ethyl (1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(6-propan-2-ylpyridin-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylate | 923605-04-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: ethyl (1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(6-propan-2-ylpyridin-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylate
• CAS: 923605-04-3
• 化学式: C₃₉H₄₈N₄O₆
• 分子量: 668.833
• InChiKey: DNYPOMZQDJFRIE-ZSAPEQOUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  49
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl (1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(6-propan-2-ylpyridin-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 生成 (1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(6-propan-2-ylpyridin-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid
  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
• 作为产物：
  描述：

  ethyl (1R,2S)-2-ethenyl-1-[[(1R,2R,4R)-2-[hex-5-enyl(methyl)carbamoyl]-4-[7-methoxy-8-methyl-2-(6-propan-2-ylpyridin-2-yl)quinolin-4-yl]oxycyclopentanecarbonyl]amino]cyclopropane-1-carboxylate 在 二氯(邻异丙氧基苯基亚甲基)(三环己基膦)钌 作用下， 以 二氯甲烷 为溶剂， 生成 ethyl (1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(6-propan-2-ylpyridin-2-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylate
  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

• Macrocyclic Inhibitors Of Hepatitis C Virus
  申请人：Simmen Kenneth Alan

  公开号：US20120171157A1

  公开（公告）日：2012-07-05

  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）和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，当X带有双键时，它为C；R1为-OR7，- 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，C3-7环烷基；R4为芳基或Het；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Het；R6为C1-6烷氧基或二甲基氨基；R7为氢，芳基，Het，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Het取代；R8为芳基，Het，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Het取代；芳基为苯基，可选地用一个，两个或三个取代基取代；Het为含有1至4个异原子的5或6成员饱和，部分不饱和或完全不饱和的杂环环，所述异原子为氮，氧和硫，并可用一个，两个或三个取代基取代；含有化合物（I）的制药组合物以及制备化合物（I）的过程。还提供了公式（I）的HCV抑制剂与利托那韦的可生物利用性组合物。
• MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
  申请人：Janssen Sciences Ireland UC

  公开号：US20160235737A1

  公开（公告）日：2016-08-18

  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、盐和立体异构体抑制HCV复制的抑制剂，其中每个虚线表示可选的双键；X为N、CH，当X带有双键时，它是C；R1为—OR7、—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、C3-7环烷基；R4为芳基或杂环基；n为3、4、5或6；R5为卤、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，可选地被一个、两个或三个取代基取代；杂环基是一个5或6成员饱和、部分不饱和或完全不饱和的杂环环，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；含有化合物（I）的制药组合物和制备化合物（I）的过程也提供。还提供了公式（I）的抑制HCV的生物利用度与利托那韦的组合。
• Intermediates for the preparation of Macrocyclic inhibitors of hepatitis c virus
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：EP2322516A1

  公开（公告）日：2011-05-18

  A process for the preparation of a compound of formula comprising the ring closure and dehydration of a compound of formula

  一种制备式化合物的工艺 包括一种式化合物的闭环和脱水过程
• Macrocylic inhibitors of hepatitis c virus
  申请人：Janssen Sciences Ireland UC

  公开号：EP2937339A1

  公开（公告）日：2015-10-28

  Combinations comprising 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.

  由式(I)的HCV复制抑制剂组成的组合物 及其 N-氧化物、盐和立体异构体的组合物，其中每条虚线代表一个任选双键； X 是 N、CH，如果 X 含有双键，则是 C； R1 是-OR7、-NH-SO2R8； R2 是氢，当 X 是 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 Het；n 是 3、4、5 或 6； R5 是卤素、C1-6烷基、羟基、C1-6烷氧基、苯基或 Het； R6 是 C1-6 烷氧基或二甲基氨基； R7 是氢；芳基；Het；被 C1-6 烷基任选取代的 C3-7 环烷基；或被 C3-7 环烷基、芳基或 Het 任选取代的 C1-6 烷基； R8 是芳基；Het；被 C1-6 烷基任选取代的 C3-7 环烷基；或被 C3-7 环烷基、芳基或 Het 任选取代的 C1-6 烷基； 芳基 是任选被一个、两个或三个取代基取代的苯基； Het 是 5 或 6 个成员的饱和、部分不饱和或完全不饱和杂环，含有 1 至 4 个选自氮、氧和硫的杂原子，并可任选被 1、2 或 3 个取代基取代。
• US20140255347A1
  申请人：——

  公开号：US20140255347A1

  公开（公告）日：2014-09-11