3-(4-aza-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine | 31804-66-7

• 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: 3-(4-aza-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
• 英文别名: 6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione；6-(2,6-dioxopiperidin-3-yl)pyrrolo[3,4-b]pyridine-5,7(6H)-dione；6-(2,6-dioxo-piperidin-3-yl)-pyrrolo[3,4-b]pyridine-5,7-dione；2-(2,6-dioxo-3-piperidinyl)-4-azaisoindoline-1,3-dione；6-(2,6-Dioxopiperidin-3-yl)pyrrolo[3,4-b]pyridine-5,7-dione
• CAS: 31804-66-7
• 化学式: C₁₂H₉N₃O₄
• 分子量: 259.221
• InChiKey: QQNDEDWAPQTWHF-UHFFFAOYSA-N

物化性质

• 沸点：
  545.7±40.0 °C(Predicted)
• 密度：
  1.571±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  96.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(4-aza-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine 在 溶剂黄146 、 锌 作用下， 反应 0.17h， 以95%的产率得到3-(7-Hydroxy-5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-piperidine-2,6-dione
  参考文献：
  名称：

  Efficient Synthesis of Aryl Hydroxylactams by Reducing Imides With Activated Zinc Dust

  摘要：

  DOI：

  10.1080/00397910500383485
• 作为产物：
  描述：

  (S)-5-氨基-2-(Boc-氨基)-5-酮基戊酸 在 4-二甲氨基吡啶 、 2,2,2-三氟乙醇 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 生成 3-(4-aza-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine
  参考文献：
  名称：

  免疫调节药物类似物的有效合成使得结构-降解关系的探索成为可能。

  摘要：

  免疫调节药物 (IMiD) 沙利度胺、泊马度胺和来那度胺已被批准用于治疗多发性骨髓瘤多年。最近，它们作为 E3 连接酶招募元件用于小分子诱导的蛋白质降解，引起了人们对 IMiD 合成和功能化的兴趣重新兴起。传统的 IMiD 合成遵循具有多个纯化步骤的逐步路线。在此，我们描述了一种无需纯化的新型一锅合成法，可快速获得多种 IMiD 类似物。 IMiD 靶蛋白 cereblon (CRBN) 的结合研究揭示了狭窄的结构活性关系，仅少数化合物在泊马度胺和来那度胺范围内显示出亚微摩尔结合亲和力。然而，可以鉴定两种 IMiD 类似物的抗增殖活性以及 Aiolos 降解作用。这项研究为了解此类分子的结构-降解关系提供了有用的见解，并为 IMiD 合成提供了一种快速而可靠的方法。

  DOI：

  10.1002/cmdc.201800271

文献信息

• TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas, Inc.

  公开号：US20180125821A1

  公开（公告）日：2018-05-10

  The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为tau蛋白的调节剂具有实用性。具体而言，本公开涉及含有一端结合到E3泛素连接酶的VHL或cereblon配体，另一端结合到tau蛋白的双功能化合物，使得tau蛋白与泛素连接酶靠近，以实现tau蛋白的降解（和抑制）。本公开展示了与tau蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由tau蛋白聚集或积累导致的疾病或紊乱。
• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20190151295A1

  公开（公告）日：2019-05-23

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为白细胞介素-1受体相关激酶4（IRAK-4；目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合E3泛素连接酶的Von Hppel-Lindau、cereblon配体的双功能化合物，另一端结合目标蛋白的部分，使得目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。
• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR
  申请人：Arvinas, Inc.

  公开号：US20180099940A1

  公开（公告）日：2018-04-12

  The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

  本公开涉及双功能化合物，其用于降解和（抑制）雄激素受体。具体而言，本公开涉及包含一端结合到E3泛素连接酶的谷氨酰腺苷环配体，另一端结合到雄激素受体的部分的化合物，使得雄激素受体与泛素连接酶靠近，以实现雄激素受体的降解（和抑制）。本公开展示了与根据本公开涉及的化合物相关的广泛的药理活性范围，与雄激素受体的降解/抑制一致。
• TETRAHYDRONAPHTHALENE AND TETRAHYDROISOQUINOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
  申请人：Arvinas, Inc.

  公开号：US20180155322A1

  公开（公告）日：2018-06-07

  The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end at least one of a Von Hippel-Lindau ligand, a cereblon ligand, Inhibitors of Apoptosis Proteins ligand, mouse double-minute homolog 2 ligand, or a combination thereof, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，这些化合物可用作雌激素受体（目标蛋白）的调节剂。特别是，本公开涉及包含在一段至少有一种Von Hippel-Lindau配体、一种cereblon配体、凋亡抑制蛋白配体、小鼠双分钟同源2配体或其组合的双功能化合物，这些配体与相应的E3泛素连接酶结合，在另一端有一个与目标蛋白结合的部分，使得目标蛋白被置于泛素连接酶附近，以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白降解/抑制相关的广泛药理活性。可以通过本公开的化合物和组合物治疗或预防由目标蛋白聚集或积累引起的疾病或障碍。
• Design, synthesis and biological assessment of novel N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6-dioxopiperidines for TNF-α inhibitory activity
  作者：Weiming Luo、Qian-sheng Yu、Isidro Salcedo、Harold W. Holloway、Debomoy K. Lahiri、Arnold Brossi、David Tweedie、Nigel H. Greig

  DOI：10.1016/j.bmc.2011.05.029

  日期：2011.7

  Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11–14 and 3-substituted 2,6-dioxopiperidines 16and 18were synthesized as tumor necrosis factor-α (TNF-α) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination

  八种新型 2-(2,6-二氧代哌啶-3-基)邻苯二甲酰亚胺 EM-12 二硫代氨基甲酸酯9和10，N-取代的 3-(邻苯二甲酰亚胺-2-基)-2,6-二氧代哌啶11 – 14和 3-取代 2合成了,6-二氧哌啶16和18作为肿瘤坏死因子-α (TNF-α) 合成抑制剂。合成涉及利用一种新颖的缩合方法，即涉及加成、亚胺重排和消除的一锅反应，以生成创建化合物9 – 14所需的邻苯二甲酰亚胺环。此后，利用培养的 RAW 264.7 细胞，定量评估了药物在脂多糖 (LPS) 攻击的小鼠巨噬细胞样细胞筛选中抑制 TNF-α 合成的能力。化合物9、14和16表现出有效的TNF-α降低活性，在30μM时使TNF-α降低高达48%，而化合物12、17和18则表现出中等的TNF-α抑制作用。事实证明，这些类似物的 TNF-α 降低特性比来那度胺 (revlimid) ( 3 ) 和沙利度胺 (thalidomide)