tert-butyl 4-[N-(3-hydroxyphenyl)carbamoyl]piperidine-1-carboxylate | 1124219-52-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 4-[N-(3-hydroxyphenyl)carbamoyl]piperidine-1-carboxylate
• 英文别名: t-butyl 4-[N-(3-hydroxyphenyl)carbamoyl]piperidine-1-carboxylate；Tert-butyl 4-[(3-hydroxyphenyl)carbamoyl]piperidine-1-carboxylate
• CAS: 1124219-52-8
• 化学式: C₁₇H₂₄N₂O₄
• mdl: MFCD24388951
• 分子量: 320.389
• InChiKey: DPOOBTFNPACZJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.529
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-[N-(3-hydroxyphenyl)carbamoyl]piperidine-1-carboxylate 在 盐酸 、 sodium hydride 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.75h， 生成 N-[3-[[4-(3-chlorophenyl)phenyl]methoxy]phenyl]piperidine-4-carboxamide;hydrochloride
  参考文献：
  名称：

  Biarylmethoxy isonipecotanilides as potent and selective inhibitors of blood coagulation factor Xa

  摘要：

  New chloro-substituted biarylmethoxyphenyl piperidine-4-carboxamides were synthesized and assayed in vitro as inhibitors of the blood coagulation enzymes factor Xa (fXa) and thrombin. An investigation of effects of the amidine and isopropyl groups attached at the piperidine nitrogen and 5-(halogenoaryl)isoxazol-3-yl groups as biaryl substituents led us to identify new compounds which proved to be selective fXa inhibitors, with inhibition constants in the low nanomolar range. The most potent compound 21e, that incorporates 2-Cl-thiophen-5-yl group as the P1 motif and 1-isopropylpiperidine P4 group, inhibited fXa with K-i value of 0.3 nM and very high selectivity over thrombin and some other tested serine proteases, achieving moderate levels of anticoagulant activity in the low micromolar range, as assessed by the prothrombin time clotting assay (PT2 = 3.30 mu M). Based on reliable docking simulations, molecular modeling provided a rationale for interpreting structure-activity relationships. The predicted binding modes highlighted the structural requirements for addressing the subsites S1 and S4 of the fXa enzyme. (C) 2010 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2010.11.010
• 作为产物：
  描述：

  tert-butyl 4-{[3-(benzyloxy)phenyl]-carbamoyl}piperidine-1-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 反应 12.0h， 以98%的产率得到tert-butyl 4-[N-(3-hydroxyphenyl)carbamoyl]piperidine-1-carboxylate
  参考文献：
  名称：

  Fluorinated Benzyloxyphenyl Piperidine-4-carboxamides with Dual Function against Thrombosis: Inhibitors of Factor Xa and Platelet Aggregation

  摘要：

  A series of benzyloxy anilides of nipecotic (5, 6) and isonipecotic (7, 8) acids were synthesized and assayed in vitro as inhibitors of ADP-induced platelet aggregation and the blood coagulation enzymes factor Xa (FXa) and thrombin (FIIa). An exploration of effects of the amidine group attached at the piperidine nitrogen,position and substitution (F, phenyl) of the benzyloxy group, and addition of fluorine/s on the second (distal) phenyl ring, led us to single out some promising isonipecotamide derivatives 7. Addition of meta-F and para-CF3 on the distal phenyl ring resulted in a 6-to-18-fold enhancement of the FXa potency and in 2-to-4-fold increase of the antiplatelet potency, the last depending to a large extent upon lipophilicity. Two congeners of N-{[3-(1,1'-biphenyl-4-yl)methoxy]phenyl}piperidine-4-carboxamide (7m and 7p) proved to be potent FXa-selective inhibitors (K-i = 130 and 57 nM, respectively) and antiplatelet agents and were identified as leads for developing new dual function antithrombotic drugs.

  DOI：

  10.1021/jm801141f

文献信息

• Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors
  作者：Zhuoer Zhi、Wenting Zhang、Jingchun Yao、Yanguo Shang、Qingjing Hao、Zhong Liu、Yushan Ren、Jie Li、Guimin Zhang、Jinxin Wang

  DOI：10.1021/acs.jmedchem.9b02137

  日期：2020.6.11

  creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly ameliorated depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for

  当前大多数的单酰基甘油脂肪酶（MAGL）抑制剂通过不可逆的作用机理发挥作用，引起一系列副作用。在此，从不可逆抑制剂开始，合成了25种化合物并进行了体外MAGL抑制评估，其中，化合物36表现出最强的抑制活性（IC 50 = 15 nM）。至关重要的是，对接研究表明，米-氯基取代的苯胺片段占用由Val191，Tyr194，Val270，和Lys273的侧链，其创造性标识新的关键点的锚定为新MAGL抑制剂发展包围的疏水副袋中。此外，体内评估创新地揭示了这种可逆抑制剂36显着改善了利血平引起的抑郁样行为。据我们所知，这是首次开发可逆性MAGL抑制剂来支持MAGL作为抑郁症的潜在治疗靶标。
• New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity
  作者：Modesto de Candia、Elisabetta Marini、Giorgia Zaetta、Saverio Cellamare、Antonella Di Stilo、Cosimo D. Altomare

