4-羟基咪达唑仑 | 59468-85-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: 4-羟基咪达唑仑
• 中文别名: 4-羟基咪哒唑伦
• 英文名称: 4-hydroxymidazolam
• 英文别名: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-4-ol
• CAS: 59468-85-8
• 化学式: C₁₈H₁₃ClFN₃O
• 分子量: 341.772
• InChiKey: ZYISITHKPKHPKG-UHFFFAOYSA-N

物化性质

• 熔点：
  186-187 °C
• 沸点：
  550.6±60.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 保留指数：
  2580

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  50.4
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

4-羟基咪达唑仑是咪达唑仑在人身体内已知的一种代谢物。

4-Hydroxymidazolam is a known human metabolite of midazolam.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  4-羟基咪达唑仑 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 2.5h， 生成 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methyl-1H-imidazole-5-carbaldehyde
  参考文献：
  名称：

  咪达唑仑或其药物组合物的杂质A和杂质B及 其用途

  摘要：

  本发明属于医药化学领域，具体涉及咪达唑仑或其药物组合物的杂质A和杂质B，及其制备方法，以及其作为咪达唑仑或其药物组合物的质量控制的参照标准品的应用，

  公开号：

  CN111410658B
• 作为产物：
  描述：

  4-乙酰氧基-8-氯-6-(2-氟苯基)-1-甲基-4H-咪唑并[1,5-a][1,4]苯并二氮杂卓 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 生成 4-羟基咪达唑仑
  参考文献：
  名称：

  咪达唑仑或其药物组合物的杂质A和杂质B及 其用途

  摘要：

  本发明属于医药化学领域，具体涉及咪达唑仑或其药物组合物的杂质A和杂质B，及其制备方法，以及其作为咪达唑仑或其药物组合物的质量控制的参照标准品的应用，

  公开号：

  CN111410658B

文献信息

• Metabolism of 1′- and 4-Hydroxymidazolam by Glucuronide Conjugation Is Largely Mediated by UDP-Glucuronosyltransferases 1A4, 2B4, and 2B7
  作者：Kyung-Ah Seo、Soo Kyung Bae、Young-Kil Choi、Chang Soo Choi、Kwang-Hyeon Liu、Jae-Gook Shin

  DOI：10.1124/dmd.110.035295

  日期：2010.11

  Midazolam undergoes oxidative hydroxylation by CYP3A to its metabolites, which are excreted mainly as glucuronidated conjugates into the urine. In this study, we examined the glucuronidation of hydroxymidazolam in human liver microsomes (HLMs) and characterized the UDP-glucuronosyltransferases (UGTs) involved in 1′- and 4-hydroxymidazolam glucuronidation. Among the 12 UGT isoforms tested, the O - and N -glucuronidation of 1′-hydroxymidazolam was mediated by UGT2B4/2B7 and 1A4, respectively. In contrast, the glucuronidation of 4-hydroxymidazolam was mediated by UGT1A4. Consistent with these observations, the UGT1A4 inhibitor hecogenin and the UGT2B7 substrate diclofenac potently inhibited the N - and O -glucuronidation of 1′-hydroxymidazolam in HLMs, respectively. A correlation analysis of UGT enzymatic activity and the formation rate of glucuronide metabolites from 1′- and 4-hydroxymidazolam in 25 HLMs showed that hydroxymidazolam glucuronidation is correlated with UGT1A4-mediated lamotrigine glucuronidation and UGT2B7-mediated diclofenac glucuronidation activity. Taken together, these findings indicate that UGT1A4, 2B4, and 2B7 are major isoforms responsible for glucuronide conjugate formation from 1′- and 4-hydroxymidazolam, which are the two major oxidative metabolites of midazolam.

  咪达唑仑通过 CYP3A 氧化羟基化为其代谢物，主要以葡萄糖醛酸化结合物形式排泄到尿液中。在这项研究中，我们检测了羟基咪达唑仑在人肝微粒体 (HLM) 中的葡萄糖醛酸化，并表征了参与 1'- 和 4-羟基咪达唑仑葡萄糖醛酸化的 UDP-葡萄糖醛酸基转移酶 (UGT)。在测试的 12 种 UGT 亚型中，1'-羟基咪达唑仑的 O - 和 N - 葡萄糖醛酸化分别由 UGT2B4/2B7 和 1A4 介导。相反，4-羟基咪达唑仑的葡萄糖醛酸化是由 UGT1A4 介导的。与这些观察结果一致，UGT1A4 抑制剂 hecogenin 和 UGT2B7 底物双氯芬酸分别有效抑制 HLM 中 1'-羟基咪达唑仑的 N - 和 O - 葡萄糖醛酸化。对 25 个 HLM 中 UGT 酶活性与 1′- 和 4-羟基咪达唑仑葡萄糖醛酸代谢物形成率的相关性分析表明，羟基咪达唑仑葡萄糖醛酸化与 UGT1A4 介导的拉莫三嗪葡萄糖醛酸化和 UGT2B7 介导的双氯芬酸葡萄糖醛酸化活性相关。总而言之，这些发现表明 UGT1A4、2B4 和 2B7 是负责从 1'- 和 4-羟基咪达唑仑（咪达唑仑的两种主要氧化代谢物）形成葡萄糖醛酸结合物的主要亚型。
• Prediction of metabolic clearance using fresh human hepatocytes: Comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines
  作者：D. Hallifax、A. Galetin、J. B. Houston

