4-[[4-fluoro-3-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone | 763111-49-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-[[4-fluoro-3-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone
• 英文别名: 4-[3-([1,4]diazepane-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one；4-[3-(1,4-diazepan-1-ylcarbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one；4-[[3-(1,4-diazepane-1-carbonyl)-4-fluorophenyl]methyl]-2H-phthalazin-1-one
• CAS: 763111-49-5
• 化学式: C₂₁H₂₁FN₄O₂
• 分子量: 380.422
• InChiKey: HGEPGGJUGUMFHT-UHFFFAOYSA-N

物化性质

• 熔点：
  >150°C (dec.)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  73.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[[4-fluoro-3-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone 、 4-吗啉碳酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 4-[[4-fluoro-3-[4-(morpholine-4-carbonyl)-1,4-diazepane-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
  参考文献：
  名称：

  4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1

  摘要：

  Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.

  DOI：

  10.1021/jm8001263
• 作为产物：
  描述：

  1,4-二氮杂环庚烷-1-甲酸叔丁酯 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基乙酰胺 为溶剂， 生成 4-[[4-fluoro-3-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone
  参考文献：
  名称：

  Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase

  摘要：

  We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.10.081

文献信息

• Small Molecule Microarray Based Discovery of PARP14 Inhibitors
  作者：Bo Peng、Ann-Gerd Thorsell、Tobias Karlberg、Herwig Schüler、Shao Q. Yao

  DOI：10.1002/anie.201609655

  日期：2017.1.2

  cellular processes. Most small‐molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray‐based strategy for high‐throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the

  聚（ADP-核糖）聚合酶（PARP）是多种细胞过程中的关键酶。迄今为止，大多数开发的小分子PARP抑制剂都针对PARP1，并且选择性较差。PARP14最近已成为潜在的治疗靶标，但其抑制剂的开发却落后了。本文中，我们描述了一种基于小分子微阵列的高通量合成策略，筛选了> 1000种潜在的PARPs双齿抑制剂，并成功发现了一种有效的PARP14抑制剂H10，其选择性是PARP1的> 20倍。PARP14 / H10复合物的共结晶指示为H10结合烟酰胺和腺嘌呤亚位点。进一步的结构-活性关系研究确定了腺嘌呤亚位点的重要结合元素。在肿瘤细胞中，H10能够化学敲低内源性PARP14活性。
• [EN] PHTHALAZINONE DERIVATIVES<br/>[FR] DERIVES DE PHTALAZINONE
  申请人：KUDOS PHARM LTD

  公开号：WO2004080976A1

  公开（公告）日：2004-09-23

  Compounds of the formula (I): wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NRX or CRXRY; if X NRX then n is 1 or 2 and if X = CRXRY then n is 1; RX is selected from the group consisting of H, optionally substituted C1-20 alkyl, C5-20 aryl, C3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; RY is selected from H, hydroxy, amino; or RX and RY may together form a spiro-C3-7 cycloalkyl or heterocyclyl group; RC1 and RC2 are both hydrogen, or when X is CRX RY, RC1, RC2, RX and RY, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R1 is selected from H and halo.

  式（I）化合物：其中A和B一起代表一个可选取代的融合芳香环；X可以是NRX或CRXRY；如果X是NRX，则n为1或2，如果X = CRXRY，则n为1；RX从H，可选取代的C1-20烷基，C5-20芳基，C3-20杂环烷基，酰胺，硫酰胺，酯，酰基和磺酰基组中选择；RY从H，羟基，氨基中选择；或RX和RY可以一起形成螺环C3-7环烷基或杂环烷基；RC1和RC2都是氢，或当X是CRXRY时，RC1，RC2，RX和RY，与它们连接的碳原子一起，可以形成一个可选取代的融合芳香环；R1从H和卤素中选择。
• [EN] HETEROCYCLIC DERIVATES,PREPARATION PROCESSES AND MEDICAL USES THEREOF<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES, LEURS PROCÉDÉS DE PRÉPARATION ET LEURS UTILISATIONS MÉDICALES
  申请人：SHANGHAI DE NOVO PHARMATECH CO LTD

  公开号：WO2012071684A1

  公开（公告）日：2012-06-07

  Disclosed are heterocyclic derivatives, methods for making them, compositions containing the same and uses thereof. Particularly, their pharmaceutical use as inhibitors of PARP is disclosed.

  揭示了杂环衍生物，制备它们的方法，含有它们的组合物以及它们的用途。特别地，揭示了它们作为PARP抑制剂的药用。
• HETEROCYCLIC DERIVATES, PREPARATION PROCESSES AND MEDICAL USES THEREOF
  申请人：Gao Daxin

  公开号：US20130224107A1

  公开（公告）日：2013-08-29

  Disclosed are heterocyclic derivatives, methods for making them, compositions containing the same and uses thereof. Particularly, their pharmaceutical use as inhibitors of PARP is disclosed.

  揭示了杂环衍生物，制备方法，含有它们的组合物以及它们的用途。特别地，揭示了它们作为PARP抑制剂的药用。
• Phthalazinone derivatives
  申请人：Martin Barr Niall Morrison

  公开号：US20050059663A1

  公开（公告）日：2005-03-17

  Compounds of the formula (I): wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NR X or CR X R Y ; if X═NR X then n is 1 or 2 and if X═CR X R Y then n is 1; R X is selected from the group consisting of H, optionally substituted C 1-20 alkyl, C 5-20 aryl, C 3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; R Y is selected from H, hydroxy, amino; or R X and R Y may together form a spiro-C 3-7 cycloalkyl or heterocyclyl group; R C1 and R C2 are both hydrogen, or when X is CR X R Y , R C1 , R C2 , R X and R Y , together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R 1 is selected from H and halo.

  式(I)的化合物：其中A和B共同表示可选择地取代的、融合的芳香环；X可以是NRX或CRXRY；如果X═NRX，则n为1或2，如果X═CRXRY，则n为1；RX选自H、可选择取代的C1-20烷基、C5-20芳基、C3-20杂环烷基、酰胺、硫酰胺、酯、酰基和磺酰基基团；RY选自H、羟基、氨基；或者RX和RY可以共同形成螺环C3-7环烷基或杂环烷基；RC1和RC2均为氢，或当X为CRXRY时，RC1、RC2、RX和RY，连同它们连接的碳原子，可以形成可选择地取代的融合的芳香环；R1选自H和卤素。