ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate | 955886-29-0

• 物质功能分类: 医药中间体
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate
• 英文别名: ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate；6-Benzofurancarboxylic acid, 4-(acetyloxy)-2-methyl-, ethyl ester；ethyl 4-acetyloxy-2-methyl-1-benzofuran-6-carboxylate
• CAS: 955886-29-0
• 化学式: C₁₄H₁₄O₅
• 分子量: 262.262
• InChiKey: ULWXTKQBDUGGTB-UHFFFAOYSA-N

物化性质

• 沸点：
  385.5±42.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  65.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate 在 potassium carbonate 作用下， 以 乙醇 为溶剂， 生成 4-羟基-2-甲基苯并呋喃-6-羧酸乙酯
  参考文献：
  名称：

  Duocarmycin C1和C2的新型呋喃喃类似物：癸二异环丙基呋喃并[2,3-e]吲哚啉（seco-iso-CFI）和癸二环丙基四氢呋喃呋喃并[2,3-f]喹啉的设计，合成和生物学评价seco-CFQ）类似物。

  摘要：

  新型癸二酸-异-环丙基呋喃并[2,3-e]二氢吲哚（seco-iso-CFI）和癸二酸-环丙基四氢呋喃[2,3-f]喹啉（seco-CFQ）类似物的设计，合成和生物学评价描述了杜卡霉素。设计这些新颖的类似物（4-7），前提是呋喃氧原子上的孤对电子可以与由HCl损失形成的异环丙基呋喃并[e]吲哚酮（iso-CFI）烷基化部分偶联在化合物4-7中。通过使用氯乙烯的5-exo-trig芳基自由基环化的先验方法合成了seco-iso-CFI DNA烷基化药效团。在我们的研究中，除了形成顺式-异-CFI产物外，在自由基环化反应过程中还产生了等量的不可预期的顺式-CFQ产物。像CC-1065和adozelesin，使用Taq DNA聚合酶终止和热裂解分析，显示seco-iso-CFI化合物（4和6）和seco-CFQ化合物（5和7）优先使长片段小沟中的腺嘌呤-N3位置烷基化A残基。化合物6与DNA 1

  DOI：

  10.1016/s0968-0896(02)00157-8
• 作为产物：
  描述：

  (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid 以100的产率得到ethyl 4-(acetyloxy)-2-methyl-1-benzofuran-6-carboxylate
  参考文献：
  名称：

  Benzofuranyl Derivatives

  摘要：

  本发明提供了公式(I)的化合物，其作为葡萄糖激酶激活剂；其药物组合物；以及治疗由葡萄糖激酶介导的疾病、障碍或病情的方法。

  公开号：

  US20100234285A1

文献信息

• FUSED PHENYL AMIDO HETEROCYCLIC COMPOUNDS
  申请人：Bai Hao

  公开号：US20080280875A1

  公开（公告）日：2008-11-13

  The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A is (4-12)-membered heterocyclyl; Ring B is a fused benzene ring selected from the group consisting of: Ring A, ring B, ring C, R 1 , R 1a , R 2 , R 3 , R 4 , L 2 , n, t, w, and z are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a condition that is mediated by the modulation of glucokinase, the method comprising administering to a mammal an effective amount of a compound of formula (I).

  本发明涉及以下式(I)的化合物：或其药用可接受的盐或溶剂，其中：环A为(4-12)成员杂环基；环B是从以下组中选择的融合苯环之一：环A、环B、环C、R1、R1a、R2、R3、R4、L2、n、t、w和z如规范中所定义。本发明还涉及包括式(I)的化合物的药物组合物以及治疗通过调节葡萄糖激酶介导的疾病的方法，该方法包括向哺乳动物施用有效量的式(I)的化合物。
• Metabolites in Safety Testing Assessment in Early Clinical Development: A Case Study with a Glucokinase Activator
  作者：Raman Sharma、John Litchfield、Karen Atkinson、Heather Eng、Neeta B. Amin、William S. Denney、John C. Pettersen、Theunis C. Goosen、Li Di、Esther Lee、Jeffrey A. Pfefferkorn、Deepak K. Dalvie、Amit S. Kalgutkar

  DOI：10.1124/dmd.114.060087

  日期：2014.11

  The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N -dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N -Demethylation to metabolite M1 [ N -methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse-effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (∼7.7× and 1.8×) and area under the plasma concentration-time curve (AUC; 3.6× and 0.8× AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 μ M; M1: EC50 = 4.69 μ M). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 μ M), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319.

