地尔硫卓 | 56209-45-1

• 物质功能分类: 原料药 - 循环系统用药 - 防治心绞痛药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 中文名称: 地尔硫卓
• 中文别名: 5-[2-(二甲基氨基)乙基]-2-(4-甲氧基苯基)-4-氧代-2,3,4,5-四氢-1,5-苯并硫氮杂卓-3-基乙酸酯
• 英文名称: diltiazem
• 英文别名: [(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate
• CAS: 56209-45-1；42399-41-7
• 化学式: C₂₂H₂₆N₂O₄S
• mdl: MFCD00868239
• 分子量: 414.525
• InChiKey: HSUGRBWQSSZJOP-RTWAWAEBSA-N

物化性质

• 熔点：
  212 °C (decomp)
• 沸点：
  594.4±50.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  White crystalline powder
• 稳定性/保质期：

  Intact vials should be stored under refrigeration and protected from freezing. Diltiazem HCl may be stored for up to one month at room temp but should then be destroyed. /Diltiazem HCl/

• Caco2细胞的药物渗透性：
  -4.38
• 解离常数：
  pKa = 8.06
• 碰撞截面：
  197.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.363
• 拓扑面积：
  84.4
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

地尔硫卓经历广泛的首过代谢，这解释了它相对较低的绝对口服生物利用度。它主要通过CYP3A4介导的N-去甲基化。CYP2D6负责O-去甲基化，酯酶介导脱乙酰化。在健康志愿者中，循环血浆中代谢物的水平存在很大的个体间变异性。在健康志愿者中，血浆中的主要循环代谢物是N-单去甲基地尔硫卓、脱乙酰地尔硫卓和脱乙酰N-单去甲基地尔硫卓，这些都具有药理活性。脱乙酰地尔硫卓保持了大约25-50%的母体化合物的药理活性。脱乙酰地尔硫卓可以进一步转化为脱乙酰地尔硫卓N-氧化物或脱乙酰O-去甲基地尔硫卓。N-单去甲基地尔硫卓可以进一步代谢为N,O-双去甲基地尔硫卓。脱乙酰N-单去甲基地尔硫卓可以进一步代谢为脱乙酰N,O-双去甲基地尔硫卓，这可以被葡萄糖醛酸化或硫酸化。地尔硫卓可以通过CYP2D6的O-去甲基化形成O-去甲基地尔硫卓。

Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem.

来源:DrugBank

代谢

地尔硫卓的主要代谢物是去乙酰地尔硫卓，其作为血管扩张剂的效力约为地尔硫卓的一半。

A major metabolite of diltiazem is desacetyldiltiazem, which has about 1/2 of diltiazem's potency as a vasodilator.

来源:Hazardous Substances Data Bank (HSDB)

代谢

地尔硫卓在肝脏和肝外组织中广泛代谢。去乙酰地尔硫卓（M1）和N-去甲基地尔硫卓（MA）是地尔硫卓的两种主要基本代谢物，它们保留了药理活性。这种药物在成人患者中慢性给药后，会损害自身的代谢。

Diltiazem undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-demethyldiltiazem (MA) are 2 of the main basic metabolites of diltiazem that retain pharmacological activity. This drug impairs its own metab after chronic admin in the adult patient.

来源:Hazardous Substances Data Bank (HSDB)

代谢

地尔硫卓已知的人类代谢物包括N-去甲基地尔硫卓和O-去甲基地尔硫卓。

Diltiazem has known human metabolites that include N-Demethyldiltiazem and O-Demethyldiltiazem.

来源:NORMAN Suspect List Exchange

代谢

地尔硫卓被CYP3A4酶代谢，并作为该酶的抑制剂。 半衰期：3.0 - 4.5小时

Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme. Half Life: 3.0 - 4.5 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

可能通过变形通道、抑制离子控制门控机制和/或干扰肌质网释放钙，地尔硫卓（diltiazem）与维拉帕米（verapamil）一样，抑制了细胞外钙通过心肌和血管平滑肌细胞膜的流入。这种结果性的抑制心肌平滑肌细胞的收缩过程，导致冠状动脉和体循环动脉扩张，并改善心肌组织的氧供。

Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, diltiazem, like verapamil, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

地尔硫卓治疗与血清转氨酶水平轻度短暂升高有关，这通常是无需症状的，并且即使继续治疗也往往会自行解决。临床上明显的，由于地尔硫卓引起的急性肝损伤并伴有黄疸的情况是罕见的，只有零星的案例报告被发表。在药物引起的肝损伤的大型案例系列中，钙通道阻滞剂很少被提及。归因于地尔硫卓的大多数案例都有一个短暂潜伏期（3到14天）并且表现出超敏反应的特征，如发热、皮疹和嗜酸性粒细胞增多。肝损伤的模式从胆汁淤积到肝细胞损伤不等。黄疸通常不存在或较轻。自体抗体形成尚未被描述。因此，地尔硫卓引起的肝损伤可能是特异质性的，通常是轻微和自限性的，停药后4到8周内会解决。急性肝损伤在地尔硫卓产品标签中被列为可能的副作用事件。

Diltiazem therapy is associated with a low rate of mild and transient elevations in serum aminotransferase levels which are usually asymptomatic and often resolve even with continuation of therapy. Clinically apparent, acute liver injury with jaundice due to diltiazem is rare and only isolated case reports have been published. In large case series of drug induced liver injury, calcium channel blockers are rarely mentioned. Most cases attributed to diltiazem have been marked by a short latency period (3 to 14 days) and features of hypersensitivity with fever, rash and eosinophilia. The pattern of liver injury was ranged from cholestatic to hepatocellular. Jaundice is often absent and usually mild. Autoantibody formation has not been described. Thus, liver injury from diltiazem is likely to be idiosyncratic in nature and is typically mild and self-limited with resolution within 4 to 8 weeks of stopping. Acute hepatic injury is listened as a possible adverse event in the diltiazem product label.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：地尔硫卓

