3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one | 501022-57-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one
• 英文别名: benzyl N-[[3-methyl-6-oxo-5-(phenylmethoxycarbonylaminomethyl)-1H-pyrazin-2-yl]methyl]carbamate
• CAS: 501022-57-7
• 化学式: C₂₃H₂₄N₄O₅
• 分子量: 436.467
• InChiKey: AUYXKXWOYPLUIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  118
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one 在 N-甲基吗啉 、 氢溴酸 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.0h， 生成 3,6-bis[(Nα-Boc-Tyr)aminomethyl]-5-methyl-2(1H)-pyrazinone
  参考文献：
  名称：

  Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH₂)_n]-2(1H)-pyrazinone with Central-Mediated Analgesia

  摘要：

  The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.

  DOI：

  10.1021/jm0304616
• 作为产物：
  描述：

  N-叔丁氧羰基-3-[(苄氧羰基)氨基]-L-丙氨酸 在 盐酸 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 生成 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one
  参考文献：
  名称：

  Studies on the Mechanism of 1,2-Dihydropyrazin-2-one Ring Formation from Dipeptidyl Chloromethyl Ketone and Its Chemical Properties: Immediate Deamination during Catalytic Hydrogenation

  摘要：

  在3和6位具有两个氨基烷基团的1,2-二氢吡嗪-2-酮衍生物被发现是构建强效、选择性和长效类吗啡模拟物的有效工具。在准备过程中，我们发现3,6-双(苄氧羰基氨基甲基)-5-甲基-1,2-二氢吡嗪-2-酮的催化氢化以去除苄氧羰基基团导致了副反应。通过质谱和核磁共振研究以及制备额外的1,2-二氢吡嗪-2-酮衍生物，副产物的结构被鉴定为3-氨基甲基-5,6-二甲基-1,2-二氢吡嗪-2-酮。制备含有氘的额外化合物为我们提供了足够的信息以确认产物的结构并支持其形成的环化机制。

  DOI：

  10.1248/cpb.53.1152

文献信息

• Potent Dmt-Tic Pharmacophoric δ- and μ-Opioid Receptor Antagonists
  作者：Tingyou Li、Yoshio Fujita、Kimitaka Shiotani、Anna Miyazaki、Yuko Tsuda、Akihiro Ambo、Yusuke Sasaki、Yunden Jinsmaa、Ewa Marczak、Sharon D. Bryant、Severo Salvadori、Lawrence H. Lazarus、Yoshio Okada

  DOI：10.1021/jm050377l

  日期：2005.12.1

  A series of dimeric Dmt-Tic (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) analogues (8-14, 18-22) were covalently linked through diaminoalkane and symmetric or asymmetric 3,6-diaminoalkyl-2(1H)-pyrazinone moieties. All the compounds exhibited high affinity for both 6-opioid receptors K(6) = 0.06-1.53 nM] andy-opioid receptors [K-i(mu) = 1.375.72 nM], resulting in moderate delta-receptor selectivity [K-i(mu)/K-i(delta) = 3-46]. Regardless of the type of linker between the Dmt-Tic pharmacophores, delta-opioid-mediated antagonism was extraordinarily high in all analogues (pA(2) = 10.42-11.28), while in vitro agonism (MVD and GPI bioassays) was essentially absent (ca. 3 to > 10 mu M). While an unmodified N-terminus (9, 13, 18) revealed weaku-opioid antagonism (pA(2) = 6.78-6.99), N,N'-dimethylation (21, 22), which negatively impacts on mu-opioid-associated agonism (Balboni et al., Bioorg. Med. Chem. 2003, 11, 5435-5441), markedly enhanced mu-opioid antagonism (pA(2) = 8.34 and 7.71 for 21 and 22, respectively) without affecting 6-opioid activity. These data are the first evidence that a single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potent 6- andy-opioid antagonist activities.
• Immediate deamination from the aminomethyl group attached to 1,2-dihydropyrazin-2-one derivative during catalytic hydrogenation
  作者：Yoshio Okada、Yutaka Fujisawa、Akihisa Morishita、Kimitaka Shiotani、Anna Miyazaki、Yoshio Fujita、Tingyou Li、Yuko Tsuda、Toshio Yokoi、Sharon D. Bryant、Lawrence H. Lazarus

  DOI：10.1016/s0040-4039(02)01944-5

  日期：2002.11

  The catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove benzyloxycarbonyl (Z) groups resulted ill a side reaction. Purification by reverse-phase HPLC and analysis by proton unclear magnetic resonance (H-1 NMR) spectroscopy identified the product as 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one. It was determined through the synthesis of two 1,2-dihydropyrazin-2-one derivatives, composed of alanine and 2,3-diaminopropionic acid that deamination occurred specifically and easily (under atmospheric pressure and at the room temperature) Only in the case of 6-benzyloxycarbonylaminomethyl-3,5-dimethyl-1,2-dihydropyrazin-2-one. The catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one specifically yields the deaminated product, 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Studies on the Mechanism of 1,2-Dihydropyrazin-2-one Ring Formation from Dipeptidyl Chloromethyl Ketone and Its Chemical Properties: Immediate Deamination during Catalytic Hydrogenation
  作者：Anna Miyazaki、Yutaka Fujisawa、Kimitaka Shiotani、Yoshio Fujita、Tingyou Li、Yuko Tsuda、Toshio Yokoi、Sharon D. Bryant、Lawrence H. Lazarus、Yoshio Okada

  DOI：10.1248/cpb.53.1152

  日期：——

  1,2-Dihydropyrazin-2-one derivatives, which have two aminoalkyl groups at the positions 3 and 6, were found to be efficient tools for the construction of potent, selective and long-acting opioid mimetics. During the course of preparation, we found that the catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove the benzyloxycarbonyl groups resulted in a side reaction. By MS and NMR studies and by preparation of additional 1,2-dihydropyrazin-2-one derivatives, the structure of the by-product was identified as 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one. Preparation of additional compounds substituted with deuterium provided us with sufficient information to confirm the structure of the product and to support a cyclization mechanism in its formation.

  在3和6位具有两个氨基烷基团的1,2-二氢吡嗪-2-酮衍生物被发现是构建强效、选择性和长效类吗啡模拟物的有效工具。在准备过程中，我们发现3,6-双(苄氧羰基氨基甲基)-5-甲基-1,2-二氢吡嗪-2-酮的催化氢化以去除苄氧羰基基团导致了副反应。通过质谱和核磁共振研究以及制备额外的1,2-二氢吡嗪-2-酮衍生物，副产物的结构被鉴定为3-氨基甲基-5,6-二甲基-1,2-二氢吡嗪-2-酮。制备含有氘的额外化合物为我们提供了足够的信息以确认产物的结构并支持其形成的环化机制。
• Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH₂)<i>_n</i>]-2(1<i>H</i>)-pyrazinone with Central-Mediated Analgesia
  作者：Yunden Jinsmaa、Anna Miyazaki、Yoshio Fujita、Tingyou Li、Yutaka Fujisawa、Kimitaka Shiotani、Yuko Tsuda、Toshio Yokoi、Akihiro Ambo、Yusuke Sasaki、Sharon D. Bryant、Lawrence H. Lazarus、Yoshio Okada

  DOI：10.1021/jm0304616

  日期：2004.5.1

  The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.