  DOI：10.1080/00498250701834665

  日期：2008.4

  1. Predictions of in vivo intrinsic clearance from cryopreserved human hepatocytes may be systematically low. In the current study, the metabolite kinetics of a series of CYP3A4 substrates (benzodiazepines) in fresh human hepatocytes from five donors, via a major UK supplier, were investigated and compared with those previously reported (by the authors' laboratory) for cryopreserved human hepatocytes and hepatic microsomes.2. A high incidence of autoactivation (up to tenfold) and heteroactivation (by testosterone, up to 14-fold) among the major pathways was observed. CYP capacity (V-max) was marginally lower and 'affinity' constants (K-M, S-50) were marginally greater compared with cryopreserved hepatocytes.3. Average intrinsic clearance (based on maximal clearance, CLmax) was sevenfold lower than in cryopreserved hepatocytes (reflecting sensitivity of intrinsic clearance estimation in vitro to mechanistic parameter values, particularly those involving atypical kinetics), but scaled intrinsic clearances for fresh (and cryopreserved) hepatocytes were within the range previously determined in hepatic microsomes.4. There was no evidence from this series of studies that fresh hepatocytes provide quantitatively improved estimates of intrinsic clearance over cryopreserved hepatocytes.
• IN VITRO HEPATIC METABOLISM OF CYP3A-MEDIATED DRUGS QUININE AND MIDAZOLAM IN THE COMMON BRUSH-TAILED POSSUM (TRICHOSURUS VULPECULA)
  作者：Ping-Chuen Ho、Xiao-Xing Luo、Jackie S. Macauley、Murray R. Grigor、Sompon Wanwimolruk

  DOI：10.1897/1551-5028(1998)017<0317:ivhmoc>2.3.co;2

  日期：——
• Differential induction of midazolam metabolism in the small intestine and liver by oral and intravenous dexamethasone pretreatment in rat
  作者：S. L. Eeckhoudt、Y. Horsmans、R. K. Verbeeck

  DOI：10.1080/0049825021000012655

  日期：2002.1

  1. Midazolam is metabolized in the rat by CYP3A enzymes to 4-OH-midazolam (4-OH-MDZ) and 1'-OH-midazolam (1'-OH-MDZ). The induction of midazolam metabolism was studied in male Wistar rats treated with dexamethasone (50 mg kg(-1) day(-1)) during 4 days via the oral or intravenous routes. Microsomes were prepared from the liver and the proximal small intestine and in vitro metabolism of midazolam was determined. In addition, CYP3A1- and CYP3A2-like protein levels were measured by gel electrophoresis and immunoblotting.2. The V-max's (mean SEM) for 4-OH-MDZ and 1'-OH-MDZ formation were much lower in intestinal (0.078 +/- 0.002 and 0.074 +/- 0.002 muM min(-1) mg(-1) protein, respectively) compared with hepatic microsomes prepared from the uninduced rat (0.870 +/- 0.007 and 0.310 +/- 0.020 muM min(-1) mg-1 protein, respectively). Induction by oral or intravenous dexamethasone pretreatment led to significant increases in V-max for 4-OH-MDZ and VOH-MDZ by both intestinal and hepatic microsomes. Oral dexamethasone pretreatment via the oral route resulted in a more pronounced increase in compared with intravenous administration of the inducer.3. CYP3A1 and CYP3A2 protein levels in liver microsomes were significantly increased following oral (3.7- and 3.2-fold, respectively) or intravenous (2.6- and 2.1-fold, respectively) pretreatment with dexamethasone. On the contrary, only oral dexamethasone pretreatment resulted in a significant change in intestinal CYP3A2-hke protein (7.3-fold). A slight difference in the migration distance of the immunoreactive band for CYP3A2 was also observed for intestinal microsomes.4. These results suggest that intestinal CYP3A enzymes in the rat differ from hepatic CYP3A1 and CYP3A2. They also demonstrate that systemic dexamethasone administration can induce intestinal microsome activity.
• Vree; Baars; Booij, Arzneimittel-Forschung/Drug Research, 1981, vol. 31, # 12 a, p. 2215 - 2219
  作者：Vree、Baars、Booij、Driessen

  DOI：——

  日期：——