1,4-dibenzyl-2-(phenoxycarbonyloxymethyl)piperazine | 148228-20-0

• 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: 1,4-dibenzyl-2-(phenoxycarbonyloxymethyl)piperazine
• 英文别名: 1,4-Dibenzyl-2-phenoxycarbonyloxymethylpiperazine；(1,4-dibenzylpiperazin-2-yl)methyl phenyl carbonate
• CAS: 148228-20-0
• 化学式: C₂₆H₂₈N₂O₃
• 分子量: 416.52
• InChiKey: JSPPDJNNGQPNPB-UHFFFAOYSA-N

物化性质

• 沸点：
  542.1±48.0 °C(Predicted)
• 密度：
  1.174±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  42
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1,4-dibenzyl-2-(phenoxycarbonyloxymethyl)piperazine 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 以 乙醇 为溶剂， 反应 63.0h， 生成 2-(pyrrolidinocarbonyloxymethyl)piperazine dihydrochloride
  参考文献：
  名称：

  Structure−Activity Relationships in Platelet-Activating Factor (PAF). 10. From PAF Antagonism to Inhibition of HIV-1 Replication

  摘要：

  Excessive levels of PAF and cells of macrophage lineage appear to play an important role in neuronal cell injury, inflammatory syndrome, and HIV replication in CNS resulting in AIDS dementia complex (ADC). The beneficial effects of PAF receptor antagonists are evident and give rise to expected therapeutic strategies for neurotrauma. Piperazine derivatives bearing a "cache-oreilles" (ear-muff) electronic distribution are able to inhibit in vitro PAF effects and, thus, could be used in pathologies where this mediator is involved. Therefore, their potential anti-HIV activity was investigated, and we find that (i) these PAF antagonists are effectively active in HIV-infected monocyte-derived macrophages (MDM) but there is no correlation between both anti-HIV and anti-PAF activities; (ii) the presence of a carbamate function (compounds 1a-d) is favorable to the antiviral activity; (iii) the lipophilicity of the substituent on the piperazinic cycle seems to be less important for the anti-PAF activity than for the antiviral one. Our leading compound, PMS 601 (compound la), presents a dual activity with IC50 of 8 and 11 mu M for anti-PAF and anti-HIV activity, respectively, without cytotoxic events at 1000 mu M in MDM. Although its mode of action is not clearly defined, these data suggest that PMS 601, which displays no effect on acellular reverse transcriptase or protease tests, deserves further investigation in the treatment of HIV-1-associated dementia.

  DOI：

  10.1021/jm9911276
• 作为产物：
  描述：

  氯甲酸苯酯 、 1,4-dibenzyl-2-hydroxypiperazine 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以88%的产率得到1,4-dibenzyl-2-(phenoxycarbonyloxymethyl)piperazine
  参考文献：
  名称：

  血小板活化因子中的构效关系。12.具有抗HIV-1活性的血小板活化因子拮抗剂的合成和生物学评价。

  摘要：

  HIV-1中枢神经系统感染导致称为AIDS痴呆综合症（ADC）的神经功能障碍的发作。PAF在这种病理学中起着重要作用，因为它是由HIV-1诱导的神经毒素，它是由感染或激活的巨噬细胞和小胶质细胞在大脑中产生的。我们以前报道过，带有三取代哌嗪的PAF拮抗剂在人巨噬细胞中具有体外抗HIV-1活性。为了改善我们的先导化合物1a的药理活性，我们修改了其氨基甲酸酯功能并评估了其抗逆转录病毒和抗PAF活性。一种氨基甲酸酯衍生物（10c）具有相似的抗病毒活性，但具有更高的抗PAF效力，而具有酰脲功能的4a具有增强的抗病毒活性，可以视为纯的抗逆转录病毒药物，因为它不表现出PAF拮抗作用。此外，我们使用原位小鼠脑灌注方法及其静脉内和口服给药后的血浆浓度，测量了1a穿过血脑屏障的能力。测得的转运参数（K（in））证明1a能够穿越该生物屏障，但是药代动力学研究表明其在大鼠体内的生物利用度较弱。

  DOI：

  10.1021/jm040860g

文献信息

• Piperazine derivatives inhibiting human immunodeficiency virus replication
  申请人：Universite Paris 7 - Denis Diderot

  公开号：US06531476B1

  公开（公告）日：2003-03-11

  The invention concerns the use of a piperazine derivative of formula (I) wherein: A and B=C═O, C═S or CR7R8 with R7=H, methyl, cyano, cyanomethyl, CO2CH3 or (C═O)CH3 and R8=H or phenyl; R1 to R6=H, OH, or C1-C5 alkoxy; X represents: either C═O, O(C═O), O(C═S), O(SO2), NH(C═O), NH(C═S), NH(SO2), S(C═O) or S(C═S), then Y=NR9R10, CR9R10R11 in which R9, R10 and R11=H, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl or Y=nitrogenous heterocycle comprising 5 to 10 atoms; or X represents O, S, O(C═O)O, NH(C═O)O, or S(C═O)O, then Y=CR9R10R11 with R9, R10, R11 as above; or one of its pharmaceutically acceptable salts for preparing a medicine inhibiting HIV. The invention is useful for treating HIV infection.

