7-甲氧基-8-甲基-4-氧代-1H-喹啉-3-羧酸乙酯 | 922520-00-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 7-甲氧基-8-甲基-4-氧代-1H-喹啉-3-羧酸乙酯
• 英文名称: ethyl 4-hydroxy-7-methoxy-8-methylquinoline-3-carboxylate
• 英文别名: ethyl 7-methoxy-8-methyl-4-oxo-1H-quinoline-3-carboxylate
• CAS: 922520-00-1
• 化学式: C₁₄H₁₅NO₄
• 分子量: 261.277
• InChiKey: NCKHXYXGTXKGGS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  7-甲氧基-8-甲基-4-氧代-1H-喹啉-3-羧酸乙酯 在 草酰氯 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 、 二氯甲烷 为溶剂， 反应 8.5h， 生成 7-methoxy-6-methyl-2-phenyl-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one
  参考文献：
  名称：

  设计和合成对 γ-氨基丁酸 A 型受体 (GABAAR) α6 亚型具有功能选择性的新型氘代配体，具有改善的代谢稳定性和增强的生物利用度。

  摘要：

  最近的报告表明，α6β2/3γ2 GABAAR 选择性配体可能对治疗三叉神经激活相关的疼痛和感觉运动门控缺陷的神经精神疾病很重要。基于 3 种功能性 α6β2/3γ2 GABAAR 选择性吡唑喹啉酮，合成了 42 种新型类似物，并研究了它们的体外代谢稳定性和细胞毒性以及它们的体内药代动力学、基本行为药理学和对运动的影响。将氘掺入配体的甲氧基取代基通过改善代谢稳定性和生物利用度增加了它们的作用持续时间，同时保留了它们对 GABAAR α6 亚型的选择性。8b 被确定为具有显着改善的药代动力学特征的先导化合物。配体对地西泮不敏感的α6β2/3γ2 GABAARs 进行变构调节，并且对地西泮敏感的α1β2/3γ2 GABAARs 功能沉默，因此未检测到镇静作用。此外，这些类似物没有细胞毒性，这使它们成为治疗由 GABAAR α6β2/3γ2 亚型介导的 CNS 疾病的有趣候选者。

  DOI：

  10.1021/acs.jmedchem.7b01664
• 作为产物：
  描述：

  C₁₆H₂₁NO₅ 以 二苯醚 为溶剂， 生成 7-甲氧基-8-甲基-4-氧代-1H-喹啉-3-羧酸乙酯
  参考文献：
  名称：

  Structure–activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350

  摘要：

  SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0(4,6)]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K-i = 0.36 nM) and viral replication (replicon EC50 = 7.8 nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.07.088

文献信息

• MACROCYLIC INHIBITORS OF HEPATITIS C VIRUS
  申请人：Simmen Kenneth Alan

  公开号：US20090062311A1

  公开（公告）日：2009-03-05

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers thereof, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1a and R 1b are hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with halo, C 1-6 alkoxy, cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, aryl, or with Het; or R 1a and R 1b together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring which may be optionally substituted; L is a direct bond, —O—, —O—C 1-4 alkanediyl-, —O—CO—, —O—C(═O)—NR 5a — or —O—C(═O)—NR 5a —C 1-4 alkanediyl-; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkyl, amino, mono- or diC 1-6 alkylamino; R 4 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 9 to 12 membered bicyclic heterocyclic ring system wherein said ring system contains one nitrogen, and optionally one to three additional heteroatoms selected from O, S and N, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents; and Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S, being optionally condensed with a benzene ring, and wherein Het may be optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I).

  公式（I）及其N-氧化物、盐和立体异构体的HCV复制抑制剂，其中每个虚线表示可选的双键；X为N、CH，其中X带有双键时为C；R1a和R1b为氢、C3-7环烷基、芳基、Het、C1-6烷氧基、C1-6烷基（可选用卤代、C1-6烷氧基、氰基、多卤代C1-6烷氧基、C3-7环烷基、芳基或Het取代）、或R1a和R1b与它们所连接的氮一起形成一个4到6成员杂环环，该环可以选择性地被取代；L为直接键，-O-，-O-C1-4烷二基-，-O-CO-，-O-C（═O）-NR5a-或-O-C（═O）-NR5a-C1-4烷二基-；R2为氢，当X为C或CH时，R2也可以是C1-6烷基；R3为氢、C1-6烷基、C1-6烷氧基C1-6烷基、C3-7环烷基、氨基、单取代或二取代C1-6烷基氨基；R4为芳基或饱和、部分不饱和或完全不饱和的5或6成员单环或9到12成员的双环杂环系统，其中所述杂环系统含有一个氮，且可以选择性地含有一个到三个来自O、S和N的其他杂原子，其余环成员为碳原子；其中所述环系统可以选择性地被取代；n为3、4、5或6；p为1或2；芳基为苯基、萘基、茚基或1,2,3,4-四氢萘基，每个都可以选择性地取代一个、两个或三个取代基；Het是一个5或6成员饱和、部分不饱和或完全不饱和的杂环环，其中包含1到4个来自N、O和S的杂原子，可以选择性地与苯环融合，且Het可以选择性地取代一个、两个或三个取代基；含有化合物（I）的制药组合物和制备化合物（I）的方法。
• Macrocyclic inhibitors of hepatitis c virus
  申请人：Simmen Kenneth Alan

