5-(1-{2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-ethyl}-1H-pyrazol-3-yl)-thiophene-2-carboxylic acid methyl ester | 656227-21-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: 5-(1-{2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-ethyl}-1H-pyrazol-3-yl)-thiophene-2-carboxylic acid methyl ester
• 英文别名: Methyl 5-[1-[2-(1,3-benzodioxol-5-ylmethylamino)ethyl]pyrazol-3-yl]thiophene-2-carboxylate
• CAS: 656227-21-3
• 化学式: C₁₉H₁₉N₃O₄S
• 分子量: 385.444
• InChiKey: QIFQRWLJWWMDSV-UHFFFAOYSA-N

物化性质

• 沸点：
  566.3±50.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-(1-{2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-ethyl}-1H-pyrazol-3-yl)-thiophene-2-carboxylic acid methyl ester 、 2-溴乙醇 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 生成 5-(1-{2-[benzo[1,3]dioxol-5-ylmethyl-(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-3-yl)thiophene-2-carboxylic acid methyl ester
  参考文献：
  名称：

  [EN] SUBSTITUTED THIENYL-HYDROXAMIC ACIDS HAVING HISTONE DEACETYLASE ACTIVITY
  [FR] ACIDES HYDROXAMIQUES DE THIENYLE SUBSTITUES PRESENTANT UNE ACTIVITE DE DEACETYLASE

  摘要：

  化合物的化学式（I）：其中A代表可选择取代的单环杂环芳基或苯基，B代表可选择取代的杂环芳基、芳基、芳基-融合-杂环烷基、杂环烷基-融合-环烷基、杂环烷基-融合-杂环烷基或芳基-融合-环烷基，X和Y，可以相同也可以不同，每个独立代表-0-、-NR1-、CO-、-SO2-、-SO-、-S-、-NR1CO-、-NR1SO2-、CONR1-、-SO2NR1-、-NR1CONR1或当Y代表-NR1-、-NR1CO-、-NR1SO2-、-CONR1-、-SO2NR1-或-NR1CONRI-时，X可以是直接键，条件是R1代表由-OR2、-NR3R4、NR4COR5、NR4SO2R5、CONR3R4或-S02NR3R4取代的烷基，R1代表H、烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、环烷基烷基或由-OR2、-NR3R4、-NR4COR5、-NR4S02R5、-CONR3R4或-S02NR3R4取代的烷基，R2代表H、烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、环烷基烷基、芳基、杂环芳基、杂环烷基或环烷基，R3代表H或烷基，R4代表H、烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、环烷基烷基、芳基、杂环芳基、杂环烷基或环烷基，或NR3R4代表环胺，R5代表烷基、芳基、杂环芳基、环烷基、杂环烷基、芳基烷基、杂环芳基烷基、环烷基烷基、杂环烷基烷基，n代表0-3，m代表1-3，p代表0-3，以及相应的N-氧化物、药学上可接受的盐、溶剂合物和前药；以及用于治疗一种可以通过抑制组蛋白去乙酰化酶来预防、抑制或改善疾病的病理和/或症状的疾病。

  公开号：

  WO2005014588A1
• 作为产物：
  描述：

  5-(1H-pyrazol-3-yl)-thiophene-2-carbonitrile 在 盐酸 、 sodium hydroxide 、 sodium tetrahydroborate 、 potassium carbonate 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 54.0h， 生成 5-(1-{2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-ethyl}-1H-pyrazol-3-yl)-thiophene-2-carboxylic acid methyl ester
  参考文献：
  名称：

  Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

  摘要：

  Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.10.048

文献信息

• [EN] SUBSTITUTED THIENYL-HYDROXAMIC ACIDS AS HISTONE DEACETYLASE INHIBITORS<br/>[FR] ACIDES SUBSTITUES THIENYLHYDROXAMIQUES UTILISES EN TANT QU'INHIBITEURS D'HISTONE DESACETYLASE
  申请人：ARGENTA DISCOVERY LTD

  公开号：WO2004013130A1

  公开（公告）日：2004-02-12

  A compound of formula (I): which can be used in the treatment of diseases associated with histone deacetylase enzymatic activity.

  化合物的化学式（I）：可用于治疗与组蛋白去乙酰化酶活性相关的疾病。
• Substituted thienyl-hydroxamic acids as histone deacetylase inhibitors
  申请人：Archer Ann Janet

  公开号：US20060122234A1

  公开（公告）日：2006-06-08

  A compound of formula (I): which can be used in the treatment of diseases associated with histone deacetylase enzymatic activity.

