((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone | 1781244-77-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone
• 英文别名: CORT125281；exicorilant；Exicorilant；[(4aR,8aS)-1-(4-fluorophenyl)-6-(2-methyltriazol-4-yl)sulfonyl-4,5,7,8,8a,9-hexahydropyrazolo[3,4-g]isoquinolin-4a-yl]-[4-(trifluoromethyl)pyridin-2-yl]methanone
• CAS: 1781244-77-6
• 化学式: C₂₆H₂₃F₄N₇O₃S
• 分子量: 589.573
• InChiKey: HWJYJKAURRIWJM-GKVSMKOHSA-N

物化性质

• 沸点：
  719.4±70.0 °C(Predicted)
• 密度：
  1.59±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  41
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  124
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate 在 palladium 10% on activated carbon 、 氢气 、 异丙基溴化镁 、 三氟乙酸 作用下， 以 2-甲基四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 20.75h， 生成 ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone
  参考文献：
  名称：

  Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist

  摘要：

  The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing's syndrome. While this drug is highly effective, lack, of selectivity for GR leads to unwanted side effects in Sonic patients. Optimization pf the previously described fused azadecalin series of selective GR antagonists l'ed to the identification of CORT125134, which is currently being eValuateddp a phase 2 clinical study in patients with Cushing's syndrome.

  DOI：

  10.1021/acs.jmedchem.7b00162

文献信息

• OCTAHYDRO FUSED AZADECALIN GLUCOCORTICOID RECEPTOR MODULATORS
  申请人：Corcept Therapeutics, Inc.

  公开号：US20150148341A1

  公开（公告）日：2015-05-28

  The present invention provides octahydro fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

  本发明提供了八氢融合的阿扎德卡林化合物以及将这些化合物用作糖皮质激素受体调节剂的方法。
• Glucocorticoid receptor modulators to treat pancreatic cancer
  申请人：Corcept Therapeutics, Inc.

  公开号：US10117852B2

  公开（公告）日：2018-11-06

  Methods and compositions for treating a subject hosting a non-ACTH-secreting pancreatic tumor are disclosed. The methods include administering to the subject a chemotherapeutic agent and a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), to reduce the tumor load in the subject. The GRM may be a nonsteroidal GRM, and may be a nonsteroidal SGRM. The non-ACTH-secreting pancreatic tumor may be an exocrine pancreatic tumor. The nonsteroidal SGRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure. Pharmaceutical compositions comprising a chemotherapeutic agent and a GRM are disclosed. The GRM in such pharmaceutical compositions may be a nonsteroidal GRM, and may be a SGRM, such as a nonsteroidal SGRM. The nonsteroidal SGRM may comprise: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

  本发明公开了用于治疗患有非 ACTH 分泌性胰腺肿瘤的受试者的方法和组合物。这些方法包括向受试者施用化疗剂和糖皮质激素受体调节剂（GRM），最好是选择性糖皮质激素受体调节剂（SGRM），以减少受试者体内的肿瘤负荷。GRM可以是非类固醇GRM，也可以是非类固醇SGRM。非 ACTH 分泌性胰腺肿瘤可以是外分泌性胰腺肿瘤。 非甾体 SGRM 可以是一种非甾体化合物，包括：融合氮杂环丁烷结构；杂芳酮融合氮杂环丁烷结构；或八氢融合氮杂环丁烷结构。公开了包含化疗药物和 GRM 的药物组合物。此类药物组合物中的 GRM 可以是非类固醇 GRM，也可以是 SGRM，例如非类固醇 SGRM。非甾体 SGRM 可包括：融合氮杂萘结构；杂芳酮融合氮杂萘结构；或八氢融合氮杂萘结构。
• Octahydro fused azadecalin glucocorticoid receptor modulators
  申请人：Corcept Therapeutics, Inc.

  公开号：US10323034B2

  公开（公告）日：2019-06-18

  The present invention provides octahydro fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

  本发明提供了八氢融合氮杂十环素化合物以及将这些化合物用作糖皮质激素受体调节剂的方法。
• Glucocorticoid receptor modulators to treat cervical cancer
  申请人：Corcept Therapeutics, Inc.

  公开号：US10413540B2

  公开（公告）日：2019-09-17

  Methods for treating a subject having a cancerous tumor are disclosed. The methods comprise administering to the subject an effective amount of a non-steroidal selective glucocorticoid receptor modulator (SGRM) and an effective amount of a chemotherapeutic agent. The tumor may be cervical cancer. The SGRM may be a fused azadecalin. In embodiments, the SGRM may be a heteroaryl ketone fused azadecalin or an octahydro fused azadecalin.

  本发明公开了治疗患有癌症肿瘤的受试者的方法。这些方法包括向受试者施用有效量的非甾体类选择性糖皮质激素受体调节剂（SGRM）和有效量的化疗药物。肿瘤可以是宫颈癌。SGRM 可以是一种融合的氮杂环十四烷。在实施方案中，SGRM 可以是杂芳基酮类融合氮杂环十四烷或八氢融合氮杂环十四烷。
• Use of glucocorticoid receptor modulators to potentiate checkpoint inhibitors
  申请人：Corcept Therapeutics Incorporated

  公开号：US10980797B2

  公开（公告）日：2021-04-20

  This invention provides a method that combines a checkpoint inhibitor and a glucocorticoid receptor modulator to treat cancer, e.g., a checkpoint inhibitor sensitive cancer.

  本发明提供了一种结合检查点抑制剂和糖皮质激素受体调节剂来治疗癌症（如对检查点抑制剂敏感的癌症）的方法。