N-(4-aminobiphenyl-3-yl)-4-(1,8-diazaspiro[4.5]dec-8-ylmethyl)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(4-aminobiphenyl-3-yl)-4-(1,8-diazaspiro[4.5]dec-8-ylmethyl)benzamide
• 英文别名: N-(2-amino-5-phenylphenyl)-4-{1,8-diazaspiro[4.5]decan-8-ylmethyl}benzamide；N-(2-amino-5-phenylphenyl)-4-(1,8-diazaspiro[4.5]decan-8-ylmethyl)benzamide
• 化学式: C₂₈H₃₂N₄O
• 分子量: 440.588
• InChiKey: LZBKXQAVFZXXKI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  70.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-氯甲基苯甲酰氯 在 potassium carbonate 、 三乙胺 、 三氟乙酸 、 potassium iodide 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 15.0h， 生成 N-(4-aminobiphenyl-3-yl)-4-(1,8-diazaspiro[4.5]dec-8-ylmethyl)benzamide
  参考文献：
  名称：

  图像引导合成揭示了有效的血脑屏障可渗透组蛋白脱乙酰酶抑制剂

  摘要：

  最近的研究表明，用于研究/治疗脑部疾病的几种组蛋白去乙酰化酶 (HDAC) 抑制剂显示出低血脑屏障 (BBB) 渗透率。除了观察到的低 HDAC 效力和选择性外，脑外显率差可能是实现治疗效果所需的高剂量的原因。在这里，我们报告了基于图像引导方法的用于 CNS 应用的高效和血脑屏障可渗透 HDAC 抑制剂的开发和评估，该方法涉及基于苯甲酰胺 HDAC 抑制剂 MS-275 的一系列化合物的平行合成和放射性标记，如一个模板。BBB 渗透通过狒狒模型中的快速碳 11 标记和 PET 成像进行优化，并使用来自每种化合物的 BBB 渗透的成像衍生数据反馈到设计过程中。总共评估了 17 种化合物，揭示了具有高结合亲和力和 BBB 渗透性的分子。在该苯甲酰胺系列中赋予 BBB 渗透的关键元素是碱性苄胺。这些衍生物对重组人 HDAC1 和 HDAC2 表现出 1-100 nM 的抑制活性。三种碳 11 标记的氨基甲基苯甲酰胺衍生物显示出高

  DOI：

  10.1021/cn500021p

文献信息

• Spirocyclic compounds
  申请人：Berk C. Scott

  公开号：US20070117824A1

  公开（公告）日：2007-05-24

  The present invention relates to a novel class of substituted spirocyclic compounds. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.

  本发明涉及一类新型的取代螺环化合物。这些化合物可以抑制组蛋白去乙酰化酶，并适用于在选择性诱导终末分化、阻止肿瘤细胞生长和/或凋亡的过程中使用，从而抑制这些细胞的增殖。因此，本发明的化合物在治疗具有肿瘤特征的患者方面是有用的，这些肿瘤具有肿瘤细胞的增殖。本发明的化合物还可能在预防和治疗TRX介导的疾病方面有用，例如自身免疫、过敏和炎症性疾病，以及预防和/或治疗中枢神经系统（CNS）疾病，如神经退行性疾病。本发明还提供了包括本发明化合物的药物组合物和这些药物组合物的安全用药方案，这些方案易于遵循，并在体内产生这些化合物的治疗有效量。
• Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization
  作者：Solomon D. Kattar、Laura M. Surdi、Anna Zabierek、Joey L. Methot、Richard E. Middleton、Bethany Hughes、Alexander A. Szewczak、William K. Dahlberg、Astrid M. Kral、Nicole Ozerova、Judith C. Fleming、Hongmei Wang、Paul Secrist、Andreas Harsch、Julie E. Hamill、Jonathan C. Cruz、Candia M. Kenific、Melissa Chenard、Thomas A. Miller、Scott C. Berk、Paul Tempest

  DOI：10.1016/j.bmcl.2008.12.083

  日期：2009.2

  successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays

  固相和溶液相文库合成的成功应用以及紧密整合到药物化学研究中，导致了MRL-波士顿并行药物化学小组对选择性HDAC1 / HDAC2抑制剂的新型结构系列的有效优化。在小型生化分析中，发现一个来自小型平行文库的起始引物有效且具有选择性。先进的化合物是迭代文库设计的高潮，并具有出色的生化和细胞效能，以及在动物模型中可接受的PK和功效。
• SPIROCYCLIC COMPOUNDS
  申请人：Mampreian Dawn M.

  公开号：US20110098268A1

  公开（公告）日：2011-04-28

  The present invention relates to a novel class of substituted spirocyclic compounds. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.

  本发明涉及一种新型的取代螺环化合物。这些化合物可以抑制组蛋白去乙酰化酶，并适用于在选择性诱导末端分化、阻止肿瘤细胞的增殖和/或凋亡，从而抑制这些细胞的增殖中使用。因此，本发明的化合物可用于治疗具有肿瘤细胞增殖特征的患者。本发明的化合物还可用于预防和治疗TRX介导的疾病，例如自身免疫性、过敏性和炎症性疾病，并用于预防和/或治疗中枢神经系统（CNS）疾病，例如神经退行性疾病。本发明还提供了包含本发明化合物的药物组合物和这些药物组合物的安全剂量方案，这些方案易于遵循，并在体内产生治疗有效量的这些化合物。
• Spirocyclic Compounds
  申请人：Berk Scott C.

  公开号：US20090209566A1

  公开（公告）日：2009-08-20

  The present invention relates to a novel class of substituted spirocyclic compounds, represented by the following structural Formula: I Wherein A, B and D are independently selected from CR 1 2 , NR 1a , C(O) and O; E is selected from a bond, CR 1 2 , NR 1a , C(O) and O; wherein at least one of A, B, D or E is CR 1 2 ; and provided that when A is O, then E is not O; G is CR 1 2 ; R is selected from NH 2 and OH; These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing termin differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.

  本发明涉及一类新颖的取代螺环化合物，其结构式如下：I，其中A、B和D独立地选自CR12、NR1a、C（O）和O；E选自键、CR12、NR1a、C（O）和O；其中至少一个A、B、D或E为CR12；并且当A为O时，E不为O；G为CR12；R选自NH2和OH。这些化合物可以抑制组蛋白去乙酰化酶，并适用于在选择性诱导终止分化、阻止肿瘤细胞生长和/或凋亡，从而抑制这些细胞的增殖。因此，本发明的化合物在治疗具有肿瘤细胞增殖特征的患者中非常有用。本发明的化合物还可以用于预防和治疗TRX介导的疾病，例如自身免疫、过敏和炎症性疾病，以及中枢神经系统（CNS）疾病的预防和/或治疗，例如神经退行性疾病。本发明还提供了包含本发明化合物的药物组合物和这些药物组合物的安全剂量方案，易于遵循，并在体内产生治疗有效量的这些化合物。
• SPIROCYCLIC COMPOUNDS AS HDAC INHIBITORS
  申请人：Merck & Co., Inc.

  公开号：EP1954698A1

  公开（公告）日：2008-08-13