(R)-4A-(乙氧基甲基)-1-(4-氟苯基)-6-((4-(三氟甲基)苯基)磺酰基)-4,4A,5,6,7,8-六氢-1H-吡唑并[3,4-G]异喹啉 | 1018679-79-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: (R)-4A-(乙氧基甲基)-1-(4-氟苯基)-6-((4-(三氟甲基)苯基)磺酰基)-4,4A,5,6,7,8-六氢-1H-吡唑并[3,4-G]异喹啉
• 中文别名: 果糖二磷酸镁
• 英文名称: (R)-4-a-ethoxymethyl-1-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene
• 英文别名: (R)-4α-(ethoxymethyl)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline；CORT 108279；CORT108297；(R)-4A-(ethoxymethyl)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline；(4aR)-4a-(ethoxymethyl)-1-(4-fluorophenyl)-6-[4-(trifluoromethyl)phenyl]sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinoline
• CAS: 1018679-79-2
• 化学式: C₂₆H₂₅F₄N₃O₃S
• 分子量: 535.562
• InChiKey: SLKURXRZHJOZOD-RUZDIDTESA-N

物化性质

• 沸点：
  610.2±65.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  72.8
• 氢给体数：
  0
• 氢受体数：
  9

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H320,H335
• 储存条件：
  2-8℃

制备方法与用途

Cort108297是一种高亲和性的特异性糖皮质激素受体拮抗剂，其半数抑制浓度（IC50）为0.45 nM。

反应信息

• 作为产物：
  描述：

  (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)methanol 生成 (R)-4A-(乙氧基甲基)-1-(4-氟苯基)-6-((4-(三氟甲基)苯基)磺酰基)-4,4A,5,6,7,8-六氢-1H-吡唑并[3,4-G]异喹啉
  参考文献：
  名称：

  Bioorg. Med. Chem. Lett. 2008, 18, 1312-1317

  摘要：

  DOI：

文献信息

• 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。
• Glucocorticoid receptor modulators to treat pancreatic cancer
  申请人：Corcept Therapeutics, Inc.

  公开号：US10449178B2

  公开（公告）日：2019-10-22

  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。
• Methods of treating neuroepithelial tumors using selective glucocorticoid receptor modulators
  申请人：Corcept Therapeutics, Inc.

  公开号：US11213526B2

  公开（公告）日：2022-01-04

  Applicant discloses methods for treating a glucocorticoid receptor positive (GR+) neuroepithelial tumor in a subject, comprising administering a selective glucocorticoid receptor modulator (SGRM) in an amount effective to reduce the tumor load in a subject. The GR+ neuroepithelial tumor may be a neurofibromatosis type 2 (NF 2) tumor; the GR+ neuroepithelial tumor may be a schwannoma, meningioma, or ependymoma. In embodiments, the GR+ neuroepithelial tumor is not an adrenocorticotropic hormone (ACTH)-secreting tumor. In embodiments, the SGRM comprises a steroidal backbone. In embodiments, the SGRM is mifepristone. In embodiments, the SGRM comprises a non-steroidal backbone, such as, e.g., a cyclohexyl pyrimidine, a fused azadecalin, a heteroaryl ketone fused azadecalin, or an octahydro fused azadecalin backbone. The SGRM may be administered orally. The SGRM may be administered alone. In embodiments, the SGRM is administered with at least one non-SGRM therapy, e.g., a chemotherapy, a radiation therapy, or other therapeutic agents.

  申请人公开了治疗受试者体内糖皮质激素受体阳性（GR+）神经上皮肿瘤的方法，包括施用选择性糖皮质激素受体调节剂（SGRM），施用量应能有效减少受试者体内的肿瘤负荷。GR+神经上皮肿瘤可以是神经纤维瘤病2型（NF 2）肿瘤；GR+神经上皮肿瘤可以是分裂瘤、脑膜瘤或上皮瘤。在实施方案中，GR+神经上皮肿瘤不是分泌促肾上腺皮质激素（ACTH）的肿瘤。在实施方案中，SGRM 包括类固醇骨架。在实施方案中，SGRM 是米非司酮。在实施方案中，SGRM包括非类固醇骨架，例如，环己基嘧啶、融合氮杂环丁烷、杂芳酮融合氮杂环丁烷或八氢融合氮杂环丁烷骨架。SGRM 可以口服给药。SGRM 可单独给药。在实施方案中，SGRM与至少一种非SGRM疗法（如化疗、放疗或其他治疗剂）一起给药。
• 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity
  作者：Robin D. Clark、Nicholas C. Ray、Karen Williams、Paul Blaney、Stuart Ward、Peter H. Crackett、Christopher Hurley、Hazel J. Dyke、David E. Clark、Peter Lockey、Rene Devos、Melanie Wong、Soraya S. Porres、Colin P. Bright、Robert E. Jenkins、Joseph Belanoff

  DOI：10.1016/j.bmcl.2008.01.027

  日期：2008.2

  Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered ( e. g., 52: GR binding K-i 0.7 nM; GR reporter gene functional K-i 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had > 50% oral bioavailability in the dog. (c) 2008 Elsevier Ltd. All rights reserved.
• SOLID FORMS AND PROCESS FOR PREPARING
  申请人：Corcept Therapeutics, Inc.

  公开号：EP2429529A1

  公开（公告）日：2012-03-21