(S)-desazadesferrithiocin

• 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)-desazadesferrithiocin
• 英文别名: DADFT；4-Methylaeruginoic acid；(4S)-2-(2-hydroxyphenyl)-4-methyl-5H-1,3-thiazole-4-carboxylic acid
• 化学式: C₁₁H₁₁NO₃S
• 分子量: 237.279
• InChiKey: OXCVIPGXPILNPT-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  95.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  邻羟基苯甲腈 、 2-甲基半胱氨酸 在 phosphate buffer 作用下， 以 甲醇 为溶剂， 反应 120.0h， 以32%的产率得到(S)-desazadesferrithiocin
  参考文献：
  名称：

  C-4立体化学和C-4'羟基化对去铁硫代类似物的铁清除效率和毒性的影响。

  摘要：

  进行了去铁硫霉素类似物的其他结构活性研究。使用对映体4,5-二氢-2-（2,4-二羟基苯基）噻唑-4（R）-羧酸和4,5对映体评估和评估C-4上立体化学对配体铁清除效率的影响-二氢-2-（2,4-二羟基苯基）噻唑-4（S）-羧酸。还通过4，5-二氢-2-（2-羟苯基）-4-甲基噻唑-4（S）的合成和体内比较进一步研究了4'-羟基化作为降低脱氮杂脱铁硫霉素类似物毒性的方法的实用性。 ）-羧酸，它是天然产物4-甲基芥子酸，和4，5-二氢-2-（2,4-二羟基苯基）-4-甲基噻唑-4（S）-羧酸。C-4处的立体化学显示对去铁硫代类似物的铁清除效率有实质性影响，C-4'-羟基化对毒性谱也有显着影响。所有化合物均在胆管插管的啮齿动物模型中进行评估，以确定铁清除效率，并将其运用于重载铁的灵长类动物中进行铁清除测试。根据当前工作的结果，尽管4,5-二氢-2-（2,4-二羟基苯基）噻唑-4（S）-羧酸仍然是临床评估中最有希望的候选药物，但是4

  DOI：

  10.1021/jm990058s

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。
• Process for the preparation of substituted thiazolines and their intermediates
  申请人：——

  公开号：US20030088105A1

  公开（公告）日：2003-05-08

  Process for the preparation of substituted thiazolines of the formula (I) 1 in which Ar is a phenyl, naphthyl, thienyl, pyridyl or quinolinyl radical which can optionally be substituted by one or more substituents from the group consisting of halogen, OH, benzyloxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, COOR 1 where R 1 is H or C 1 -C 4 -alkyl, by coupling of (S)-&agr;-methylcysteine hydrochloride of the formula (II) 2 with a nitrile of the formula (III) Ar—CN in which Ar is as defined above, or a corresponding C 1 -C 4 -alkyl imidate, in which (S)-a-methylcysteine hydrochloride of the formula (II) is reacted in a suitable solvent with a nitrile of the formula (III) or a corresponding C 1 -C 4 -alkyl imidate in the presence of a tertiary base at a pH of 6.5 to 10 at 50° C. up to the reflux temperature to give the corresponding thiazoline of the formula (I), and processes for the preparation of (S)-&agr;-methylcysteine hydrochloride and its use for the preparation of thiazolines of the formula (I).

  制备式(I)的取代噻唑环的过程，其中Ar是苯基、萘基、噻吩基、吡啶基或喹啉基，可以选择性地由卤素、OH、苄氧基、C1-C4烷基、C1-C4烷氧基、COOR1（其中R1为H或C1-C4烷基）中的一个或多个取代基取代，通过(S)-α-甲基半胱氨酸盐酸盐的配对反应，配对反应的反应物为式(II)2和式(III)Ar—CN的腈或相应的C1-C4烷基亚胺，其中(S)-α-甲基半胱氨酸盐酸盐的配对反应物式(II)在适当的溶剂中与式(III)的腈或相应的C1-C4烷基亚胺在三级碱存在下，在pH为6.5至10、50℃至回流温度下反应，得到相应的式(I)的噻唑环，以及制备(S)-α-甲基半胱氨酸盐酸盐的过程及其用于制备式(I)的噻唑环的方法。
• [EN] SYNTHESIS OF 2-ALKYLCYSTEINES, 2-(HYDROXYLATED PHENYL)-4-ALKYLTHIAZOLINE-4-CARBOXYLIC ACIDS AND DERIVATIVES THEREOF<br/>[FR] SYNTHESE DES ACIDES 2-ALKYLCYSTEINES, 2-(PHENYLE HYDROXYLE)-4-ALKYLTHIAZOLINE-4-CARBOXYLIQUES ET DE LEURS DERIVES
  申请人：GENZYME CORP

