(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone
• 英文别名: (R)-(1-(4-flurophenyl)-6-((4- (trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone；CORT122928；[(4aR)-1-(4-fluorophenyl)-6-[4-(trifluoromethyl)phenyl]sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinolin-4a-yl]-(1,3-thiazol-2-yl)methanone
• 化学式: C₂₇H₂₀F₄N₄O₃S₂
• 分子量: 588.606
• InChiKey: VFLIGUOJPWIXKF-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  122
• 氢给体数：
  0
• 氢受体数：
  11

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 盐酸 、 正丁基锂 作用下， 以 正己烷 为溶剂， 反应 4.25h， 生成 (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone
  参考文献：
  名称：

  [EN] HETEROARYL-KETONE FUSED AZADECALIN GLUCOCORTICOID RECEPTOR MODULATORS
  [FR] MODULATEURS DES RÉCEPTEURS DE GLUCOCORTICOÏDES CONSISTANT EN AZADÉCALINES À HÉTÉROARYLE CÉTONE FUSIONNÉ

  摘要：

  公开号：

  WO2013177559A3

文献信息

• Heteroaryl-Ketone Fused Azadecalin Glucocorticoid Receptor Modulators
  申请人：Corcept Therapeutics, Inc.

  公开号：US20140038926A1

  公开（公告）日：2014-02-06

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

  本发明提供了杂环基酮融合的氮杂十环化合物，以及使用这些化合物作为糖皮质激素受体调节剂的方法。
• HETEROARYL-KETONE FUSED AZADECALIN GLUCOCORTICOID RECEPTOR MODULATORS
  申请人：Corcept Therapeutics, Inc.

  公开号：US20150080389A1

  公开（公告）日：2015-03-19

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

  本发明提供了杂环酰酮融合的氮杂十二烷化合物以及使用这些化合物作为糖皮质激素受体调节剂的方法。
• Treatment and differential diagnosis of Cushing's disease and ectopic Cushing's syndrome
  申请人：Corcept Therapeutics, Inc.

  公开号：US10151763B2

  公开（公告）日：2018-12-11

  Improved methods and systems for diagnosing and for treating Cushing's syndrome and Cushing's Disease are provided herein, including methods and systems for concurrently treating Cushing's syndrome and differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome in a patient with an established diagnosis of ACTH-dependent Cushing's syndrome. Treatment methods can use glucocorticoid receptor antagonists (GRAs), which differentially affect the ratio of cortisol to ACTH levels in patients having Cushing's Disease versus patients having Ectopic Cushing's Syndrome. Methods for concurrently treating and differentially diagnosing Cushing's Disease from Ectopic Cushing's Syndrome include obtaining baseline cortisol and ACTH levels of a patient, treating the patient with a GRA according to a protocol that would typically substantially elevate cortisol levels, obtaining post-treatment cortisol and ACTH levels of the patient, determining a differential relationship between baseline cortisol and ACTH levels and post-treatment cortisol and ACTH levels and providing a positive diagnosis based on the differential relationship.

  本文提供了诊断和治疗库欣综合征和库欣病的改进方法和系统，包括同时治疗库欣综合征和在已确诊为ACTH依赖性库欣综合征的患者中将库欣病与异位库欣综合征区分开来的方法和系统。治疗方法可以使用糖皮质激素受体拮抗剂（GRAs），它能对库欣病患者与异位库欣综合征患者的皮质醇与促肾上腺皮质激素水平的比率产生不同的影响。同时治疗和鉴别诊断库欣病与异位库欣综合征的方法包括：获取患者的皮质醇和促肾上腺皮质激素（ACTH）基线水平；根据通常会显著升高皮质醇水平的方案，用 GRA 治疗患者；获取患者治疗后的皮质醇和促肾上腺皮质激素（ACTH）水平；确定皮质醇和促肾上腺皮质激素（ACTH）基线水平与治疗后皮质醇和促肾上腺皮质激素（ACTH）水平之间的鉴别关系，并根据鉴别关系提供阳性诊断。
• Heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators
  申请人：Corcept Therapeutics, Inc.

  公开号：US10456392B2

  公开（公告）日：2019-10-29

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

  本发明提供了杂芳基酮融合氮杂环丁烷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。
• Therapeutic uses of relacorilant, a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator
  申请人：Corcept Therapeutics Incorporated

  公开号：US11058670B2

  公开（公告）日：2021-07-13

  Methods and compositions are disclosed for diagnosing a patient suspected of suffering from, and for treating a patient suffering from, a disorder such as hypercortisolemia, metabolic syndrome, pre-diabetes, diabetes, Cushing's syndrome, Cushing's Disease, hyperglycemia secondary to hypercortisolemia, a liver disease, a cardiac disorder, high blood pressure, a blood clotting disorder, a cancer, a psychological disorder, weight gain, a disorder of glucose control, a bone disorder (e.g., osteoporosis), hypogonadism, pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTH secreting tumors, peripheral neuropathy, dyslipidemia and other disorders. The methods and compositions include administration of a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (GRM). The preferred heteroaryl-ketone fused azadecalin GRM is relacorilant ((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). In some cases, the GRM (e.g., relacorilant) is orally administered. In some cases, the GRM (e.g., relacorilant) is orally administered without food.

  本发明公开了用于诊断疑似高皮质醇血症、代谢综合征、糖尿病前期、糖尿病、库欣综合征、库欣病、继发于高皮质醇血症的高血糖症、肝脏疾病、心脏疾病、高血压、凝血障碍、癌症、心理障碍、体重增加、血糖控制障碍、骨骼障碍（例如，骨质疏松症）等疾病的患者和治疗患者的方法和组合物。g.,骨质疏松症）、性腺功能减退症、假性肢端肥大症、垂体瘤、功能性皮质醇过多症、促肾上腺皮质激素分泌肿瘤、周围神经病变、血脂异常和其他疾病。 这些方法和组合物包括施用杂芳基酮融合氮杂萘糖皮质激素受体调节剂（GRM）。优选的杂芳基酮融合氮杂十环素 GRM 是 relacorilant（(R)-(1-(4-氟苯基)-6-((1-甲基-1H-吡唑-4-基)磺酰基)-4,4a,5,6,7,8-六氢-1H-吡唑并[3,4-g]异喹啉-4a-基)(4-(三氟甲基)吡啶-2-基)甲酮）。在某些情况下，口服 GRM（例如 relacorilant）。在某些情况下，GRM（如抗逆转录酶药）不经食物口服给药。