4-(3-(piperazin-1-carbonyl)benzyl)-2H-phthalazin-1-one | 763111-46-2

• 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-(3-(piperazin-1-carbonyl)benzyl)-2H-phthalazin-1-one
• 英文别名: 4-(3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one；4-[[3-(piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one；4-[3-(piperazine-1-carbonyl)benzyl]-2H-phthalazin-1-one
• CAS: 763111-46-2
• 化学式: C₂₀H₂₀N₄O₂
• 分子量: 348.404
• InChiKey: DDQGJTMUAYKRHB-UHFFFAOYSA-N

物化性质

• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  73.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(3-(piperazin-1-carbonyl)benzyl)-2H-phthalazin-1-one 在 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 6.0h， 生成 2-(4-methylpiperazin-1-yl)ethyl 4-(3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbodithioate
  参考文献：
  名称：

  PARP-1抑制剂和PARP-1/HDAC-1抑制剂二氮杂萘酮衍生物的设计、合成及其抗肿瘤活性

  摘要：

  近年来，聚ADP核糖聚合酶1（PARP-1）和组蛋白脱乙酰酶（HDAC）已成为肿瘤治疗的重要靶点，受到广泛关注。在本研究中，我们设计并合成了两种新型二氮杂萘酮PARP-1抑制剂和双PARP-1/HDAC-1抑制剂，分别命名为“含有二硫代羧酸酯片段”和“含有异羟肟酸片段”，并评估了它们对酶和细胞的抑制活性。在 PARP-1 抑制剂中，大多数化合物对 PARP-1 酶表现出高抑制活性，特别值得注意的是，IC 值为 <0.2 nM。值得注意的是，表现出显着的抗增殖活性，抑制 MDA-MB-436、MDA-MB-231 和 MCF-7 细胞增殖的 IC 值分别达到 0.08、26.39 和 1.01 μM。进一步的研究表明，MDA-MB-231 细胞停滞在 G1 期，并以剂量​​依赖性方式诱导细胞凋亡。在设计的 PARP-1/HDAC-1 双抑制剂中，几种化合物表现出有效的双靶点抑制活性，对 PARP-1

  DOI：

  10.1016/j.bioorg.2024.107556
• 作为产物：
  描述：

  tert-butyl 4-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]piperazine-1-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以92%的产率得到4-(3-(piperazin-1-carbonyl)benzyl)-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

文献信息

• [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。
• 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。
• Nitric Oxide (NO) Releasing Poly ADP-ribose Polymerase 1 (PARP-1) Inhibitors Targeted to Glutathione S-Transferase P1-Overexpressing Cancer Cells
  作者：Anna E. Maciag、Ryan J. Holland、Youseung Kim、Vandana Kumari、Christina E. Luthers、Waheed S. Sehareen、Debanjan Biswas、Nicole L. Morris、Xinhua Ji、Lucy M. Anderson、Joseph E. Saavedra、Larry K. Keefer

  DOI：10.1021/jm401550d

  日期：2014.3.27

  ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of

  我们报告了一氧化氮 (NO) 释放 PARP-1 抑制剂奥拉帕尼衍生物的抗肿瘤作用 ( 1 )。化合物5b通过将3b的羧基与芳基化二氮烯鎓二化哌嗪4的游离氨基偶联来制备。类似物5a具有相同的结构，只是 F 被 H 取代。 化合物13与5b相同，不同的是一个 Me 2N-N(O)=NO- 基团被添加到二硝基苯环的硝基的对位和邻位。产生的前药在谷胱甘肽 S-转移酶 P1 (GSTP1) 加速的反应中被谷胱甘肽激活，GSTP1 是一种在癌症中经常过度表达的酶。这种代谢同时产生 NO 和 PARP-1 抑制剂，消耗还原当量，导致 DNA 损伤，同时抑制 DNA 修复，在13诱导蛋白质交联谷胱甘肽化的情况下。化合物5b和13降低了 A549 人肺腺癌异种移植物的生长速率，没有全身毒性的证据。
• PHTHALAZINONE DERIVATIVES
  申请人：Martin Niall Morrison Barr

  公开号：US20080200469A1

  公开（公告）日：2008-08-21

  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.

  化合物的分子式为(I)：其中A和B共同表示一个可选取取代的融合芳香环；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从以下组中选择：H，可选取代的C1-20烷基，C5-20芳基，C3-20杂环基，酰胺，硫酰胺，酯，酰基和磺酰基；RY从H，羟基，氨基中选择；或者RX和RY可以共同形成一个螺环C3-7环烷基或杂环基；RC1和RC2都是氢，或者当X为CRXRY时，RC1，RC2，RX和RY与它们连接的碳原子可以形成一个可选取取代的融合芳香环；R1从H和卤素中选择。
• Phthalazinone Derivatives
  申请人：Martin Niall Morrison Barr

  公开号：US20120010204A1

  公开（公告）日：2012-01-12

  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在一起表示一个可选择取代的融合芳香环；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从以下组中选择：H，可选择取代的C1-20烷基，C5-20芳基，C3-20杂环基，酰胺，硫酰胺，酯，酰基和磺酰基；RY从H，羟基，氨基中选择；或者RX和RY可以一起形成一个螺环C3-7环烷基或杂环基；RC1和RC2都是氢，或者当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择取代的融合芳香环；R1从H和卤素中选择。