(E)-3-(6-formylpyridin-2-yl)acrylic acid tert-butyl ester | 1123622-32-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (E)-3-(6-formylpyridin-2-yl)acrylic acid tert-butyl ester
• 英文别名: tert-butyl (E)-3-(6-formylpyridin-2-yl)acrylate；tert-butyl (E)-3-(6-formyl-pyridin-2-yl)-acrylate；tert-butyl (E)-3-(6-formylpyridin-2-yl)prop-2-enoate
• CAS: 1123622-32-1
• 化学式: C₁₃H₁₅NO₃
• 分子量: 233.267
• InChiKey: RUGKTQNSYQYKTD-BQYQJAHWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  56.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (E)-3-(6-formylpyridin-2-yl)acrylic acid tert-butyl ester 在 氢氧化钾 、 O-(四氢-2H-吡喃-2-基)羟基胺 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 (E)-N-hydroxy-3-(6-{(E)-3-[4-(4-methylpiperazin-1-yl)phenyl]-3-oxo-1-propen-1-yl}pyridin-2-yl)acrylamide
  参考文献：
  名称：

  A new class of histone deacetylase inhibitors

  摘要：

  这项发明涉及新的组蛋白去乙酰化酶抑制剂，其通式为（I），其中：Q是键，CH2，NR5或氧，X是CH或氮，Y是键，CH2，氧或NR6，Z是CH或氮，R1，R2分别是氢或C1-C6烷基，R3，R4分别是氢，卤素，C1-C6烷基，C1-C6烷氧基，C1-C6卤代烷基或C1-C6卤代烷氧基，R5和R6的进一步定义在说明书中，并且其药用盐是可以接受的。

  公开号：

  EP2033956A1
• 作为产物：
  描述：

  6-溴吡啶-2-甲醛 、 丙烯酸叔丁酯 在 palladium diacetate n-BuNBr 、 potassium carbonate 、 1,5-diazabicyclo<3.3.2>decane 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 以64%的产率得到(E)-3-(6-formylpyridin-2-yl)acrylic acid tert-butyl ester
  参考文献：
  名称：

  Heterocyclic derivatives as HDAC inhibitors

  摘要：

  这项发明涉及新的组蛋白去乙酰化酶抑制剂，其通式如下（I）：其中：虚线是可选的额外键；R1是氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤烷基或C1-C6卤烷氧基；R2、R3分别是氢、C1-C6烷基、芳基；或者与它们相结合的碳原子形成桥接的双环或融合的杂环；X是CH或氮；Y是键、氧、（CH2）mCR4R5（CH2）n、或（CH2）oNR6（CH2）p；m、n、o、p、R4、R5和R6如规范中进一步定义；以及其药用可接受盐。

  公开号：

  EP2133334A1

文献信息

• Synthesis and Biological Characterization of Amidopropenyl Hydroxamates as HDAC Inhibitors
  作者：Florian Thaler、Mario Varasi、Andrea Colombo、Roberto Boggio、Davide Munari、Nickolas Regalia、Marco G. Rozio、Veronica Reali、Anna E. Resconi、Antonello Mai、Stefania Gagliardi、Giulio Dondio、Saverio Minucci、Ciro Mercurio

  DOI：10.1002/cmdc.201000166

  日期：——

  A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at <100 nM in the HDAC inhibition assays, sub‐micromolar IC50 values in tests against three tumor cell lines, and remarkable stability in human and mouse microsomes was observed. Three representative compounds were selected for further characterization

  制备了一系列酰胺基丙烯基异羟肟酸衍生物，作为人类组蛋白脱乙酰基酶（HDAC）的新型抑制剂。在HDAC抑制试验中，几种化合物在<100 n M时表现出效价，亚微摩尔IC 50在针对三种肿瘤细胞系的测试中获得了最佳值，并观察到了人类和小鼠微粒体的显着稳定性。选择了三种代表性化合物进行进一步表征，并针对一系列I类和II类HDAC进行了选择性分析，并进行了初步的体内药代动力学（PK）实验。尽管它们具有很高的微粒体稳定性，但它们在体内PK研究以及大鼠和人类肝细胞中均显示出中到高的清除率，这表明非微粒体酶催化了主要的代谢途径。
• HETEROCYCLIC DERIVATIVES AS HDAC INHIBITORS
  申请人：Thaler Florian