  公开号：WO2003097622A2

  公开（公告）日：2003-11-27

  The present invention provides methods of preparing 2-alkylcysteine derivatives, many of which can be performed stereoselectively. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. An example of these iron chelating agents are 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-alkyl-thiazole-4-carboxylic acids, such as 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-thiazole-4-carboxylic acid.

  本发明提供了制备2-烷基半胱氨酸衍生物的方法，其中许多可以进行立体选择性。本发明还披露了一种制备与去铁蒺藜菌素相关的一类铁螯合剂的方法，所有这些铁螯合剂都含有噻唑环。这些铁螯合剂的一个例子是4,5-二氢-2-(2,4-二羟基苯基)-4-烷基噻唑-4-羧酸，例如4,5-二氢-2-(2,4-二羟基苯基)-4-甲基噻唑-4-羧酸。
• Synthesis of 2-alkylcysteine via substituted thiazoline amide
  申请人：Genzyme Corporation

  公开号：US20030236434A1

  公开（公告）日：2003-12-25

  Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention relates to a method of preparing 2-alkylcysteine comprising condensing cysteine with an aryl nitrile to form a 2-arylthiazoline-4-carboxylic acid, forming a 2-arylthiazoline-4-amide using an amine group comprising at least one substituted or unsubstituted alkyl group that comprises one or more chiral carbon atoms, and alkylating at the 4-position of the thiazoline ring to form a 2-aryl-4-alkyl-thiazoline-4-amide. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one embodiment, an aryl nitrile or imidate is condensed with cysteine or a 2-alkyl cysteine.

  非天然氨基酸，如2-烷基化氨基酸，可以合成更多种类的肽类和非肽类药物。在一种实施方式中，本发明涉及一种制备2-烷基半胱氨酸的方法，包括将半胱氨酸与芳基腈缩合形成2-芳基噻唑啉-4-羧酸，使用含有至少一个取代或未取代烷基的胺基团形成2-芳基噻唑啉-4-酰胺，该烷基包含一个或多个手性碳原子，并且在噻唑啉环的4位烷基化形成2-芳基-4-烷基噻唑啉-4-酰胺。本发明还公开了一种与去铁螯合素相关的铁螯合剂类的制备方法，所有这些类都含有噻唑啉环。在一种实施方式中，芳基腈或咪唑酯与半胱氨酸或2-烷基半胱氨酸缩合。
• Synthesis of 2-alkylcysteine via phase transfer catalysis
  申请人：Genzyme Corporation

  公开号：US20030236404A1

  公开（公告）日：2003-12-25

  Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention provides methods of preparing 2-alkylcysteine derivatives. In another embodiment, the method comprises forming a 2-alkylcysteine derivative from a cysteine derivative in the presence of a phase transfer catalyst. In particular, the present invention provides methods for preparing 2-methylcysteine derivatives. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one aspect, an aryl nitrile or imidate is condensed with cysteine or a 2-alkyl cysteine. The present invention also relates to the preparation of 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-alkyl-thiazole-4-carboxylic acids, such as 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-thiazole-4-carboxylic acid.

  非天然氨基酸（如2-烷基氨基酸）可以合成更广泛的肽类和非肽类药物活性剂。在一种实施例中，本发明提供了制备2-烷基半胱氨酸衍生物的方法。在另一种实施例中，该方法包括在相转移催化剂存在下从半胱氨酸衍生物形成2-烷基半胱氨酸衍生物。特别地，本发明提供了制备2-甲基半胱氨酸衍生物的方法。本发明还揭示了一种制备与去铁血胱铁类似的一类铁螯合剂的方法，其中所有铁螯合剂都含有噻唑环。在一个方面，芳基腈或亚胺酯与半胱氨酸或2-烷基半胱氨酸缩合。本发明还涉及制备4,5-二氢-2-(2,4-二羟基苯基)-4-烷基噻唑-4-羧酸，如4,5-二氢-2-(2,4-二羟基苯基)-4-甲基噻唑-4-羧酸。