17-alpha-乙酰氧基-6-氯-2-氧杂-4,6-孕甾二烯-3,20-二酮 | 105149-00-6

• 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: 17-alpha-乙酰氧基-6-氯-2-氧杂-4,6-孕甾二烯-3,20-二酮
• 中文别名: 1H-吡咯-3-甲酰胺,4-(4-氨基苯基)-
• 英文名称: 17α-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione
• 英文别名: osaterone acetate；2-oxachlormadinone acetate；Osaterone acetate ester；17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione
• CAS: 105149-00-6
• 化学式: C₂₂H₂₇ClO₅
• 分子量: 406.906
• InChiKey: KKTIOMQDFOYCEN-OFUYBIASSA-N

物化性质

• 熔点：
  253-255°
• 沸点：
  537.8±50.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  69.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  17-alpha-乙酰氧基-6-氯-2-氧杂-4,6-孕甾二烯-3,20-二酮 在 Α-D-吡喃葡萄糖6-磷酸 、 mouse hepatic microsomes 、 还原型辅酶II(NADPH)四钠盐 作用下， 以 phosphate buffer 为溶剂， 生成 17α-acetoxy-6-chloro-11β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione
  参考文献：
  名称：

  Characterizations of mouse hepatic microsomal monooxygenase catalyzing 11β-hydroxylation of osaterone acetate

  摘要：

  Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione,OA) is a new steroidal antiandrogen. There is a marked species difference in the metabolism of OA in that 11 beta-hydroxylated metabolites are found in the plasma, feces, and urine of mice after oral administration of OA, but there is very little metabolism in rats and humans. OA reduces the adrenal gland weight in mice, but not in rats, and this effect in mice might be explained by the species difference in 11 beta-hydroxylation activity. The objectives of this study were to elucidate the enzyme(s) involved in this particular oxidation and to explain the species difference observed. Mouse hepatic microsomes oxidize OA to 11 beta-OH OA, and this oxidation requires NADPH as a cofactor. The use of various competitive and allosteric inhibitors of cytochrome P450 and flavin-containing monooxygenase (i.e. CO, N-octylamine, and methimazole) showed that the oxidation of OA was catalyzed by cytochrome P450. In microsomes from mice pretreated with phenobarbital (a CYP2B-selective inducer), 3-methylcholanthrene (a CYP2E selective inducer), pregnenolone-16 alpha-carbonitrile (a CYP3A-selective inducer), and EtOH (a CYP2E-selective inducer), an increase in the rates of oxidation was seen only in microsomes from EtOH treated animals. However, metyrapone, a selective inhibitor for enzymes of the cytochrome P45011B and P4502B family, inhibited mouse hepatic microsomal 11 beta-hydroxylation by < 30%. The results obtained showed that the production of 11 beta-OH OA may be catalyzed by a novel cytochrome P450 in mouse liver. (C) 1999 Elsevier Science Inc.

  DOI：

  10.1016/s0006-2952(99)00098-2

文献信息

• [EN] CONTROLLED-RELEASE TYROSINE KINASE INHIBITOR COMPOUNDS WITH LOCALIZED PK PROPERTIES<br/>[FR] COMPOSÉS INHIBITEURS DE TYROSINE KINASE À LIBÉRATION CONTRÔLÉE PRÉSENTANT DES PROPRIÉTÉS PHARMACOCINÉTIQUES LOCALISÉES
  申请人：ASCENDIS PHARMA ONCOLOGY DIV A/S

  公开号：WO2020254613A1

  公开（公告）日：2020-12-24

  The present invention relates to a water-insoluble controlled-release tyrosine kinase inhibitor ("TKI") compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration and wherein the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue 3 days after said intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by said intra-tissue administration; and to related aspects.

