2-[2-[2,4-Bis(trifluoromethyl)anilino]-6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]pyridin-3-yl]ethanol | 491864-86-9

• 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: 2-[2-[2,4-Bis(trifluoromethyl)anilino]-6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]pyridin-3-yl]ethanol
• CAS: 491864-86-9
• 化学式: C₂₂H₁₇F₆N₅OS
• 分子量: 513.466
• InChiKey: XBLRWTZVPSXDQS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  2-[2-[2,4-Bis(trifluoromethyl)anilino]-6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]pyridin-3-yl]ethanol 在 甲基磺酰氯 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-(2,4-bis-trifluoromethylphenyl)-6-methyl-4-(3-thiazol-2-ylpyazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
  参考文献：
  名称：

  Dihydropyrrole[2,3-d]pyridine Derivatives as Novel Corticotropin-Releasing Factor-1 Antagonists: Mapping of the Receptor Binding Pocket by in Silico Docking Studies

  摘要：

  In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.

  DOI：

  10.1021/jm800743q
• 作为产物：
  描述：

  N-[2,4-bis(trifluoromethyl)phenyl]-3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]pyridin-2-amine 在 triethylamine tris(hydrogen fluoride) 作用下， 以 四氢呋喃 为溶剂， 反应 15.0h， 生成 2-[2-[2,4-Bis(trifluoromethyl)anilino]-6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]pyridin-3-yl]ethanol
  参考文献：
  名称：

  Dihydropyrrole[2,3-d]pyridine Derivatives as Novel Corticotropin-Releasing Factor-1 Antagonists: Mapping of the Receptor Binding Pocket by in Silico Docking Studies

  摘要：

  In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.

  DOI：

  10.1021/jm800743q

文献信息

• 1,8-Naphthyridines as CRF antagonists
  申请人：GLAXO GROUP LIMITED

  公开号：EP1695974A1

  公开（公告）日：2006-08-30

  The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof wherein Ris aryl or heteroaryl, each of which may be substituted by I to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, -C(O)R5, nitro, -NR6R7, cyano, and a group R8; R1is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR6R7 or cyano; R2 and R3corresponds to; R4is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R5is a C1-C4 alkyl, -OR6 or -NR6R7; R6is hydrogen or C1-C6 alkyl; R7is hydrogen or C1-C6 alkyl; R8is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R11 groups; R11is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR6R7; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

  本发明提供了式 (I) 化合物，包括其立体异构体、原药和药学上可接受的盐或溶液 其中 Ris芳基或杂芳基，其中每个芳基或杂芳基可被 I 至 4 个基团取代，这些基团选自 卤素、C1-C6 烷基、C1-C6 烷氧基、卤代 C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷氧基、-C(O)R5、硝基、-NR6R7、氰基和基团 R8； R1 是氢、C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷基、卤代 C1-C6 烷氧基、卤素、NR6R7 或氰基； R2 和 R3 对应于； R4 是氢、C1-C6 烷基、卤素或卤代 C1-C6 烷基； R5 是 C1-C4 烷基、-OR6 或-NR6R7； R6 是氢或 C1-C6 烷基； R7是氢或C1-C6烷基； R8 是 5-6 个成员的杂环，可以是饱和的，也可以含有 1 到 3 个双键，并且可以被 1 个或多个 R11 基团取代； R11 是 C3-C7 环烷基、C1-C6 烷基、C1-C6 烷氧基、卤代 C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷氧基、羟基、卤素、硝基、氰基或 C(O)NR6R7； 它们的制备工艺、含有它们的药物组合物，以及它们在治疗促肾上腺皮质激素释放因子（CRF）介导的疾病中的用途。
• Chemical compounds
  申请人：——

