methyl 2-(2-(4-amino-3-fluorophenyl)benzo[d]oxazol-5-yl)acetate | 695186-53-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: methyl 2-(2-(4-amino-3-fluorophenyl)benzo[d]oxazol-5-yl)acetate
• 英文别名: Methyl 2-[2-(4-amino-3-fluorophenyl)-1,3-benzoxazol-5-yl]acetate
• CAS: 695186-53-9
• 化学式: C₁₆H₁₃FN₂O₃
• 分子量: 300.289
• InChiKey: IFOVPCNSRFOADT-UHFFFAOYSA-N

物化性质

• 沸点：
  429.5±45.0 °C(Predicted)
• 密度：
  1.339±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  78.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2-(2-(4-amino-3-fluorophenyl)benzo[d]oxazol-5-yl)acetate 在 lithium hydroxide 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 2-(2-(4-(3-(2-Chlorophenyl)acrylamido)-3-fluorophenyl)benzo[d]oxazol-5-yl)acetic acid
  参考文献：
  名称：

  Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor

  摘要：

  Using a furanylthiazole acetic acid as a starting point, a novel series of benzoxazol-5-yl acetic acid derivatives have been identified as heparanase inhibitors. Several compounds possess an IC50 of similar to 200 nM against heparanase, for example, trans 2-[4-[3-(3,4-dichlorophenylamino)-3-oxo-1-propenyl]-2-fluorophenyl]benzoxazol-5-yl acetic acid (16e). Several of the compounds show anti-angiogenic properties. Improvement to the DMPK profile of compounds has provided compounds of potential use in in vivo models. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.03.014
• 作为产物：
  描述：

  4-羟基-3-硝基苯乙酸 在 palladium on activated charcoal 盐酸 、 氢气 、 对甲苯磺酸 、 溶剂黄146 、 锌 作用下， 以 四氢呋喃 、 乙醇 、 乙酸乙酯 、 甲苯 为溶剂， 生成 methyl 2-(2-(4-amino-3-fluorophenyl)benzo[d]oxazol-5-yl)acetate
  参考文献：
  名称：

  Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor

  摘要：

  Using a furanylthiazole acetic acid as a starting point, a novel series of benzoxazol-5-yl acetic acid derivatives have been identified as heparanase inhibitors. Several compounds possess an IC50 of similar to 200 nM against heparanase, for example, trans 2-[4-[3-(3,4-dichlorophenylamino)-3-oxo-1-propenyl]-2-fluorophenyl]benzoxazol-5-yl acetic acid (16e). Several of the compounds show anti-angiogenic properties. Improvement to the DMPK profile of compounds has provided compounds of potential use in in vivo models. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.03.014

文献信息

• Novel Symmetrical Benzazolyl Derivatives Endowed with Potent Anti-Heparanase Activity
  作者：Antonella Messore、Valentina Noemi Madia、Luca Pescatori、Francesco Saccoliti、Valeria Tudino、Alessandro De Leo、Martina Bortolami、Daniela De Vita、Luigi Scipione、Federico Pepi、Roberta Costi、Silvia Rivara、Laura Scalvini、Marco Mor、Fabiana Fosca Ferrara、Emiliano Pavoni、Giuseppe Roscilli、Giuliana Cassinelli、Ferdinando M. Milazzo、Gianfranco Battistuzzi、Roberto Di Santo、Giuseppe Giannini

  DOI：10.1021/acs.jmedchem.8b01497

  日期：2018.12.13

  Previously, we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues,

  乙酰肝素酶是唯一的哺乳动物内毒素-β- d-葡糖醛酸糖苷酶涉及多种主要疾病。乙酰肝素酶表达的上调增加了肿瘤的大小，血管生成和转移，代表了在抗癌领域中已被验证的靶标。迄今为止，仅描述了几种小分子抑制剂，但尚未通过临床前开发获得。以前，我们探索了2-（4-（4-（溴-甲氧基苯甲酰胺基）苄氨基）苯基）苯并唑衍生物作为抗乙酰肝素酶的药物，建议将该支架用于开发广泛有效的乙酰肝素酶抑制剂。本文中，我们报告了对新的对称的2-氨基苯基-苯并甲氮基-5-乙酸酯衍生物的扩展研究，证明了对称化合物比不对称类似物更有效，其中最有效的化合物为7g，在纳摩尔浓度下对乙酰肝素酶有活性。对作用最佳的化合物5c和7g进行了分子对接研究，以使它们与酶的相互作用合理化。此外，侵袭分析证实了化合物5c，7a和7g的抗转移潜力，证明抑制了肿瘤细胞中促血管生成因子的表达。
• SYMMETRICAL 2-AMINOPHENYL-BENZAZOLYL-5-ACETATE COMPOUNDS AND THEIR USE AS ANTI-HEPARANASE
  申请人：Leadiant Biosciences SA

