N-双去甲米非司酮 | 104004-92-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: N-双去甲米非司酮
• 中文别名: 去二甲基米非司酮
• 英文名称: RU 42848
• 英文别名: Didemethylmifepristone；N,N-Didesmethylmifepristone；(8S,11R,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
• CAS: 104004-92-4
• 化学式: C₂₇H₃₁NO₂
• mdl: MFCD00872129
• 分子量: 401.549
• InChiKey: MIPBCIAEOBOEKD-YEEPMTPTSA-N

物化性质

• 熔点：
  268-270°C
• 沸点：
  632.4±55.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.518
• 拓扑面积：
  63.3
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

去甲基米非司酮是单去甲基米非司酮的人类已知代谢物。

Didemethylated mifepristone is a known human metabolite of Monodemethylated mifepristone.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  米非司酮 在 还原型辅酶II(NADPH)四钠盐 作用下， 以 aq. buffer 为溶剂， 生成 N-去甲米非司酮 、 N-双去甲米非司酮 、 (8S,11R,13S,14S,17S)-17-Hydroxy-17-(3-hydroxy-prop-1-ynyl)-13-methyl-11-(4-methylamino-phenyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-cyclopenta[a]phenanthren-3-one
  参考文献：
  名称：

  Bacterial Biosynthetic P450 Enzyme PikC_D50N: A Potential Biocatalyst for the Preparation of Human Drug Metabolites

  摘要：

  DOI：

  10.1021/acs.joc.1c01407

文献信息

• [EN] INHIBITORS OF GLUCOCORTICOID RECEPTOR<br/>[FR] INHIBITEURS DE RÉCEPTEURS GLUCOCORTICOÏDES
  申请人：ORIC PHARMACEUTICALS INC

  公开号：WO2017112904A1

  公开（公告）日：2017-06-29

  The present invention relates generally to compositions and methods for treating cancer and hypercortisolism. Provided herein are substituted steroidal derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of glucocorticoid receptors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer and hypercortisolism.

  本发明一般涉及治疗癌症和高皮质醇血症的组合物和方法。本文提供了替代类固醇衍生物化合物和包含该化合物的药物组合物。所述化合物和组合物对于抑制糖皮质激素受体是有用的。此外，所述化合物和组合物对于治疗癌症和高皮质醇血症是有用的。
• Concomitant administration of glucocorticoid receptor modulators and CYP3A inhibitors
  申请人：Corcept Therapeutics, Inc.

  公开号：US10195214B2

  公开（公告）日：2019-02-05

  Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor antagonist (GRA) and steroidogenesis inhibitors, and by concomitant administration of a GRA and CYP3A inhibitors. Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of mifepristone and ketoconazole. Subjects treated with CYP3A inhibitors or steroidogenesis inhibitors may suffer from toxicity or other serious adverse reactions; concomitant administration of other drugs would be expected to increase the risk of such toxicity and adverse reactions. Applicant has surprisingly found that GRAs may be administered to subjects receiving CYP3A inhibitors or steroidogenesis inhibitors such as ketoconazole without increasing risk adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole (a CYP3A inhibitor and a steroidogenesis inhibitor), providing safe concomitant administration of the GRA and ketoconazole. In embodiments, the GRA dose may be reduced.

  申请人提供了通过同时服用糖皮质激素受体拮抗剂（GRA）和类固醇生成抑制剂，以及同时服用GRA和CYP3A抑制剂来治疗包括库欣综合征和激素敏感性癌症在内的疾病的方法。申请人提供了通过同时服用米非司酮和酮康唑治疗包括库欣综合征和激素敏感性癌症在内的疾病的方法。 接受 CYP3A 抑制剂或类固醇生成抑制剂治疗的受试者可能会出现毒性或其他严重的不良反应；同时服用其他药物预计会增加这种毒性和不良反应的风险。申请人令人惊奇地发现，GRA 可用于接受 CYP3A 抑制剂或类固醇生成抑制剂（如酮康唑）的受试者，而不会增加不良反应的风险；例如，申请人发现米非司酮可与酮康唑（一种 CYP3A 抑制剂和一种类固醇生成抑制剂）同时给药，提供 GRA 和酮康唑的安全同时给药。在实施例中，可减少 GRA 的剂量。
• Use of ACTH in assessment and prophylactic treatment of hypokalemia associated with glucocorticoid receptor modulator treatment of Cushing's syndrome patients
  申请人：Corcept Therapeutics, Inc.