  本发明涉及一种水不溶性控释酪氨酸激酶抑制剂（“TKI”）化合物，用于治疗细胞增殖紊乱，其中所述水不溶性控释TKI化合物释放一种或多种TKI药物，所述水不溶性控释TKI化合物通过组织内给药给予，并且在所述组织内给药后的第3天，所述组织中残留的TKI基团和TKI药物分子的总量至少为所述组织内给药给予的TKI基团或TKI药物分子总量的25％；以及相关方面。
• [EN] MINIMIZATION OF SYSTEMIC INFLAMMATION<br/>[FR] MINIMISATION DE L'INFLAMMATION SYSTÉMIQUE
  申请人：ASCENDIS PHARMA AS

  公开号：WO2020141225A1

  公开（公告）日：2020-07-09

  The present invention relates to a water-insoluble controlled-release pattern recognition receptor agonist ("PRRA") for use in the treatment of a cell-proliferation disorder, wherein the water-insoluble controlled-release PRRA is administered by intra-tissue administration, and wherein the protein levels of at least one cytokine selected from the group consisting of IL-6, CCL2 and IL-10 in plasma has a more than 10-fold lower maximum protein level within 24 hours compared to an equivalent molar dose of the corresponding free PRRA upon intra/tissue administration; and to related aspects.

  本发明涉及一种用于治疗细胞增殖障碍的水不溶性控制释放模式识别受体激动剂（"PRRA"），其中水不溶性控制释放PRRA通过组织内给药进行，并且其中血浆中至少一种由IL-6、CCL2和IL-10组成的细胞因子的蛋白水平在24小时内与相应自由PRRA等摩尔剂量给药相比，最大蛋白水平降低超过10倍；以及相关方面。
• METHODS OF TREATING ADVANCED PROSTATE CANCER
  申请人：City of Hope

  公开号：US20180311261A1

  公开（公告）日：2018-11-01

  Provided herein are methods for treating metastatic prostate cancer using anti-androgen compounds and radionuclide-labeled androgens.

  本文提供了使用抗雄激素化合物和放射性核素标记的雄激素治疗转移性前列腺癌的方法。
• [EN] CONTROLLED-RELEASE TYROSINE KINASE INHIBITOR COMPOUNDS WITH LOCALIZED PD PROPERTIES<br/>[FR] COMPOSÉS INHIBITEURS DE TYROSINE KINASES À LIBÉRATION CONTRÔLÉE PRÉSENTANT DES PROPRIÉTÉS PHARMACODYNAMIQUES LOCALISÉES
  申请人：ASCENDIS PHARMA ONCOLOGY DIV A/S

  公开号：WO2020254612A1

  公开（公告）日：2020-12-24

  The present invention relates to a water-insoluble controlled-release TKI compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein upon intra-tissue administration of a single dose of the water-insoluble controlled-release TKI compound anti-tumor activity is observed between 7 and 21 days following administration of the water-insoluble controlled-release TKI compound, and wherein the change in mean arterial blood pressure as measured in mmHg is less than 50% of the change in mean arterial blood pressure observed in the same animal species treated with a daily equimolar dose of the corresponding free TKI drug; and to related aspects.

  本发明涉及一种水不溶性控释TKI化合物，用于治疗细胞增殖紊乱，其中所述水不溶性控释TKI化合物释放一种或多种TKI药物，在给予一剂量的水不溶性控释TKI化合物后，在给予水不溶性控释TKI化合物后的7至21天内观察到抗肿瘤活性，并且所测得的平均动脉血压的变化以mmHg为单位，小于相同动物种类中用相应的游离TKI药物进行每日等摩尔剂量处理时观察到的平均动脉血压变化的50％以下；以及相关方面。
• [EN] TYROSINE KINASE INHIBITOR CONJUGATES<br/>[FR] CONJUGUÉS INHIBITEUR DE TYROSINE KINASE
  申请人：ASCENDIS PHARMA ONCOLOGY DIV A/S

  公开号：WO2020254609A1

  公开（公告）日：2020-12-24

  The present invention relates to a tyrosine kinase inhibitor ("TKI") conjugate or a pharmaceutically acceptable salt thereof, wherein said conjugate comprises a plurality of TKI moieties -D covalently conjugated via at least one moiety -L1 -L2 - to a polymeric moiety Z, wherein -L - is covalently and reversibly conjugated to -D and -L2 - is covalently conjugated to Z and wherein -L1- is a linker moiety and -L2- is a chemical bond or a spacer moiety; and to related aspects.

  本发明涉及一种酪氨酸激酶抑制剂（"TKI"）共轭物或其药学上可接受的盐，其中所述共轭物包括多个TKI基团-D，通过至少一个基团-L1-L2-共价连接到聚合物基团Z，其中-L-与-D共价可逆地结合，-L2-与Z共价结合，-L1-是连接基团，-L2-是化学键或间隔基团；以及相关方面。