ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(N-phthalimido)ethyl]-1H-indole-2-carboxylate | 191864-69-4

• 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: ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(N-phthalimido)ethyl]-1H-indole-2-carboxylate
• 英文别名: ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(1,3-dioxoisoindol-2-yl)ethyl]-1H-indole-2-carboxylate
• CAS: 191864-69-4
• 化学式: C₂₅H₂₇N₃O₄
• 分子量: 433.507
• InChiKey: YMXWFSNFGRUCRB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  82.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(N-phthalimido)ethyl]-1H-indole-2-carboxylate 在 palladium on activated charcoal titanium(IV) isopropylate 、 氢气 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 66.0h， 生成 N-(2-Aminobenzyl)-3-[2-(dimethylamino)ethyl]-5-[2-(phthalimido)ethyl]-1H-indole-2-carboxamide
  参考文献：
  名称：

  Synthesis and serotonergic activity of a series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT1B-like receptors

  摘要：

  0)。

  DOI：

  10.1039/a903141c
• 作为产物：
  描述：

  N,N-二甲氨基氯丙烷盐酸盐 在 盐酸 、 sodium ethanolate 、 sodium acetate 作用下， 以 乙醇 为溶剂， 反应 43.0h， 生成 ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(N-phthalimido)ethyl]-1H-indole-2-carboxylate
  参考文献：
  名称：

  一种新型的2,5-取代的色胺衍生物作为血管5HT1B / 1D受体拮抗剂。

  摘要：

  描述了在血管5HT1B样受体上一系列新的2,5-取代的色胺衍生物的设计，合成和活性。在对2-取代基，特别是对亚甲基或乙烯连接的5-侧链进行各种修饰之后，已经提出了5HT1B-样受体的几个重要的辅助结合位点。基于5HT1B样受体的拟药模型对新分子的仔细设计导致发现乙基3- [2-（二甲基氨基）乙基] -5- [2-（2,5-二氧代-1-咪唑啉基] ）[乙基] -1H-吲哚-2-羧酸酯（40），一种高效，沉默，竞争和选择性的拮抗剂，仅对血管5HT1B样受体具有亲和力。2酯取代基大小的变化对5HT1B样受体和其他受体的亲和力有重要影响。在5侧链的杂环中谨慎地放置羰基取代基对于5HT2A和其他受体的良好亲和力和选择性至关重要。确定了几个关键的结构和电子特征，这些特征对基于色胺的系列药物产生拮抗作用至关重要。为了实现拮抗作用，缺电子的吲哚环系统似乎是必不可少的，这是通过在吲哚环的2-位包含吸电子基团

  DOI：

  10.1021/jm9605849

文献信息

• Synthesis and serotonergic activity of 2-oxadiazolyl-5-substituted-N,N-dimethyltryptamines: novel antagonists for the vascular 5-HT1B-like receptor
  作者：Gerard P. Moloney、Graeme R. Martin、Neil Mathews、Steve MacLennan、Susan Dodsworth、Pang Yih Sang、Cameron Knight、Miles Maxwell、Robert C. Glen

  DOI：10.1039/a903325d

  日期：——

  The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-oxadiazolyl-5-substituted tryptamine derivatives 2 is described. Modifications to the 2-oxadiazolyl group R1, the heterocycle R2 and the length of the linking chain (n) have been explored. Several compounds were identified which exhibited moderate 5-HT1B-like receptor affinity. In particular, 2-(3-ethyl-1,2,4-oxadiazol-5-yl)-3-[2-(dimethylamino)ethyl]-5-[(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)methyl]-1H-indole (20) in which n = 1 had a pKB = 7.23 at the 5-HT1B-like receptor and >60 fold selectivity over α1-adrenoceptor affinity. This contrasts with the higher homologue derivatives such as 10 and 11 where n = 2 which exhibited decreased potency and selectivity for the 5-HT1B-like receptor. The 2-oxadiazolyl-5-substituted-N,N-dimethyltryptamine derivatives were found to be silent (as judged by the inability of angiotensin II to unmask 5-HT1B-like receptor mediated agonist activity in the rabbit femoral artery) and competitive 5-HT1B-like receptor antagonists with half lives of up to 1.5 hours in dog plasma and with good oral bioavailability.

