N-(2-morpholin-4-yl-ethyl)-N'-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide | 1394929-76-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: N-(2-morpholin-4-yl-ethyl)-N'-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide
• 英文别名: N-(2-morpholin-4-ylethyl)-N'-(6-trifluoromethoxybenzothiazol-2-yl)-succinamide；N-(2-morpholin-4-ylethyl)-N'-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]butanediamide
• CAS: 1394929-76-0
• 化学式: C₁₈H₂₁F₃N₄O₄S
• 分子量: 446.45
• InChiKey: FDFBDSPDVOWQMU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  N-(2-氨基乙基)吗啉 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 N-(2-morpholin-4-yl-ethyl)-N'-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide
  参考文献：
  名称：

  Riluzole prodrugs for melanoma and ALS: Design, synthesis, and in vitro metabolic profiling

  摘要：

  Riluzole (1) is an approved therapeutic for the treatment of ALS and has also demonstrated anti-melanoma activity in metabotropic glutamate GRM1 positive cell lines, a mouse xenograft assay and human clinical trials. Highly variable drug exposure following oral administration among patients, likely due to variable first pass effects from heterogeneous CYP1A2 expression, hinders its clinical use. In an effort to mitigate effects of this clearance pathway and uniformly administer riluzole at efficacious exposure levels, several classes of prodrugs of riluzole were designed, synthesized, and evaluated in multiple in vitro stability assays to predict in vivo drug levels. The optimal prodrug would possess the following profile: stability while transiting the digestive system, stability towards first pass metabolism, and metabolic lability in the plasma releasing riluzole. (S)-O-Benzyl serine derivative 9 was identified as the most promising therapeutically acceptable prodrug. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.07.004

文献信息

• [EN] PRODRUGS OF RILUZOLE AND THEIR METHOD OF USE<br/>[FR] PROMÉDICAMENTS DE RILUZOLE ET LEUR MÉTHODE D'UTILISATION
  申请人：FOX CHASE CHEMICAL DIVERSITY CT INC

  公开号：WO2013138753A1

  公开（公告）日：2013-09-19

  Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

  该发明的药物组合物包括替代利鲁唑前药，通过释放利鲁唑用于治疗包括黑色素瘤、乳腺癌、脑癌和前列腺癌在内的癌症。利鲁唑的前药具有增强的对肝代谢的稳定性，并通过口服途径输送到全身循环中，然后通过酶促或一般生物物理释放过程在血浆中释放利鲁唑。
• PRO-DRUGS OF RILUZOLE AND THEIR METHOD OF USE FOR THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS
  申请人：Fox Chase Chemical Diversity Center, Inc.

  公开号：US20150148329A1

  公开（公告）日：2015-05-28

  Pharmaceutical compositions of the invention include substituted riluzole pro drugs useful for the treatment of amyotrophic lateral sclerosis (ALS) and related disorders through the release of riluzole, especially to avoid patient to patient variability in first pass, hepatic metabolism promoted by Cyp 1A2. Pro-drugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. The invention further includes pro-drugs of riluzole useful for the treatment of disease states that can be treated with riluzole through the release of riluzole from a pro-drug agent.

  本发明的药物组合物包括替代利鲁唑前药，通过释放利鲁唑，特别是为了避免Cyp 1A2促进的首过肝代谢引起的患者间变异性，用于治疗肌萎缩侧索硬化症（ALS）和相关疾病。利鲁唑的前药具有增强的肝代谢稳定性，并通过口服途径进入系统循环，然后通过酶促或一般生物物理释放过程在血浆中裂解释放利鲁唑。本发明还包括利鲁唑前药，通过释放利鲁唑治疗可以用利鲁唑治疗的疾病状态。
• PRODRUGS OF RILUZOLE AND THEIR METHOD OF USE
  申请人：Fox Chase Chemical Diversity Center, Inc.

  公开号：US20150045401A1

  公开（公告）日：2015-02-12

  Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

  本发明的药物组合物包括用于治疗癌症（包括黑色素瘤、乳腺癌、脑癌和前列腺癌）的取代riluzole前药，通过释放riluzole来发挥作用。riluzole的前药具有增强的肝代谢稳定性，并通过口服给药进入全身循环，然后通过酶促或一般生物物理释放过程在血浆中裂解以释放riluzole。
• Pro-drugs of riluzole and their method of use for the treatment of amyotrophic lateral sclerosis
  申请人：Biohaven Pharmaceutical Holding Company Limited

  公开号：US10357497B2

  公开（公告）日：2019-07-23

  Pharmaceutical compositions of the invention include substituted riluzole pro drugs useful for the treatment of amyotrophic lateral sclerosis (ALS) and related disorders through the release of riluzole, especially to avoid patient to patient variability in first pass, hepatic metabolism promoted by Cyp 1A2. Pro-drugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. The invention further includes pro-drugs of riluzole useful for the treatment of disease states that can be treated with riluzole through the release of riluzole from a pro-drug agent.

  本发明的药物组合物包括通过释放利鲁唑治疗肌萎缩性脊髓侧索硬化症（ALS）和相关疾病的取代利鲁唑原药，特别是避免了由Cyp 1A2促进的肝脏代谢中患者与患者之间的首过差异。利鲁唑原药对肝脏代谢的稳定性增强，通过口服进入全身循环，然后通过酶或一般生物物理释放过程裂解，在血浆中释放利鲁唑。本发明还包括可用于治疗疾病的利鲁唑原药，这些疾病可以通过利鲁唑原药释放利鲁唑来治疗。
• Prodrugs of riluzole and their method of use
  申请人：Biohaven Pharmaceutical Holding Company Ltd.

  公开号：US10562870B2

  公开（公告）日：2020-02-18

  Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

  本发明的药物组合物包括取代的利鲁唑原药，可通过释放利鲁唑治疗癌症，包括黑色素瘤、乳腺癌、脑癌和前列腺癌。利鲁唑原药对肝脏代谢的稳定性增强，通过口服进入全身循环，然后通过酶或一般生物物理释放过程裂解，在血浆中释放利鲁唑。