Hept-6-enyl (4-nitrophenyl) carbonate | 923278-38-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Hept-6-enyl (4-nitrophenyl) carbonate
• CAS: 923278-38-0
• 化学式: C₁₄H₁₇NO₅
• 分子量: 279.293
• InChiKey: DONAMWZPMCHYPJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  20
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  81.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-{[4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester 、 Hept-6-enyl (4-nitrophenyl) carbonate 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 hept-6-en-1-yl (2S,4R)-2-(((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

  摘要：

  A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K-i = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 mu M) inhibitor, displaying an excellent PK pro. le in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.10.004
• 作为产物：
  描述：

  6-庚烯-1-醇 、 对硝基苯基氯甲酸酯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 以73%的产率得到Hept-6-enyl (4-nitrophenyl) carbonate
  参考文献：
  名称：

  Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

  摘要：

  A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K-i = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 mu M) inhibitor, displaying an excellent PK pro. le in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.10.004

文献信息

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

  公开号：US20100120855A1

  公开（公告）日：2010-05-13

  Inhibitors of HCV replication of formula (I), the N-oxides, salts, and stereochemically isomeric forms thereof, wherein each dashed line (represented by represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 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 the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted on any carbon or nitrogen ring atom with one, two, three, or four substituents; L is a direct bond, —O—, —O—C 1-4 alkanediyl-, —O—C(═O)—, —O—C(═O)—NR 4a — or —O—C(═O)—NR 4a C 1-4 alkanediyl-; R 2 is hydrogen, —OR 5 , —C(O)OR 5 , —C(═O)R 6 , —C(═O)NR 4a R 4b , —C(═O)NHR 4c , —NR 4a R 4b , —NHR 4c , —NR 4a SO p NR 4a R 4b , —NR 4a SO p R 7 , or B(OR 5 ) 2 ; R 3 is hydrogen, and where X is C or CH, R 3 may also be C 1-6 alkyl; 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; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be 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，其中N-氧化物，盐和立体化学异构体，其中每个虚线（由表示，表示可选的双键; X是N，CH，其中X带有双键，则为C; R1是芳基或饱和，部分不饱和或完全不饱和的5个或6个成员的单环或9至12个成员的双环杂环环系，其中所述环系含有一个氮，并且可选地含有一个至三个选自氧，硫和氮的群组的其他杂原子，其中剩余的环成员是碳原子;其中所述环系可以在任何碳或氮环原子上选择一个，两个，三个或四个取代基; L是直接键，-O-，-O-C1-4烷二基，-O-C（=O）-，-O-C（=O）-NR4a-或-O-C（=O）-NR4aC1-4烷二基; R2是氢，-OR5，-C（O）OR5，-C（=O）R6，-C（=O）NR4aR4b，-C（=O）NHR4c，-NR4aR4b，-NHR4c，-NR4aSOpNR4aR4b，-NR4aSOpR7或B（OR5）2; R3是氢，其中X是C或CH时，R3也可以是C1-6烷基; n为3、4、5或6; p为1或2;芳基是苯基，萘基，茚基或1,2,3,4-四氢萘基，每个都可以选择性地用一个，两个或三个取代基取代; Het是一个5个或6个成员的饱和，部分不饱和或完全不饱和的杂环环，其中每个独立选择自氮，氧和硫的1至4个杂原子，可选择地与苯环缩合，并且整个Het基团可以选择性地用一个，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：Simmen Kenneth Alan

  公开号：US20110237621A1

  公开（公告）日：2011-09-29

  Inhibitors of HCV replication of formula (I) the N-oxides, salts, and stereochemically isomeric forms thereof, wherein each dashed line (represented by ) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 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 the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted on any carbon or nitrogen ring atom with one, two, three, or four substituents; L is a direct bond, —O—, —O—C 1-4 alkanediyl-, —O—C(═O)—, —O—C(═O)—NR 4a — or —O—C(═O)—NR 4a C 1-4 alkanediyl-; R 2 is hydrogen, —OR 5 , —C(═O)OR 5 , —C(═O)R 6 , —C(═O)NR 4a R 4b , —C(═O)NHR 4c , —NR 4a R 4b , —NHR 4c , —NR 4a SO p NR 4a R 4b , —NR 4a SO p R 7 , or B(OR 5 ) 2 ; R 3 is hydrogen, and where X is C or CH, R 3 may also be C 1-6 alkyl; 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; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be 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复制抑制剂包括其N-氧化物，盐和立体化学异构体，其中每个虚线（表示）代表可选的双键；X为N，CH，其中X带有双键时为C；R1为芳基或饱和的，部分不饱和的或完全不饱和的5或6个环成员的单环或9至12个环成员的双环杂环环系，其中所述环系含有一个氮，且可选地含有选自氧，硫和氮的一至三个附加杂原子，且所述剩余环成员为碳原子；其中所述环系可以在任何碳或氮环原子上可选地用一，二，三或四个取代基取代；L为直接键，—O—，—O—C1-4烷基二基，—O—C（═O）—，—O—C（═O）—NR4a—或—O—C（═O）—NR4aC1-4烷基二基；R2为氢，—OR5，—C（═O）OR5，—C（═O）R6，—C（═O）NR4aR4b，—C（═O）NHR4c，—NR4aR4b，—NHR4c，—NR4aSOpNR4aR4b，—NR4aSOpR7或B（OR5）2；R3为氢，且当X为C或CH时，R3也可以为C1-6烷基；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，每个芳基可以选择地用一个，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个成员饱和的，部分不饱和的或完全不饱和的杂环环，每个异原子可独立地选自氮，氧和硫，可选择地与苯环融合，且作为整体的Het基团可以选择地用一个，两个或三个取代基取代；还提供了含有化合物（I）的制药组合物和制备化合物（I）的过程。公式（I）的HCV抑制剂与利托那韦的生物利用度组合也提供。
• MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：EP1912996A1

