7-Methoxy-2-pyrrol-1-yl-quinolin-4-ol | 300831-11-2

• 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
• 英文名称: 7-Methoxy-2-pyrrol-1-yl-quinolin-4-ol
• 英文别名: 7-methoxy-2-pyrrol-1-yl-1H-quinolin-4-one
• CAS: 300831-11-2
• 化学式: C₁₄H₁₂N₂O₂
• 分子量: 240.261
• InChiKey: YYAJHFCNTLIFFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  43.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  7-Methoxy-2-pyrrol-1-yl-quinolin-4-ol 、 methyl (2S,6S,12Z,13aS,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-2-hydroxy-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxylate 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 生成 (Z)-(1S,4R,6S,14S,18R)-14-tert-Butoxycarbonylamino-18-(7-methoxy-2-pyrrol-1-yl-quinolin-4-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0^4,6]nonadec-7-ene-4-carboxylic acid methyl ester
  参考文献：
  名称：

  Structure−Activity Study on a Novel Series of Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease Leading to the Discovery of BILN 2061

  摘要：

  From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were per-formed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.

  DOI：

  10.1021/jm0342414
• 作为产物：
  描述：

  2,5-二甲氧基四氢呋喃 、 2-amino-7-methoxy-quinolin-4-ol 在 溶剂黄146 作用下， 生成 7-Methoxy-2-pyrrol-1-yl-quinolin-4-ol
  参考文献：
  名称：

  Structure−Activity Study on a Novel Series of Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease Leading to the Discovery of BILN 2061

  摘要：

  From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were per-formed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.

  DOI：

  10.1021/jm0342414

文献信息

• [EN] MACROCYCLIC PEPTIDES ACTIVE AGAINST THE HEPATITIS C VIRUS<br/>[FR] PEPTIDES MACROCYCLIQUES ACTIFS CONTRE LE VIRUS DE L'HEPATITE C
  申请人：BOEHRINGER INGELHEIM CA LTD

  公开号：WO2000059929A1

  公开（公告）日：2000-10-12

  The present invention covers macrocyclic compounds of formula (I) active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus wherein W is CH or N; R21 is H, halo, C¿1-6? alkyl, cycloalkyl, haloalkyl, C1-6 alkoxy, cycloalkoxy, hydroxy, or N(R?23)¿2, wherein each R23 is independently H, C¿1-6? alkyl or cycloalkoxy; and R?22¿ is H, halo, C¿1-6? alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Het being substituted with R?24¿, wherein R24 is H, C¿1-6? alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R?25)¿2, NH-C(O)-R25; or NH-C(O)-NH-R25, wherein each R25 is independently: H, C¿1-6? alkyl or C3-6 cycloalkyl; or R?24¿ is NH-C(O)-OR26 wherein R26 is C¿1-6? alkyl or C3-6 cycloalkyl; R?3¿ is hydroxy, NH¿2?, or a group of formula -NH-R?31¿, wherein R31 is C6 or 10 aryl, heteroaryl, -C(O)-R32, -C(O)-OR32 or -C(O)-NHR32, wherein R32 is: C¿1-6? alkyl or C3-6 cycloalkyl; D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N-R?41¿, wherein R41 is H, C¿1-6? alkyl, cycloalkyl or -C(O)-R?42¿, wherein R42 is C¿1-6? alkyl, cycloalkyl or C6 or 10 aryl; R?4¿ is H or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C¿1-6? alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio or C1-6 thioalkyl, and A is an amide of formula -C(O)-NH-R?5¿, wherein R5 is selected from the group consisting of: C¿1-8? alkyl, C3-6 cycloalkyl, C6 or 10 aryl or C7-16 aralkyl; or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.

  本发明涵盖了式（I）的大环化合物，该化合物在体外和细胞试验中对丙型肝炎病毒的NS3蛋白酶具有活性，其中W为CH或N; R21为H，卤素，C1-6烷基，环烷基，卤代烷基，C1-6烷氧基，环烷氧基，羟基或N（R23）2，其中每个R23独立地为H，C1-6烷基或环烷氧基; R22为H，卤素，C1-6烷基，C3-6环烷基，C1-6卤代烷基，C1-6硫代烷基，C1-6烷氧基，C3-6环烷氧基，C2-7烷氧基烷基，C3-6环烷基，C6或10芳基或Het，其中Het是含有1至4个从氮，氧和硫选择的杂原子的五元，六元或七元饱和或不饱和杂环; 所述的环烷基，芳基或Het被R24取代，其中R24为H，C1-6烷基，C3-6环烷基，C1-6烷氧基，C3-6环烷氧基，NO2，N（R25）2，NH-C（O）-R25; 或NH-C（O）-NH-R25，其中每个R25独立地为：H，C1-6烷基或C3-6环烷基; 或R24为NH-C（O）-OR26，其中R26为C1-6烷基或C3-6环烷基; R3为羟基，NH2或式-NH-R31的基团，其中R31为C6或10芳基，杂芳基，-C（O）-R32，-C（O）-OR32或-C（O）-NHR32，其中R32为：C1-6烷基或C3-6环烷基; D为5至10个原子的饱和或不饱和烷基链，可选地包含从O，S或N-R41中独立选择的1至3个杂原子，其中R41为H，C1-6烷基，环烷基或-C（O）-R42，其中R42为C1-6烷基，环烷基或C6或10芳基; R4为H或在链D的任何碳原子上的1至3个取代基，所述取代基独立地选择自以下群：C1-6烷基，C1-6卤代烷基，C1-6烷氧基，羟基，卤素，氨基，氧代，硫代或C1-6硫代烷基; A为式-C（O）-NH-R5的酰胺，其中R5选择自以下群：C1-8烷基，C3-6环烷基，C6或10芳基或C7-16芳基烷基; 或A为羧酸或其药学上可接受的盐或酯。
• Macrocyclic peptides active against the hepatitis C virus
  申请人：Boehringer Ingelheim (Canada) Ltd.

