(2alpha,6alpha,11R*)-1,2,3,4,5,6-六氢-6,11-二甲基-2,6-甲桥-3-苯并氮杂环辛四烯-8-醇 | 25144-78-9

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 6,7-苯并吗啡烷
• 中文名称: (2alpha,6alpha,11R*)-1,2,3,4,5,6-六氢-6,11-二甲基-2,6-甲桥-3-苯并氮杂环辛四烯-8-醇
• 中文别名: dl-甲硝唑嗪
• 英文名称: (+)-cis-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan
• 英文别名: (+)-cis-normetazocine；(+)-cis-N-Normetazocine；(+)-Normetazocine；(1S,9S,13S)-1,13-dimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-ol
• CAS: 25144-78-9
• 化学式: C₁₄H₁₉NO
• 分子量: 217.311
• InChiKey: DXESFJJJWBHLJX-IIMNLJJBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  32.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2alpha,6alpha,11R*)-1,2,3,4,5,6-六氢-6,11-二甲基-2,6-甲桥-3-苯并氮杂环辛四烯-8-醇 在 palladium on activated charcoal potassium carbonate 作用下， 以 乙醇 、 环己烷 、 丙酮 为溶剂， 反应 41.0h， 生成 (+)-5,9α-dimethyl-6,7-benzomorphan
  参考文献：
  名称：

  Synthesis and .sigma. Binding Properties of 2'-Substituted 5,9.alpha.-Dimethyl-6,7-benzomorphans

  摘要：

  The synthesis and sigma 1 and sigma 2 binding properties of several (+)- and (-)-2-benzyl- and 2-dimethylallyl-2'-substituted-5,9 alpha-dimethyl-6,7-benzomorphans (3 and 4) are presented. In agreement with previously reported binding data for 2-substituted 5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans (N-substituted-N-normetazocine), all (1S,5S,SS)-(+)-isomers showed higher affinity for the sigma 1 site than the corresponding (1R,5R,9R)-(-)-isomers. Replacement of the 2'-hydroxy group of (+)-2-benzyl-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1f] with a 2'-NH2 and 2'-N(CH3)(2) [(+)-3b and (+)-3c, respectively] had only a small effect on the sigma 1 K-i values. Changing the 2'-hydroxy group of (+)-1f to an H, F, Cl, Br, I, NHAc, or NHSO2CH3 resulted in a 5-fold or greater loss in potency. In contrast, replacement of the 2'-hydroxy group of (+)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphan [(+)-1b, (+)-pentazocine] with a 2'-H or 2'-F group resulted in a 2-fold increase in potency. Conversion of (+)-1f to its 2'-desoxy analogue (+)-2d resulted in a 27.5-fold loss in affinity. This suggests that (+)-1f and other N-substituted benzomorphan analogues may be binding to single al receptors in a different way or to different sigma 1 receptors. (-)-Pentazocine [(-)-1b] and its 2'-fluoro analogue, (-)-2-(dimethylallyl)-5,9 alpha-dimethyl-2'-fluoro-6,7-benzomorphan [(-)-4a] showed the highest potency for the sigma 2 binding site.

  DOI：

  10.1021/jm00015a022
• 作为产物：
  描述：

  4-methoxybenzylmagnesium chloride 在 palladium on activated charcoal 盐酸 、 sodium tetrahydroborate 、 氢溴酸 、 氢气 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 39.5h， 生成 (2alpha,6alpha,11R*)-1,2,3,4,5,6-六氢-6,11-二甲基-2,6-甲桥-3-苯并氮杂环辛四烯-8-醇
  参考文献：
  名称：

  A stereocontrolled alkylation of chiral pyridinium salts with Grignard reagents: synthesis of (+)-normetazocine and (+)-nordextrorphan

  摘要：

  The synthesis of chiral pyridinium salts 3, bearing lipophilic counteranions, is described. These salts, soluble in THF or toluene, undergo nucleophilic alkylation with benzylic Grignard reagents to give, after reduction of the unstable dihydropyridine intermediates, adducts 4 with regio- and stereoselective attack at position 2, the observed stereoselectivity ranging from 8:1 to 12.5:1. These results allowed an asymmetric synthesis, following Grewe's route, of (+)-normetazocine and (+)-nordextrorphan, key precursors of various benzomorphan or morphinan drugs.

