1-(4-chlorophenyl)-2,2-dimethylpiperazine | 748766-90-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-(4-chlorophenyl)-2,2-dimethylpiperazine
• CAS: 748766-90-7
• 化学式: C₁₂H₁₇ClN₂
• 分子量: 224.733
• InChiKey: YVOBWKOQTIPYQM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  15.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-(4-chlorophenyl)-2,2-dimethylpiperazine 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 tert-butyl (1S,2R)-2-(4-(4-chlorophenyl)-3,3-dimethylpiperazine-1-carbonyl)cyclopentylcarbamate
  参考文献：
  名称：

  PIPERAZINYL DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

  摘要：

  本申请描述了式(I)的MIP-1α的调节剂，或其立体异构体或药学上可接受的盐，其中m、T、W、R1、R4、R5、R5a和R5b如本文所定义。此外，还公开了使用这些调节剂治疗和预防哮喘、过敏病等炎症性疾病，以及类风湿性关节炎和动脉粥样硬化等自身免疫病理的方法。

  公开号：

  US20070179148A1
• 作为产物：
  描述：

  1-(4-chlorophenyl)-6,6-dimethylpiperazine-2,5-dione 在 lithium aluminium tetrahydride 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以95%的产率得到1-(4-chlorophenyl)-2,2-dimethylpiperazine
  参考文献：
  名称：

  PIPERAZINYL DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

  摘要：

  本申请描述了式(I)的MIP-1α的调节剂，或其立体异构体或药学上可接受的盐，其中m、T、W、R1、R4、R5、R5a和R5b如本文所定义。此外，还公开了使用这些调节剂治疗和预防哮喘、过敏病等炎症性疾病，以及类风湿性关节炎和动脉粥样硬化等自身免疫病理的方法。

  公开号：

  US20070179148A1

文献信息

• [EN] COMPOSITION AND METHODS OF USE OF SMALL MOLECULES AS BINDING LIGANDS FOR THE MODULATION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9(PCSK9) PROTEIN ACTIVITY<br/>[FR] COMPOSITION ET PROCÉDÉS D'UTILISATION DE PETITES MOLÉCULES EN TANT QUE LIGANDS DE LIAISON POUR LA MODULATION DE L'ACTIVITÉ PROPROTÉINE CONVERTASE SUBTILISINE/PROTÉINE KEXINE DE TYPE 9 (PCSK9)
  申请人：SRX CARDIO LLC

  公开号：WO2016029037A1

  公开（公告）日：2016-02-25

  This invention is related to the field of PCSK9 biology and the composition and methods of use of small molecule ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small molecule compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small molecule ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small molecule ligands that can raise LDL levels.

  这项发明涉及PCSK9生物学领域，以及用于调节PCSK9生物活性的小分子配体的组成和使用方法。具体而言，该发明提供了调节低密度脂蛋白循环水平的小分子化合物组合物，通过改变蛋白质PCSK9的构象来实现。将这些小分子配体与PCSK9结合会改变蛋白质的构象，修改PCSK9与内源性低密度脂蛋白受体之间的相互作用，并可能导致循环LDL胆固醇水平降低或增加。高LDL胆固醇水平与心脏疾病风险增加相关。低LDL胆固醇水平在其他情况下可能会有问题，比如肝功能障碍；因此，开发能够提高LDL水平的小分子配体也具有实用性。
• Piperazinyl derivatives as modulators of chemokine receptor activity
  申请人：Bristol-Myers Squibb Company

  公开号：US07615556B2

  公开（公告）日：2009-11-10

  The present application describes modulators of MIP-1α of formula (I): or stereoisomers or pharmaceutically acceptable salts thereof, wherein m, T, W, R1, R4, R5, R5a and R5b are as defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using said modulators are disclosed.

  本申请描述了MIP-1α的调节剂的化学式(I)或其立体异构体或药学上可接受的盐，其中m、T、W、R1、R4、R5、R5a和R5b如本文所定义。此外，还公开了使用该调节剂治疗和预防炎症性疾病，如哮喘和过敏性疾病，以及自身免疫病理如类风湿性关节炎和动脉硬化的方法。
• Composition and methods of use of small molecules as binding ligands for the modulation of proprotein convertase subtilisin/kexin type 9(PCSK9) protein activity
  申请人：SRX CARDIO, LLC

  公开号：US10034892B2

  公开（公告）日：2018-07-31

  This invention is related to the field of PCSK9 biology and the composition and methods of use of small molecule ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small molecule compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small molecule ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small molecule ligands that can raise LDL levels.

  本发明涉及 PCSK9 生物学领域以及用于调节 PCSK9 生物活性的小分子配体的组成和使用方法。特别是，本发明提供了通过改变蛋白质 PCSK9 的构象来调节循环中低密度脂蛋白水平的小分子化合物组合物。将这些小分子配体与 PCSK9 结合可改变该蛋白的构象，改变 PCSK9 与内源性低密度脂蛋白受体之间的相互作用，并可导致循环中低密度脂蛋白胆固醇水平的降低或升高。低密度脂蛋白胆固醇水平高与心脏病风险增加有关。低密度脂蛋白胆固醇水平过低可能会对肝功能障碍等其他疾病造成困扰；因此，能提高低密度脂蛋白水平的小分子配体也很有用。
• Method to treat lipid dysregulation by modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein activity with small molecule ligands
  申请人：SRX CARDIO, LLC

  公开号：US11026957B2

  公开（公告）日：2021-06-08

  This invention is related to the field of PCSK9 biology and the composition and methods of use of small molecule ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small molecule compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small molecule ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small molecule ligands that can raise LDL levels.

  本发明涉及 PCSK9 生物学领域以及用于调节 PCSK9 生物活性的小分子配体的组成和使用方法。特别是，本发明提供了通过改变蛋白质 PCSK9 的构象来调节循环中低密度脂蛋白水平的小分子化合物组合物。将这些小分子配体与 PCSK9 结合可改变该蛋白的构象，改变 PCSK9 与内源性低密度脂蛋白受体之间的相互作用，并可导致循环中低密度脂蛋白胆固醇水平的降低或升高。低密度脂蛋白胆固醇水平高与心脏病风险增加有关。低密度脂蛋白胆固醇水平过低可能会对肝功能障碍等其他疾病造成困扰；因此，能提高低密度脂蛋白水平的小分子配体也很有用。
• Discovery of (1<i>S</i>,2<i>R</i>,3<i>R</i>)-2,3-Dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: Novel and Highly Selective Aggrecanase Inhibitors
  作者：Makoto Shiozaki、Katsuya Maeda、Tomoya Miura、Masayuki Kotoku、Takayuki Yamasaki、Isamu Matsuda、Kenta Aoki、Katsutaka Yasue、Hiroto Imai、Minoru Ubukata、Akira Suma、Masahiro Yokota、Takahiro Hotta、Masahiro Tanaka、Yasunori Hase、Julia Haas、Andrew M. Fryer、Ellen R. Laird、Nicole M. Littmann、Steven W. Andrews、John A. Josey、Takayuki Mimura、Yuichi Shinozaki、Hiromi Yoshiuchi、Takashi Inaba

  DOI：10.1021/jm101609j

  日期：2011.4.28

  Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A cries of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, aid orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazin e-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo [1,2-a]-pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.