5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile | 99329-52-9

• 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: 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile
• 英文别名: 5-bromo-2-(3,4-dimethoxyphenyl)-2-(methylethyl)pentanenitrile；5-bromo-2-(3,4-dimethoxyphenyl)-2-propan-2-ylpentanenitrile
• CAS: 99329-52-9
• 化学式: C₁₆H₂₂BrNO₂
• 分子量: 340.26
• InChiKey: XOTRONYGHIFSLG-UHFFFAOYSA-N

物化性质

• 沸点：
  431.1±45.0 °C(Predicted)
• 密度：
  1.227±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  42.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile 在 18-冠醚-6 、 一水合肼 作用下， 以 四氢呋喃 、 乙醇 、 甲苯 为溶剂， 反应 9.0h， 生成 4-氰基-4-(3,4-二甲氧基苯基)-5-甲基己胺
  参考文献：
  名称：

  Design, Synthesis, and in Vitro Activity of Catamphiphilic Reverters of Multidrug Resistance:  Discovery of a Selective, Highly Efficacious Chemosensitizer with Potency in the Nanomolar Range

  摘要：

  On the basis of the results obtained in previous research, three series of compounds (A-C), derived from verapamil, were designed and synthesized to obtain drugs able to revert multidrug resistance (MDR), an acquired resistance that frequently impairs cancer chemotherapy. The ability of the obtained compounds to revert MDR was evaluated on anthracycline-resistant erythroleukemia K 562 cells, measuring the uptake of THP-adriamycin (pirarubicin) by continuous spectrofluorometric monitoring of the decrease of the fluorescence signal of the anthracycline at 590 nm (lambda(ex) = 480 nm), after incubation with cells. Cardiovascular activity, which is responsible for unwanted side effects, was also evaluated. The results obtained show that many of the compounds studied are potent reverters of MDR and are endowed with reduced cardiovascular activity. One of the compounds (7, MM36) presents a pharmacological profile (unprecedented nanomolar potency, high reversal of MDR, low cardiovascular activity) that makes it a promising drug candidate to treat MDR and a useful tool for studying P-glycoprotein.

  DOI：

  10.1021/jm980440p
• 作为产物：
  描述：

  3,4-二甲氧基苯乙腈 在 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 34.34h， 生成 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile
  参考文献：
  名称：

  [EN] HIGHLY WATER-SOLUBLE SALTS OF A SHORT ACTING PHENYLALKYLAMINE CALCIUM CHANNEL BLOCKER AND USES THEREOF
  [FR] SELS TRÈS HYDROSOLUBLES D'UN INHIBITEUR DES CANAUX CALCIQUES À BASE DE PHÉNYLALKYLAMINE À ACTION COURTE ET LEURS UTILISATIONS

  摘要：

  本发明包括一种令人惊讶的苯基烷基胺化合物的水溶性盐，这些盐是L型钙通道的有效拮抗剂。包括本发明盐的水溶液被配制用于鼻腔给药，并为稳定型心绞痛、偏头痛和心律失常（如阵发性上室性心动过速）的治疗提供了一种新颖的治疗平台。

  公开号：

  WO2016165014A1

文献信息

• Design and synthesis of new potent N,N -bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents
  作者：Silvia Dei、Marcella Coronnello、Gianluca Bartolucci、Dina Manetti、Maria Novella Romanelli、Chatchanok Udomtanakunchai、Milena Salerno、Elisabetta Teodori

  DOI：10.1016/j.ejmech.2018.01.092

  日期：2018.3

  A series of 1,4-substituted arylalkyl piperazine derivatives were synthesized and studied with the aim to obtain potent P-gp-dependent multidrug-resistant (MDR) reversers. The new compounds were designed on the basis of the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity. All new compounds were active in the pirarubicin

  合成和研究了一系列1,4-取代的芳基烷基哌嗪衍生物，目的是获得有效的P-gp依赖性多药耐药（MDR）反向剂。这些新化合物是在我们以前的芳胺酯衍生物具有高P-gp依赖性多药耐药性逆转活性的结构的基础上设计的。所有新化合物在耐阿霉素的红白血病K562细胞（K562 / DOX）的吡柔比星摄取测定中均具有活性。特别地，带有甲氧基芳族部分的化合物显示出相当高的逆转活性。通过评估它们对阿霉素的细胞毒性增强作用（逆向折叠，RF）以及P-gp介导的若丹明-123（Rhd 123）外排对K562 / DOX的抑制作用，进一步研究了最有效的化合物8、9、10和13。细胞系。所有药理学测定的结果表明，碱性哌嗪支架与芳基烷基残基的结合使我们获得了非常有趣的P-gp调节化合物。确定了两个持久的P-gp泵调制器（9和10）；他们能够在60分钟后显着抑制P-gp底物罗丹明123在耐药K562 / DOX细胞系上的流出
• Design, Synthesis, and Preliminary Pharmacological Evaluation of 4-Aminopiperidine Derivatives as N-Type Calcium Channel Blockers Active on Pain and Neuropathic Pain
  作者：Elisabetta Teodori、Elisabetta Baldi、Silvia Dei、Fulvio Gualtieri、Maria Novella Romanelli、Serena Scapecchi、Cristina Bellucci、Carla Ghelardini、Rosanna Matucci

