4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)aniline | 1423126-83-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)aniline
• CAS: 1423126-83-3
• 化学式: C₁₁H₉N₅O
• 分子量: 227.225
• InChiKey: DSMOSTFTDMVZCA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  89.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)aniline 在 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 20.5h， 生成 1-(5-tert-butylisoxazol-3-yl)-3-(4-(1-(2-morpholinoethyl)-1Hpyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)urea
  参考文献：
  名称：

  Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model

  摘要：

  Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structureactivity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.

  DOI：

  10.1021/acs.jmedchem.6b00604
• 作为产物：
  描述：

  4-(BOC-氨基)酚 在 caesium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)aniline
  参考文献：
  名称：

  发现吡咯并[2,3-d]嘧啶衍生物作为有效和选择性的集落刺激因子 1 受体激酶抑制剂

  摘要：

  集落刺激因子 1 受体激酶 (CSF1R) 在肿瘤相关巨噬细胞复极化中发挥着不可或缺的作用，并已成为癌症免疫治疗的新治疗靶点。大多数当前的 CSF1R 激酶抑制剂在 CSF1R 激酶和其他 III 型生长因子受体成员之间缺乏选择性。在此，我们报告了一种有效的选择性 CSF1R 抑制剂18h，其对 CSF1R 的 IC 50值为 5.14 nM，并且比其他 III 型受体酪氨酸激酶具有选择性（>38 倍）。18小时抑制 RAW264.7、THP-1 和 M-NFS-60 细胞中 CSF1R 的磷酸化及其下游信号通路。用这种化合物处理会导致 RAW264.7 巨噬细胞中巨噬细胞极化以剂量依赖性方式发生改变。在体内，18h显示出可接受的药代动力学特征，并在接种 M-NFS-60 细胞的小鼠异种移植模型中抑制肿瘤生长。

  DOI：

  10.1016/j.ejmech.2022.114782

文献信息

• Structure–Activity Relationship Studies of Pyrazolo[3,4-<i>d</i>]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in Vivo
  作者：Ling-Ling Yang、Guo-Bo Li、Shuang Ma、Chan Zou、Shu Zhou、Qi-Zheng Sun、Chuan Cheng、Xin Chen、Li-Jiao Wang、Shan Feng、Lin-Li Li、Sheng-Yong Yang

  DOI：10.1021/jm301537p

  日期：2013.2.28

  We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo [3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.
• 4-POSITION SUBSTITUTED PYRAZOLOPYRIMIDINE DERIVATIVE, AND USE THEREOF IN DRUG PREPARATION
  申请人：GUANGXI WUZHOU PHARMACEUTICALS (GROUP) CO., LTD.

  公开号：EP2889298B1

  公开（公告）日：2018-05-02
• 4-Position Substituted Pyrazolopyrimidine Derivative, And Use Thereof In Drug Preparation
  申请人：Guangxi Wuzhou Pharmaceuticals (Group) Co., Ltd.

  公开号：US20150315191A1

  公开（公告）日：2015-11-05

  The invention belongs to the technical field of organic synthetic drugs, and particularly relates to a pyrazolopyrimidine derivative and a preparation method and medical uses thereof. The invention provides a new pyrazolopyrimidine derivative mainly having position 4 substituted, i.e., position substituted by Y in formula I. The pyrazolopyrimidine derivative of the invention has a structural formula I as follows: The invention provides a new pyrazolopyrimidine derivative and a simple, efficient and low-cost preparation method thereof. The pyrazolopyrimidine derivative of the invention has good inhibitory activity for multiple kinases, has inhibitory action on multiple solid tumors, leukemia and autoimmune diseases, provides a new effective choice for preparation of kinase inhibitors, medicines for autoimmune diseases, angiogenesis inhibitors and antitumor drugs, and has good application prospect.
• US9828375B2
  申请人：——

  公开号：US9828375B2

  公开（公告）日：2017-11-28
• Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1<i>H</i>-Pyrazolo[3,4-<i>d</i>]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(<i>tert</i>-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model
  作者：Guo-Bo Li、Shuang Ma、Ling-Ling Yang、Sen Ji、Zhen Fang、Guo Zhang、Li-Jiao Wang、Jie-Min Zhong、Yu Xiong、Jiang-Hong Wang、Shen-Zhen Huang、Lin-Li Li、Rong Xiang、Dawen Niu、Ying-Chun Chen、Sheng-Yong Yang

  DOI：10.1021/acs.jmedchem.6b00604

  日期：2016.9.22

  Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structureactivity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.