  本文总结了关于一种葡萄糖激酶激活剂 N,N-二甲基-5-((2-甲基-6-((5-甲基吡嗪-2-基)氨基)苯并呋喃-4-基)氧)pyrimidine-2-羧酰胺（PF-04937319）的代谢物安全性测试（MIST）研究，该药物正在开发用于治疗2型糖尿病。对大鼠、犬和人类肝细胞的代谢谱分析显示，PF-04937319通过氧化（主要）和水解（次要）途径代谢。N-去甲基化生成代谢物M1（N-甲基-5-((2-甲基-6-((5-甲基吡嗪-2-基)氨基)苯并呋喃-4-基)氧)pyrimidine-2-羧酰胺）是PF-04937319在人体肝细胞中的主要代谢去向（而在大鼠或犬肝细胞中则不是），由CYP3A和CYP2C亚型催化。对人类在14天多剂量研究中100mg和300mg剂量下的循环代谢物的定性分析显示，未改变的母药和M1是主要成分。由于M1在稳态时占药物相关物质的65%，因此合成了一个真实标准并用于人类和在无观察到不良反应水平下的大鼠和犬的3个月安全性研究中稳态暴露的比较。尽管在比格犬和雌性大鼠中M1的循环水平非常低，但在雄性大鼠中的总最大血浆浓度（约7.7倍和1.8倍）及血浆浓度-时间曲线下面积（AUC；3.6倍和0.8倍AUC）相对于100mg和300mg剂量仍获得了足够的覆盖。对主要药理学的检查显示M1作为葡萄糖激酶激活剂的效能低于母药（化合物PF-04937319: EC50 = 0.17 μM; M1: EC50 = 4.69 μM）。此外，M1不抑制主要人类P450酶（IC50 > 30 μM），在Salmonella Ames试验中呈阴性，基于CEREP的广谱配体配置分析显示其具有最小的非靶向药理学。从该分析中获得的见解应能指导PF-04937319的MIST要求的更有效和更有针对性的开发计划。
• [EN] BENZOFURANYL DERIVATIVES USED AS GLUCOKINASE INHIBITORS<br/>[FR] DÉRIVÉS DE BENZOFURANYLE UTILISÉS COMME INHIBITEURS DE LA GLUCOKINASE
  申请人：PFIZER

  公开号：WO2010103437A1

  公开（公告）日：2010-09-16

  The present invention provides compounds of Formula (I) that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase.

  本发明提供了式（I）的化合物，其作为葡萄糖激酶激活剂；其药物组合物；以及治疗由葡萄糖激酶介导的疾病，紊乱或状况的方法。
• Fused phenyl amido heterocyclic compounds
  申请人：Pfizer Inc

  公开号：US07842713B2

  公开（公告）日：2010-11-30

  The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A is (4-12)-membered heterocyclyl; Ring B is a fused benzene ring selected from the group consisting of: Ring A, ring B, ring C, R1, R1a, R2, R3, R4, L2, n, t, w, and z are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a condition that is mediated by the modulation of glucokinase, the method comprising administering to a mammal an effective amount of a compound of formula (I).

  本发明涉及式（I）的化合物：或其药学上可接受的盐或溶剂，其中：环A是（4-12）成员的杂环；环B是选自以下组的融合苯环：环A，环B，环C，R1，R1a，R2，R3，R4，L2，n，t，w和z在规范中定义。本发明还涉及包括式（I）的化合物的制药组合物和治疗通过调节葡萄糖激酶介导的疾病的方法，该方法包括向哺乳动物施用式（I）的化合物的有效量。
• Benzofuranyl derivatives
  申请人：Pfefferkorn Jeffrey Allen

  公开号：US08455496B2

  公开（公告）日：2013-06-04

  The present invention provides compounds of Formula (I) that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase.

  本发明提供了式（I）的化合物，其作为葡萄糖激酶激活剂；其制备的药物组成物；以及治疗由葡萄糖激酶介导的疾病，紊乱或状况的方法。