  公开号：US20090281140A1

  公开（公告）日：2009-11-12

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 , —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy, or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  公式（I）及其N-氧化物，盐和立体异构体的HCV复制抑制剂，其中每个虚线表示一个可选的双键; X是N，CH，其中X带有双键时是C; R1是-OR7，-NH-SO2R8; R2是氢，当X为C或CH时，R2也可以是C1-6烷基; R3是氢，C1-6烷基，C1-6烷氧基C1-6烷基，C3-7环烷基; R4是芳基或杂环基; n为3、4、5或6; R5是卤素，C1-6烷基，羟基，C1-6烷氧基，苯基或杂环基; R6是C1-6烷氧基或二甲基氨基; R7是氢; 芳基; 杂环基; C3-7环烷基，可选地用C1-6烷基取代; 或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代; R8是芳基; 杂环基; C3-7环烷基，可选地用C1-6烷基取代; 或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代; 芳基是苯基，可选地用一个、两个或三个取代基取代; 杂环基是一个含有1-4个氮、氧和硫杂原子的5或6元饱和、部分不饱和或完全不饱和的杂环环，可选地用一个、两个或三个取代基取代; 包含化合物（I）的药物组合物和制备化合物（I）的过程也提供。还提供了公式（I）的HCV抑制剂与利托那韦的生物利用度组合。
• Macrocyclic inhibitors of hepatitis C virus
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：US08153800B2

  公开（公告）日：2012-04-10

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7 or —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, or C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het; R6 is C1-6alkoxy or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  HCV复制抑制剂的化学式(I)，其N-氧化物、盐和立体异构体，其中每个虚线代表一个可选的双键；X为N，CH，其中X带有双键时为C；R1为—OR7或—NH—SO2R8；R2为氢，当X为C或CH时，R2也可以是C1-6烷基；R3为氢，C1-6烷基，C1-6烷氧基C1-6烷基或C3-7环烷基；R4为芳基或杂环基；n为3、4、5或6；R5为卤素、C1-6烷基、羟基、C1-6烷氧基、苯基或杂环基；R6为C1-6烷氧基或二甲氨基；R7为氢、芳基、杂环基、C3-7环烷基，可选地用C1-6烷基取代；或C1-6烷基，可选地用C3-7环烷基、芳基或杂环基取代；R8为芳基、杂环基、C3-7环烷基，可选地用C1-6烷基取代；或C1-6烷基，可选地用C3-7环烷基、芳基或杂环基取代；芳基为苯基，可选地用一个、两个或三个取代基取代；杂环基为含有1至4个氮、氧和硫杂原子的5或6成员饱和、部分不饱和或完全不饱和的杂环环，可选地用一个、两个或三个取代基取代；含有化合物(I)的药物组合物和制备化合物(I)的方法。还提供了与利托那韦的HCV抑制剂的生物利用度组合。
• Macrocyclic Inhibitors Of Hepatitis C Virus
  申请人：Simmen Kenneth Alan

  公开号：US20110295012A1

  公开（公告）日：2011-12-01

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 or —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, or C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  公式（I）的HCV复制抑制剂及其N-氧化物，盐和立体异构体，其中每个虚线表示可选的双键；X为N，CH，其中X带有双键时为C；R1为—OR7或—NH—SO2R8；R2为氢，其中X为C或CH时，R2也可以是C1-6烷基；R3为氢，C1-6烷基，C1-6烷氧基C1-6烷基或C3-7环烷基；R4为芳基或杂环基；n为3、4、5或6；R5为卤素，C1-6烷基，羟基，C1-6烷氧基，苯基或杂环基；R6为C1-6烷氧基或二甲基氨基；R7为氢，芳基，杂环基，C3-7环烷基，可选地用C1-6烷基取代；或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代；R8为芳基，杂环基，C3-7环烷基，可选地用C1-6烷基取代；或C1-6烷基，可选地用C3-7环烷基，芳基或杂环基取代；芳基为苯基，可选地用一个、两个或三个取代基取代；杂环基为含有1到4个氮、氧和硫杂原子的5或6成员饱和、部分不饱和或完全不饱和的杂环环，可选地用一个、两个或三个取代基取代；包含化合物（I）的药物组合物和制备化合物（I）的方法。还提供了公式（I）的HCV抑制剂与利托那韦的生物利用度组合。
• Macrocylic inhibitors of hepatitis C virus
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：US08349869B2

  公开（公告）日：2013-01-08

  Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R1 is —OR7, —NH—SO2R8; R2 is hydrogen, and where X is C or CH, R2 may also be C1-6alkyl; R3 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het; R6 is C1-6alkoxy, or dimethylamino; R7 is hydrogen; aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

  公式（I）及其N-氧化物，盐和立体异构体的HCV复制抑制剂，其中每个虚线表示可选的双键; X为N，CH，其中X带有双键时为C; R1为—OR7，—NH—SO2R8; R2为氢，其中X为C或CH时，R2也可以是C1-6烷基; R3为氢，C1-6烷基，C1-6烷氧基C1-6烷基，C3-7环烷基; R4为芳基或杂环基; n为3、4、5或6; R5为卤素，C1-6烷基，羟基，C1-6烷氧基，苯基或杂环基; R6为C1-6烷氧基或二甲氨基; R7为氢，芳基，杂环基，C3-7环烷基，可选地被C1-6烷基取代; 或C1-6烷基，可选地被C3-7环烷基，芳基或杂环基取代; R8为芳基，杂环基，C3-7环烷基，可选地被C1-6烷基取代; 或C1-6烷基，可选地被C3-7环烷基，芳基或杂环基取代; 芳基为苯基，可选地被一、二或三个取代基取代; 杂环基是一个5或6成员的饱和，部分不饱和或完全不饱和的杂环环，其中包含1到4个从氮，氧和硫中选择的杂原子，并可选地被一个，两个或三个取代基取代; 包含化合物（I）的制药组合物和制备化合物（I）的过程。还提供了公式（I）的HCV抑制剂与利托那韦的生物利用度组合。