(1R,3S,4Z,12R,14R,16R)-14-[7-methoxy-8-methyl-2-(3-propan-2-ylpyrazol-1-yl)quinolin-4-yl]oxy-10-methyl-18-oxa-10,20-diazatetracyclo[15.2.1.01,3.012,16]icosa-4,17(20)-diene-11,19-dione | 1073118-94-1

• 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: (1R,3S,4Z,12R,14R,16R)-14-[7-methoxy-8-methyl-2-(3-propan-2-ylpyrazol-1-yl)quinolin-4-yl]oxy-10-methyl-18-oxa-10,20-diazatetracyclo[15.2.1.01,3.012,16]icosa-4,17(20)-diene-11,19-dione
• CAS: 1073118-94-1
• 化学式: C₃₅H₄₁N₅O₅
• 分子量: 611.741
• InChiKey: BGNKAZVDLMLCDB-AEEHPACPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  45
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  108
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1R,3S,4Z,12R,14R,16R)-14-[7-methoxy-8-methyl-2-(3-propan-2-ylpyrazol-1-yl)quinolin-4-yl]oxy-10-methyl-18-oxa-10,20-diazatetracyclo[15.2.1.01,3.012,16]icosa-4,17(20)-diene-11,19-dione 在 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 4-{4-[2-(2-methyl-2H-pyrazol-3-yl)-ethanesulfinylmethyl]-phenoxymethyl}-2-[2-(E)-(4-trifluoromethyl-phenyl)-vinyl]-oxazole
  参考文献：
  名称：

  US2007/49621

  摘要：

  公开号：
• 作为产物：
  描述：

  (1R,4R,6S,7Z,15R,17R)-17-[7-methoxy-8-methyl-2-(3-propan-2-ylpyrazol-1-yl)quinolin-4-yl]oxy-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 0.83h， 生成 (1R,3S,4Z,12R,14R,16R)-14-[7-methoxy-8-methyl-2-(3-propan-2-ylpyrazol-1-yl)quinolin-4-yl]oxy-10-methyl-18-oxa-10,20-diazatetracyclo[15.2.1.01,3.012,16]icosa-4,17(20)-diene-11,19-dione
  参考文献：
  名称：

  WO2007/14925

  摘要：

  公开号：

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。
• 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
  作者：Pierre Raboisson、Herman de Kock、Åsa Rosenquist、Magnus Nilsson、Lourdes Salvador-Oden、Tse-I Lin、Natalie Roue、Vladimir Ivanov、Horst Wähling、Kristina Wickström、Elizabeth Hamelink、Michael Edlund、Lotta Vrang、Sandrine Vendeville、Wim Van de Vreken、David McGowan、Abdellah Tahri、Lili Hu、Carlo Boutton、Oliver Lenz、Frederic Delouvroy、Geert Pille、Dominique Surleraux、Piet Wigerinck、Bertil Samuelsson、Kenneth Simmen

  DOI：10.1016/j.bmcl.2008.07.088

  日期：2008.9

  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.
• US8227407B2
  申请人：——

  公开号：US8227407B2

  公开（公告）日：2012-07-24