8-chloro-2-ethyl-3-phenethylquinazolin-4(3H)-one | 1450618-78-6

• 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: 8-chloro-2-ethyl-3-phenethylquinazolin-4(3H)-one
• 英文别名: 8-chloro-2-ethyl-3-(2-phenylethyl)quinazolin-4-one
• CAS: 1450618-78-6
• 化学式: C₁₈H₁₇ClN₂O
• 分子量: 312.799
• InChiKey: YJJLFAHVYWIRAC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  32.7
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  8-chloro-2-ethyl-3-phenethylquinazolin-4(3H)-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium hydroxide 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 为溶剂， 反应 31.5h， 生成 4-((2-ethyl-4-oxo-3-phenethyl-3,4-dihydroquinazolin-8-yl)-methyl)-N-hydroxybenzamide
  参考文献：
  名称：

  Quinazolin-4-one Derivatives as Selective Histone Deacetylase-6 Inhibitors for the Treatment of Alzheimer’s Disease

  摘要：

  Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4h, NHis the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of g-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated beta-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydroquinazolin-7-yl)-acrylarnide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50,29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 mu M) or cytochrome P450 activity (IC50 >63 mu M) in vitro, and significantly improves learning-based performances of mice with beta-amyloid-induced hippocampal lesions.

  DOI：

  10.1021/jm400564j
• 作为产物：
  描述：

  2-氨基-3-氯苯甲酸 在 吡啶 、 亚磷酸三苯酯 作用下， 反应 0.42h， 生成 8-chloro-2-ethyl-3-phenethylquinazolin-4(3H)-one
  参考文献：
  名称：

  Quinazolin-4-one Derivatives as Selective Histone Deacetylase-6 Inhibitors for the Treatment of Alzheimer’s Disease

  摘要：

  Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4h, NHis the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of g-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated beta-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydroquinazolin-7-yl)-acrylarnide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50,29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 mu M) or cytochrome P450 activity (IC50 >63 mu M) in vitro, and significantly improves learning-based performances of mice with beta-amyloid-induced hippocampal lesions.

  DOI：

  10.1021/jm400564j

文献信息

• HISTONE DEACETYLASES (HDACS) INHIBITORS
  申请人：ANNJI PHARMACEUTICAL CO., LTD.

  公开号：US20130267542A1

  公开（公告）日：2013-10-10

  Histone deacetylases inhibitors (HDACIs) and compositions comprising the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit are also disclosed.

  揭示了组蛋白去乙酰化酶抑制剂（HDACIs）和包含其的组合物。还公开了通过抑制HDAC来获益的治疗疾病和病况的方法。
• Histone deacetylases (HDACs) inhibitors
  申请人：ANNJI PHARMACEUTICAL CO., LTD.

  公开号：US09155739B2

  公开（公告）日：2015-10-13

  Histone deacetylases inhibitors (HDACIs) and methods for treating cancer in a subject in need thereof are disclosed. The HDACIs comprise a compound of Formula X. or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, R1 is ethyl; R2 is 2-phenylethyl; R3 is hydrogen; R4 is fluoro; R5 is (2E)-3-N-hydroxyamino-3-oxo-propenyl; and R6 is hydrogen, or a salt thereof. In another embodiment of the invention, R1 is ethyl; R2 is 2-phenylethyl; R3 is hydrogen; R4 is (2E)-3-N-hydroxyamino-3-oxo-propenyl; R5 is chloro or fluoro; and R6 is hydrogen.

  本发明揭示了组蛋白去乙酰化酶抑制剂（HDACIs）及其治疗需要的患者的癌症的方法。HDACIs包括化合物X的一个衍生物或其药学上可接受的盐。在本发明的一个实施例中，R1为乙基；R2为2-苯乙基；R3为氢；R4为氟；R5为（2E）-3-N-羟基氨基-3-氧代丙烯基；R6为氢，或其盐。在本发明的另一个实施例中，R1为乙基；R2为2-苯乙基；R3为氢；R4为（2E）-3-N-羟基氨基-3-氧代丙烯基；R5为氯或氟；R6为氢。
• US9155739B2
  申请人：——

  公开号：US9155739B2

  公开（公告）日：2015-10-13
• US9387209B2
  申请人：——

  公开号：US9387209B2

  公开（公告）日：2016-07-12
• [EN] HISTONE DEACETYLASES (HDACS) INHIBITORS<br/>[FR] INHIBITEURS D'HISTONE DÉSACÉTYLASES (HDAC)
  申请人：ANNJI PHARM CO LTD

  公开号：WO2013154870A1

  公开（公告）日：2013-10-17

  Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit are also disclosed. In an embodiment of the invention, the compound is (2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquina20lin-7-yl)-N-hydroxyacrylamide, or a salt thereof. In another embodiment of the invention, the compound is (2E)-3-(2-ethyl-7-f1uoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide, (2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide, or a salt thereof. In another aspect the invention relates to a composition comprising a therapeutically effective amount of a compound as aforementioned, or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable carrier or vehicle.