%的对映体过量下。

  公开号：

  WO2020167829A1

文献信息

• [EN] NOVEL GLUTAMINE ANTAGONISTS AND USES THEREOF<br/>[FR] NOUVEAUX ANTAGONISTES DE LA GLUTAMINE ET LEURS UTILISATIONS
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2019071110A1

  公开（公告）日：2019-04-11

  Glutamine antagonists and their use for treating oncological, immunological, and neurological diseases are disclosed. Also disclosed are methods for treating an oncological, immunological, infectious or neurological disease or disorder, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof. Also disclosed are methods of enhancing the effects of an immune checkpoint inhibitor, enabling a subject to respond to an immune checkpoint inhibitor, or enabling the toxicity or the dose or number of treatments with an immune checkpoint inhibitor to be reduced, comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof, and an immune checkpoint inhibitor. Also disclosed are methods for treating an oncological, immunological, infectious or neurological disease or disorder that is refractory to checkpoint inhibitor therapy, the method comprising administering to a subject in need thereof, and having the refractory disease or disorder, a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof.

  谷氨酰胺拮抗剂及其用于治疗肿瘤、免疫和神经系统疾病的方法已被披露。还披露了治疗肿瘤、免疫、传染性或神经系统疾病或紊乱的方法，该方法包括向需要治疗的受试者施用本公开的谷氨酰胺拮抗剂或其药物组成的治疗有效量。还披露了增强免疫检查点抑制剂效果的方法，使受试者对免疫检查点抑制剂产生反应，或减少免疫检查点抑制剂的毒性或剂量或治疗次数的方法，包括向需要治疗的受试者施用本公开的谷氨酰胺拮抗剂或其药物组成的治疗有效量，以及免疫检查点抑制剂。还披露了治疗对检查点抑制剂疗法无效的肿瘤、免疫、传染性或神经系统疾病或紊乱的方法，该方法包括向需要治疗的受试者施用本公开的谷氨酰胺拮抗剂或其药物组成的治疗有效量。
• NQO1激活型6-重氮基-5-氧代-L-正亮氨酸前药及其制备方法和应用
  申请人：中国药科大学

  公开号：CN113461563B

  公开（公告）日：2022-05-10

  本发明公开了一种NQO1激活型6‑重氮基‑5‑氧代‑L‑正亮氨酸前药及其制备方法和应用。由于多数肿瘤细胞中均高表达NQO1，引入NQO1激活的醌酸基团可以实现对肿瘤靶向作用，能够在肿瘤细胞中高效、快速释放DON前药，达到抑制肿瘤增殖的目的。该前药对NQO1显示出高度的亲和性，可以在NQO1高度表达的肿瘤细胞中快速、高效的定向释放出谷氨酰胺代谢拮抗剂DON，进而降低该药物的毒副作用并提高对肿瘤治疗的靶向效率，为抗肿瘤药物的开发提供了新思路。
• [EN] METHOD OF PREPARING A DON PRODRUG FROM L-PYROGLUTAMIC ACID<br/>[FR] PROCÉDÉ DE PRÉPARATION D'UN PROMÉDICAMENT DE DON À PARTIR D'ACIDE L-PYROGLUTAMIQUE
  申请人：DRACEN PHARMACEUTICALS INC

  公开号：WO2020167829A1

  公开（公告）日：2020-08-20

  The present disclosure provides a method of preparing a compound of Formula I, wherein R1 is C1-C4 alkyl; R2 is C1-C4 alkyl; and R3 is selected from the group consisting of C1-C6 alkyl, (aryl)alkyl, and (heteroaryl)alkyl in >95% chemical purity and >95% enantiomeric excess.

  本公开提供了一种制备化合物I的方法，其中R1为C1-C4烷基；R2为C1-C4烷基；R3从C1-C6烷基、(芳基)烷基和(杂环芳基)烷基组成的群体中选择，在>95%的化学纯度和>95%的对映体过量下。
• [EN] NOVEL GLUTAMINE ANALOGS<br/>[FR] NOUVEAUX ANALOGUES DE LA GLUTAMINE
  申请人：JACOBIO PHARMACEUTICALS CO LTD

  公开号：WO2022022612A1

  公开（公告）日：2022-02-03

  The invention relates to novel glutamine analogs shown as the formula I, a composition containing the glutamine analogs and the use thereof.

  本发明涉及一种新型谷氨酰胺类似物，其表示为公式I，以及含有谷氨酰胺类似物的组合物和其用途。
• [EN] PRODRUGS OF 6-DIAZO-5-OXO-L-NORLEUCINE<br/>[FR] PROMÉDICAMENTS DE 6-DIAZO-5-OXO-L-NORLEUCINE
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2022232565A1

  公开（公告）日：2022-11-03

  The present disclosure provides prodrugs of 6-diazo-5-oxo-L-norleucine (DON) for use in treating or preventing a disease, disorder, or condition in which the inhibition of glutamineutilizing enzymes provides a benefit.

  本公开提供了6-重氮-5-氧代-L-异亮氨酸（DON）的前药，用于治疗或预防抑制谷氨酰胺利用酶有益的疾病、紊乱或状况。