1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid chloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid chloride
• 英文别名: 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid chloride；7-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl chloride；7-chloro-1-(oxan-4-ylmethyl)indole-3-carbonyl chloride
• 化学式: C₁₅H₁₅Cl₂NO₂
• 分子量: 312.196
• InChiKey: HZSOTAASSFDJNM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  31.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid chloride 在 四磷十氧化物 、 盐酸羟胺 、 氨 、 sodium hydride 、 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.5h， 生成 7-chloro-3-[(5-chloromethyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole
  参考文献：
  名称：

  Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists

  摘要：

  Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.01.082
• 作为产物：
  描述：

  7-氯吲哚 在 草酰氯 、 水 、 sodium hydride 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid chloride
  参考文献：
  名称：

  设计，合成和（吲哚-3-基）杂环衍生物作为CB1受体激动剂的结构活性关系。发现临床候选者

  摘要：

  我们报告了一种新型的吲哚-3-杂环CB1受体激动剂的结构-活性关系（SAR）的扩展。从强力但难溶的铅开始，1，采取了一种合理的方法来平衡溶解度，hERG活性和效价，同时在小鼠甩尾试验中保持所需的长效作用。这导致了化合物38的发现，该化合物成功地进入了临床开发阶段。

  DOI：

  10.1016/j.bmcl.2011.02.023

文献信息

• Indole derivatives
  申请人：Ratcliffe David Paul

  公开号：US20070082931A1

  公开（公告）日：2007-04-12

  Disclosed herein are indole derivatives of the formula (I) wherein each of the substitutents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the indole derivatives and use of the derivatives for the treatment of pain.

  本文披露了化学式（I）中的吲哚衍生物，其中每个取代基的定义如规范和索赔中所述。还披露了含有吲哚衍生物的药物组合物以及利用这些衍生物治疗疼痛的用途。
• Design, synthesis and structure–activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate
  作者：Paul Ratcliffe、Julia M. Adam、James Baker、Roberta Bursi、Robert Campbell、John K. Clark、Jean E. Cottney、Maureen Deehan、Anna-Marie Easson、Daniel Ecker、Darren Edwards、Ola Epemolu、Louise Evans、Ruth Fields、Stuart Francis、Paul Harradine、Fiona Jeremiah、Takao Kiyoi、Duncan McArthur、Angus Morrison、Paul Passier、Jack Pick、Peter G. Schnabel、Jurgen Schulz、Heinz Steinbrede、Glenn Walker、Paul Westwood、Grant Wishart、Joanna Udo de Haes

  DOI：10.1016/j.bmcl.2011.02.023

  日期：2011.4

  We report an expansion of the structure–activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38

  我们报告了一种新型的吲哚-3-杂环CB1受体激动剂的结构-活性关系（SAR）的扩展。从强力但难溶的铅开始，1，采取了一种合理的方法来平衡溶解度，hERG活性和效价，同时在小鼠甩尾试验中保持所需的长效作用。这导致了化合物38的发现，该化合物成功地进入了临床开发阶段。
• INDOLE DERIVATIVES
  申请人：Adam Julia

  公开号：US20080207598A1

  公开（公告）日：2008-08-28

  The invention relates to indole derivative having the general Formula I wherein A represents a 5-membered aromatic heterocyclic ring, wherein X 1 , X 2 and X 3 are independently selected from N, O, S and CH; Y represents CH 2 , O, S or SO 2 ; R 1 is H, (C 1-4 )-alkyl, (C 1-4 )alkyloxy, CN or halogen; R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 and R 5 ′ are independently hydrogen, (C 1-4 )alkyl (optionally substituted with OH) or CO—OR 8 ; or one pair of geminal substituents R 3 and R 3 ′ or R 5 and R 5 ′ together represent a keto group, and the others are all hydrogen or (C 1-4 )alkyl; or R 2 and R 5 together represent a methylene or an ethylene bridge, and R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′ and R 5 ′ are hydrogen; n is 1 or 2; R 6 is H, (C 1-4 )alkyl (optionally substituted with OH(C 1-4 )alkyloxy, CO—NR 9 R 10 , CO—OR 11 or 1,2,4-oxadiazol-3-yl), SO 2 NR 12 R 13 or COOR 14 ; R 7 is H or halogen; R 8 is (C 1-4 )alkyl; R 9 and R 10 are independently hydrogen, (C 1-4 )alkyl or (C 3-7 )cycloalkyl, the alkyl groups being optionally substituted with OH or (C 1-4 )alkyloxy; R 11 is H or (C 1-4 )alkyl; R 12 and R 13 are independently H or (C 1-4 )alkyl; R 14 is (C 1-6 )alkyl; or a pharmaceutically acceptable salt thereof, as agonists of the cannabinoid CB1 receptor, which can be used in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

  该发明涉及一种具有通式I的吲哚衍生物，其中A代表一个5-成员芳香杂环环，其中X1、X2和X3独立选择自N、O、S和CH；Y代表CH2、O、S或SO2；R1为H、(C1-4)-烷基、(C1-4)烷氧基、CN或卤素；R2、R2'、R3、R3'、R4、R4'、R5和R5'独立地为氢、(C1-4)烷基（可选地用OH取代）或CO—OR8；或一对重氮基R3和R3'或R5和R5'共同代表酮基，其他都是氢或(C1-4)烷基；或R2和R5共同代表亚甲基或乙烯桥，而R2'、R3、R3'、R4、R4'和R5'为氢；n为1或2；R6为H、(C1-4)烷基（可选地用OH(C1-4)烷氧基、CO—NR9R10、CO—OR11或1,2,4-噁二唑-3-基）、SO2NR12R13或COOR14；R7为H或卤素；R8为(C1-4)烷基；R9和R10独立地为氢、(C1-4)烷基或(C3-7)环烷基，烷基可能用OH或(C1-4)烷氧基取代；R11为H或(C1-4)烷基；R12和R13独立地为H或(C1-4)烷基；R14为(C1-6)烷基；或其药用可接受的盐，作为大麻素CB1受体的激动剂，可用于治疗疼痛，例如围手术期疼痛、慢性疼痛、神经性疼痛、癌症疼痛以及与多发性硬化症相关的疼痛和痉挛。
• WO2007/23143
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists
  作者：Takao Kiyoi、Julia M. Adam、John K. Clark、Keneth Davies、Anna-Marie Easson、Darren Edwards、Helen Feilden、Ruth Fields、Stuart Francis、Fiona Jeremiah、Duncan McArthur、Angus J. Morrison、Alan Prosser、Paul D. Ratcliffe、Jurgen Schulz、Grant Wishart、James Baker、Robert Campbell、Jean E. Cottney、Maureen Deehan、Ola Epemolu、Louise Evans

  DOI：10.1016/j.bmcl.2011.01.082

  日期：2011.3

  Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia. (C) 2011 Elsevier Ltd. All rights reserved.