methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate | 886041-55-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate
• 英文别名: methyl 19-cyclohexyl-10-oxo-8-oxa-12-azatetracyclo[10.7.0.02,7.013,18]nonadeca-1(19),2,4,6,13(18),14,16-heptaene-15-carboxylate
• CAS: 886041-55-0
• 化学式: C₂₅H₂₅NO₄
• 分子量: 403.478
• InChiKey: ACJSARGXDKZDBW-UHFFFAOYSA-N

物化性质

• 沸点：
  634.0±55.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  57.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate 在 palladium on activated charcoal 、 sodium acetate 、 三乙酰氧基硼氢化钠 作用下， 以 甲醇 、 DCE 为溶剂， 生成 methyl (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)-amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate
  参考文献：
  名称：

  Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor

  摘要：

  The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol, The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at > 8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.

  DOI：

  10.1021/op200002u
• 作为产物：
  描述：

  2-羟基苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 、 caesium carbonate 、 戴斯-马丁氧化剂 、 cesium fluoride 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 53.0h， 生成 methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate
  参考文献：
  名称：

  Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

  DOI：

  10.1021/jm1013105

文献信息

• [EN] MACROCYCLIC AND 7-AMINOALKYL-SUBSTITUTED BENZOXAZOCINES FOR TREATMENT OF HEPATITIS C INFECTIONS<br/>[FR] COMPOSÉS BENZOXAZOCINES SUBSTITUÉS 7-AMINOALKYLE MACROCYCYCLIQUES DESTINÉS AU TRAITEMENT DES INFECTIONS PAR HÉPATITE C
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2010082050A1

  公开（公告）日：2010-07-22

  The present invention provides a compound of formula (I), wherein R1 is selected from hydrogen, hydroxyl, fluoro or a C1-4alkoxy group or R1 is linked to R3 to form a 4, 5 or 6-membered aliphatic ring optionally containing one N or O atom; R2 is selected from cyclopentyl or cyclohexyl optionally substituted by a fluoro; R3 is hydrogen or is linked to R1 as hereinbeforedefined; R4 is hydrogen, a C1-4alkyl group optionally substituted by a group NR8R9 in which R8 and R9 are each hydrogen or a C1-4alkyl group or R4 is linked to R6 to form a (CH2)mNR10SO2N group wherein m is an integer selected from 2 or 3 and R10 is a C1-4 alkyl group; R5 is hydrogen or a C1-4 alkyl group; R6 is hydroxyl or is linked to R4 as hereinbefore defined; R7 is hydrogen or an aliphatic ring of 4-7 ring atoms containing one or two heteroatoms selected from O, N or S or a group S(O), S(O)2,NH or NC1-4alkyl and optionally substituted by fluoro or R7 is a 5- 10-membered heteroaromatic ring system containing 1 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted by one or two halo atoms or C1-4alkyl or C1-4alkoxy groups; Y is a single bond or a CH2 group; when R4 is linked to R6 and m is 3 then Y is a single bond; when R4 is linked to R6 and m is 2 then Y is a CH2 group; n is an integer from zero to four, with the proviso that when R1 is hydrogen, n is not zero; or a pharmaceutically acceptable salt thereof, pharmaceutical formulations containing it and its use in medicine, particularly for the treatment of HCV infections. Hepatitis C (HCV) is a cause of viral infections. Methods of preparing compounds of the formula (I) arc also disclosed.

  本发明提供了一种化合物，其化学式为(I)，其中R1选自氢、羟基、氟或C1-4烷氧基，或者R1与R3连接形成一个含有一个N或O原子的4、5或6元脂环；R2选自环戊基或环己基，可以选择地被氟取代；R3为氢或与上述定义的R1连接；R4为氢，一个C1-4烷基，可以选择地被NR8R9基团取代，其中R8和R9分别为氢或C1-4烷基，或者R4与R6连接形成(CH2)mNR10SO2N基团，其中m为2或3的整数，R10为C1-4烷基；R5为氢或C1-4烷基；R6为羟基或与上述定义的R4连接；R7为氢或含有一个或两个来自O、N或S的杂原子的4-7环原子的脂环，或者为S(O)、S(O)2、NH或NC1-4烷基基团，可以选择地被氟取代，或者R7为含有1至4个来自N、O和S的杂原子的5-10元杂芳环系统，该环可以选择地被一个或两个卤原子或C1-4烷基或C1-4烷氧基取代；Y为单键或CH2基团；当R4与R6连接且m为3时，Y为单键；当R4与R6连接且m为2时，Y为CH2基团；n为0到4的整数，但当R1为氢时，n不为零；或其药学上可接受的盐，包含它的药物制剂以及其在医学上的应用，特别是用于治疗丙型肝炎（HCV）感染。丙型肝炎（HCV）是病毒感染的原因。还公开了制备化合物(I)的方法。
• Development of a Scalable Chiral Synthesis of MK-3281, an Inhibitor of the Hepatitis C Virus NS5B Polymerase
  作者：Stefania Colarusso、Jörg Habermann、Immacolata Conte、Marcello Di Filippo、Caterina Ercolani、Angela Mackay、Maria Palumbi、Maria del Rosario Rico Ferreira、Ian Stansfield、Simone Zaramella、Frank Narjes

  DOI：10.1055/s-0030-1260790

  日期：2011.7

  The development of a scalable chiral synthesis for the HCV NS5B inhibitor MK-3281 is being reported. Several alternative routes were explored and are being described.

  本报告介绍了 HCV NS5B 抑制剂 MK-3281 的可扩展手性合成方法。对几种替代路线进行了探索，现予以介绍。
• Tetracyclic indole derivatives as antiviral agents
  申请人：Conte Immacolata

  公开号：US20060100262A1

  公开（公告）日：2006-05-11

  The present invention relates to tetracyclic indole compounds of formula (I): wherein R 1 , R 2 , A, Ar, W, X, Y and Z are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, and their use for the treatment or prevention of infection by hepatitis C virus.

  本发明涉及公式（I）的四环吲哚化合物，其中R1、R2、A、Ar、W、X、Y和Z的定义如下，以及其药学上可接受的盐，包括它们的药物组成物，并用于治疗或预防丙型肝炎病毒感染的用途。
• WO2006/46030
  申请人：——

  公开号：——

  公开（公告）日：——
• US7795247B2
  申请人：——

  公开号：US7795247B2

  公开（公告）日：2010-09-14