ethyl (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylate | 847829-15-6

• 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: ethyl (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylate
• 英文别名: ethyl (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylate；ehyl (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylate；ethyl ester of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid；ethyl (4S)-2-(2,4-dihydroxyphenyl)-4-methyl-5H-1,3-thiazole-4-carboxylate
• CAS: 847829-15-6
• 化学式: C₁₃H₁₅NO₄S
• 分子量: 281.332
• InChiKey: MKUBNBQHMDNSMQ-CYBMUJFWSA-N

物化性质

• 沸点：
  453.8±55.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylate 在 sodium hydroxide 、 sodium ethanolate 作用下， 以 乙醇 为溶剂， 反应 33.0h， 生成 (S)-4,5-dihydro-2-[2-hydroxy-4-(8-amino-5-azaoctyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid bis(trifluoroacetate)
  参考文献：
  名称：

  Polyamine-Vectored Iron Chelators:  The Role of Charge

  摘要：

  The utility of polyamines as vectors for the intracellular transport of iron chelators is further described. Consistent with earlier results with polyamine analogues, these studies underscore the importance of charge in the design of polyamine-vectored chelators. Four polyamine conjugates are synthesized, two of tereplithalic acid [N-1-(4-carboxy)benzoylspermine (7) and its methyl ester (6)] and two of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT] [(S)-4,5-dihydro-2-[2-hydroxy-4-(12-amino-5,9-diazadodecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (10) and its ethyl ester (9)]. These four molecules were evaluated in murine leukemia L1210 cells for their impact on cell proliferation (48- and 96-h IC50 values), their ability to compete with spermidine for the polyamine transport apparatus (K-i), and their intracellular accumulation. The data revealed that when neutral molecules (cargo fragments) were fixed to the polyamine vector, the conjugates competed well with spermidine for transport and were accumulated intracellularly to millimolar levels. However, this was not the case when the cargo fragments were negatively charged. Metabolic studies of the polyamine-vectored (S)-4'-(HO)-DADFTs in rodents indicated that not only did the expected deaminopropylation step occur, but also a surprisingly high level of oxidative deamination at the terminal primary nitrogens took place. Finally, the iron-clearing efficiency of the (S)-4'-(HO)-DADFT conjugates was determined in a bile-duct-cannulated rodent model. Attaching the ligand to a polyamine vector had a profound effect on increasing the iron-clearing efficiency of this chelator relative to its parent drug.

  DOI：

  10.1021/jm048974f
• 作为产物：
  描述：

  碘乙烷 、 地夫立群 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以100%的产率得到ethyl (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylate
  参考文献：
  名称：

  光学活性ジヒドロチアゾールカルボン酸誘導体の製造法

  摘要：

  提供一种不使用具有遗传毒性试剂，在短工序中制备用作药物的有用光学活性二氢噻唑甲酸衍生物的方法。通过在碱存在下使（S）-4,5-二氢-2-(2,4-二羟基苯基)-4-甲基-4-噻唑甲酸和甘醇单甲醚衍生物反应，制备光学活性二氢噻唑酯衍生物，然后水解得到光学活性二氢噻唑甲酸衍生物，其制备方法由式（4）表示。该制备方法可以在短工序中制备用作药物的有用二氢噻唑甲酸衍生物，减少杂质的副产生。

  公开号：

  JP2017137262A

文献信息

• [EN] METABOLICALLY PROGRAMMED METAL CHELATORS AND USES THEREOF<br/>[FR] AGENTS CHÉLATEURS MÉTALLIQUES PROGRAMMÉS MÉTABOLIQUEMENT ET LEURS UTILISATIONS
  申请人：UNIV FLORIDA

  公开号：WO2016176343A1

  公开（公告）日：2016-11-03

  The present invention provides compounds of Formula (I), which are "metabolically programmed" metal chelators, e.g., lipophilic, absorbable (e.g., orally absorbable), and effective metal chelators that are converted in vivo to their hydrophilic, nontoxic metabolites. The present invention also provides compounds of Formula (II), which are also "metabolically programmed" metal chelators. The invention also provides pharmaceutical compositions, kits, methods, and uses that include a compound described herein. The compounds, pharmaceutical compositions, kits, and methods may be useful in treating or preventing a disease (e.g., metal overload, oxidative stress, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, reperfusion injury, metal poisoning, or infectious disease).

  本发明提供了式（I）的化合物，这些化合物是“代谢程序化”的金属螯合剂，例如，亲脂性、可吸收（例如，口服可吸收）和有效的金属螯合剂，在体内转化为其亲水性、无毒的代谢物。本发明还提供了式（II）的化合物，这些化合物也是“代谢程序化”的金属螯合剂。本发明还提供了包括本文所述化合物的药物组合物、试剂盒、方法和用途。这些化合物、药物组合物、试剂盒和方法可能对治疗或预防疾病（例如，金属过载、氧化应激、糖尿病、肝病、心脏病、癌症、放射损伤、神经系统或神经退行性疾病、弗里德雷希氏共济失调症（FRDA）、黄斑变性、闭合性头部损伤、肠易激综合征、再灌注损伤、金属中毒或传染性疾病）具有用处。
• Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators
  作者：Raymond Bergeron、Shailendra Singh、Neelam Bharti、Yi Jiang

  DOI：10.1055/s-0030-1258245

  日期：2010.11

  Iron chelators have been shown to control the growth of cancer cells in culture by sequestering exogenous iron in the media. Thus, the ligands prevent cellular access to the metal. However, because transferrin provides iron to tumor cells in animals, chelators have not been effective antitumor agents. Polyamine chelator conjugates in which the polyamine vectored ligands into cells were far more active than the free chelators themselves. However, the free ligands were not released from the vector once in the cell. The current study focuses on the synthesis and preliminary evaluation of a polyamine chelator conjugate capable of releasing the free ligand intracellularly via a nonspecific esterase.