  一种式（I）化合物：可用于治疗与组蛋白去乙酰化酶酶活性有关的疾病。
• SUBSTITUTED THIENYL-HYDROXAMIC ACIDS AS HISTONE DEACETYLASE INHIBITORS
  申请人：Argenta Discovery Limited

  公开号：EP1525199A1

  公开（公告）日：2005-04-27
• [EN] SUBSTITUTED THIENYL-HYDROXAMIC ACIDS HAVING HISTONE DEACETYLASE ACTIVITY<br/>[FR] ACIDES HYDROXAMIQUES DE THIENYLE SUBSTITUES PRESENTANT UNE ACTIVITE DE DEACETYLASE
  申请人：ARGENTA DISCOVERY LTD

  公开号：WO2005014588A1

  公开（公告）日：2005-02-17

  A compound of formula (I): in which A represents optionally substituted monocyclic heteroaryl or phenyl B represents optionally substituted heteroaryl, aryl, aryl-fused-heterocycloalkyl, heteroaryl-fused-cycloalkyl, heteroaryl-fused-heterocycloalkyl or aryl-fused-cycloalkyl X and Y, which may be the same or different, each independently represent -0-, -NR1-, CO-, -S02-, -SO-, -S-, -NR1CO-, -NR1S02-, -CONR1-, -SO2NR1-, -NR1CONR1 or X may be a direct bond when Y represents -NR1-, -NR1CO-, -NR1SO2-, -CONR1-, - SO2NR1- or -NR1CONRI- provided that R1 represents alkyl substituted by -OR2, -NR3R4, - NR4COR5, -NR4SO2R5, -CONR3R4 or -S02NR3R4 R1 represents H, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, or alkyl substituted by -OR2, -NR3R4, -NR4COR5, -NR4S02R5, -CONR3R4 or -S02NR3R4 R2 represents H, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl R3 represents H or alkyl R4 represents H, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl or NR3R4 represents a cyclic amine R5 represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl n represents 0-3 m represents 1-3 p represents 0-3 and corresponding N-oxides, pharmaceutically acceptable salts, solvates and prodrugs thereof; and use to treat a disease in which inhibition of histone deacetylase can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease.

  化合物的化学式（I）：其中A代表可选择取代的单环杂环芳基或苯基，B代表可选择取代的杂环芳基、芳基、芳基-融合-杂环烷基、杂环烷基-融合-环烷基、杂环烷基-融合-杂环烷基或芳基-融合-环烷基，X和Y，可以相同也可以不同，每个独立代表-0-、-NR1-、CO-、-SO2-、-SO-、-S-、-NR1CO-、-NR1SO2-、CONR1-、-SO2NR1-、-NR1CONR1或当Y代表-NR1-、-NR1CO-、-NR1SO2-、-CONR1-、-SO2NR1-或-NR1CONRI-时，X可以是直接键，条件是R1代表由-OR2、-NR3R4、NR4COR5、NR4SO2R5、CONR3R4或-S02NR3R4取代的烷基，R1代表H、烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、环烷基烷基或由-OR2、-NR3R4、-NR4COR5、-NR4S02R5、-CONR3R4或-S02NR3R4取代的烷基，R2代表H、烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、环烷基烷基、芳基、杂环芳基、杂环烷基或环烷基，R3代表H或烷基，R4代表H、烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、环烷基烷基、芳基、杂环芳基、杂环烷基或环烷基，或NR3R4代表环胺，R5代表烷基、芳基、杂环芳基、环烷基、杂环烷基、芳基烷基、杂环芳基烷基、环烷基烷基、杂环烷基烷基，n代表0-3，m代表1-3，p代表0-3，以及相应的N-氧化物、药学上可接受的盐、溶剂合物和前药；以及用于治疗一种可以通过抑制组蛋白去乙酰化酶来预防、抑制或改善疾病的病理和/或症状的疾病。
• Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors
  作者：Steve Price、Walter Bordogna、Richard J. Bull、David E. Clark、Peter H. Crackett、Hazel J. Dyke、Matthew Gill、Neil V. Harris、Julia Gorski、Julia Lloyd、Peter M. Lockey、Julia Mullett、Alan G. Roach、Fabien Roussel、Anne B. White

  DOI：10.1016/j.bmcl.2006.10.048

  日期：2007.1

  Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment. (c) 2006 Elsevier Ltd. All rights reserved.