chlorbipram

• 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: chlorbipram
• 英文别名: 2-[[3-(3-Chlorophenyl)-4-methoxyphenyl]methyl]-6-[2-(2-methoxyphenoxy)ethylamino]pyridazin-3-one；2-[[3-(3-chlorophenyl)-4-methoxyphenyl]methyl]-6-[2-(2-methoxyphenoxy)ethylamino]pyridazin-3-one
• 化学式: C₂₇H₂₆ClN₃O₄
• 分子量: 491.974
• InChiKey: ZMKVNEGSOKFNDH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  72.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,5-二羟基苯甲酸 、 chlorbipram 在 乙醇 作用下， 生成
  参考文献：
  名称：

  Crystal structures, dissolution and pharmacokinetic study on a novel phosphodiesterase-4 inhibitor chlorbipram cocrystals

  摘要：

  Cocrystallization of chlorbipram (ChBP), a novel phosphodiesterase-4 (PDE) inhibitor with water insoluble property developed in our lab, was performed to improve the physicochemical properties and bioavailability in the present study. Three new cocrystals with fumaric aicd (FA), gentisic acid (GA) and salicylic acid (SA) as coformers were synthesized and fully characterized by using the combination of multi-techniques. The cocrystals are phase stable even under high humidity conditions. In vitro study indicates that the solubility of ChBP-GA and ChBP-SA cocrystals increase to 3724.4 +/- 58.7, 2897.4 +/- 81.9 mu g/mL in comparison with ChBP (2561.3 +/- 150.4 mu g/mL), the intrinsic dissolution rates (IDRs) of ChBP-GA and ChBP-SA cocrystals (721.3 +/- 8.0, 614.4 +/- 13.2 mu g/min/cm(2)) are both higher than ChBP (537.9 +/- 12.0 mu g/min/cm(2)). The blood concentration peak values of ChBP-GA and ChBP-SA cocrystals (165.8 +/- 50.9, 105.3 +/- 35.6 ng/mL) are both higher than ChBP (51.3 +/- 15.1 ng/mL) in in vivo evaluation. It presents the same order in in vitro/vivo study: ChBP-GA > ChBP-SA > ChBP > ChBP-FA. ChBP-FA cocrystal presents a longer elimination half life (t(1)(/2) = 10.0 +/- 2.6 h), which makes it a potential candidate for prolonged controlled release formulation. ChBP-GA and ChBP-SA cocrystals both present enhanced solubility and bioavailability in comparison with ChBP, making them a better candidate for the solid dosage formulation development.

  DOI：

  10.1016/j.ijpharm.2019.118984
• 作为产物：
  描述：

  2-甲氧基苯氧基乙胺 在 sodium acetate 、 potassium carbonate 、 溶剂黄146 作用下， 以 乙二醇二甲醚 、 乙醇 为溶剂， 生成 chlorbipram
  参考文献：
  名称：

  一种PDE4抑制剂氯比普兰的制备方法

  摘要：

  本发明公开了一种PDE4抑制剂氯比普兰的制备方法。该方法以3‑溴‑4‑甲氧基苯甲醛为起始原料，经还原反应，Suzuki反应、氯化等步骤合成目标产物E氯比普兰。本方法相对于现有技术，产率得到大幅度提高，经实验证明，产率高达71％。且原料易得价廉，反应条件温和，对设备要求低，可实现产业化生产。本发明为氯比普兰的合成方法提供了一条高效易行的途径。

  公开号：

  CN106632070B

文献信息

• Lattice water provides hydrogen atom donor to form hydrate: A case study of chlorbipram: m-hydroxybenzoic acid (1:1) cocrystal
  作者：Dandan Huang、Dezhi Yang、Yang Lv、Jianle Zhou、Liang Li、Jiangping Xu、Xuemei Yang、Zhengzheng Zhou

  DOI：10.1016/j.molstruc.2021.131891

  日期：2022.2

  Chlorbipram, is prepared and characterized using multi-techniques. The dissolution behavior, ternary phase diagram and theoretical calculations are further performed and discussed. Chlorbipram: m-Hydroxybenzoic acid (ChBP-MHBA, 1: 1) cocrystal hydrate presents approximate equivalent dissolution (1.61 mg/mL) in comparison with ChBP (1.90 mg/mL) in isopropanol/water (1: 1, v/v) solution. Ternary phase diagram