  DOI：10.1021/jm049923l

  日期：2004.11.1

  Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies

  已经合成了几种具有4-氨基哌啶骨架的化合物，它们在两个氮原子上都被包含维拉帕米和氟那利嗪的结构基序的烷基或酰基部分修饰，以及在已知的N型钙通道拮抗剂中更常见的那些。使用小鼠热板试验的抗伤害感受活性来选择要进一步研究的分子。在PC12大鼠嗜铬细胞瘤克隆细胞系上对活性化合物进行了体外测试，以评估其对N型钙通道和神经性疼痛大鼠模型的作用。已选择了两种具有N型钙通道拮抗作用且对疼痛和神经性疼痛具有有效作用的化合物（3和18）进行进一步研究。
• SHORT ACTING PHENYLALKYLAMINE CALCIUM CHANNEL BLOCKERS AND USES THEREOF
  申请人：Milestone Pharmaceuticals Inc.

  公开号：US20170312243A1

  公开（公告）日：2017-11-02

  The present invention relates to the use of a pharmaceutically effective amount of an short-acting calcium channel blocking compound to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension before, during, or after surgery, no-reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.

  本发明涉及使用药效学有效量的短效钙通道阻滞剂来治疗缺血性心脏病、心脏心律失常、急诊室高血压危机、手术前、手术中或手术后的高血压、再灌注后无反流现象以及与骨骼肌血流减少相关的疾病。本发明还涉及制备用于这些方法的制药组合物以及用于这些方法的工具箱。
• N-arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine and
  申请人：Vyzkumny Ustav Pro Farmacii A Biochemii s.p.

  公开号：US05424456A1

  公开（公告）日：1995-06-13

  New N-Arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine and its (+)- and (-)- enantiomers represented by general formula (I), where R.sub.1, R.sub.2 and R.sub.3 represent H, or R.sub.1 and R.sub.2 represent H and R.sub.3 represent H or R.sub.1 and R.sub.2 represent methoxy and R.sub.3 represents H and their pharmaceutically acceptable organic or inorganic acid addition salts exhibit in pharmacological tests pronounced hypotensive activity as a result of their calcium channel blocking and alpha.sub.1 -adrenergic blocking activity and pronounced antithrombotic action. In a form of pharmaceutical preparations, they are suitable for the treatment and prevention of cardiovascular diseases and other disorders. New compounds of general formula (I) by N-alkylation of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine and its (+)- and (-)-enantiomers by derivatives of 2 phenyl-2-isopropyl-5-oxovaleronitrile under the conditions of reductive alkylation or with derivatives of 5-bromo-2-phenyl-2-isopropylvaleronitrile, which can be prepared by allylation of alpha-isopropylbenzyl cyanide and subsequent addition of hydrogen bromide under free radical conditions to the obtained alpha-allyl-alpha-isopropylbenzyl cyanide and its derivatives.

  2-氨甲基-2,3-二氢-1,4-苯并二氧杂环的新的N-芳基烷基衍生物及其(+)-和(-)-对映异构体由通式(I)表示，其中R.sub.1，R.sub.2和R.sub.3代表H，或者R.sub.1和R.sub.2代表H且R.sub.3代表H，或者R.sub.1和R.sub.2代表甲氧基且R.sub.3代表H，以及它们的药物可接受的有机或无机酸盐，在药理学测试中表现出显著的降压活性，这是由于它们的钙通道阻滞和α.sub.1-肾上腺素能阻滞活性以及显著的抗血栓作用。以药物制剂的形式，它们适用于心血管疾病和其他疾病的治疗和预防。通过2-苯基-2-异丙基-5-氧代戊二腈衍生物的还原烷基化条件或5-溴-2-苯基-2-异丙基戊二腈衍生物的衍生物对2-氨甲基-2,3-二氢-1,4-苯并二氧杂环及其(+)-和(-)-对映异构体进行N-烷基化，这些衍生物可以通过α-异丙基苄基氰化物的联苄反应和对所得的α-烯丙基-α-异丙基苄基氰化物及其衍生物进行自由基条件下的氢溴酸加成来制备。
• Short acting phenylalkylamine calcium channel blockers and uses thereof
  申请人：Milestone Pharmaceuticals Inc.

  公开号：US09227918B2

  公开（公告）日：2016-01-05

  The present invention relates to the use of a pharmaceutically effective amount of an short-acting calcium channel blocking compound to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension before, during, or after surgery, no-reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.

  本发明涉及使用药理有效量的短效钙通道阻滞剂化合物来治疗缺血性心脏病、心脏心律失常、急诊室高血压危机、手术前、期间或后的高血压、再灌注后的无反流现象以及与骨骼肌血流减少相关的疾病。本发明还涉及用于上述方法的制剂的制备以及用于该方法的工具包。