旦著能 | 7261-97-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 中文名称: 旦著能
• 中文别名: 达者仑
• 英文名称: dantrolene
• 英文别名: 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione；1-[[5-(4-nitrophenyl)-2-furyl]methylideneamino]imidazolidine-2,4-dione；Dantrolen；1-[[5-(4-Nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione
• CAS: 7261-97-4
• 化学式: C₁₄H₁₀N₄O₅
• mdl: MFCD00867709
• 分子量: 314.257
• InChiKey: OZOMQRBLCMDCEG-UHFFFAOYSA-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：
  0.071
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

丹曲林通过肝混合功能氧化酶系统代谢为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为氨基硝林，后者抑制肝混合功能氧化酶系统。氨基硝林的乙酰化作用阻断了其抑制作用。硝基还原酶途径中的中间体形成葡萄糖苷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丹曲林治疗中相对不常见（1%），但临床上的肝损伤估计发生在每千人接受治疗的人中有1到2人（0.1%到0.2%）。肝损伤可能是严重的；已经描述了急性肝衰竭甚至死亡的病例（案例1）。临床明显肝损伤发病的潜伏期从一周到几个月不等，但通常在开始治疗的头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。像发热、皮疹和嗜酸性粒细胞增多这样的过敏表现是罕见的，自身免疫特征也很少见。酶升高的模式主要是肝细胞型的。肝脏组织学显示急性肝炎样的图片。恢复通常在1到3个月内完全完成。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，可能更倾向于使用另一种药物，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天内从乳汁中排出。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ 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60天或更长时间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生率高达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的早期出现，但通常是暂时的...

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、神经紧张和失眠...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，在服用100毫克剂量后。它被肝脏缓慢代谢，5-羟基和乙酰胺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

反应信息

• 作为反应物：
  描述：

  旦著能 在 potassium carbonate 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.0h， 生成
  参考文献：
  名称：

  丹曲林前药及其用法

  摘要：

  本公开涉及丹曲林前药，其组合物，及其在疾病治疗中的用法。

  公开号：

  CN111344286A
• 作为产物：
  描述：

  dantrolene sodium 在 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以98%的产率得到旦著能
  参考文献：
  名称：

  丹曲林前药及其用法

  摘要：

  本公开涉及丹曲林前药，其组合物，及其在疾病治疗中的用法。

  公开号：

  CN111344286A

文献信息

• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• Ascorbic Acid as an Initiator for the Direct CH Arylation of (Hetero)arenes with Anilines Nitrosated In Situ
  作者：Fernando Pinacho Crisóstomo、Tomás Martín、Romen Carrillo

  DOI：10.1002/anie.201309761

  日期：2014.2.17

  direct CH arylation of (hetero)arenes. Starting from an aniline, the corresponding arenediazonium ion is generated in situ and immediately reduced by vitamin C to an aryl radical that undergoes a homolytic aromatic substitution with a (hetero)arene. Notably, neither heating nor irradiation is required. This procedure is mild, operationally simple, and constitutes a greener approach to arylation.

  抗坏血酸（维生素C）已被用作（杂）芳烃的无金属直接CH芳基化反应中的自由基引发剂。从苯胺开始，相应的苯二氮杂鎓离子在原位生成，并立即被维生素C还原为芳基，该芳基经历了（杂）芳烃的均相芳族取代。值得注意的是，既不需要加热也不需要辐照。该过程是温和的，操作简单的，并且构成了芳构化的绿色方法。
• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。
• [EN] CANNABINOID DERIVATIVES<br/>[FR] DÉRIVÉS CANNABINOÏDES
  申请人：CANOPY GROWTH CORP

  公开号：WO2021113958A1

  公开（公告）日：2021-06-17

  This disclosure relates generally to cannabinoid derivatives, pharmaceutical compositions comprising them, and methods of using the cannabinoid derivatives.

  这份公开文件通常涉及大麻素衍生物、包含它们的药物组合物以及使用大麻素衍生物的方法。
• PYRIDINE AND PIPERIDINE DERIVATIVES AND USE THEREOF
  申请人：Purdue Pharma L.P.

  公开号：US20150141434A1

  公开（公告）日：2015-05-21

  The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: or pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein R 1 , R 4 , X, G, n, p, W 1 , W 2 , W 3 , W 4 , and the E ring are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II-XIII as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.

  本发明提供了一种用作钠通道阻断剂的化合物。在一方面，本发明提供了公式I的化合物： 或其药用可接受的盐、溶剂化物、水合物或对映异构体，其中R1、R4、X、G、n、p、W1、W2、W3、W4和E环在公开中定义。在某些实施例中，本发明提供了上述公式II-XIII的化合物。本发明还提供了使用上述任何讨论公式的化合物来治疗对钠通道阻断有反应的疾病。在一个实施例中，发明化合物用于治疗疼痛。