3,6-Bis-(2-amino-ethyl)-5-methyl-1H-pyrazin-2-one | 501022-73-7

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3,6-Bis-(2-amino-ethyl)-5-methyl-1H-pyrazin-2-one
• 英文别名: 3,6-bis(2-aminoethyl)-5-methyl-1H-pyrazin-2-one
• CAS: 501022-73-7
• 化学式: C₉H₁₆N₄O
• 分子量: 196.252
• InChiKey: IVOGEURLOOGGSZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  93.5
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3,6-Bis-(2-amino-ethyl)-5-methyl-1H-pyrazin-2-one 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 苯甲醚 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 (3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-N-[2-[5-[2-[[(3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]ethyl]-3-methyl-6-oxo-1H-pyrazin-2-yl]ethyl]-3,4-dihydro-1H-isoquinoline-3-carboxamide
  参考文献：
  名称：

  Potent Dmt-Tic Pharmacophoric δ- and μ-Opioid Receptor Antagonists

  摘要：

  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.

  DOI：

  10.1021/jm050377l
• 作为产物：
  描述：

  (3-tert-Butoxycarbonylamino-5-chloro-4-oxo-pentyl)-carbamic acid benzyl ester 在 盐酸 、 氢溴酸 、 溶剂黄146 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 为溶剂， 反应 4.0h， 生成 3,6-Bis-(2-amino-ethyl)-5-methyl-1H-pyrazin-2-one
  参考文献：
  名称：

  Potent Dmt-Tic Pharmacophoric δ- and μ-Opioid Receptor Antagonists

  摘要：

  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.

  DOI：

  10.1021/jm050377l

文献信息

• 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。
• 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.
• 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.