6,7-dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolinium chloride

• 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: 6,7-dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolinium chloride
• 英文别名: (1S,2S)-6,7-Dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolinium chloride；3-[(1S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propan-1-ol;chloride
• 化学式: C₂₄H₃₄NO₆*Cl
• 分子量: 467.99
• InChiKey: WVHFCWPFYUIXHV-CPRVELNDSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  0.21
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  66.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  chlorofumaryl chloride 、 6,7-dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolinium chloride 以 1,2-二氯乙烷 为溶剂， 生成
  参考文献：
  名称：

  Bis- and Mixed-Tetrahydroisoquinolinium Chlorofumarates:  New Ultra-Short-Acting Nondepolarizing Neuromuscular Blockers

  摘要：

  DOI：

  10.1021/jm980597h
• 作为产物：
  描述：

  (1S)-6,7-dimethoxy-2-methyl-1-(2,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline 、 丁酮 、 3-氯-1-丙醇 在 sodium iodide 、 sodium carbonate 作用下， 以 水 为溶剂， 以99%的产率得到6,7-dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolinium chloride
  参考文献：
  名称：

  Substituted isoquinolines as ultra short acting neuromuscular blockers

  摘要：

  本发明涉及公式（I）的超短作用神经肌肉松弛剂，其在紧急插管、常规手术和术后情况下作为骨骼肌松弛剂非常有用，其中q和t独立地为0到4；X1和X2独立地为卤素；ha和hb独立地为0到2；Z1和Z2独立地为氢、C1-6烷基、C2-6烯基或C2-6炔基，但须满足Z1和Z2不同时为氢；Y1、Y2、Y3和Y4独立地为氢、卤素或C1-3烷氧基；m和p独立地为1到6；n和r独立地为0到4；但须满足如果ha和hb都为0，则r为0且n为0到2；R1到R14独立地为氢、卤素、C1-3烷氧基，或者R2和R3与它们所结合的碳原子、R5和R6与它们所结合的碳原子、R9和R10与它们所结合的碳原子、R12和R13与它们所结合的碳原子可以独立地形成包含在五元或六元环中的亚甲二氧基或乙撑二氧基基团；W1和W2为碳；A是一种药学上可接受的阴离子。

  公开号：

  US06177445B1

文献信息

• Isoquinolines and preparation thereof
  申请人：Avera Pharmaceuticals, Inc.

  公开号：EP1380573A2

  公开（公告）日：2004-01-14

  A compound of Formula (III): wherein Y is selected from the group consisting of hydrogen or methoxy, W comprises a chiral center selected from the group consisting of a carbon atom having an R configuration and a carbon atom having an S configuration, n comprises 0 or 1, and A- comprises a pharmaceutically acceptable anion and process of preparation.

  式（III）化合物： 其中 Y 选自由氢或甲氧基组成的组，W 包括一个手性中心，该手性中心选自由具有 R 构型的碳原子和具有 S 构型的碳原子组成的组，n 包括 0 或 1，A- 包括一个药学上可接受的阴离子，以及制备方法。
• Synthesis of Ultra-Short-Acting Neuromuscular Blocker GW 0430:  A Remarkably Stereo- and Regioselective Synthesis of Mixed Tetrahydroisoquinolinium Chlorofumarates
  作者：Vicente Samano、John A. Ray、James B. Thompson、Robert A. Mook、David K. Jung、Cecilia S. Koble、Michael T. Martin、Eric C. Bigham、Craig S. Regitz、Paul L. Feldman、Eric E. Boros

  DOI：10.1021/ol9911573

  日期：1999.12.1

  [GRAPHICS]The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is described. Key steps involved the enantioselective transfer hydrogenation of imine 8 employing Noyori's catalyst, the stereoselective crystallization and methanolysis of trans-betaines 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride from 14, The latter transformation allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.
• Neuromuscular Blocking Activity and Therapeutic Potential of Mixed-Tetrahydroisoquinolinium Halofumarates and Halosuccinates in Rhesus Monkeys
  作者：Eric E. Boros、Vicente Samano、John A. Ray、James B. Thompson、David K. Jung、Istvan Kaldor、Cecilia S. Koble、Michael T. Martin、Virgil L. Styles、Robert A. Mook、Paul L. Feldman、John J. Savarese、Matthew R. Belmont、Eric C. Bigham、G. Evan Boswell、Mir A. Hashim、Sanjay S. Patel、James C. Wisowaty、Gary D. Bowers、Caroline L. Moseley、John S. Walsh、Mindy J. Reese、Randy D. Rutkowske、Andrea M. Sefler、Timothy D. Spitzer

  DOI：10.1021/jm020574+

  日期：2003.6.1

  Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED95 = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED95) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED95 value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED95 = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED95 = 0.103 mg/kg), difluorosuccinate (27c; ED95 = 0.056 mg/kg), and fluorofumarate (28a; ED95 = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 mug/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.
• SUBTITUTED ISOQUINOLINES AS ULTRA SHORT ACTING NEUROMUSCULAR BLOCKERS
  申请人：Avera Pharmaceuticals, Inc.

  公开号：EP0975599B1

  公开（公告）日：2003-11-12
• SUBSTITUTED ISOQUINOLINES AS ULTRA SHORT ACTING NEUROMUSCULAR BLOCKERS
  申请人：Avera Pharmaceuticals, Inc.

  公开号：EP0971898B1

  公开（公告）日：2005-05-11