  公开号：US20110105474A1

  公开（公告）日：2011-05-05

  This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: the dotted line is an optional additional bond; R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 C 6 haloalkoxy; R 2 , R 3 are, independently, hydrogen; C 1 -C 6 alkyl; aryl; or taken together with the carbon atoms to which they are bound form a bridged bicyclic ring or a fused heterocycle; X is CH or nitrogen; Y is a bond, oxygen, (CH 2 ) m CR 4 R 5 (CH 2 ) n , or (CH 2 ) o NR 6 (CH 2 ) p ; m, n, o, p, R 4 , R 5 and R 6 are as further defined in the specification; and pharmaceutical acceptable salts thereof.

  这项发明涉及到新的组蛋白去乙酰化酶抑制剂，其一般式为（I），其中：虚线是可选的附加键；R1是氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6卤代烷氧基；R2、R3独立地是氢、C1-C6烷基、芳基或者与它们所结合的碳原子形成桥接的双环环或融合的杂环；X是CH或氮；Y是键、氧、（CH2）mCR4R5（ ）n或（ ）oNR6（ ）p；m、n、o、p、R4、R5和R6如规范中所定义；以及其药物可接受的盐。
• NEW CLASS OF HISTONE DEACETYLASE INHIBITORS
  申请人：Minucci Saverio

  公开号：US20120115867A1

  公开（公告）日：2012-05-10

  This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: Q is a bond, CH 2 , NR 5 or oxygen, X is CH or nitrogen, Y is a bond, CH 2 , oxygen or NR 6 , Z is CH or nitrogen, R 1 , R 2 are, independently, hydrogen or C 1 -C 6 alkyl, R 3 , R 4 are, independently, hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy, and R 5 and R 6 are as further defined in the specification, and pharmaceutical acceptable salts thereof.

  本发明涉及一种新的组蛋白去乙酰化酶抑制剂，其通式为(I)，其中：Q是键，CH2，NR5或氧，X是CH或氮，Y是键， ，氧或NR6，Z是CH或氮，R1、R2是独立的氢或C1-C6烷基，R3、R4是独立的氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基或C1-C6卤代烷氧基，R5和R6的定义在说明书中进一步给出，以及其药物可接受的盐。
• CLASS OF HISTONE DEACETYLASE INHIBITORS
  申请人：Thaler Florian

  公开号：US20100305123A1

  公开（公告）日：2010-12-02

  This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: Q is a bond, CH 2 , NR 5 or oxygen, X is CH or nitrogen, Y is a bond, CH 2 , oxygen or NR 6 , Z is CH or nitrogen, R 1 , R 2 are, independently, hydrogen or C 1 -C 6 alkyl, R 3 , R 4 are, independently, hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy, and R 5 and R 6 are as further defined in the specification, and pharmaceutical acceptable salts thereof.

  本发明涉及一种新的组蛋白去乙酰化酶抑制剂，其通式为（I），其中：Q是键，CH2，NR5或氧，X是CH或氮，Y是键， ，氧或NR6，Z是CH或氮，R1，R2独立地是氢或C1-C6烷基，R3，R4独立地是氢，卤素，C1-C6烷基，C1-C6烷氧基，C1-C6卤代烷基或C1-C6卤代烷氧基，R5和R6的进一步定义在规范中，并且包括其药学上可接受的盐。
• Synthesis and Biological Evaluation of <i>N</i>-Hydroxyphenylacrylamides and <i>N</i>-Hydroxypyridin-2-ylacrylamides as Novel Histone Deacetylase Inhibitors
  作者：Florian Thaler、Andrea Colombo、Antonello Mai、Raffaella Amici、Chiara Bigogno、Roberto Boggio、Anna Cappa、Simone Carrara、Tiziana Cataudella、Fulvia Fusar、Eleonora Gianti、Samuele Joppolo di Ventimiglia、Maurizio Moroni、Davide Munari、Gilles Pain、Nickolas Regalia、Luca Sartori、Stefania Vultaggio、Giulio Dondio、Stefania Gagliardi、Saverio Minucci、Ciro Mercurio、Mario Varasi

  DOI：10.1021/jm901502p

  日期：2010.1.28

  The historic deacetylases (HDACs) are able to regulate gene expression, and historic deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous Solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.