(S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid | 76045-30-2

• 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-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid
• 英文别名: desferrithiocin；(4S)-2-(3-hydroxypyridin-2-yl)-4-methyl-5H-1,3-thiazole-4-carboxylic acid
• CAS: 76045-30-2
• 化学式: C₁₀H₁₀N₂O₃S
• 分子量: 238.267
• InChiKey: MJWAGSZZOQMRNY-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid 在 sodium hydroxide 作用下， 以 水 为溶剂， 生成 desferrithiocin
  参考文献：
  名称：

  [EN] DESFERRITHIOCIN ANALOGS AND USES THEREOF
  [FR] ANALOGUES DE LA DESFERRITHIOCINE ET LEURS UTILISATIONS

  摘要：

  铁过载与病理条件相关，如氧化应激、输血性铁过载、地中海贫血、原发性血色病、继发性血色病、糖尿病、肝病、心脏病、癌症、放射损伤、神经或神经退行性疾病、弗里德雷希共济失调（FRDA）、黄斑变性、闭合性头部损伤、肠易激综合征和再灌注损伤。本发明提供使用式（A）和（J）的去铁胱醇类似物的方法和药物组合物，用于治疗和/或预防这些病理条件、金属（如铁、铝、镧系元素或锕系元素（如铀））过载症状和传染病（如疟疾）。

  公开号：

  WO2015077655A1
• 作为产物：
  描述：

  2-氰基-3-羟基吡啶 、 2-甲基-D-半胱氨酸盐酸盐 在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以97%的产率得到(S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid
  参考文献：
  名称：

  Synthesis of the thiazoline-based siderophore (S)-desferrithiocin

  摘要：

  A total synthesis of the new thiazoline-based siderophore desferrithiocin 1, isolated from Streptomyces antibioticus, is described. Thus, a concise synthesis of (S)-2-methylcysteine hydrochloride 11 is first developed based on a modification of Seebach's ''self-reproduction of chirality'' protocol using the thiazolidine intermediate 8 derived from (S)-cysteine and pivaldehyde as a key intermediate. When a solution of (S)-2-methylcysteine hydrochloride is heated with 2-cyano-3-hydroxypyridine in the presence of triethylamine, (S)-desferrithiocin is produced in 97% yield. In a similar manner, use of (R)-2-methylcysteine in a cyclocondensation with 2-cyano-3-hydroxypyridine led to (R)-desferrithiocin, in a similar yield.

  DOI：

  10.1016/s0040-4020(01)82385-1

文献信息

• Effects of C-4 Stereochemistry and C-4‘ Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogues
  作者：Raymond J. Bergeron、Jan Wiegand、James S. McManis、Bruce H. McCosar、William R. Weimar、Gary M. Brittenham、Richard E. Smith

  DOI：10.1021/jm990058s

  日期：1999.7.1

  S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct-cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On

  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
• [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。
• 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-[(CH2)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。
• Remote loading of sparingly water-soluble drugs into lipid vesicles
  申请人：ZONEONE PHARMA, INC.

  公开号：US10004759B2

  公开（公告）日：2018-06-26

  The present invention provides liposome compositions containing sparingly soluble drugs that are used to treat life-threatening diseases. A preferred method of encapsulating a drug inside a liposome is by remote or active loading. However, this process as described in the literature has been limited to drugs that are freely soluble in aqueous solution or solubilized as a water-soluble complex. This invention describes compositions and methods for remote loading drugs with low water solubility (<2 mg/mL). In the preferred embodiment the drug in the solubilizing agent is mixed with the liposomes in aqueous suspension so that the concentration of solubilizing agent is lowered to below its capacity to completely solubilize the drug. This results in the drug precipitating but remote loading is capability retained. The process is scalable and the resulting drug-loaded liposomes are characterized by a high drug-to-lipid ratios and predictable drug retention when the liposome encapsulated drug is administered in patients.

  本发明提供的脂质体组合物含有用于治疗危及生命的疾病的稀溶性药物。将药物封装在脂质体内的一种优选方法是远程或主动装载。然而，文献中描述的这种方法仅限于可自由溶于水溶液或溶解为水溶性复合物的药物。本发明描述了远程装载低水溶性（<2 mg/mL）药物的组合物和方法。在优选的实施方案中，溶解剂中的药物与水悬浮液中的脂质体混合，使溶解剂的浓度降低到低于其完全溶解药物的能力。这将导致药物沉淀，但远程负载能力得以保留。该工艺具有可扩展性，产生的药物负载脂质体的特点是药物与脂质的比率高，在患者服用脂质体包裹的药物时，药物保留率可预测。