Compound:diltiazem

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：4

Severity Grade:4

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

地尔硫卓（Diltiazem）从胃肠道吸收良好。最低治疗性血浆地尔硫卓浓度似乎在50至200 ng/mL的范围内。在口服长效制剂360毫克地尔硫卓后，药物在血浆中在3到4小时内可检测到，血浆浓度峰值在服药后11到18小时之间达到。地尔硫卓的峰浓度和系统暴露不受同时进食的影响。由于肝脏首过代谢，口服给药的绝对生物利用度约为40%，由于个体间首过效应的差异很大，这个值范围在24%到74%之间。在肝功能损害的患者中，生物利用度可能会增加。

Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment.

来源:DrugBank

吸收、分配和排泄

• 消除途径

由于其广泛的代谢作用，只有2%到4%的未改变药物可以在尿液中检测到。在健康志愿者中，主要的尿液代谢物是N-单脱甲基地尔硫卓，其次是脱乙酰基N,O-双脱甲基地尔硫卓、脱乙酰基N-单脱甲基地尔硫卓和脱乙酰基地尔硫卓；然而，DTZ及其代谢物在尿液排泄方面似乎存在很大的个体间差异。

Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

单次静脉注射后，地尔硫卓在健康男性志愿者体内的表观分布容积大约为305升。

The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康男性志愿者单次静脉注射后，地尔硫卓的系统清除率大约为65升/小时。在恒速静脉输注后，系统清除率降低到48升/小时。

Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h.

来源:DrugBank

吸收、分配和排泄

地尔硫卓的蛋白结合率为80-90%，分布容积约为5.3升/公斤。口服摄入后，地尔硫卓的清除遵循一级动力学，半衰期为5-10小时，与摄入量无关。然而，在缓释制剂中，由于持续的胃肠道吸收，吸收高峰时间延迟，半衰期可能非常延长。

The protein binding of diltiazem is 80-90%, & the volume of distribution is approx 5.3 L/kg. Clearance of diltiazem after oral ingestion follows first-order kinetics, with a half-life of 5-10 hr, independent of the amount ingested. In sustained release preparations, however, the peak absorption time is delayed & the half-life may be very prolonged because of continued GI absorption.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

根据提供的信息,我们可以总结地尔硫卓的主要特点和用途如下:

1. 主要用于治疗高血压急症。

2. 属于钙通道阻滞剂,可扩张血管,降低血压。

3. 可用于治疗心绞痛、心律失常等心血管疾病。

4. 是一种相对较安全的抗心律失常药物,不良反应较少。

5. 临床上主要用于控制房颤和室上性心动过速。

6. 对于严重低血压患者应慎用或避免使用。

7. 静脉给药时需监测心率、血压等指标。

8. 儿童、孕妇及哺乳期妇女应权衡利弊后谨慎使用。

9. 使用过程中需密切观察可能出现的毒性反应,如心动过缓、低血压等,并及时处理。

10. 与其他药物联合应用时应注意相互作用。

总之,地尔硫卓是一种较为安全有效的抗心律失常和降压药,但在临床应用中仍需谨慎规范用药。

反应信息

• 作为反应物：
  描述：

  地尔硫卓 在 氯甲酸-2,2,2-三氯乙酯 、 溶剂黄146 、 锌 作用下， 以 甲苯 为溶剂， 反应 26.25h， 生成 N-demethyldiltiazem
  参考文献：
  名称：

  WO2006/79077

  摘要：

  公开号：
• 作为产物：
  描述：

  Ethyl 2(S)-hydroxy-3(S)-<(O-aminophenyl)thio>-3-(p-methoxyphenyl)propionate 在 水 、 4-甲基苯磺酸吡啶 、 potassium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 、 甲苯 为溶剂， 反应 12.0h， 生成 地尔硫卓
  参考文献：
  名称：

  Anchimerically assisted unprecedented SNi-type cleavage of cyclic sulfites: application in the synthesis of the calcium channel blocker diltiazem

  摘要：

  DOI：

  10.1021/jo00123a045

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] SUPRAMOLECULAR GEL SUPPORTED ON OPEN-CELL POLYMER FOAM<br/>[FR] GEL SUPRAMOLÉCULAIRE SUPPORTÉ SUR MOUSSE POLYMÈRE À CELLULES OUVERTES
  申请人：UNIV STRASBOURG

  公开号：WO2021048199A1

  公开（公告）日：2021-03-18

  The present invention relates to a polymer foam, said polymer foam comprising pores forming an open-cell polymer foam, said polymer foam comprising a supramolecular gel inside pores, and said polymer foam comprising at least one enzyme. The present invention relates to a supramolecular gel; its preparation and its applications, notably in chemical synthesis and kinetic resolution, in particular of organic compounds. The present invention also relates to flow chemistry.

  本发明涉及一种聚合物泡沫，所述聚合物泡沫包括形成开孔聚合物泡沫的孔隙，所述聚合物泡沫包括孔隙内的超分子凝胶，以及所述聚合物泡沫包括至少一种酶。本发明涉及一种超分子凝胶；其制备及其应用，特别是在化学合成和动力学分辨中的应用，特别是有机化合物的动力学分辨。本发明还涉及流动化学。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。