trans-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline | 90390-64-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: trans-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline
• 英文别名: (+/-)-trans-1,2,3,5,6,10b-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline；cis-6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline；McN-5652；(6R,10bS)-6-(4-methylsulfanylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline
• CAS: 90390-64-0；96795-89-0；103729-13-1；103729-16-4；119341-63-8；125410-76-6；142759-08-8；142759-12-4
• 化学式: C₁₉H₂₁NS
• 分子量: 295.448
• InChiKey: YVKDUIAAPBKHMJ-MOPGFXCFSA-N

物化性质

• 溶解度：
  1当量中<14.77mg/ml盐酸； <22.16mg/ml，溶于 DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  28.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  trans-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline 在 氨 、 sodium 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652

  摘要：

  An improved synthesis of the enantiomerically pure thioester precursors of [C-11](+)-McN-5652 ([C-11](+)-1), and [C-11](-)-McN5652 ([C-11](-)-1) starting from racemic McN-5652 ((+/-)-1) is described. The Synthetic method includes the resolution of (+/-)-1 by:repeated crystallization of the (+)- and (-)-di-p-toluoyltartrates yielding (+)-McN-5652 ((+)-1) and (-)-McN-5652 ((-)-1), each with >98% enantiomeric purity. S-Demethylation of (+/-)-1, (+)-1 and (-)-1, respectively was achieved by:treatment with sodium amide at low temperatures (-78 degrees C) followed by conversion of the intermediate thiols 2 with acetyl chloride to give the corresponding thioester precursors (+/-)-3, (+)-3 oy:(-)-3. This demethylation method almost completely suppressed the isomerization of the pharmacologically active trans diastereomer into the inactive cis form. Chiral HPLC analyses confirmed that the S-demethylation proceeded without any racemization. C-11-labelling of(+)-3 or (-)-3 yields :enantiomerically pure [C-11](+)-McN-5652 or [C-11](-)-McN5652, each in 22 % radiochemical yield (decay-corrected, related to [C-11]CO2) and a specific radioactivity of 74 GBq/mu mol (2 Ci/mu mol) at the end of synthesis (EOS).

  DOI：

  10.1002/(sici)1099-1344(19991230)42:13<1301::aid-jlcr298>3.0.co;2-2
• 作为产物：
  描述：

  4-methylthiomandelic acid 在 BH₂-THF 、 硫酸 、 对甲苯磺酸 作用下， 以 三氟乙酸 、 xylene 为溶剂， 生成 trans-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline
  参考文献：
  名称：

  The structure of McN-5652

  摘要：

  The configuration of the diastereoisomers of 6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2, I-a]isoquinoline I (McN-5652) is determined and unequivocally assigned by NMR spectroscopy (NOE measurements) and an X-ray structural analysis of the trans dia stereo isomer. The enantiomers of cis-1 are separated by preparative HPLC on a chiral phase. One of the enantiomers of cis-1 represents the precursor for imaging the serotonin 5-HT transporter with positron emission tomography (PET). (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00117-1

文献信息

• Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships
  作者：Bruce E. Maryanoff、David F. McComsey、Joseph F. Gardocki、Richard P. Shank、Michael J. Costanzo、Samuel O. Nortey、Craig R. Schneider、Paulette E. Setler

  DOI：10.1021/jm00391a028

  日期：1987.8

  verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and

  一系列吡咯并[2,1-a]异喹啉和相关化合物由于对丁苯那嗪诱导的上睑下垂和镇静作用以及对生物胺吸收的抑制作用而被检测为抗抑郁样活性。因此，我们已经鉴定出有史以来报道的一些最有效的TBZ诱导上睑下垂拮抗剂和一些最有效的多巴胺，去甲肾上腺素和血清素摄取抑制剂（在大鼠脑突触体中）。在这方面，特别值得注意的化合物分别是52b，29b，22b和48b。生物活性主要由反式异构体表现出来。而且，通过拆分四种化合物7b，24b，37b和48b，发现生物活性与（+）对映异构体亚组（在589 nm在MeOH中测得的盐）相关，对应于6S，10bR的绝对构型7b，37b，和48b，以及24b的6R，10bR配置。在（+）-24b X HBr上进行X射线测定，确定了其绝对构型；通过（+）-（R）-2-苯基吡咯烷开始的对映体特异性合成，验证了其他化合物的构型。关于侧苯环，研究了多种取代方式。那些特别不利的取代基是3'
• 4-Haloethenyphenyl tropane:serotonin transporter imaging agents
  申请人：——

  公开号：US20020099184A1

  公开（公告）日：2002-07-25

  A series of compounds in the 4-fluoroalkyl-3-halophenyl nortropanes and 4-haloethenylphenyl tropane families are described as diagnostic and therapeutic agents for diseases associated with serotonin transporter dysfunction. These compounds bind to serotonin transporter protein with high affinity and selectivity. The invention provides methods of synthesis which incorporate radioisotopic halogens at a last step which permit high radiochemical yield and maximum usable product life. The radiolabeled compounds of the invention are useful as imaging agents for visualizing the location and density of serotonin transporter by PET and SPECT imaging.

  本研究描述了一系列 4-氟烷基-3-卤代苯基去甲托烷和 4-卤代乙烯基苯基托烷家族的化合物，这些化合物可作为诊断和治疗与血清素转运体功能障碍有关的疾病的药物。这些化合物与血清素转运体蛋白的结合具有很高的亲和力和选择性。本发明提供了在最后一步加入放射性同位素卤素的合成方法，这种方法可以获得较高的放射化学收率和最长的产品使用寿命。本发明的放射性标记化合物可用作成像剂，通过 PET 和 SPECT 成像观察血清素转运体的位置和密度。
• Pyrroloisoquinoline antidepressants. 3. A focus on serotonin
  作者：Bruce E. Maryanoff、Jeffry L. Vaught、Richard P. Shank、David F. McComsey、Michael J. Costanzo、Samuel O. Nortey

  DOI：10.1021/jm00172a018

  日期：1990.10

  A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
• Stereoconservative synthesis of the enantiomerically pure precursors of [11C](+)-McN 5652 and [11C](−)-McN 5652
  作者：Yiyun Huang、Khalid Mahmood、Norman R. Simpson、N. Scott Mason、Chester A. Mathis

  DOI：10.1002/(sici)1099-1344(199801)41:1<9::aid-jlcr47>3.0.co;2-8

  日期：1998.1
• 4-FLUOROALKYL-3-HALOPHENYL NORTROPANES
  申请人：Emory University

  公开号：EP1212103B1

  公开（公告）日：2004-11-03