1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-2-(N-methylaminocarbonyloxymethyl)-4-(3,4,5-trimethoxybenzyl)piperazine

• 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-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-2-(N-methylaminocarbonyloxymethyl)-4-(3,4,5-trimethoxybenzyl)piperazine
• 英文别名: 1(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-2-N-methylcarbamoyloxymethyl-4-(3,4,5-trimethoxybenzyl)piperazine；[1-(2,3-dimethoxy-8,9-dihydro-7H-benzo[7]annulene-6-carbonyl)-4-[(3,4,5-trimethoxyphenyl)methyl]piperazin-2-yl]methyl N-methylcarbamate
• 化学式: C₃₁H₄₁N₃O₈
• 分子量: 583.682
• InChiKey: GDCKKSKKYLMWDW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-哌嗪甲酸乙酯 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 6.25h， 生成 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-2-(N-methylaminocarbonyloxymethyl)-4-(3,4,5-trimethoxybenzyl)piperazine
  参考文献：
  名称：

  Synthesis and Platelet-Activating Factor (PAF)-Antagonistic Activities of Trisubstituted Piperazine Derivatives.

  摘要：

  2-或3-取代的1-(2,3-二甲氧基-6,7-二氢-5H-苯并环庚烯-8-基羰基)-4-(3,4,5-三甲氧基苯甲酰基)和4-(3,4,5-三甲氧基苄基)哌嗪（2a-s，3a，b）被制备并评估了它们对血小板活化因子（PAF）诱导的血小板聚集和血压降低的拮抗活性。其中，2-甲氧甲基衍生物（2f）显示出系列中最强的活性。从苄氧羰基-O-苄基-L-和D-丝氨酸经过几个步骤合成了其对映体（R）-(+)-2f和（S）-(-)-2f。在结合实验中，（S）-(-)-2f对PAF受体的亲和力是R异构体的三十倍。

  DOI：

  10.1248/cpb.42.551

文献信息

• Trisubstituted piperazine compounds, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04997836A1

  公开（公告）日：1991-03-05

  Novel trisubstituted piperazine compounds of the formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are lower alkyl groups; A is a phenyl group, a hydrocarbon group formed by condensation of two or three 5- to 8-membered rings, a monocyclic 5- to 8-membered heterocyclic group containing 1 to 3 hetero-atoms selected from the class consisting of nitrogen, oxygen and sulfur, a dicyclic heterocyclic group formed by condensation of a benzene ring with a 5- to 8-membered hetero-ring containing 1 to 3 hetero-atoms selected from the class consisting of nitrogen, oxygen and sulfur, a tricyclic heterocyclic group formed by condensation of (i) a 5- to 8-membered hetero-ring containing 1 to 3 hetero-atoms selected from the class consisting of nitrogen, oxygen and sulfur, and (ii) a benzene ring, and (iii) a benzene ring or a 5- to 8-membered hetero-ring containing 1 to 3 hetero-atoms selected from the class consisting of nitrogen, oxygen and sulfur, or a styryl group of the formula: Ar--CR.sup.4 .dbd.CR.sup.5 -- wherein Ar is a phenyl group, and R.sup.4 and R.sup.5 are independently hydrogen or a lower alkyl group, the phenyl group represented by A or Ar, the hydrocarbon group represented by A, the monocyclic 5- to 8-membered heterocyclic group represented by A, the dicyclic heterocyclic group represented by A and the tricyclic heterocyclic group represented by A being unsubstituted or substituted by one or more substituents selected from the class consisting of a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, an acyloxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, a lower alkenyloxy group, aralkyloxy group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, carboxyl group, carbamoyl group, an N,N-di-lower alkylcarbamoyl group, an N-lower alkylcarbamoyl group, halo group, cyano group, nitro group, hydroxy group, acyloxy group, amino group, a lower alkylsulfonylamino group, acylamino group, a lower alkoxycarbonylamino group, acyl group, mercapto group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group and oxo group; X is methylene group, carbonyl group or thiocarbonyl group and G is a group of the formula: --CH.sub.2 --.sub.n Z--R.sup.6 wherein n is an integer of 0 to 2, Z is a chemical bond, O, S, SO, SO.sub.2, CO, COO, OCO, OCONR.sup.7, CONR.sup.7 or NR.sup.7 (wherein R.sup.7 is hydrogen, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group or a lower alkoxycarbonyl group), and R.sup.6 is hydrogen, a lower alkyl group, a lower haloalkyl group or a lower alkenyl group, provided that, when n is O and Z is chemical bond, R.sup.6 is not hydrogen or a lower alkyl group are useful as a platelet activating factor antagonist.

