17-<(N,N'-diethoxycarbonylhydrazino)methyl>northebaine | 101064-81-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: 17-<(N,N'-diethoxycarbonylhydrazino)methyl>northebaine
• 英文别名: ethyl N-[[(4R,7aR,12bS)-7,9-dimethoxy-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-yl]methyl]-N-(ethoxycarbonylamino)carbamate
• CAS: 101064-81-7
• 化学式: C₂₅H₃₁N₃O₇
• 分子量: 485.537
• InChiKey: SOOLOKPJIMZENA-MCCOCYNGSA-N

物化性质

• 熔点：
  168-170 °C
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  98.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  17-<(N,N'-diethoxycarbonylhydrazino)methyl>northebaine 在 lithium aluminium tetrahydride 、 吡啶盐酸盐 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 3.5h， 生成 N-(cyclopropylmethyl)northebaine
  参考文献：
  名称：

  Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives

  摘要：

  Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the S-35-GTP[gamma S] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.05.027
• 作为产物：
  描述：

  蒂巴因 、 偶氮二甲酸二乙酯 以 苯 为溶剂， 生成 17-<(N,N'-diethoxycarbonylhydrazino)methyl>northebaine
  参考文献：
  名称：

  Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives

  摘要：

  Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the S-35-GTP[gamma S] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.05.027

文献信息

• Diels-alder reaction of thebaine via N-formylnorthebaine with nitroethene; reduction of the nitro group in 7α-nitroethenoisomorphinans (chemistry of opium alkaloids, part XX)
  作者：L. Maat、J. A. Peters、M. A. Prazeres

  DOI：10.1002/recl.19851040705

  日期：——

  Thebaine (1) was converted into N-formylnorthebaine (4) via N-demethylation using diethyl azodicarboxylate followed by treatment with ethyl formate. Diels-Alder reaction of 4 with nitroethene yielded 5 exclusively with the 6α,14α-etheno bridge and the nitro group in the 7α-position. Hydrolysis of 5 and methylation then gave 7, the nitroethene addition product of thebaine. Reduction of 5 and 7 with

  通过使用偶氮二羧酸二乙酯的N-去甲基化将蒂巴因（1）转化为N-甲酰基去甲茶碱（4），然后用甲酸乙酯处理。4与硝基乙烯的Diels-Alder反应仅在6α，14α-乙烯桥和7α位的硝基上产生5。5的水解和甲基化然后得到7，蒂巴因的硝基乙烯加成产物。用铝汞合金还原5和7分别得到相应的7α-胺11和8。减少7用甲am亚磺酸或氢化铝锂只得到肟9。
• Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity
  作者：Yunyun Yuan、Saheem A. Zaidi、Orgil Elbegdorj、Lindsey C. K. Aschenbach、Guo Li、David L. Stevens、Krista L. Scoggins、William L. Dewey、Dana E. Selley、Yan Zhang

  DOI：10.1021/jm4012214

  日期：2013.11.27

  On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue-facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine-dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment.
• Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives
  作者：Yan Zhang、Orgil Elbegdorj、Yunyun Yuan、Irina O. Beletskaya、Dana E. Selley

  DOI：10.1016/j.bmcl.2013.05.027

  日期：2013.7

  Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the S-35-GTP[gamma S] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. Published by Elsevier Ltd.