  本文描述了一系列新型2-噁二唑基-5-取代色胺衍生物2的合成及其血管5-HT1B样受体活性。对2-噁二唑基团的R1、杂环的R2以及连接链的长度（n）进行了探索性修改。发现了几种具有中等5-HT1B样受体亲和力的化合物。特别是，2-(3-乙基-1,2,4-噁二唑-5-基)-3-[2-(二甲基氨基)乙基]-5-[(4,4-二甲基-2,5-二氧咪唑啉-1-基)甲基]-1H-吲哚（20），其中n = 1，在5-HT1B样受体上的pKB = 7.23，相对于α1-肾上腺素受体亲和力有超过60倍的特异性。这与n = 2的高同系物衍生物（如10和11）形成对比，后者显示出对5-HT1B样受体的效能和选择性降低。发现2-噁二唑基-5-取代-N,N-二甲基色胺衍生物是无活性的（根据血管紧张素II无法在兔股动脉中揭示5-HT1B样受体介导的激动剂活性来判断），并且是竞争性的5-HT1B样受体拮抗剂，犬血浆中的半衰期可达1.5小时，并具有良好的口服生物利用度。
• A Novel Series of 2,5-Substituted Tryptamine Derivatives as Vascular 5HT_1B/1D Receptor Antagonists
  作者：Gerard P. Moloney、Alan D. Robertson、Graeme R. Martin、Steven MacLennan、Neil Mathews、Susan Dodsworth、Pang Yih Sang、Cameron Knight、Robert Glen

  DOI：10.1021/jm9605849

  日期：1997.7.1

  silent, competitive, and selective antagonist which shows affinity at the vascular 5HT1B-like receptors only. Changes to the size of the 2-ester substituent have a significant effect on affinity at the 5HT1B-like receptor and other receptors. Prudent placement of the carbonyl substituent in the heterocycle of the 5-side chain is crucial for good affinity and selectivity over the 5HT2A and other receptors

  描述了在血管5HT1B样受体上一系列新的2,5-取代的色胺衍生物的设计，合成和活性。在对2-取代基，特别是对亚甲基或乙烯连接的5-侧链进行各种修饰之后，已经提出了5HT1B-样受体的几个重要的辅助结合位点。基于5HT1B样受体的拟药模型对新分子的仔细设计导致发现乙基3- [2-（二甲基氨基）乙基] -5- [2-（2,5-二氧代-1-咪唑啉基] ）[乙基] -1H-吲哚-2-羧酸酯（40），一种高效，沉默，竞争和选择性的拮抗剂，仅对血管5HT1B样受体具有亲和力。2酯取代基大小的变化对5HT1B样受体和其他受体的亲和力有重要影响。在5侧链的杂环中谨慎地放置羰基取代基对于5HT2A和其他受体的良好亲和力和选择性至关重要。确定了几个关键的结构和电子特征，这些特征对基于色胺的系列药物产生拮抗作用至关重要。为了实现拮抗作用，缺电子的吲哚环系统似乎是必不可少的，这是通过在吲哚环的2-位包含吸电子基团
• Synthesis and serotonergic activity of a series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT1B-like receptors
  作者：Gerard P. Moloney、Graeme R. Martin、Neil Mathews、Heather Hobbs、Susan Dodsworth、Pang Yih Sang、Cameron Knight、Miles Maxwell、Robert C. Glen

  DOI：10.1039/a903141c

  日期：——

  The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives is described. Modifications to the 5-ethylene linked heterocycle are explored. Compounds such as N-benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide 22 (pKB = 7.33), the 2-aminobenzyl analogue 24 (pKB = 7.19), which both contain a phthalimide group, and N-benzyl-5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide 81 (pKB = 7.05), which incorporates an N-benzylhydantoin moiety, have good 5-HT1B-like affinity and indicate that there may be a hydrophobic binding pocket within the vascular 5-HT1B-like receptor previously not considered. Compounds including N-benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(2,4-dioxo-1,3-thiazolidinyl)ethyl]-1H-indole-2-carboxamide 39 (pKB = 7.35) and the dimethyl analogue 46 (pKB = 7.48) which contain a 2,4-thiazolidinedione moiety have good vascular 5-HT1B-like receptor affinity and show that the sulfur atom is well tolerated. Compound 61 which includes a methylsulfonyl substituent on the 1-nitrogen of the hydantoin ring system has the highest recorded 5-HT1B-like affinity for this series (pKB = 7.54) and it is proposed that this functional group can interact with a secondary hydrogen bonding region within the receptor. Compounds 22, 24, 39, 46, 61 and 81 also exhibited good selectivity over the α1-adrenoceptors. The most selective compound from this series is 46 which contains a 5,5-dimethylthiazolidine-2,4-dione group and which is 66-fold selective over the α1-adrenoceptors. This finding is consistent with the previous discovery that 5,5-dimethyl substitution on the hydantoin group in a related series of compounds afforded superior selectivity for 5-HT1B-like receptors over α1-adrenoceptors and other 5-HT receptors, in particular 5-HT2A receptors, relative to unsubstituted hydantoin analogues. The selectivity of these compounds for the vascular 5-HT1B-like receptor is discussed. Structure–activity relationship indicated a significant steric requirement of the 5-HT1B-like receptor subtype. Potential modes of binding for several of the compounds to a vascular 5-HT1B-like receptor pharmacophore model are also proposed.

  0)。