  公开号：US20040002448A1

  公开（公告）日：2004-01-01

  The present invention covers macrocyclic compounds of formula I active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus. 1 wherein W, R 21 , R 22 , R 3 , R 4 , D and A are as defined herein, or a pharmaceutically acceptable salt or ester thereof.

  本发明涵盖了公式I的大环化合物，该化合物在体外和细胞测定中对丙型肝炎病毒的NS3蛋白酶具有活性。 其中，W，R21，R22，R3，R4，D和A如此处所定义，或其药学上可接受的盐或酯。
• Macrocyclic peptides inhibiting the hepatitis C virus ns3 protease
  申请人：BOEHRINGER INGELHEIM (CANADA) LTD.

  公开号：EP1437362A1

  公开（公告）日：2004-07-14

  The present invention covers macrocyclic compounds of formula I active in-vitro and in cellular assays against the NS3 protease of the hepatitis C virus. wherein W is CH or N; R21 is H, halo, C1-6 alkyl, cycloalkyl, haloalkyl, C1-6 alkoxy, cycloalkoxy, hydroxy, or N(R23)2, wherein each R23 is independently H, C1-6 alkyl or cycloalkoxy; and R22 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur; said cycloalkyl, aryl or Het being substituted with R24, wherein R24 is H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R25)2, NH-C(O)-R25; or NH-C(O)-NH-R25, wherein each R25 is independently: H, C1-6 alkyl or C3-6 cycloalkyl; or R24 is NH-C(O)-OR26 wherein R26 is C1-6 alkyl or C3-6 cycloalkyl; R3 is hydroxy, NH2, or a group of formula - NH-R31, wherein R31 is C6 or 10 aryl, heteroaryl, -C(O)-R32, -C(O)-OR32 or -C(O)-NHR32, wherein R32 is: C1-6 alkyl or C3-6 cycloalkyl; D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S, or N-R41, wherein R41 is H, C1-6 alkyl, cycloalkyl or -C(O)-R42, wherein R42 is C1-6 alkyl, cycloalkyl or C6 or 10 aryl; R4 is H or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio or C1-6 thioalkyl, and A is an amide of formula -C(O)-NH-R5, wherein R5 is selected from the group consisting of: C1-8 alkyl, C3-6 cycloalkyl, C6 or 10 aryl or C7-16 aralkyl; or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.

  本发明包括在体外和细胞检测中对丙型肝炎病毒 NS3 蛋白酶具有活性的式 I 大环化合物。 其中 W 是 CH 或 N；R21 是 H、卤代、C1-6 烷基、环烷基、卤代烷基、C1-6 烷氧基、环烷氧基、羟基或 N(R23)2，其中每个 R23 独立地是 H、C1-6 烷基或环烷氧基；R22 是 H、卤素、C1-6 烷基、C3-6 环烷基、C1-6 卤代烷基、C1-6 硫代烷基、C1-6 烷氧基、C3-6 环烷氧基、C2-7 烷氧基烷基、C3-6 环烷基、C6 或 10 芳基或 Het，其中 Het 是含有一至四个选自氮、氧和硫的杂原子的五元、六元或七元饱和或不饱和杂环；所述环烷基、芳基或 Het 被 R24 取代，其中 R24 是 H、C1-6 烷基、C3-6 环烷基、C1-6 烷氧基、C3-6 环烷氧基、NO2、N(R25)2、NH-C(O)-R25 或 NH-C(O)-NH-R25，其中每个 R25 独立地是：H、C1-6 烷基或 C3-6 环烷基；或 R24 是 NH-C(O)-OR26，其中 R26 是 C1-6 烷基或 C3-6 环烷基；R3 是羟基、NH2 或式-NH-R31 的基团，其中 R31 是 C6 或 10 芳基、杂芳基、-C(O)-R32、-C(O)-OR32 或-C(O)-NHR32，其中 R32 是：C1-6烷基或C3-6环烷基； D是5至10原子的饱和或不饱和亚烷基链，可任选含有1至3个独立选自以下的杂原子： O、S或N-R41，其中R41是H、C1-6烷基、环烷基或-C(O)-R42，其中R42是C1-6烷基、环烷基或C6或10芳基； R4是H或在所述链D的任一碳原子上的1至3个取代基，所述取代基独立选自以下组成的组：C1-6烷基、C1-6卤代烷基、C1-6烷氧基、羟基、卤代、氨基、氧代、硫代或 C1-6 硫代烷基，以及 A 是式-C(O)-NH-R5 的酰胺，其中 R5 选自由下列组成的组C1-8 烷基、C3-6 环烷基、C6 或 10 芳基或 C7-16 芳烷基；或 A 是羧酸或其药学上可接受的盐或酯。
• MACROCYCLIC PEPTIDES INHIBITING THE HEPATITIS C VIRUS NS3 PROTEASE
  申请人：BOEHRINGER INGELHEIM (CANADA) LTD.

  公开号：EP1169339A1

  公开（公告）日：2002-01-09
• US6608027B1
  申请人：——

  公开号：US6608027B1

  公开（公告）日：2003-08-19