  DOI：10.1016/j.ejps.2015.03.004

  日期：2015.5

  a benzyl nitrate analog (15) of compound 1 was also achieved. The in vitro vasodilatory activities, as well as platelet anti-aggregatory effects, of the newly synthesized organic nitrates were assessed. The (ONO2)methyl carbamate-based derivative 5a and the benzyl nitrate analog 15, which on the other hand retain activity as inhibitors of ADP-induced platelet aggregation, exhibited strong NO-mediated

  通过将含硝酸盐的部分接枝到已被报道为中度有效的抗血小板药的苄氧基异壬基苯甲酰苯胺衍生物1和2的结构上，合成了许多新的一氧化氮（NO）前体。通过氨基甲酸酯和酰胺键将各种硝基氧基（ONO 2）-烷基侧链共价连接到母体化合物的哌啶氮上，并且还实现了化合物1的硝酸苄基酯类似物（15）的合成。评估了新合成的有机硝酸盐的体外血管舒张活性以及血小板的抗聚集作用。（ONO 2）氨基甲酸甲酯基衍生物5a另一方面，硝酸苄酯类似物15保留作为ADP诱导的血小板聚集抑制剂的活性，对预收缩的大鼠主动脉条显示出强烈的NO介导的血管舒张作用，EC 50值在低纳摩尔范围内（13和分别为29 nM）。用选择性抑制的可溶性鸟苷酸环化酶（s GC）（是NO介导的导致血管平滑肌松弛的途径的关键酶）进行的实验证实，NO参与了观察到的血管舒张。硝酸盐衍生物在酸性水溶液中和pH 7.4下均稳定。在人血清中，与5a不同，后者没有显示出酶催化的分解作用，另一种经过测试（ONO
• Biarylmethoxy isonipecotanilides as potent and selective inhibitors of blood coagulation factor Xa
  作者：Gianfranco Lopopolo、Filomena Fiorella、Modesto de Candia、Orazio Nicolotti、Sophie Martel、Pierre-Alain Carrupt、Cosimo Altomare

  DOI：10.1016/j.ejps.2010.11.010

  日期：2011.2

  New chloro-substituted biarylmethoxyphenyl piperidine-4-carboxamides were synthesized and assayed in vitro as inhibitors of the blood coagulation enzymes factor Xa (fXa) and thrombin. An investigation of effects of the amidine and isopropyl groups attached at the piperidine nitrogen and 5-(halogenoaryl)isoxazol-3-yl groups as biaryl substituents led us to identify new compounds which proved to be selective fXa inhibitors, with inhibition constants in the low nanomolar range. The most potent compound 21e, that incorporates 2-Cl-thiophen-5-yl group as the P1 motif and 1-isopropylpiperidine P4 group, inhibited fXa with K-i value of 0.3 nM and very high selectivity over thrombin and some other tested serine proteases, achieving moderate levels of anticoagulant activity in the low micromolar range, as assessed by the prothrombin time clotting assay (PT2 = 3.30 mu M). Based on reliable docking simulations, molecular modeling provided a rationale for interpreting structure-activity relationships. The predicted binding modes highlighted the structural requirements for addressing the subsites S1 and S4 of the fXa enzyme. (C) 2010 Elsevier B.V. All rights reserved.
• Fluorinated Benzyloxyphenyl Piperidine-4-carboxamides with Dual Function against Thrombosis: Inhibitors of Factor Xa and Platelet Aggregation
  作者：Modesto de Candia、Francesco Liantonio、Andrea Carotti、Raimondo De Cristofaro、Cosimo Altomare

  DOI：10.1021/jm801141f

  日期：2009.2.26

  A series of benzyloxy anilides of nipecotic (5, 6) and isonipecotic (7, 8) acids were synthesized and assayed in vitro as inhibitors of ADP-induced platelet aggregation and the blood coagulation enzymes factor Xa (FXa) and thrombin (FIIa). An exploration of effects of the amidine group attached at the piperidine nitrogen,position and substitution (F, phenyl) of the benzyloxy group, and addition of fluorine/s on the second (distal) phenyl ring, led us to single out some promising isonipecotamide derivatives 7. Addition of meta-F and para-CF3 on the distal phenyl ring resulted in a 6-to-18-fold enhancement of the FXa potency and in 2-to-4-fold increase of the antiplatelet potency, the last depending to a large extent upon lipophilicity. Two congeners of N-[3-(1,1'-biphenyl-4-yl)methoxy]phenyl}piperidine-4-carboxamide (7m and 7p) proved to be potent FXa-selective inhibitors (K-i = 130 and 57 nM, respectively) and antiplatelet agents and were identified as leads for developing new dual function antithrombotic drugs.