  公开号：EP3381907A1

  公开（公告）日：2018-10-03

  The present invention relates to symmetrical 2-aminophenyl-benzazolyl-5-acetate compounds of formula (I). Such compounds are endowed with an anti-heparanase activity. The present invention also relates to the use of such compounds as a medicament, in particular for the treatment of diseases and disorders associated with a heparanase activity, and to pharmaceutical compositions comprising the same.

  本发明涉及符合式(I)的对称2-氨基苯基-苯并咪唑-5-乙酸酯化合物。这些化合物具有抗肝素酶活性。本发明还涉及将这些化合物用作药物，特别是用于治疗与肝素酶活性相关的疾病和紊乱，并涉及包含这些化合物的药物组合物。
• Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
  作者：Valentina Noemi Madia、Antonella Messore、Luca Pescatori、Francesco Saccoliti、Valeria Tudino、Alessandro De Leo、Martina Bortolami、Luigi Scipione、Roberta Costi、Silvia Rivara、Laura Scalvini、Marco Mor、Fabiana Fosca Ferrara、Emiliano Pavoni、Giuseppe Roscilli、Giuliana Cassinelli、Ferdinando M. Milazzo、Gianfranco Battistuzzi、Roberto Di Santo、Giuseppe Giannini

  DOI：10.1021/acs.jmedchem.8b00908

  日期：2018.8.9

  heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar

  乙酰肝素酶是唯一能够切割硫酸乙酰肝素蛋白聚糖的糖胺聚糖硫酸乙酰肝素侧链的哺乳动物酶。其活性的改变与肿瘤的生长，血管生成和转移密切相关。因此，其对癌症进展的影响使其成为抗癌治疗中有吸引力的靶标。在这里，我们描述了新型乙酰唑类乙酰肝素酶抑制剂的设计，合成和生物学评估。大多数设计的衍生物在微摩尔或亚微摩尔浓度下均具有活性，最有前途的化合物是氟化和/或氨基酸衍生物13a，14d和15，它们的IC 50为500.16-0.82μM。进行了分子对接研究以合理化它们与酶催化位点的相互作用。重要的是，入侵试验证实了化合物14d和15的抗转移潜力。与抑制乙酰肝素酶的能力一致，化合物15被证明可以减少肿瘤细胞中编码促血管生成因子（如MMP-9，VEGF和FGF）的基因的表达。
• Synthetic Route to a Benzooxazole Derivative with Heparanase Inhibitory Activity
  作者：Chiara Da Pieve、Pravin Patel、Sotiris Missailidis

  DOI：10.1080/00397910902994186

  日期：2010.2.2

  The synthesis of a benzooxazol-5-yl acetic acid derivative (9) with strong heparanase and angiogenesis inhibitory activity, and thus possible commercial interest, is described in detail.
• [EN] BENZOXAZOLE, BENZTHIAZOLE AND BENZIMIDAZOLE ACID DERIVATIVES AND THEIR USE AS HEPARANASE INHIBITORS<br/>[FR] DERIVES D'ACIDES DE BENZOXAZOLE, DE BENZOTHIAZOLE, ET DE BENZIMIDAZOLE PHARMACEUTIQUEMENT ACTIFS
  申请人：OXFORD GLYCOSCIENCES UK LTD

  公开号：WO2004046122A2

  公开（公告）日：2004-06-03

  Compounds of formula (I): wherein R1, R2 and R3 are independently, hydrogen, halogen, CF3, OR6, NR7R8, NR8COR10, NR8SO2R10 or C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy or NR7R8; R4 is NR8CONR8R9, NR8COR9, NR8SO2R9, or W-CONR8R9, where W is a bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene; and R5 is Formula (A) methods for their synthesis, pharmaceutical compositions comprising them and their use in medicine, in particular for the treatment of cancer.