cis-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: cis-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline
• 英文别名: trans-6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline；(6R,10bR)-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-RTBURBONSA-N

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：

  cis-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline 在 sodium periodate 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 48.0h， 以42%的产率得到cis-1,2,3,5,6,10b-hexahydro-6-<4-(methylsulfinyl)phenyl>pyrrolo<2,1-a>isoquinoline
  参考文献：
  名称：

  Pyrroloisoquinoline antidepressants. 3. A focus on serotonin

  摘要：

  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.

  DOI：

  10.1021/jm00172a018
• 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 cis-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'
• MARYANOFF, BRUCE E.;MCCOMSEY, DAVID F.;MUTTER, MARTIN S.;SORGI, KIRK L.;M+, TETRAHEDRON LETT., 29,(1988) N 40, C. 5073-5076
  作者：MARYANOFF, BRUCE E.、MCCOMSEY, DAVID F.、MUTTER, MARTIN S.、SORGI, KIRK L.、M+

  DOI：——

  日期：——
• 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.
• The structure of McN-5652
  作者：Oliver Schulze、Ulrich Schmidt、Jürgen Voss、Bruno Nebeling、Gunadi Adiwidjaja、Klaus Scharwächter

  DOI：10.1016/s0968-0896(01)00117-1

  日期：2001.8

  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.