1-(3-(4-(3-氯苯基)-1-哌嗪基)丙基)-5-甲氧基-3,4-二氢-2-喹啉酮 | 145969-30-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 1-(3-(4-(3-氯苯基)-1-哌嗪基)丙基)-5-甲氧基-3,4-二氢-2-喹啉酮
• 中文别名: 化合物 T28256
• 英文名称: 1-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-5-methoxy-3,4-dihydro-2-quinolinone
• 英文别名: 1-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-5-methoxy-1,2,3,4-tetrahydroquinolin-2-one；1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4-dihydro-5-methoxy-2(1H)-quinolinone；5-methoxy-1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril；OPC-14523；VPI-013；1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2(1H)-quinolone；1-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-5-methoxy-3,4-dihydroquinolin-2-one
• CAS: 145969-30-8
• 化学式: C₂₃H₂₈ClN₃O₂
• 分子量: 413.947
• InChiKey: TZZGTNZBLPCBIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  36
• 氢给体数：
  0
• 氢受体数：
  4

制备方法与用途

生物活性

OPC-14523 free base 是一种具有口服活性的 sigma 和 5-HT1A 受体激动剂，对 sigma 受体（σ1/2 IC50=47/56 nM）、5-HT1A 受体（IC50=2.3 nM）和 5-HT 转运体（IC50=80 nM）具有高度亲和力。OPC-14523 free base 显示抗抑郁药样活性。

靶点

• 5-HT1A 受体：2.3 nM (IC50)
• sigma 1：47 nM (IC50)
• sigma 2：56 nM (IC50)

体内研究

OPC-14523 free base（剂量：0.3-100 mg/kg；口服，每日一次，连续给药 0、2、4 或 7 天）在强迫游泳试验（FST）中对大鼠和小鼠表现出显著的抗抑郁样效果，同时不影响一般运动活动。

实验结果

实验模型：Wistar 系的大鼠（体重140-245 g）

• 剂量：0.3-100 mg/kg
• 给药方式：口服，连续7天
• 结果：单次给药1 mg/kg及以上可减少强迫游泳试验中的不动时间。ED50 值为 27 mg/kg。第7天时，OPC-14523 的 ED50 值降至 18 mg/kg。

实验模型：ICR 系的小鼠（体重 25-45 g）

• 剂量：0.3-100 mg/kg
• 给药方式：口服，连续7天
• 结果：单次口服给予 OPC-14523 可显著减少小鼠在强迫游泳试验中的不动时间，ED50 值为 20 mg/kg。经过七天连续治疗后，OPC-14523 减少不动时间的效力更强，其 ED50 值降至 2 mg/kg。

反应信息

• 作为反应物：
  描述：

  1-(3-(4-(3-氯苯基)-1-哌嗪基)丙基)-5-甲氧基-3,4-二氢-2-喹啉酮 在 47percent HBr 作用下， 反应 4.0h， 以74%的产率得到1-{3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-propyl}-5-hydroxy-3,4-dihydro-1H-quinolin-2-one
  参考文献：
  名称：

  3,4-Dihydro-2(1H)-quinolinone as a Novel Antidepressant Drug:  Synthesis and Pharmacology of 1-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and Its Derivatives

  摘要：

  To develop a novel antidepressant drug with central nervous system-stimulating activity, me prepared a series of 1-[w-(4-substituted phenyl-1-piperazinyl)alkyl]-3,4-dihydro-2(1H)-quinlinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for a receptors by evaluating their ability to inhibit [H-3]-1,3-di(o-tolyl)guanidine ([H-3]DTG) binding to the rat whole brain membrane in comparison with three putative a receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethylmethano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5,6-hexahydro-6, 11-dimethyl-3(3 -methyl-2-butenyl)-2,6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-3-[4-(3-chlorophenyl)-1-piperazinyl]-3p linone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [H-3]DTG binding for a receptors. The putative a receptor agonists reduced the sleeping time and the time for recovery from coma whereas two a receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl) piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative a receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the a receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are a receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.

  DOI：

  10.1021/jm980333v
• 作为产物：
  描述：

  1-(3-chloropropyl)-3,4-dihydro-5-methoxy-2(1H)-quinolinone 在 potassium carbonate 、 sodium iodide 作用下， 以 乙腈 为溶剂， 反应 2.5h， 生成 1-(3-(4-(3-氯苯基)-1-哌嗪基)丙基)-5-甲氧基-3,4-二氢-2-喹啉酮
  参考文献：
  名称：

  3,4-Dihydro-2(1H)-quinolinone as a Novel Antidepressant Drug:  Synthesis and Pharmacology of 1-[3-[4-(3-Chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and Its Derivatives

