1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]imino]-2,4-imidazolidinedione | 7261-97-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]imino]-2,4-imidazolidinedione
• 英文别名: 1-{[5-(4-nitrophenyl)furan-2-yl]methyleneamino}imidazolidine-2,4-dione；dantrolene；Dantrium；Dantro；DANT；1-[5-(4-nitro-phenyl)-furan-2-ylmethyleneamino]-imidazolidine-2,4-dione；1-[(Z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione
• CAS: 7261-97-4
• 化学式: C₁₄H₁₀N₄O₅
• 分子量: 314.257
• InChiKey: OZOMQRBLCMDCEG-CHHVJCJISA-N

物化性质

• 熔点：
  279-280°
• 沸点：
  453.94°C (rough estimate)
• 密度：
  1.3452 (rough estimate)
• 溶解度：
  DMSO（微溶）、甲醇（微溶，超声处理）
• 物理描述：
  Crystals (in aqueous DMF). (NTP, 1992)
• 颜色/状态：
  CRYSTALS FROM AQ DIMETHYLFORMAMIDE
• 稳定性/保质期：
  STABLE IN LIGHT, AIR & HEAT; HYDROLYZES IN WATER /DANTROLENE SODIUM SALT HYDRATE/
• 解离常数：
  PKA ABOUT 7.5 (FREE ACID)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

丹曲林通过肝脏混合功能氧化酶系统代谢成5-羟基丹曲林，它与葡萄糖醛酸或硫酸结合。它还通过硝基还原酶代谢成氨曲林，后者抑制肝脏混合功能氧化酶系统。氨曲林的乙酰化作用阻断了其抑制效果。硝基还原酶途径中的中间体形成葡萄糖醛酸和巯基尿酸结合物。巯基尿酸结合反应是丹曲林电负性代谢物的一种解毒机制。

DANTROLENE IS METABOLIZED BY THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM TO 5-HYDROXYDANTROLENE WHICH IS CONJUGATED WITH GLUCURONIC ACID OR WITH SULFATE. IT IS ALSO METABOLIZED BY NITROREDUCTASE TO AMINODANTROLENE WHICH INHIBITS THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM. ACETYLATION OF AMINODANTROLENE BLOCKS THE INHIBITORY EFFECTS. INTERMEDIATES IN THE NITROREDUCTASE PATHWAY FORM GLUCURONIDE & MERCAPTURIC ACID CONJUGATES. THE MERCAPTURIC ACID CONJUGATION REACTION IS A DETOXIFICATION MECHANISM FOR AN ELECTROPHILIC METABOLITE OF DANTROLENE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

轻度的、无症状的血清转氨酶升高在使用丹曲林治疗期间相对不常见（1%），但临床上估计每千人治疗中会有1到2人发生肝损伤（0.1%到0.2%）。肝损伤可能是严重的；有急性肝衰竭甚至死亡的病例报道（案例1）。临床明显肝损伤的潜伏期从一周到几个月不等，但通常在开始治疗的前6个月内（案例2）。更严重的病例通常突然发作，伴有黄疸、恶心和疲劳，并且迅速进展。过敏表现如发热、皮疹和嗜酸性粒细胞增多是罕见的，自身免疫特征也很少见。酶升高的模式主要是肝细胞型。肝脏组织学显示急性肝炎样的图片。通常在1到3个月内完全恢复。女性、老年患者和服用更高剂量的患者似乎更容易发生丹曲林肝毒性。

Mild, asymptomatic serum aminotransferase elevations during dantrolene therapy are relatively uncommon (1%), but clinically over liver injury is estimated to occur in 1 to 2 per thousand treated persons (0.1% to 0.2%). The liver injury can be severe; cases of acute liver failure and even death have been described (Case 1). The latency to onset of clinically apparent liver injury ranges from one week to several months, but is usually within the first 6 months of starting therapy (Case 2). More serious cases are associated with a sudden onset with jaundice, nausea and fatigue, and rapid progression. Allergic manifestations such as fever, rash and eosinophilia are rare, as are autoimmune features. The pattern of enzyme elevations is predominantly hepatocellular. Liver histology demonstrates an acute-hepatitis like picture. Recovery is usually complete within 1 to 3 months. Women, the elderly, and patients taking higher doses appear to be more susceptible to developing dantrolene hepatotoxicity.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：由于缺乏关于在哺乳期间长期使用丹曲林的信息，可能更倾向于选择其他药物，特别是在哺乳新生儿或早产儿时。短期使用后，预计药物将在1到2天内从乳汁中消除。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Because no information is available on the long-term use of dantrolene during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. After short-term use, the drug would be expected to be eliminated from milk in 1 to 2 days. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

