4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidineacetic acid methyl ester | 132875-59-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidineacetic acid methyl ester
• 英文别名: methyl 1-(2-methoxy-2-oxoethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate
• CAS: 132875-59-3
• 化学式: C₁₉H₂₆N₂O₅
• 分子量: 362.426
• InChiKey: NHHVNGILDILSEI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  76.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-(苯基丙酰氨基)哌啶-4-羧酸甲酯 、 溴乙酸甲酯 在 potassium carbonate 、 sodium iodide 作用下， 以 乙腈 为溶剂， 反应 5.0h， 生成 4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidineacetic acid methyl ester
  参考文献：
  名称：

  Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgesics

  摘要：

  In an effort to discover a potent ultrashort-acting mu-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu-agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

  DOI：

  10.1021/jm00111a041

文献信息

• N-phenyl-N-(4-piperidinyl)amides useful as analgesics
  申请人：Glaxo Inc.

  公开号：US05019583A1

  公开（公告）日：1991-05-28

  N-Phenyl-N-(4-piperdinyl)amide derivatives are disclosed having the general formula (I): ##STR1## wherein X is a member selected from the group consisting of alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy-(C.sub.1-2)-alkoxy-carbonyl-lower alkyl, and Ar, R, R.sup.1 and R.sup.2 are defined hereinafter, including isomeric forms thereof and acid addition salts thereof. The compounds exhibit analgesic activity having relatively short durations of analgesic action. The invention embraces the compounds (I), pharmaceutical compositions of (I) and methods of providing analgesia with (I). Also included are certain novel intermediates for making (I).

  披露了具有通式（I）的N-苯基-N-（4-哌啶基）酰胺衍生物：##STR1## 其中X是从羟基氧羰基较低烷基，较低烷基羰氧较低烷基，烯氧羟基氧羰基较低烷基和（C.sub.1-2）烷氧（C.sub.1-2）-烷氧羰基较低烷基中选择的成员，而Ar，R，R.sup.1和R.sup.2在此定义，包括其同分异构体和酸加成盐。这些化合物表现出相对短的镇痛作用持续时间的镇痛活性。该发明涵盖化合物（I），化合物（I）的制药组合物以及使用（I）提供镇痛的方法。还包括用于制备（I）的某些新型中间体。
• US5019583A
  申请人：——

  公开号：US5019583A

  公开（公告）日：1991-05-28
• Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgesics
  作者：Paul L. Feldman、Michael K. James、Marcus F. Brackeen、Joanne M. Bilotta、Suzanne V. Schuster、Avis P. Lahey、Michael W. Lutz、M. Ross Johnson、H. Jeff Leighton

  DOI：10.1021/jm00111a041

  日期：1991.7

  In an effort to discover a potent ultrashort-acting mu-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu-agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.