3-(4-Amino-butyl)-6-(3-amino-propyl)-5-methyl-1H-pyrazin-2-one | 1027208-65-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-(4-Amino-butyl)-6-(3-amino-propyl)-5-methyl-1H-pyrazin-2-one
• 英文别名: 3-(4-aminobutyl)-6-(3-aminopropyl)-5-methyl-1H-pyrazin-2-one
• CAS: 1027208-65-6
• 化学式: C₁₂H₂₂N₄O
• 分子量: 238.333
• InChiKey: OEMUEFGZKOKZLI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 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-(4-Amino-butyl)-6-(3-amino-propyl)-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-[4-[6-[3-[[(3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]propyl]-5-methyl-2-oxo-1H-pyrazin-3-yl]butyl]-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：

  Boc-Orn(Cbz)-OH 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 16.42h， 生成 3-(4-Amino-butyl)-6-(3-amino-propyl)-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

• Synthesis of 3,6-bis[H-Tyr/H-Dmt-NH(CH2)m,n]-2(1H)pyrazinone derivatives: Function of alkyl chain length on opioid activity
  作者：Kimitaka Shiotani、Tingyou Li、Anna Miyazaki、Yuko Tsuda、Sharon D. Bryant、Akihiro Ambo、Yusuke Sasaki、Lawrence H. Lazarus、Yoshio Okada

  DOI：10.1016/j.bmcl.2006.08.079

  日期：2006.11

  Dimeric opioid analogues linked to a pyrazinone platform, 3-[Tyr/Dmt-NH(CH2)(m)]-6-[Tyr/Dmt-NH(CH2)(n)]-2(1H)-pyrazinone (m, n = 3 or 4), were synthesized. The Tyr-containing compound (m = 4, n = 3) exhibited mu-receptor affinity (K-i mu; 7.58 nM) comparable to that of morphine, while the Dmt derivatives exhibited considerably higher affinity (K-i mu; 0.021-0.051 nM) with corresponding agonism (IC50 = 1.79-4.93 nM). Interestingly one compound (m = 4, n = 3) revealed modest delta-opioid agonism; the converse analogue (m = 3, n = 4), however, was inactive in MVD assay. (c) 2006 Elsevier 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.