3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester | 914780-24-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester
• 英文别名: methyl 3-(1,4-dioxaspiro[4.5]decan-8-ylamino)thiophene-2-carboxylate；3-(1,4-dioxa-spiro[4.5]dec-8-yl-amino)-thiophene-2-carboxylic acid methyl ester
• CAS: 914780-24-8
• 化学式: C₁₄H₁₉NO₄S
• 分子量: 297.375
• InChiKey: KMTPLRIOOJYJQD-UHFFFAOYSA-N

物化性质

• 沸点：
  443.2±45.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  85
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester 在 吡啶 、 盐酸 、 甲醇 、 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 sodium tetrahydroborate 、 copper(l) iodide 、 正丁基锂 、 lithium hydroxide monohydrate 、 三乙胺 、 二异丙胺 作用下， 以 四氢呋喃 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 47.0h， 生成 5-(3,3-dimethylbut-1-ynyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid
  参考文献：
  名称：

  Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection

  摘要：

  Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

  DOI：

  10.1021/jm401420j
• 作为产物：
  描述：

  1,4-环己二酮单乙二醇缩酮 、 3-氨基-2-噻吩甲酸甲酯 生成 3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester
  参考文献：
  名称：

  [EN] METHODS FOR PREPARATION OF THIOPHENE COMPOUNDS
  [FR] PROCÉDÉS DE PRÉPARATION DE COMPOSÉS DU THIOPHÈNE

  摘要：

  制备化合物（1）或其药学上可接受的盐的方法包括：a）在选择自Pd（PPh3）4和Pd（PPh3）2Cl2组成的一种或多种钯催化剂和选择自Cul，CuBr和CuCl组成的一种或多种铜催化剂的存在下，将化合物（A）与3,3-二甲基丁-1-炔反应，生成化合物（B）；b）用酸处理化合物（B），生成化合物（C）；c）将化合物（C）的环己酮还原为环己醇，生成化合物（D）；和d）将化合物（D）与碱反应，生成化合物（1），其中化合物（A），（B），（C）和（D）如此处所示。

  公开号：

  WO2013016499A1

文献信息

• [EN] COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS<br/>[FR] COMPOSÉS ET MÉTHODES DE TRAITEMENT OU DE PRÉVENTION D'INFECTIONS À FLAVOVIRUS
  申请人：VERTEX PHARMA

  公开号：WO2012006060A1

  公开（公告）日：2012-01-12

  A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables of Structural Formula (I) are as described in the specification and the claims. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

  化合物由结构式（I）表示：或其药学上可接受的盐，其中结构式（I）的变量如规范和权利要求中所述。一种药物组合物包括由结构式（I）表示的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。一种治疗受试者HCV感染的方法包括向受试者施用由结构式（I）表示的化合物或其药学上可接受的盐的治疗有效量。一种抑制或减少受试者或生物体外样本中HCV聚合酶活性的方法包括向受试者或样本施用由结构式（I）表示的化合物或其药学上可接受的盐的治疗有效量。
• [EN] COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS<br/>[FR] COMPOSÉS ET MÉTHODES DE TRAITEMENT OU DE PRÉVENTION D'INFECTIONS À FLAVIVIRUS
  申请人：VERTEX PHARMA

  公开号：WO2012006070A1

  公开（公告）日：2012-01-12

  A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables of Structural Formula (I) are as described in the specification and the claims. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A biological probe comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

  一种化合物由结构式（I）表示：或其药学上可接受的盐，其中结构式（I）的变量如说明书和权利要求中所述。一种药物组合物包括一种由结构式（I）表示的化合物或其药学上可接受的盐，以及一种药学上可接受的载体或赋形剂。一种生物探针包括一种由结构式（I）表示的化合物或其药学上可接受的盐。一种治疗HCV感染的方法包括向受试者施用一种由结构式（I）表示的化合物或其药学上可接受的盐的治疗有效量。一种抑制或减少受试者或生物体外样本中HCV聚合酶活性的方法包括向受试者或样本施用一种由结构式（I）表示的化合物或其药学上可接受的盐的治疗有效量。
• [EN] THIOPHENE COMPOUNDS<br/>[FR] COMPOSÉS DE TYPE THIOPHÈNE
  申请人：VERTEX PHARMA

  公开号：WO2013016490A1

  公开（公告）日：2013-01-31

  Polymorph Forms M, H, P, X, and ZA of Compound (1) represented by the following structural formula: are described. A method of preparing polymorph Form M of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes isopropanol, ethyl acetate, n-butyl acetate, methyl acetate, acetone, 2-butanone (methylethylketone (MEK)), or heptane, or a combination thereof at a temperature in a range of 10 °C to 47 °C to form From M of Compound (1). A method of preparing polymorph Form H of Compound (1) includes stirring a solution of Compound (1) at a temperature in a range of 48 °C to 70 °C to form Form H of Compound (1). A method of preparing polymorph Form P of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes a solvent selected from the group consisting of dichloromethane and tetrahydrofuran (THF), and a mixture thereof at room temperature to form Form P of Compound (1). A method of preparing polymorph Form X of Compound (1) includes removing ethyl acetate from ethylacetate solvate G of Compound (1). A method of preparing polymorph Form ZA of Compound (1) includes removing n-butyl acetate from n-butyl acetate solvate A of Compound (1).

  化合物（1）的多形式M、H、P、X和ZA由以下结构式代表：被描述。制备化合物（1）的多形式M的方法包括搅拌包含异丙醇、乙酸乙酯、正丁酯、乙酸甲酯、丙酮、2-丁酮（甲基乙基酮（MEK））或庚烷的溶剂体系的化合物（1）和溶剂体系的混合物，在10°C至47°C范围内的温度下形成化合物（1）的M形式。制备化合物（1）的多形式H的方法包括在48°C至70°C范围内的温度下搅拌化合物（1）的溶液以形成化合物（1）的H形式。制备化合物（1）的多形式P的方法包括在室温下搅拌化合物（1）和包括二氯甲烷和四氢呋喃（THF）中选择的溶剂以及它们的混合物的溶剂体系的混合物以形成化合物（1）的P形式。制备化合物（1）的多形式X的方法包括从化合物（1）的乙酸乙酯溶剂G中去除乙酸乙酯。制备化合物（1）的多形式ZA的方法包括从化合物（1）的正丁酯溶剂A中去除正丁酯。
• COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20130203706A1

  公开（公告）日：2013-08-08

  A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables of Structural Formula (I) are as described in the specification and the claims. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

  化合物由结构式（I）表示，或其药学上可接受的盐，其中结构式（I）的变量如说明书和权利要求所述。一种制药组合物包括由结构式（I）表示的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。一种治疗HCV感染的方法包括向患者投予结构式（I）表示的化合物或其药学上可接受的盐的治疗有效量。一种抑制或减少HCV聚合酶在体内或体外生物样品中活性的方法包括向患者或样品投予结构式（I）表示的化合物或其药学上可接受的盐的治疗有效量。
• Compounds and methods for the treatment or prevention of Flavivirus infections
  申请人：Denis Real

  公开号：US20060276533A1

  公开（公告）日：2006-12-07

  Compounds represented by formula I: or pharmaceutically acceptable salts and solvates thereof, wherein R 1 , X, Y, Y 1 , and Z are as defined herein, are useful for treating flaviviridae viral infections.

  公式I所代表的化合物或其药用可接受的盐和溶剂化物，其中R1、X、Y、Y1和Z的定义如本文所述，可用于治疗黄病毒科病毒感染。