  摘要：

  To develop a novel antidepressant drug with central nervous system-stimulating activity, me prepared a series of 1-[w-(4-substituted phenyl-1-piperazinyl)alkyl]-3,4-dihydro-2(1H)-quinlinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for a receptors by evaluating their ability to inhibit [H-3]-1,3-di(o-tolyl)guanidine ([H-3]DTG) binding to the rat whole brain membrane in comparison with three putative a receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethylmethano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5,6-hexahydro-6, 11-dimethyl-3(3 -methyl-2-butenyl)-2,6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-3-[4-(3-chlorophenyl)-1-piperazinyl]-3p linone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [H-3]DTG binding for a receptors. The putative a receptor agonists reduced the sleeping time and the time for recovery from coma whereas two a receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl) piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative a receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the a receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are a receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.

  DOI：

  10.1021/jm980333v

文献信息

• Combination treatment for depression
  申请人：——

  公开号：US20020099045A1

  公开（公告）日：2002-07-25

  The present invention relates to a method of treating depression, especially refractory depression, in a mammal, including a human, by administering to the mammal a sigma receptor ligand in combination with an antidepressant agent. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a sigma receptor ligand and a serotonin reuptake inhibitor.

  本发明涉及一种治疗哺乳动物，包括人类的抑郁症，特别是顽固性抑郁症的方法，通过向哺乳动物注射与抗抑郁药物结合的σ受体配体。同时涉及含有药用载体、σ受体配体和血清素再摄取抑制剂的制药组合物。
• Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy
  申请人：Pharmacia Corporation

  公开号：US20040147581A1

  公开（公告）日：2004-07-29

  Compositions and methods to treat or prevent pain, inflammation, or inflammation-related disorder, as well as a neurologic disorder involving neurodegrneration in a subject that is in need of such prevention or treatment involve a combination of a Cox-2 inhibitor and a 5-HT 1A receptor modulator.

  治疗或预防疼痛、炎症或炎症相关疾病，以及涉及神经退行性的神经系统疾病的组合物和方法，需要在需要预防或治疗的受试者中使用Cox-2抑制剂和5-HT1A受体调节剂。
• Combination of a SR inhibitor and sigma receptor ligand in the treatment ofdepression
  申请人：Pfizer Products Inc.

  公开号：EP1224930A1

  公开（公告）日：2002-07-24

  The present invention relates to a method of treating depression, especially refractory depression, in a mammal, including a human, by administering to the mammal a sigma receptor ligand in combination with an antidepressant agent. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a sigma receptor ligand and a serotonin reuptake inhibitor.

  本发明涉及一种治疗哺乳动物（包括人类）抑郁症（尤其是难治性抑郁症）的方法，其方法是向哺乳动物施用σ受体配体与抗抑郁剂组合。本发明还涉及含有药学上可接受的载体、σ受体配体和5-羟色胺再摄取抑制剂的药物组合物。
• Treatment of L-DOPA-induced dyskinesia with OPC-14523 or OPC-34712
  申请人：Merz Pharma GmbH & Co. KGaA

  公开号：EP2792359A1

  公开（公告）日：2014-10-22

  The present invention relates to the efficient treatment of an individual afflicted with L-DOPA-induced dyskinesia, which condition typically arises as a consequence of long-term treatment with L-DOPA therapy in Parkinson patients.

  本发明涉及对 L-DOPA 引起的运动障碍患者的有效治疗，这种情况通常是帕金森病人长期接受 L-DOPA 治疗的结果。
• Sigma ligands for neuronal regeneration and functional recovery
  申请人：Oksenberg Donna

  公开号：US20050020483A1

  公开（公告）日：2005-01-27

  The invention discloses methods and compositions useful for facilitating neuronal regeneration and functional recovery in neurodegenerative diseases. The methods and compositions utilize ligands for the sigma receptors. These molecules can be delivered alone or in combination with agents which treat or prevent neurodegenerative diseases such as those caused by ischemic stroke, diabetic peripheral neuropathy, cancer therapy induced neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Huntington's disease or Parkinson's disease. In other methods, the sigma receptor ligands are administered after stroke to facilitate functional recovery. The administration of the sigma receptor ligands effects faster functional recovery.

  本发明公开了促进神经元再生和神经退行性疾病功能恢复的方法和组合物。这些方法和组合物利用西格玛受体的配体。这些分子可以单独给药，也可以与治疗或预防神经退行性疾病的药物结合使用，如缺血性中风、糖尿病周围神经病变、癌症治疗诱发的神经病变、多发性硬化症、肌萎缩性脊髓侧索硬化症、脑外伤、脊髓损伤、亨廷顿氏病或帕金森氏病等引起的神经退行性疾病。在其他方法中，σ受体配体在中风后给药，以促进功能恢复。施用σ受体配体可加快功能恢复。