  铁螯合剂通过在培养基中封存外源铁来控制癌细胞的生长。因此，配体可阻止细胞获得金属。然而，由于动物体内的转铁蛋白能为肿瘤细胞提供铁，因此螯合剂并不是有效的抗肿瘤药物。多胺螯合剂轭合物中的多胺可将配体导向细胞，其活性远高于游离螯合剂本身。然而，游离配体一旦进入细胞就不会从载体中释放出来。本研究的重点是合成一种多胺螯合剂共轭物并对其进行初步评估，这种共轭物能够通过一种非特异性酯酶在细胞内释放游离配体。
• DESFERRITHIOCIN POLYETHER ANALOGUES
  申请人：Bergeron, JR. Raymond J.

  公开号：US20100093812A1

  公开（公告）日：2010-04-15

  A relatively non-toxic desazadesferrithiocin analog having the formula (I): wherein: R 1 , R 2 , R 4 and R 5 may be the same or different and may be H, straight or branched chain alkyl having up to 14 carbon atoms, e.g., methyl, ethyl, propyl and butyl, or arylalkyl wherein the aryl portion is hydrocarbyl and the alkyl portion is straight or branched chain, the arylalkyl group having up to 14 carbon atoms, R2 optionally being alkoxy having up to 14 carbon atoms; R 3 is [(CH 2 ) n —O] x —[(CH 2 ) n —O] y -alkyl; n is, independently, an integer from 1 to 8; x is an integer from 1 to 8; y is an integer from O to 8, and R 3 O may occupy any position on the phenyl ring except the 4-position, or a salt, hydrate or solvate thereof; and methods and compositions for treating the effects of trivalent metal, i.e., iron, overload.

  一种相对无毒的去除铁过载的治疗方法，使用化学式（I）的类去铁血红素衍生物，其中：R1、R2、R4和R5可以相同或不同，可以是氢，直链或支链烷基，碳数不超过14个，例如，甲基，乙基，丙基和丁基，或芳基烷基，其中芳基部分为烃基，烷基部分为直链或支链，芳基烷基的碳数不超过14个，R2可以选择为碳数不超过14个的烷氧基；R3为[(CH2)n-O]x-[( )n-O]y-烷基；n独立地为1到8的整数；x为1到8的整数；y为0到8的整数，R3O可以占据苯环上除4位以外的任何位置，或其盐，水合物或溶剂化物；以及治疗三价金属，即铁，过载的方法和组合物。
• DESFERRITHIOCIN POLYETHER ANALOGUES AND USES THEREOF
  申请人：Bergeron, JR. Raymond J.

  公开号：US20120184586A1

  公开（公告）日：2012-07-19

  Desferrithiocin analogues represents by the structural formulae described here, such as formula (I), are useful in treating conditions such as metal overload (e.g., iron overload from transfusion therapy), oxidative stress, and neoplastic and preneoplastic conditions.

  Desferrithiocin类似物由此处描述的结构式代表，例如公式（I），在治疗诸如金属过载（例如输血治疗引起的铁过载）、氧化应激以及肿瘤和癌前病变等疾病方面是有用的。
• Metabolically programmed metal chelators and uses thereof
  申请人：University of Florida Research Foundation, Incorporated

  公开号：US10570104B2

  公开（公告）日：2020-02-25

  The present invention provides compounds of Formula (I), which are “metabolically programmed” metal chelators, e.g., lipophilic, absorbable (e.g., orally absorbable), and effective metal chelators that are converted in vivo to their hydrophilic, nontoxic metabolites. The present invention also provides compounds of Formula (II), which are also “metabolically programmed” metal chelators. The invention also provides pharmaceutical compositions, kits, methods, and uses that include a compound described herein. The compounds, pharmaceutical compositions, kits, and methods may be useful in treating or preventing a disease (e.g., metal overload, oxidative stress, diabetes, liver disease, heart disease, cancer, radiation injury, neurological or neurodegenerative disorder, Friedreich's ataxia (FRDA), macular degeneration, closed head injury, irritable bowel disease, reperfusion injury, metal poisoning, or infectious disease).

  本发明提供了式(I)化合物，它们是 "代谢编程 "金属螯合剂，例如，亲脂、可吸收（例如，可口服吸收）和有效的金属螯合剂，可在体内转化为亲水、无毒的代谢物。本发明还提供式（II）化合物，它们也是 "代谢编程 "金属螯合剂。本发明还提供了包括本文所述化合物的药物组合物、试剂盒、方法和用途。这些化合物、药物组合物、试剂盒和方法可用于治疗或预防疾病（如金属超载、氧化应激、糖尿病、肝病、心脏病、癌症、辐射损伤、神经系统或神经退行性疾病、弗里德雷希氏共济失调（FRDA）、黄斑变性、闭合性头部损伤、肠易激性疾病、再灌注损伤、金属中毒或传染性疾病）。