西拉美新 | 147817-50-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 中文名称: 西拉美新
• 英文名称: siramesine
• 英文别名: 1′-[4-[1-(4-fluorphenyl)-1H-indol-3-yl]butan-1-yl]-spiro[isobenzofuran-1(3H),4′-piperidine]；1’-(4-(1-(4-fluorophenyl)-1H-indol-3-yl)butyl)-3H-spiro(2-benzofuran-1,4′-piperidine)；1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4'-piperidine]；1'-{4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl}-3H-spiro[2-benzofuran-1,4'-piperidine]；Lu 28-179；1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]
• CAS: 147817-50-3
• 化学式: C₃₀H₃₁FN₂O
• 分子量: 454.587
• InChiKey: XWAONOGAGZNUSF-UHFFFAOYSA-N

物化性质

• 沸点：
  611.4±55.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 溶解度：
  溶于 DMSO（至少 25 mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  17.4
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 储存条件：
  -20℃

制备方法与用途

生物活性

Siramesine（Lu 28-179）是一种σ-2受体激动剂，能够诱导癌细胞死亡，并在体内展现出抗癌活性。

反应信息

• 作为反应物：
  描述：

  丙酸氯甲酯 、 西拉美新 以 丁酮 为溶剂， 反应 288.0h， 以15%的产率得到trans-N-propanoyloxymethyl Lu 28-179 chloride
  参考文献：
  名称：

  Bioreversible quaternary N-acyloxymethyl derivatives of the poorly soluble tertiary amine Lu 28-179—Synthesis, pharmaceutical chemical characterization and bioavailability studies in dogs

  摘要：

  Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to possess significantly enhanced solubilities as compared to the parent amine. In the present study, the N-acyloxymethylation approach to improve the aqueous solubility of Lu 28-179 a tertiary amine exhibiting an intrinsic solubility in the nanomolar range, have been investigated. The acetyl-, propanoyl-, butanoyl-, isobutanoyl- and pivaloyloxymethyl derivatives were isolated as chloride salts and the aqueous solubilities (S) far exceeded that of the parent tertiary amine (SO). S/S-0 ratios in the range 2-4 x 10(6) were found for the most soluble prodrugs. The prodrugs were reasonable stable to hydrolysis in aqueous buffer solutions (pH 0.1-7.4), but susceptible to undergo enzyme-mediated regeneration of Lu 28-179 after incubation in human plasma, simulated intestinal fluid and duodenum juice from pigs and dogs. Despite promising in vitro properties the prodrugs were unable to improve the oral bioavailability of Lu 28-179 as compared to that obtained after administration of a reference formulation of the parent drug in the dog. (c) 2005 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2005.07.009
• 作为产物：
  描述：

  1-羟基-4-(3-吲哚基)丁烷 在 copper(l) iodide 、 sodium carbonate 、 potassium carbonate 、 三乙胺 、 zinc(II) oxide 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 、 水 、 丙酮 为溶剂， 生成 西拉美新
  参考文献：
  名称：

  吲哚与 4-[18F] 氟碘苯的 N-芳基化：合成用于正电子发射断层扫描 (PET) 的 18F 标记的 σ2 受体配体

  摘要：

  钯介导的吲哚与 4-[18F] 氟碘苯的 N-芳基化作为一种​​新的放射性标记方法已经开发出来。在吲哚与4-[18F]氟碘苯反应中，通过改变不同的催化剂体系（CuI/1,2-二胺和Pd2(dba)3/膦配体）、碱和溶剂来阐述优化的反应条件。优化的反应条件（Pd2(dba)3/(2-(dicyclohexyl-phosphino)-2'-(N,N-二甲氨基)-联苯、NaOBut、甲苯、100°C 20 min）用于合成18F -标记的 σ2 受体配体 [18F]-11 和 [18F]-13，分别以 91% 和 84% 的放射化学产率获得。版权所有 © 2004 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.893

文献信息

• .sigma. Ligands with Subnanomolar Affinity and Preference for the .sigma.2 Binding Site. 1. 3-(.omega.-Aminoalkyl)-1H-indoles
  作者：Jens Perregaard、Ejner K. Moltzen、Eddi Meier、Connie Sanchez

  DOI：10.1021/jm00011a019

  日期：1995.5

  2-methoxy substituents. High affinity for both sigma 1 and sigma 2 binding sites was achieved with these compounds. Additionally, these compounds had relatively high affinity for serotonin 5-HT1A and 5-HT2A, dopamine D2, and adrenergic alpha 1 receptors. Introduction of a 4-fluorophenyl substituent at the indole nitrogen atom rendered very selective sigma 2 ligands with subnanomolar affinity for the sigma 2

  合成了一系列的4-（1H-吲哚-3-基）-1-丁基取代的4-苯基哌啶，4-苯基-1,2,3,6-四氢吡啶和4-苯基哌嗪。苯基任选地被4-氟或2-甲氧基取代基取代。用这些化合物实现了对sigma 1和sigma 2结合位点的高亲和力。另外，这些化合物对5-羟色胺5-HT1A和5-HT2A，多巴胺D2和肾上腺素α1受体具有较高的亲和力。在吲哚氮原子处引入4-氟苯基取代基使得对σ2结合位点具有亚纳摩尔亲和力的非常选择性的σ2配体。这种化合物的原型是1-（4-氟苯基）-3- [4- [4-（4-氟苯基）-1-哌啶基] -1-丁基] -1H-吲哚，11a（代码Lu 29） -253）。该化合物具有以下结合亲和力：IC50（sigma 1）= 16 nM，IC50（sigma 2）= 0.27 nM，IC50（5-HT1A）= 22,000 nM，IC50（5-HT2A）= 270 nM，IC50（D2）=
• Novel indole-based sigma-2 receptor ligands: synthesis, structure–affinity relationship and antiproliferative activity
  作者：Fang Xie、Torsten Kniess、Christin Neuber、Winnie Deuther-Conrad、Constantin Mamat、Brian P. Lieberman、Boli Liu、Robert H. Mach、Peter Brust、Jörg Steinbach、Jens Pietzsch、Hongmei Jia

  DOI：10.1039/c5md00079c

  日期：——

  Novel sigma-2 ligand 1b induced G₁ phase cell cycle arrest in DU145 cells and displayed antiproliferative activity.