  DOI：

  10.1021/jo00060a019

文献信息

• Synthesis and Structure−Activity Relationships of 6,7-Benzomorphan Derivatives as Antagonists of the NMDA Receptor−Channel Complex
  作者：Matthias Grauert、Wolf Dietrich Bechtel、Helmut A. Ensinger、Herbert Merz、Adrian J. Carter

  DOI：10.1021/jm970131j

  日期：1997.8.1

  function was also found to influence the specificity of the compounds. Shift of the hydroxy group from the 2'-position to the 3'-position significantly increased the affinity for the NMDA receptor-channel complex and considerably reduced the affinity for the mu opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr.HCl [(2R)-[2 alpha, 3(R*),6 alpha]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6

  我们已经合成了一系列具有修饰的N-取代基的立体异构体6,7-苯并吗啡衍生物，并确定了它们在体外和体内拮抗N-甲基-D-天冬氨酸（NMDA）受体通道复合物的能力。将化合物从大鼠脑突触体膜中的NMDA受体的通道位点置换[3H] -MK-801的能力和抑制NMDA诱导的小鼠致死性的能力与它们与μ阿片受体结合的能力进行了比较。结构-活性关系的研究表明，绝对立体化学对于区分这两种作用至关重要。（-）-1R，9 beta，2“ S-对映异构体对NMDA受体通道复合物的亲和力高于对μ阿片受体的亲和力。还发现芳香族羟基官能团会影响化合物的特异性。羟基从2'-位置向3'-位置的转移显着增加了对NMDA受体-通道复合物的亲和力，并显着降低了对μ阿片样物质受体的亲和力。从这一系列的6,7-苯并吗啉衍生物中，化合物15cr.HCl [（2R）-[2 alpha，3（R *），6 alpha] -1,2,3,4,5
• Synthesis of a radiotracer for studying σ receptors in vivo using PET: (+)-N-[11C]-benzyl-N-normetazocine (1S, 5S,9S-(+)-cis-2-[11C]-2′-hydroxy-5,9-dimethyl-6,7-benzomorphan)
  作者：John L. Musachio、William B. Mathews、Hayden T. Ravert、F. Ivy Carroll、Robert F. Dannals

  DOI：10.1002/jlcr.2580340107

  日期：1994.1

  (+)-N-[11C]-Benzyl-N-normetazocine (1S,5S,9S-(+)-cis-2-[11C]-benzyl-2′-hydroxy-5,9-dimethyl-6,7-benzomorphan), a potent and selective ligand for the σ receptor, was prepared by N-benzylation of (+)-cis-N-normetazocine with [α-11C]-benzyl iodide in ethanol using sodium hydrogen carbonate as the proton acceptor. The radiotracer was purified by semi-preparative reverse-phase HPLC. The average specific activity was 746 mCi/μmol calculated at end-of-synthesis (EOS). The average time of synthesis including formulation was 35 minutes.

  (+)-N-[11C]-苄基-N-诺美他佐辛（1S,5S,9S-(+)-顺-2-[11C]-苄基-2′-羟基-5,9-二甲基-6,7-苯并吗喃）是一种强效且具有选择性的σ受体配体，通过在乙醇中使用碳酸氢钠作为质子接受体，将(+)-顺-N-诺美他佐辛与[α-11C]-苄基碘进行N-苄基化反应制备得到。该放射性示踪剂通过半制备性反相高效液相色谱法进行纯化。计算得到的平均比活度在合成结束时（EOS）为746 mCi/μmol。合成及配制的平均时间为35分钟。
• Improved Resolution of (±)-<i>cis</i>-2′-Hydroxy-5,9-dimethyl-6, 7-benzomorphan and Preparation of Racemic, (+)-, and (-)-<i>cis</i>-2-Methylcyclopropyl-2′-hydroxy-5,9-dimethyl-6,7-benzomorphan (Cyclazocine)
  作者：William A. Boulanger

  DOI：10.1080/00397919908086216

  日期：1999.6

  Abstract We report novel procedures for the efficient resolution of (±)-cis-2 -hydroxy-5, 9-dimethyl-6, 7-benzomorphan via the (-)-N-acetyl-L-glutamate and (+)-α-bromocamphor-φ-sulfonate salts, the direct N-substitution of the (+)-α-bromocamphor-φ-sulfonate salts, and the use of these methods for the synthesis of racemic, (+)-, and (-)-cyclazocine.