  公开号：US10231983B1

  公开（公告）日：2019-03-19

  This invention provides new methods for a) identifying Cushing's Syndrome patients at high risk of developing hypokalemia during glucocorticoid receptor modulator (GRM) treatment, and b) for prophylactically treating such patients to prevent, or reduce the severity of, hypokalemia. Patients at such high risk may be identified prior to their developing hypokalemia. Such a patient may be an adult patient with endogenous Cushing's Syndrome having type 2 diabetes mellitus or glucose intolerance to control hyperglycemia secondary to hypercortisolism. Patients may be identified by an above-threshold level of ACTH or cortisol in a patient sample taken post-GRM administration or pre-GRM administration, respectively. Upon identifying such a patient prior to the development of low potassium, the present methods provide for prophylactically treating the patient by administration of one or more hypokalemia treatments concurrently with an increased dose of GRM or with an initial dose of GRM to prevent hypokalemia.

  本发明提供了新的方法，用于 a) 识别在糖皮质激素受体调节剂（GRM）治疗期间有发生低钾血症高风险的库欣综合征患者，以及 b) 对这类患者进行预防性治疗，以防止或减轻低钾血症的严重程度。此类高风险患者可在出现低钾血症之前被识别出来。这类患者可能是患有内源性库欣综合征的成年患者，他们患有2型糖尿病或葡萄糖不耐受症，以控制继发于高皮质醇血症的高血糖。患者可通过 GRM 施用后或 GRM 施用前采集的患者样本中高于阈值水平的促肾上腺皮质激素或皮质醇来识别。一旦在出现低钾之前识别出此类患者，本方法可通过在增加 GRM 剂量的同时或在初始剂量 GRM 的同时给予一种或多种低钾血症治疗以预防低钾血症的发生，从而对患者进行预防性治疗。
• Use of cortisol in assessment and prophylactic treatment of hypokalemia associated with glucocorticoid receptor modulator treatment of Cushing's syndrome patients
  申请人：Corcept Therapeutics, Inc.

  公开号：US10780097B2

  公开（公告）日：2020-09-22

  This invention provides new methods for a) identifying Cushing's Syndrome patients at high risk of developing hypokalemia during glucocorticoid receptor modulator (GRM) treatment, and b) for prophylactically treating such patients to prevent, or reduce the severity of, hypokalemia. Patients at such high risk may be identified prior to their developing hypokalemia. Such a patient may be an adult patient with endogenous Cushing's Syndrome having type 2 diabetes mellitus or glucose intolerance to control hyperglycemia secondary to hypercortisolism. Patients may be identified by an above-threshold level of ACTH or cortisol in a patient sample taken post-GRM administration or pre-GRM administration, respectively. Upon identifying such a patient prior to the development of low potassium, the present methods provide for prophylactically treating the patient by administration of one or more hypokalemia treatments concurrently with an increased dose of GRM or with an initial dose of GRM to prevent hypokalemia.

  本发明提供了新的方法，用于 a) 识别在糖皮质激素受体调节剂（GRM）治疗期间有发生低钾血症高风险的库欣综合征患者，以及 b) 对这类患者进行预防性治疗，以防止或减轻低钾血症的严重程度。此类高风险患者可在出现低钾血症之前被识别出来。这类患者可能是患有内源性库欣综合征的成年患者，他们患有2型糖尿病或葡萄糖不耐受症，以控制继发于高皮质醇血症的高血糖。患者可通过 GRM 施用后或 GRM 施用前采集的患者样本中高于阈值水平的促肾上腺皮质激素或皮质醇来识别。一旦在出现低钾之前识别出此类患者，本方法可通过在增加 GRM 剂量的同时或在初始剂量 GRM 的同时给予一种或多种低钾血症治疗以预防低钾血症的发生，从而对患者进行预防性治疗。
• CONCOMITANT ADMINISTRATION OF GLUCOCORTICOID RECEPTOR MODULATORS AND CYP3A OR STEROIDOGENESIS INHIBITORS
  申请人：Corcept Therapeutics, Inc.

  公开号：US20170281651A1

  公开（公告）日：2017-10-05

  Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor antagonist (GRA) and steroidogenesis inhibitors, and by concomitant administration of a GRA and CYP3A inhibitors. Applicant provides methods of treating diseases including Cushing's syndrome and hormone-sensitive cancers by concomitant administration of mifepristone and ketoconazole. Subjects treated with CYP3A inhibitors or steroidogenesis inhibitors may suffer from toxicity or other serious adverse reactions; concomitant administration of other drugs would be expected to increase the risk of such toxicity and adverse reactions. Applicant has surprisingly found that GRAs may be administered to subjects receiving CYP3A inhibitors or steroidogenesis inhibitors such as ketoconazole without increasing risk adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole (a CYP3A inhibitor and a steroidogenesis inhibitor), providing safe concomitant administration of the GRA and ketoconazole. In embodiments, the GRA dose may be reduced.