  小说sigma-2 配体1b在DU145细胞中诱导G1期细胞周期停滞并显示抗增殖活性。
• 1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine] hydrohalogenides
  申请人：H. Lundbeck A/S

  公开号：US20030055074A1

  公开（公告）日：2003-03-20

  The present invention relates to a hydrohalogenide of 1′-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4′-piperidine], pharmaceutical compositions containing the acid addition salts and the use thereof for the treatment of psychic and neurological disorders.

  本发明涉及1'-［4-［1-(4-氟苯基)-1H-吲哚-3-基］-1-丁基］-螺［异苯并呋喃-1(3H),4'-哌啶］的氢卤化物，含有酸盐补充物的药物组合物以及其用于治疗精神和神经系统疾病的用途。
• Piperidine derivatives
  申请人：H. LUNDBECK A/S

  公开号：EP0518805A1

  公开（公告）日：1992-12-16

  Piperidine compounds having the general general Formula I wherein R¹ is a) a group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, cycloalkylalkyl, cycloalkenylalkyl, phenylalkyl or diphenylalkyl linked to the piperidyl N-atom through an at least 2 membered spacer group or; b) a group having the general Formula II : wherein X is CHR¹⁰, O, S, SO, SO₂ or NR¹⁰, R¹⁰ being hydrogen, alkyl or alkenyl, an amino group, sulfonyl, optionally substituted phenyl or a hetero aromatic group; Y is CH, CH₂, NH, C=O or C=S; Ra - Rd are substituents; U is CH₂, O or S; Q¹ is a bond , alkylene or alkenylen and Q² alkylene having at least two C-atoms or alkenylene R² and R³ are hydrogen, or alkyl or they may together form an ethylene or propylene bridge; R⁴ to R⁷ are substituents; and i) Z¹ and Z² are linked together in which case: Z¹ is CH₂, O or S; Z² and Z³ are independently (CH₂)n, n being 0 or 1, O or S or Z¹ and Z² may together represent a group -CH=CH-; or when Z³ is (CH₂)n wherein n is 0, Z¹ and Z² may together represent a 3-membered divalent group; or ii) when R¹ is a group as defined in b) Z¹ and Z² may also be unlinked, in which case: Z¹ is substituent, Z² is hydrogen and Z³ is (CH₂)n wherein n is 0; show potent sigma receptor activity. Furthermore they show effect in animal models indicative of anxiolytic properties. Accordingly they are useful as medicines for the treatment of anxiety, psychosis, epilepsy, convulsion, movement disorders, motor disturbances, amnesia, cerebrovascular diseases, senile dementia of the Alzheimer type or Parkinson's disease.

  具有一般式I的哌啶化合物，其中R¹是a)由至少2个成员的间隔基团连接到哌啶N原子的烷基，烯基，环烷基，环烯基，苯基，环烷基烷基，环烯基烷基，苯基烷基或二苯基烷基的群；或b)具有一般式II的群：其中X是CHR¹⁰，O，S，SO，SO₂或NR¹⁰，R¹⁰为氢，烷基或烯基，氨基，磺酰基，可选取代的苯基或杂环芳基；Y是CH，CH₂，NH，C=O或C=S；Ra至Rd是取代基；U是CH₂，O或S；Q¹是键，烷基或烯基，Q²是至少有两个C原子的烷基或烯基，R²和R³是氢，或烷基，或它们可以一起形成乙烯或丙烯桥；R⁴到R⁷是取代基；i）Z¹和Z²连接在一起的情况下：Z¹是CH₂，O或S；Z²和Z³是独立的（CH₂）n，n为0或1，O或S，或Z¹和Z²可以一起表示一个组-CH=CH-；或者当Z³为（CH₂）n，其中n为0时，Z¹和Z²可以一起表示一个3成员双价基团；或ii）当R¹是b）中定义的群时，Z¹和Z²也可以未连接，在这种情况下：Z¹是取代基，Z²是氢，Z³是（CH₂）n，其中n为0；具有强大的sigma受体活性。此外，它们在动物模型中表现出具有抗焦虑特性的效果。因此，它们可用作治疗焦虑症，精神病，癫痫，惊厥，运动障碍，记忆障碍，脑血管疾病，阿尔茨海默病或帕金森病的药物。
• 1'-[4-[1-(4-fluorophenyl)-1H-indole-3-Y1]-spiro[isobenzofuran-1(3H), 4'-piperidine]hydrohalogenides
  申请人：Mork Niels

  公开号：US20050171135A1

  公开（公告）日：2005-08-04

  The present invention relates to a hydrohalogenide of 1′-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H),4′-piperidine], pharmaceutical compositions containing the acid addition salts and the use thereof for the treatment of psychic and neurological disorders.

  本发明涉及1'-[4-[1-(4-氟苯基)-1H-吲哚-3-基]-1-丁基]-螺[异苯并呋喃-1(3H)，4'-哌啶]的氢卤化物，含有酸加成盐的药物组合物和其用于治疗心理和神经系统疾病的用途。