丹曲林的中枢作用可能会被镇静-抗焦虑药物增强。

CENTRAL EFFECTS OF DANTROLENE MAY BE ENHANCED BY SEDATIVE-ANTIANXIETY DRUGS.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

丹曲林具有严重的可能导致肝毒性的潜力。在大约0.1%到0.2%的接受治疗超过60天的患者中报告了致命性肝炎。在接受治疗超过60天的患者中，有0.5%可能会出现症状性肝炎，而肝功能化学异常的发病率高达1%。最常见的严重副作用是无力，这可能是其对骨骼肌作用的延伸。欣快、头晕、眩晕、嗜睡和疲劳通常在治疗初期出现，但通常是短暂的...

DANTROLENE HAS SERIOUS POTENTIAL TO CAUSE HEPATOTOXICITY. FATAL HEPATITIS HAS BEEN REPORTED IN APPROX 0.1 TO 0.2% OF PATIENTS TREATED...FOR 60 DAYS OR LONGER. SYMPTOMATIC HEPATITIS MAY OCCUR IN 0.5% OF PATIENTS TREATED...FOR MORE THAN 60 DAYS, WHILE CHEMICAL ABNORMALITIES OF HEPATIC FUNCTION ARE NOTED IN UP TO 1%. ... MOST COMMON MAJOR SIDE EFFECT...IS WEAKNESS, WHICH IS PROBABLY EXTENSION OF ITS EFFECT ON SKELETAL MUSCLE. ... EUPHORIA, LIGHT-HEADEDNESS, DIZZINESS, DROWSINESS & FATIGUE OFTEN OCCUR EARLY IN TREATMENT, BUT...ARE GENERALLY TRANSIENT...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

...腹泻...是最常见的反应之一。...它...可能是持久的，需要治疗，减少剂量，或暂时停止治疗。厌食、恶心、呕吐和类似痤疮的皮疹也是显著的副作用。较少见的是...头痛、神经质和失眠...已经发生。胸膜心包反应和视觉障碍很少发展。/丹曲林钠/

...DIARRHEA.../IS ONE OF/ MOST COMMON REACTIONS. .../IT/ MAY BE PERSISTENT & REQUIRE TREATMENT, A REDUCTION IN DOSE, OR TEMPORARY CESSATION OF THERAPY. ANOREXIA, NAUSEA, VOMITING, & AN ACNE-LIKE RASH ARE ALSO SIGNIFICANT SIDE EFFECTS. LESS FREQUENTLY...HEADACHE, NERVOUSNESS /&/ INSOMNIA...HAVE OCCURRED. PLEUROPERICARDIAL REACTIONS & VISUAL DISTURBANCES DEVELOP RARELY. /DANTROLENE SODIUM/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吸收...从胃肠道缓慢且不完全，但足以提供与剂量相关的血浆浓度。成年人体内药物的半衰期约为9小时，服用100毫克剂量后。它被肝脏缓慢代谢，5-羟基和乙酰氨基代谢物与未改变的药物一起通过尿液排出。

ABSORPTION...FROM GI TRACT IS SLOW & INCOMPLETE BUT SUFFICIENTLY CONSISTENT TO PROVIDE DOSE-RELATED PLASMA CONCN. MEAN HALF LIFE OF DRUG IN ADULTS IS ABOUT 9 HR AFTER 100-MG DOSE. IT IS SLOWLY METABOLIZED BY LIVER, & THE 5-HYDROXY & ACETAMIDO METABOLITES ARE EXCRETED WITH UNCHANGED DRUG IN URINE.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 危险性防范说明：
  P261,P264,P271,P280,P302+P352,P304+P340,P305+P351+P338,P312,P313,P337+P313,P362,P403+P233,P405,P501
• 危险性描述：
  H315,H319,H335
• 储存条件：
  温度：2-8°C，环境气体：惰性气体