  共晶水合物占难溶性药物共晶的一小部分，对其形成原因尚缺乏解释。在这项研究中，使用多种技术制备并表征了一种具有新型磷酸二酯酶-4 (PDE-4) 抑制剂氯比仑的共晶水合物。进一步进行和讨论了溶解行为、三元相图和理论计算。氯比仑：间羟基苯甲酸 (ChBP-MHBA, 1:1) 共晶水合物与 ChBP (1.90 mg/mL) 在异丙醇/水 (1: 1, v/v) 中的溶出度大致相当 (1.61 mg/mL)解决方案。在乙酸乙酯溶剂中绘制的三元相图表明，ChBP-MHBA 共晶水合物在 ChBP、MHBA 和乙酸乙酯中具有从 (2.91%: 2.64%: 94.45%) 到 (3.20%: 10.74%: 86.06%) 的最佳质量百分比范围. ChBP-MHBA共晶水合物的每个晶胞中有两个晶格水，使用接触面计算占晶胞体积的4.5%。分子静电势表面 (MEPS) 研究表明，强氢键形成于共晶格内，介于
• PHOSPHODIESTERASE 4 INHIBITOR CAPABLE OF AVOIDING VOMITING
  申请人：Xu, Jiangping

  公开号：EP2784068A1

  公开（公告）日：2014-10-01

  The present invention relates to a kind of Phosphodiesterase 4 inhibitors without vomiting, which is compounds or a prodrugs or solvates represented by formula (I), R1 is an independent methoxy, bromine and substituted aryl; X is an optionally substituted six-membered heterocyclic ring; Y is -(CH2)n-, -NH(CH2)n-, and-NH(CH2)n-O-, wherein n is any value among 0, 1, 2 and 3; Z is an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring. The present invention is relates to a kind of Phosphodiesterase 4 inhibitors without vomiting, which is a novel biphenyl series PDE4D inhibitor, and can be applied to treat depression and Alzheimer's disease, improve cognitive ability and avoid vomiting.

  本发明涉及一种不呕吐的磷酸二酯酶4抑制剂，它是式(I)代表的化合物或原药或溶液，R1是独立的甲氧基、溴和取代的芳基；X是任选取代的六元杂环；Y是-(CH2)n-、-NH(CH2)n-和-NH(CH2)n-O-，其中n是0、1、2和3中的任意值；Z是任选取代的芳香环或任选取代的杂芳香环。本发明涉及一种无呕吐的磷酸二酯酶4抑制剂，属于新型联苯系列PDE4D抑制剂，可用于治疗抑郁症和阿尔茨海默病，提高认知能力，避免呕吐。
• Chlorbipram: A novel PDE4 inhibitor with improved safety as a potential antidepressant and cognitive enhancer
  作者：Ming-Zi Zhang、Zhong-Zhen Zhou、Xin Yuan、Yu-Fang Cheng、Bing-Tian Bi、Mei-Fang Gong、Yu-Pin Chen、Jiang-Ping Xu

  DOI：10.1016/j.ejphar.2013.09.055

  日期：2013.12

  Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different closes of chlorbipram (0.5-1.5 mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5 mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0 mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency. (C) 2013 Elsevier B.V. All rights reserved.
• CN116178277
  申请人：——

  公开号：——

  公开（公告）日：——
• Crystal structures, dissolution and pharmacokinetic study on a novel phosphodiesterase-4 inhibitor chlorbipram cocrystals
  作者：Jianle Zhou、Liang Li、Hailu Zhang、Jiangping Xu、Dandan Huang、Ningbo Gong、Weili Han、Xuemei Yang、Zhengzheng Zhou

  DOI：10.1016/j.ijpharm.2019.118984

  日期：2020.2

  Cocrystallization of chlorbipram (ChBP), a novel phosphodiesterase-4 (PDE) inhibitor with water insoluble property developed in our lab, was performed to improve the physicochemical properties and bioavailability in the present study. Three new cocrystals with fumaric aicd (FA), gentisic acid (GA) and salicylic acid (SA) as coformers were synthesized and fully characterized by using the combination of multi-techniques. The cocrystals are phase stable even under high humidity conditions. In vitro study indicates that the solubility of ChBP-GA and ChBP-SA cocrystals increase to 3724.4 +/- 58.7, 2897.4 +/- 81.9 mu g/mL in comparison with ChBP (2561.3 +/- 150.4 mu g/mL), the intrinsic dissolution rates (IDRs) of ChBP-GA and ChBP-SA cocrystals (721.3 +/- 8.0, 614.4 +/- 13.2 mu g/min/cm(2)) are both higher than ChBP (537.9 +/- 12.0 mu g/min/cm(2)). The blood concentration peak values of ChBP-GA and ChBP-SA cocrystals (165.8 +/- 50.9, 105.3 +/- 35.6 ng/mL) are both higher than ChBP (51.3 +/- 15.1 ng/mL) in in vivo evaluation. It presents the same order in in vitro/vivo study: ChBP-GA > ChBP-SA > ChBP > ChBP-FA. ChBP-FA cocrystal presents a longer elimination half life (t(1)(/2) = 10.0 +/- 2.6 h), which makes it a potential candidate for prolonged controlled release formulation. ChBP-GA and ChBP-SA cocrystals both present enhanced solubility and bioavailability in comparison with ChBP, making them a better candidate for the solid dosage formulation development.