  这项发明涉及使用式（I）的哌嗪衍生物，其中：A和B=C═O，C═S或CR7R8，其中R7=H，甲基，氰基，氰甲基，CO2CH3或（C═O）CH3，R8=H或苯基；R1至R6=H，OH或C1-C5烷氧基；X代表：C═O，O（C═O），O（C═S），O（SO2），NH（C═O），NH（C═S），NH（SO2），S（C═O）或S（C═S），然后Y=NR9R10，CR9R10R11，其中R9，R10和R11=H，C1-C5烷基，C2-C5烯基或C2-C5炔基或Y=含有5至10个原子的氮杂环；或X代表O，S，O（C═O）O，NH（C═O）O或S（C═O）O，然后Y=CR9R10R11，其中R9，R10，R11如上；或其制备药用可接受的盐之一，用于制备抑制HIV的药物。这项发明对治疗HIV感染很有用。
• [EN] PIPERAZINE DERIVATIVES INHIBITING HUMAN IMMUNODEFICIENCY VIRUS REPLICATION<br/>[FR] DERIVES DE LA PIPERAZINE POUR L'INHIBITION DE LA REPLICATION DU VIRUS DE L'IMMUNODEFICIENCE HUMAINE
  申请人：UNIV PARIS 7 DENIS DIDEROT

  公开号：WO2000001677A1

  公开（公告）日：2000-01-13

  L'invention se rapporte à l'utilisation d'un dérivé de la pipérazine de formule (I), avec: A et B = C=O, C=S ou CR7R8 avec R7 = H, méthyle, cyano, cyanométhyle, CO2CH3 ou (C=O)CH3, et R8 = H ou phényle; R1 à R6 = H, OH ou alkoxy en C1 à C5; X représente: soit C=O, O(C=O), O(C=S), O(SO2), NH(C=O), NH(C=S), NH(SO2), S(C=O) ou S(C=S), alors Y = NR9R10, CR9R10R11 = H, alkyle en C1 à C5, alcényle en C2 à C5 ou alcynyle en C2 à C5 ou hétérocycle azoté comprenant 5 à 10 atomes; soit O, S, O(C=O)O, NH(C=O)O ou S(C=O)O, alors Y = CR9R10R11 avec R9, R10, R11 comme précédemment; ou l'un des ses sels pharmaceutiquement acceptables, pour la préparation d'un médicament pour inhiber la réplication du VIH. Application: traitement de l'infection par le VIH.

  本发明涉及使用式（I）的哌嗪衍生物，其中：A和B = C=O，C=S或CR7R8，其中R7 = H，甲基，氰基，氰甲基，CO2CH3或（C=O）CH3，而R8 = H或苯基; R1到R6 = H，OH或C1到C5的烷氧基; X表示：C=O，O（C=O），O（C=S），O（SO2），NH（C=O），NH（C=S），NH（SO2），S（C=O）或S（C=S）中的任意一种，那么Y = NR9R10，CR9R10R11 = H，C1到C5的烷基，C2到C5的烯基或C2到C5的炔基或含有5到10个原子的氮杂环; 或O，S，O（C=O）O，NH（C=O）O或S（C=O）O中的任意一种，那么Y = CR9R10R11，其中R9，R10，R11如前所述; 或其药学上可接受的盐之一，用于制备抑制HIV复制的药物。应用：治疗HIV感染。
• Design and modeling of new platelet-activating factor antagonists. 1. Synthesis and biological activity of 1,4-bis(3',4',5'-trimethoxybenzoyl)-2-[[(substituted carbonyl and carbamoyl)oxy]methyl]piperazines
  作者：Aazdine Lamouri、Francoise Heymans、Fabrice Tavet、Georges Dive、Jean Pierre Batt、Nicole Blavet、Pierre Braquet、Jean Jacques Godfroid

  DOI：10.1021/jm00060a006

  日期：1993.4

  To further investigate our hypothesis on the structure of the platelet-activating factor (PAF) receptor, 35 compounds derived from 1,4-bis(3',4',5'-trimethoxybenzoyl)piperazine were synthesized and their in vitro antagonistic effect was measured. Substitution of the compounds in position 2, by ester or carbamate groups, giving increased steric hindrance and hydrophobicity, increased the platelet aggregation inhibitory activity from 2 muM (without substitution, compound 2) to 0.07 muM (compound 1h) arid gave a maximum displacement of [H-3]PAF from platelet membrane of 0.05 muM (compound 1k). It appears that the PAF antagonistic effect is only weakly enantiospecific, as observed in many cases including antagonists structurally related or not to PAF. 3D electrostatic potential maps (calculated at -10 kcal/mol) of such compounds revealed a double ''Cache-oreilles'' (ear-muffs) system. One of these systems has been previously described (distance between atoms generating negative wells, 11-14 angstrom). The second shorter ''Cache-oreilles'' (6-7 angstrom) system appears to be required for increased PAF antagonistic activity. This short distance between groups generating the negative wells is present in the gingkolides, a series of naturally occurring PAF antagonists. The present study indicates that the structure of the PAF receptor may be more complicated than our initial hypothesis and may be a tetrapolarized structure, with alternants of electropositive and hydrophobic areas. This modified hypothesis is in agreement with recent publications concerning PAF antagonists bearing a cationic moiety.
• DERIVES DE LA PIPERAZINE POUR L'INHIBITION DE LA REPLICATION DU VIRUS DE L'IMMUNODEFICIENCE HUMAINE
  申请人：UNIVERSITE PARIS 7 - Denis DIDEROT

  公开号：EP1095029A1

  公开（公告）日：2001-05-02
• US6531476B1
  申请人：——

  公开号：US6531476B1

  公开（公告）日：2003-03-11