制备方法与用途

肌肉松弛剂Dantrolene（F368）以非竞争性方式抑制人红细胞谷胱甘肽还原酶，其Ki值为111.6μM，IC50值为52.3μM。丹特罗林是一种兰尼碱受体拮抗剂和钙信号稳定剂。Dantrolene可应用于研究肌肉痉挛、恶性高热、亨廷顿病及其他抗精神病药物引发的恶性综合征等病症。

反应信息

• 作为反应物：
  描述：

  茶氨酸 、 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]imino]-2,4-imidazolidinedione 以 水 、 异丙醇 为溶剂， 生成 L-theanine dantrolene cocrystal
  参考文献：
  名称：

  [EN] PLATFORM DRUG DELIVERY SYSTEM UTILIZING CRYSTAL ENGINEERING AND THEANINE DISSOLUTION
  [FR] SYSTÈME D'ADMINISTRATION DE MÉDICAMENT À PLATE-FORME UTILISANT L'INGÉNIERIE DES CRISTAUX ET LA DISSOLUTION DE LA THÉANINE

  摘要：

  一种平台药物输送系统和一种利用晶体工程和茶氯酸溶解来改善低溶解度药物输送的方法，从而提高生物活性、溶解速率和固态稳定性。

  公开号：

  WO2016144590A1
• 作为产物：
  描述：

  5-对硝基苯基糠醛 、 1-氨基海因盐酸盐 以 乙腈 为溶剂， 反应 12.0h， 以94%的产率得到1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]imino]-2,4-imidazolidinedione
  参考文献：
  名称：

  锰催化的（Het）芳烃CH连续化的连续可见光光流方法

  摘要：

  锰光催化剂通过连续的可见光光流实现了多种室温的CH芳基化反应，因此可以在30分钟内有效地进行CH芳基化。可见光诱导的克级合成显示了锰​​催化光流策略的鲁棒性，明显优于批处理性能。

  DOI：

  10.1002/anie.201805644

文献信息

• [EN] PLATFORM DRUG DELIVERY SYSTEM UTILIZING CRYSTAL ENGINEERING AND THEANINE DISSOLUTION<br/>[FR] SYSTÈME D'ADMINISTRATION DE MÉDICAMENT À PLATE-FORME UTILISANT L'INGÉNIERIE DES CRISTAUX ET LA DISSOLUTION DE LA THÉANINE
  申请人：THEAPRIN PHARMACEUTICALS INC

  公开号：WO2016144590A1

  公开（公告）日：2016-09-15

  A platform drug delivery system and a method of improving the delivery of low solubility pharmaceuticals utilizing crystal engineering and Theanine dissolution resulting in enhanced bioactivity, dissolution rate, and solid state stability.

  一种平台药物输送系统和一种利用晶体工程和茶氯酸溶解来改善低溶解度药物输送的方法，从而提高生物活性、溶解速率和固态稳定性。
• Continuous Visible‐Light Photoflow Approach for a Manganese‐Catalyzed (Het)Arene C−H Arylation
  作者：Yu‐Feng Liang、Ralf Steinbock、Long Yang、Lutz Ackermann

  DOI：10.1002/anie.201805644

  日期：2018.8.13

  Manganese photocatalysts enabled versatile room‐temperature C−H arylation reactions by means of continuous visible‐light photoflow, thus allowing for efficient C−H arylations in 30 minutes with ample scope. The robustness of the manganese‐catalyzed photoflow strategy was shown by visible light‐induced gram‐scale synthesis, clearly outperforming the batch performance.

  锰光催化剂通过连续的可见光光流实现了多种室温的CH芳基化反应，因此可以在30分钟内有效地进行CH芳基化。可见光诱导的克级合成显示了锰​​催化光流策略的鲁棒性，明显优于批处理性能。