  新型三取代哌嗪化合物的化学式（I）及其药用盐：##STR1## 其中R.sup.1、R.sup.2和R.sup.3为较低的烷基基团；A为苯基、由两个或三个5至8成员环缩合形成的烃基团、含有1至3个异原子（选自氮、氧和硫）的单环5至8成员杂环基团、由苯环与含有1至3个异原子（选自氮、氧和硫）的5至8成员杂环环缩合形成的二环杂环基团、由（i）含有1至3个异原子（选自氮、氧和硫）的5至8成员杂环环和（ii）苯环缩合形成的三环杂环基团，以及（iii）苯环或含有1至3个异原子（选自氮、氧和硫）的5至8成员杂环环或化学式为Ar--CR.sup.4 .dbd.CR.sup.5--的苯乙烯基团：其中Ar为苯基，R.sup.4和R.sup.5独立地为氢或较低的烷基基团，由A或Ar表示的苯基，由A表示的烃基团，由A表示的单环5至8成员杂环基团，由A表示的二环杂环基团以及由A表示的三环杂环基团未被取代或被选自较低烷基基团、卤代较低烷基基团、羟基较低烷基基团、酰氧基较低烷基基团、较低烷氧基较低烷基基团、较低烷氧基、卤代较低烷氧基、较低烷氧羰基较低烷氧基、较低烯氧基、芳基氧基、较低烷氧较低烷氧基、较低烷氧羰基基团、羧基、氨基、较低烷基磺酰氨基、酰胺基、较低烷氧羰胺基、酰基、巯基、较低烷硫基、较低烷硫氧基、较低烷磺基和氧代基所选的一个或多个取代基所取代；X为亚甲基基团、羰基或硫代羰基，G为化学式：--CH.sub.2--.sub.n Z--R.sup.6，其中n为0至2的整数，Z为化学键、O、S、SO、SO.sub.2、CO、COO、OCO、OCONR.sup.7、CONR.sup.7或NR.sup.7（其中R.sup.7为氢、较低烷基基团、较低卤代烷基基团、较低烯基基团或较低烷氧羰基基团），R.sup.6为氢、较低烷基基团、较低卤代烷基基团或较低烯基基团，但当n为O且Z为化学键时，R.sup.6不为氢或较低烷基基团，可用作血小板活化因子拮抗剂。
• US4997836A
  申请人：——

  公开号：US4997836A

  公开（公告）日：1991-03-05
• Synthesis and Platelet-Activating Factor (PAF)-Antagonistic Activities of Trisubstituted Piperazine Derivatives.
  作者：Hideto FUKUSHI、Hiroshi MABUCHI、Zen-ichi TERASHITA、Kohei NISHIKAWA、Hirosada SUGIHARA

  DOI：10.1248/cpb.42.551

  日期：——

  2- or 3-Substituted 1-(2, 3-dimethoxy-6, 7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3, 4, 5-trimethoxybenzoyl)- and 4-(3, 4, 5-trimethoxybenzyl)piperazines (2a-s, 3a, b) were prepared and evaluated for antagonistic activities against platelet-activating factor (PAF)-induced platelet aggregation and blood pressure reduction. The 2-methoxymethyl derivative (2f) showed the most potent activities in this series. The enantiomers (R)-(+)-2f and (S)-(-)-2f were synthesized from carbobenzoxy-O-benzyl-L- and D-serine in several steps. In the binding experiment, (S)-(-)-2f showed thirty times greater affinity than the R isomer for the PAF receptor.

  2-或3-取代的1-(2,3-二甲氧基-6,7-二氢-5H-苯并环庚烯-8-基羰基)-4-(3,4,5-三甲氧基苯甲酰基)和4-(3,4,5-三甲氧基苄基)哌嗪（2a-s，3a，b）被制备并评估了它们对血小板活化因子（PAF）诱导的血小板聚集和血压降低的拮抗活性。其中，2-甲氧甲基衍生物（2f）显示出系列中最强的活性。从苄氧羰基-O-苄基-L-和D-丝氨酸经过几个步骤合成了其对映体（R）-(+)-2f和（S）-(-)-2f。在结合实验中，（S）-(-)-2f对PAF受体的亲和力是R异构体的三十倍。