  公开号：US20040171607A1

  公开（公告）日：2004-09-02

  The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof, wherein R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 5 , nitro, —NR 6 R 7 , cyano, and a group R 8 ; R 1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7 or cyano; R 2 is hydrogen, C3-C7 cycloalkyl, or a group R 9 ; R 3 is C3-C7 cycloalkyl, or a group R 9 ; or R 2 and R 3 together with N form a 5-14 membered heterocycle, which may be substituted 1 to 3 R 10 groups; R 4 is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R 5 is a C1-C4 alkyl, —OR 6 or NR 6 R 7 ; R 6 is hydrogen or C1-C6 alkyl; R 7 is hydrogen or C1-C6 alkyl; R 8 is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11 groups; R 9 is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, hydroxy, halo C1-C6 alkyl; R 10 is a group R 8 , C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 6 R 7 , phenyl which may be substituted by 1 to 4 R 11 groups; R 11 is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ; X is carbon or nitrogen; n is 1 or 2; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF). 1

  本发明提供了式 (I) 的化合物，包括其立体异构体、原药和药学上可接受的盐或溶液，其中 R 是芳基或杂芳基，每个芳基或杂芳基可被 1 至 4 个基团取代，这些基团选自：卤素、C1-C6 烷基、C1-C6 烷氧基、卤代 C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷氧基、-C(O)R 5 、硝基、-NR 6 R 7 、氰基和一个基团 R 8 ; R 1 是氢、C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷基、卤代 C1-C6 烷氧基、卤素、NR 6 R 7 或氰基；R 2 是氢、C3-C7 环烷基或基团 R 9 ; R 3 是 C3-C7 环烷基，或基团 R 9 或 R 2 和 R 3 与 N 一起形成 5-14 个成员的杂环，可被 1 至 3 个 R 取代 10 基团；R 4 是氢、C1-C6 烷基、卤素或卤代 C1-C6 烷基；R 5 是 C1-C4 烷基、-OR 6 或 NR 6 R 7 ; R 6 是氢或 C1-C6 烷基；R 7 是氢或 C1-C6 烷基； R 8 是5-6个成员的杂环，可以是饱和的，也可以含有1-3个双键，并且可以被1个或多个R 11 基团取代；R 9 是 C1-C6 烷基，可被一个或多个基团取代，这些基团选自：C3-C7 环烷基、C1-C6 烷氧基、卤代 C1-C6 烷氧基、羟基、卤代 C1-C6 烷基；R 10 是一个基团 R 8 、C3-C7 环烷基、C1-C6 烷基、C1-C6 烷氧基、卤代 C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷氧基、羟基、卤素、硝基、氰基、C(O)NR 6 R 7 苯基，可被 1 至 4 个 R 11 基团取代；R 11 是 C3-C7 环烷基、C1-C6 烷基、C1-C6 烷氧基、卤代 C1-C6 烷基、C2-C6 烯基、C2-C6 炔基、卤代 C1-C6 烷氧基、羟基、卤素、硝基、氰基或 C(O)NR 6 R 7 X是碳或氮；n是1或2；制备工艺、含有它们的药物组合物以及它们在治疗促肾上腺皮质激素释放因子（CRF）介导的疾病中的用途。 1
• HETERO-BICYCLIC CRF ANTAGONISTS
  申请人：GLAXO GROUP LIMITED

  公开号：EP1425280B1

  公开（公告）日：2006-08-30
• Chemical Compounds
  申请人：Di Fabio Romano

  公开号：US20070219232A1

  公开（公告）日：2007-09-20

  The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof wherein R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 5 , nitro, —NR 6 R 7 , cyano, and a group R 8 ; R 1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7 or cyano; R 2 is hydrogen, C3-C7 cycloalkyl, or a group R 9 ; R 3 is C3-C7 cycloalkyl, or a group R 9 ; or R 2 and R 3 together with N form a 5-14 membered heterocycle, which may be substituted by 1 to 3 R 10 groups; R 4 is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R 5 is a C1-C4 alkyl, —OR 6 or —NR 6 R 7 ; R 6 is hydrogen or C1-C6 alkyl; R 7 is hydrogen or C1-C6 alkyl; R 8 is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11 groups; R 9 is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl; R 10 is a group R 8 , C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 6 R 7 , phenyl which may be substituted by 1 to 4 R 11 groups; R 11 is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ; X is carbon or nitrogen; n is 1 or 2; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).
• US7253284B2
  申请人：——

  公开号：US7253284B2

  公开（公告）日：2007-08-07