  公开（公告）日：2008-04-23
• US8754105B2
  申请人：——

  公开号：US8754105B2

  公开（公告）日：2014-06-17
• [EN] MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS<br/>[FR] INHIBITEURS MACROCYCLIQUES DU VIRUS DE L'HÉPATITE C
  申请人：TIBOTEC PHARM LTD

  公开号：WO2007014920A1

  公开（公告）日：2007-02-08

  [EN] Inhibitors of HCV replication of formula (I), the N-oxides, salts, and stereochemically isomeric forms thereof, wherein each dashed line (represented by -------) represents an optional double bond; X is N, CH and where X bears a double bond it is C; R¹ 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 the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted on any carbon or nitrogen ring atom with one, two, three, or four substituents; L is a direct bond, -O-. -O-C_1-4alkanediyl-, -O-C(=O)-, -O-C(=O)-NR^4a- or -O-C(=O)-NR^4aC_1-4alkanediyl-; R² is hydrogen, -OR⁵, -C(O)OR⁵, -C(=O)R⁶, -C(=O)NR^4aR^4b, -C(=O)NHR^4c,-NR^4aR^4b, -NHR^4c, -NR^4aSO_pNR^4aR^4b, -NR^4aSO_pR⁷, or B(OR⁵)₂; R³ is hydrogen, and where X is C or CH, R³ may also be C_1-6alkyl; 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 ; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be 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.
  [FR] Inhibiteurs de la réplication du VHC de formule (I) etN-oxydes, sels et formes isomériques du point de vue stéréochimique de ceux-ci, dans laquelle formule chaque trait discontinu (représenté par -------) représente une double liaison facultative ; X est N, CH et dans les cas où X porte une double liaison, X est C ; R¹ est un aryle ou un système hétérocyclique monocyclique ayant 5 ou 6 chaînons ou bicyclique ayant 9 à 12 chaînons, saturé, partiellement insaturé ou complètement insaturé, ledit système cyclique contenant un azote et facultativement un à trois hétéroatomes supplémentaires sélectionnés entre des atomes d'oxygène, de soufre et d'azote et les éléments du cycle restants étant des atomes de carbone, ledit système cyclique pouvant être facultativement substitué sur n'importe quel atome de carbone ou d'azote du cycle par un, deux , trois ou quatre substituants ; L est une liaison directe, -O-, un -O-(alcane en C_1-4)diyle-, -O-C(=O)-, -O-C(=O)-NR^4a- ou un -O-C(=O)-NR^4a(alcane en C_1-4)diyle ; R² est un hydrogène, -OR⁵, -C(O)OR⁵, -C(=O)R⁶, -C(=O)NR^4aR^4b, -C(=O)NHR^4c,-NR^4aR^4b, -NHR^4c, -NR^4aSO_pNR^4aR^4b, -NR^4aSO_pR⁷ ou B(OR⁵)₂ ; R³ est un hydrogène et dans les cas où X est C ou CH, R³ peut également être un alkyle en C_1-6 ; n est 3, 4, 5 ou 6 ; p est 1 ou 2 ; un aryle est un phényle, un naphtyle, un indanyle ou un 1,2,3,4-tétrahydronaphtyle, chacun desquels pouvant être facultativement substitué par un, deux ou trois substituants ; Het est un hétérocycle saturé, partiellement insaturé ou complètement insaturé à 5 ou 6 chaînons contenant 1 à 4 hétéroatomes sélectionnés chacun indépendamment entre l'azote, l'oxygène et le soufre, ledit hétérocycle étant facultativement condensé avec un noyau benzénique et le groupe Het pris dans son ensemble pouvant être facultativement substitué par un, deux ou trois substituants ; compositions pharmaceutiques contenant les composés (I) et procédés servant à préparer les composés (I). L'invention concerne également des associations biodisponibles des inhibiteurs du VHC de formule (I) avec du ritonavir.