(1r,4r)-6'-methoxy-N-methyl-3'-oxo-N-(2-(piperidin-1-yl)ethyl)-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-4-carboxamide | 879368-32-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: (1r,4r)-6'-methoxy-N-methyl-3'-oxo-N-(2-(piperidin-1-yl)ethyl)-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-4-carboxamide
• CAS: 879368-32-8
• 化学式: C₂₃H₃₂N₂O₄
• 分子量: 400.518
• InChiKey: WYQDIMPYESSFEU-QBNMFFNISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  59.08
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  甲基-(2-哌啶-1-乙基)-胺 、 (1r,4r)-6'-methoxy-3'-oxo-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-4-carboxylic acid 在 2-chloro-1,3-dimethyl imidazolium chloride 、 三乙胺 作用下， 以 氯仿 为溶剂， 反应 1.0h， 以95%的产率得到(1r,4r)-6'-methoxy-N-methyl-3'-oxo-N-(2-(piperidin-1-yl)ethyl)-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-4-carboxamide
  参考文献：
  名称：

  Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists

  摘要：

  Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H-3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC50 = 0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC50 of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H-3 inverse agonists. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.07.125

文献信息

• Carbamoyl-Substituted Spiro Derivative
  申请人：Jitsuoka Makoto

  公开号：US20080171753A1

  公开（公告）日：2008-07-17

  A compound represented by, e.g. the formula (I): [wherein X, Y, Z, and W each independently represent optionally substituted methine; A, B, and D each independently represent —C(O)—, etc.; Q represents a methine or a nitrogen; and R represents the formula (II-1), optionally substituted with lower alkyl, etc.; (wherein R 6 represents a lower alkyl, etc; and R 7 and R 8 each independently represents a lower alkyl, etc.)] or a pharmaceutically acceptable salt of the compound. The compounds and salt have antagonistic activity against a histamine H3 receptor or inverse agonistic activity against a histamine H3 receptor. They are useful in the prevention or treatment of metabolic diseases, circulatory diseases, or neurotic diseases.

  化合物的化学式为(I):[其中X、Y、Z和W各自独立地表示可选择性取代的甲烷基；A、B和D各自独立地表示—C(O)—等；Q表示甲烷基或氮；R表示化学式(II-1)，可选择性地取代较低的烷基等；(其中R6表示较低的烷基等；R7和R8各自独立地表示较低的烷基等)]或其药学上可接受的盐。这些化合物和盐对组胺H3受体具有拮抗活性或反向激动活性。它们可用于预防或治疗代谢性疾病、循环系统疾病或神经疾病。
• CARBAMOYL-SUBSTITUTED SPIRO DERIVATIVE
  申请人：BANYU PHARMACEUTICAL CO., LTD.

  公开号：EP1795527A1

  公开（公告）日：2007-06-13

  A compound represented by, e.g. the formula (I): [wherein X, Y, Z, and W each independently represent optionally substituted methine; A, B, and D each independently represent -C(O)-, etc.; Q represents a methine or a nitrogen; and R represents the formula (II-1), optionally substituted with lower alkyl, etc.; (wherein R6 represents a lower alkyl, etc; and R7 and R8 each independently represents a lower alkyl, etc.)] or a pharmaceutically acceptable salt of the compound. The compounds and salt have antagonistic activity against a histamine H3 receptor or inverse agonistic activity against a histamine H3 receptor. They are useful in the prevention or treatment of metabolic diseases, circulatory diseases, or neurotic diseases.

  如式(I)所代表的化合物： [其中 X、Y、Z 和 W 各自独立地代表任选取代的甲烷；A、B 和 D 各自独立地代表-C(O)-等；Q 代表甲烷或氮；R 代表式（II-1），任选被低级烷基等取代； (其中 R6 代表低级烷基等；R7 和 R8 各自独立地代表低级烷基等）]或该化合物的药学上可接受的盐。这些化合物和盐对组胺 H3 受体具有拮抗活性，或对组胺 H3 受体具有反向激动活性。它们可用于预防或治疗代谢性疾病、循环系统疾病或神经性疾病。
• US7960402B2
  申请人：——

  公开号：US7960402B2

  公开（公告）日：2011-06-14
• Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists
  作者：Makoto Jitsuoka、Daisuke Tsukahara、Sayaka Ito、Takeshi Tanaka、Norihiro Takenaga、Shigeru Tokita、Nagaaki Sato

  DOI：10.1016/j.bmcl.2008.07.125

  日期：2008.9

  Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H-3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC50 = 0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC50 of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H-3 inverse agonists. (C) 2008 Elsevier Ltd. All rights reserved.