  摘要 我们报告了通过 (-)-N-乙酰基-L-谷氨酸和 (+)-α 有效拆分 (±)-cis-2 -hydroxy-5, 9-dimethyl-6, 7-benzomorphan 的新程序-溴樟脑-φ-磺酸盐，(+)-α-溴樟脑-φ-磺酸盐的直接N-取代，以及使用这些方法合成外消旋、(+)-和(-)-环佐辛。
• Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at .sigma., PCP, and .mu. opioid receptors
  作者：F. I. Carroll、P. Abraham、K. Parham、X. Bai、X. Zhang、G. A. Brine、S. W. Mascarella、B. R. Martin、E. L. May、C Sauss、L Di Paolo、P Wallace、J. M. Walker、W. D. Bowen

  DOI：10.1021/jm00093a014

  日期：1992.7

  their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted

  N-烯丙基-N-去甲甲氮嗪的光学对映体（2; SKF 10047，NANM）是用于σ受体分类的原始化合物，与其他受体（例如PCP（NMDA），阿片类和多巴胺受体）不同。后来的研究表明（+）-N-（二甲基烯丙基）-N-去甲偶氮辛[（+）-4，（+）-戊三嗪]对sigma受体更有效且更具选择性。为了获得更多的结构-活性关系信息，制备了几种N-取代的N-正甲氮嗪类似物，并对其σ-1（[3H]-（+）-3-PPP或[3H]-（+）-戊唑嗪进行了评估），PCP（[3H] TCP）和mu阿片类药物（[3H] DAMGO）受体结合亲和力。（+）-N-苄基-N-去甲偶氮辛[（+）-10）对sigma位点具有亚纳摩尔亲和力，Ki = 0.67。类似物（+）-10的选择性分别超过14,000和2400倍，相对于PCP和mu阿片类药物受体来说是σ受体。N-取代的N-去甲氮嗪对sigma位点是对映选择性的。（+）
• (+)-and (−)-Phenazocine enantiomers: Evaluation of their dual opioid agonist/σ1 antagonist properties and antinociceptive effects
  作者：O. Prezzavento、E. Arena、C. Sánchez-Fernández、R. Turnaturi、C. Parenti、A. Marrazzo、R. Catalano、E. Amata、L. Pasquinucci、E.J. Cobos

  DOI：10.1016/j.ejmech.2016.09.077

  日期：2017.1

  the σ1 receptor affinity of (+)-and (−)-phenazocine (Ki = 3.8 ± 0.4 nM, Ki = 85 ± 2.0 nM, respectively) suggesting a σ1 antagonist profile of both enantiomers. This σ1 antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ1 receptor agonist PRE-084, was able to unmask their σ1 antagonistic component associated with the opioid activity. The

  顺式- ñ -取代Ñ -normetazocine对映异构体具有独特的药理分布。事实上，对映异构体右旋以高亲和力结合σ 1个受体而相反对映异构体结合阿片受体。尽管它们的立体化学，的顺式- ñ -2-苯乙基Ñ -normetazocine（非那佐辛）对映异构体显示出混合的阿片样物质/σ 1受体型材和体内镇痛显著。据我们所知，没有关于σ的评价没有可用的信息，1对药理个人资料的镇痛作用（+）-和（ - ）-吩唑嗪。因此，本研究旨在通过体外和体内研究确定该成分。 特别地，我们测试了σ 1通过在不存在或苯妥英（DPH）的存在下的预测性结合测定两种对映体的亲和力。我们的研究结果表明，DPH（1毫米）并没有增加σ 1的（+）受体的亲和力-和（ - ）-非那佐辛（K我 = 3.8±0.4nM的，K我 = 85±2.0纳米，分别），表明一个σ两种对映异构体的1个拮抗剂图谱。这个σ 1 2个非那佐辛对映异构体