(S)-4,5-dihydro-2-[2-hydroxy-3-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid | 1204751-09-6

• 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: (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid
• 英文别名: (s)-4,5-Dihydro-2-[2-hydroxy-3-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid；(4S)-2-[2-hydroxy-3-[2-(2-methoxyethoxy)ethoxy]phenyl]-4-methyl-5H-1,3-thiazole-4-carboxylic acid
• CAS: 1204751-09-6
• 化学式: C₁₆H₂₁NO₆S
• 分子量: 355.412
• InChiKey: QTUKMFTXQSBUBO-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,3-二羟基苯甲腈 、 2-(2-甲氧基乙氧基)乙基4-甲基苯磺酸负离子 在 sodium hydride 、 碳酸氢钠 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 25.0h， 生成 (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid
  参考文献：
  名称：

  Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity

  摘要：

  The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table 1) was halted due to nephrotoxicity. It was then shown by replacing the 4'-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure-activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand's iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICEprimate/ICErodent, are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.

  DOI：

  10.1007/s10534-010-9389-y

文献信息

• DESAZADESFERROTHIOCIN AND DESAZADESFERROTHIOCIN POLYETHER ANALOGUES AS METAL CHELATION AGENTS
  申请人：Malecha James

  公开号：US20110275636A1

  公开（公告）日：2011-11-10

  Disclosed herein are new compounds of desazadesferrothiocin polyether (DADFT-PE) analogues, as well as pharmaceutical compositions comprising them and their application as metal chelation agents for the treatment of disease. Methods of chelation of iron and other metals in a human or animal subject are also provided for the treatment of metal overload and toxicity.

  本文披露了新的去氮去除铁硫胺聚醚（DADFT-PE）类似物化合物，以及包含它们的药物组合物，以及它们作为金属螯合剂用于治疗疾病的应用。还提供了在人类或动物主体中螯合铁和其他金属的方法，用于治疗金属过载和中毒。
• DESAZADESFERROTHIOCIN ANALOGUES AS METAL CHELATION AGENTS
  申请人：FerroKin BioSciences, Inc.

  公开号：US20150259306A1

  公开（公告）日：2015-09-17

  Disclosed herein are new compounds of desazadesferrothiocin polyether (DADFT-PE) analogues, as well as pharmaceutical compositions comprising them and their application as metal chelation agents for the treatment of disease. Methods of chelation of iron and other metals in a human or animal subject are also provided for the treatment of metal overload and toxicity.

  本文披露了新的去氮去铁硫单环醚（DADFT-PE）类似物化合物，以及包含它们的制药组合物，以及它们作为金属螯合剂用于治疗疾病的应用。还提供了用于治疗人类或动物主体中金属过载和毒性的铁和其他金属螯合方法。
• Desferrithiocin analogs and uses thereof
  申请人：University of Florida Research Foundation, Incorporated

  公开号：US10010535B2

  公开（公告）日：2018-07-03

  Iron overload is associated with pathological conditions such as oxidative stress, transfusional iron overload, thalassemia, primary hemochromatosis, secondary hemochromatosis, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, and reperfusion injury. The present invention provides methods and pharmaceutical compositions using desferrithiocin analogs of Formulae (A) and (J) for treating and/or preventing these pathological conditions, metal (e.g., iron, aluminum, a lanthanide, or an actinide (e.g., uranium)) overload conditions, and infectious diseases (e.g., malaria).

  铁超载与氧化应激、输血铁超载、地中海贫血、原发性血色素沉着病、继发性血色素沉着病、糖尿病、肝病、心脏病、癌症、辐射损伤、神经或神经退行性疾病、弗里德里希共济失调（FRDA）、黄斑变性、闭合性头部损伤、肠易激性疾病和再灌注损伤等病理状况有关。本发明提供了使用式（A）和式（J）的去铁硫霉素类似物治疗和/或预防这些病理状况、金属（如铁、铝、镧系元素或锕系元素（如铀））过载状况和传染病（如疟疾）的方法和药物组合物。
• NOVEL SALTS AND POLYMORPHS OF DESAZADESFERROTHIOCIN POLYETHER ANALOGUES AS METAL CHELATION AGENTS
  申请人：Tapper Amy E.

  公开号：US20100137383A1

  公开（公告）日：2010-06-03

  Disclosed herein are new salts and polymorphs of desazadesferrithiocin polyether (DADFT-PE) analogues, as well as pharmaceutical compositions comprising them and their application as metal chelation agents for the treatment of disease. Methods of chelation of iron and other metals in a human or animal subject are also provided for the treatment of metal overload and toxicity.
• NOVEL SALTS AND POLYMORPHS OF DESAZADESFERRITHIOCIN POLYETHER ANALOGUES AS METAL CHELATION AGENTS
  申请人：Tapper Amy E.

  公开号：US20120202857A1

  公开（公告）日：2012-08-09

  Disclosed herein are new salts and polymorphs of desazadesferrithiocin polyether (DADFT-PE) analogues, as well as pharmaceutical compositions comprising them and their application as metal chelation agents for the treatment of disease. Methods of chelation of iron and other metals in a human or animal subject are also provided for the treatment of metal overload and toxicity.