夫罗曲坦 | 158747-02-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 夫罗曲坦
• 中文别名: 福伐曲坦；夫罗曲普坦；R-夫罗曲坦；R-夫罗曲普坦
• 英文名称: (R)-frovatriptan
• 英文别名: Frovatriptan；(6R)-6-(methylamino)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxamide
• CAS: 158747-02-5
• 化学式: C₁₄H₁₇N₃O
• 分子量: 243.308
• InChiKey: XPSQPHWEGNHMSK-SECBINFHSA-N

物化性质

• 沸点：
  515.2±50.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 溶解度：
  In water, 1.9X10+4 mg/L at 25 °C (est)
• 蒸汽压力：
  3.7X10-9 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 10.6 (secondary amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  70.9
• 氢给体数：
  3
• 氢受体数：
  2

ADMET

代谢

体外实验中，细胞色素P450 1A2似乎是主要参与 frovatriptan 代谢为包括羟基化 frovatriptan、N-乙酰去甲基 frovatriptan、羟基化 N-乙酰去甲基 frovatriptan 和去甲基 frovatriptan 在内的几种代谢物的主要酶，以及一些其他次要代谢物。去甲基 frovatriptan 对 5-HT_1B/1D 受体的亲和力低于母化合物。N-乙酰去甲基代谢物对 5-HT 受体没有显著亲和力。其他代谢物的活性尚不清楚。

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT_1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.

来源:DrugBank

代谢

体外实验中，细胞色素P450 1A2似乎是参与 frovatriptan 代谢的主要酶。在健康男性和女性受试者单次口服放射性标记的 frovatriptan 2.5 mg 后，剂量的32% 在尿液中回收，62% 在粪便中回收。尿液中排出的放射性标记化合物包括未改变的 frovatriptan、羟基化的 frovatriptan、N-乙酰脱甲基 frovatriptan、羟基化的 N-乙酰脱甲基 frovatriptan 和脱甲基 frovatriptan，以及几种其他微量的代谢物。脱甲基 frovatriptan 对 5-HT1B/1D 受体的亲和力低于母体化合物。N-乙酰脱甲基代谢物对 5-HT 受体没有显著亲和力。其他代谢物的活性尚不清楚。

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外实验中，细胞色素P450 1A2似乎是参与 frovatriptan 代谢为包括羟基化 frovatriptan、N-乙酰去甲基 frovatriptan、羟基化 N-乙酰去甲基 frovatriptan 和去甲基 frovatriptan 在内的几种代谢物的主要酶，以及一些其他次要代谢物。去甲基 frovatriptan 对 5-HT_1B/1D 受体的亲和力低于母化合物。N-乙酰去甲基代谢物对 5-HT 受体没有显著亲和力。其他代谢物的活性尚不清楚。 消除途径：尿液中排出的放射性化合物包括未改变的 frovatriptan、羟基化 frovatriptan、N-乙酰去甲基 frovatriptan、羟基化 N-乙酰去甲基 frovatriptan 和去甲基 frovatriptan，以及几种其他次要代谢物。口服剂量后，少于10%的 frovatriptan 通过尿液排出。 半衰期：26小时

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT_1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. Route of Elimination: Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose. Half Life: 26 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

曲普坦类药物的抗偏头痛作用被认为涉及三种不同的药理作用：(1) 刺激突触前5-HT_1D受体，这有助于抑制硬脑膜血管舒张和炎症；(2) 通过在大脑干中的5-HT_1B/1D受体激动作用直接抑制三叉神经核细胞的兴奋性；(3) 由于血管5-HT_1B受体激动作用，导致脑膜、硬脑膜、大脑或软脑膜血管的血管收缩。

Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT_1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT_1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT_1B receptor agonism.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

合成物：福罗伐曲坦

Compound:frovatriptan

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

Frovatriptan 从十二指肠迅速吸收，但口服生物利用度较低。

Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.

来源:DrugBank

吸收、分配和排泄

• 消除途径

放射性标记化合物在尿液中排泄时，原型的frovatriptan、羟基化的frovatriptan、N-乙酰脱甲基的frovatriptan、羟基化的N-乙酰脱甲基的frovatriptan和脱甲基的frovatriptan均保持不变，同时还有几种其他微量的代谢物。口服剂量后，少于10%的frovatriptan通过尿液排泄。

Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose.

来源:DrugBank

吸收、分配和排泄

• 分布容积

4.2 升/千克 [男性]

4.2 L/kg [males]

来源:DrugBank

吸收、分配和排泄

• 清除

220毫升/分钟 [男性接受0.8毫克的静脉注射剂量]

220 mL/min [male receiving IV dose of 0.8 mg]

来源:DrugBank

吸收、分配和排泄

蛋白质结合：与血清蛋白的结合率低（大约15%）。

Protein binding: Low (approximately 15%) to serum proteins.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

佛伐曲坦是一种有效的5-HT1B/D受体激动剂，在曲普坦类药物中拥有最高的5-HT1B效力。弗罗瓦特里普坦显然具有大脑选择性。在先兆偏头痛发作的头痛阶段服用佛伐曲坦，其在某些终点方面不仅有效，甚至优于氟伐曲坦。

反应信息

• 作为反应物：
  描述：

  夫罗曲坦 在 硫酸 、 水 、 sodium nitrite 作用下， 以 乙醇 为溶剂， 以99.6 %的产率得到indole carboxylic acid
  参考文献：
  名称：

  一种琥珀酸呋罗曲坦降解杂质的制备方法

  摘要：

  本发明涉及有机化学领域，公开了一种琥珀酸呋罗曲坦降解杂质的制备方法，以化合物1或化合物2为起始物料合成琥珀酸呋罗曲坦酰胺降解杂质，为药品研发提供必需的标准品，同时大幅降低了制备该杂质的研发成本，提高了制备该杂质的效率，具体包括以下步骤：步骤一：化合物1在有机溶剂一中于酸性条件或碱性条件下反应得到化合物3，或包括以下步骤：步骤一：化合物2在有机溶剂一中于酸性条件或碱性条件下反应得到化合物3，即得琥珀酸呋罗曲坦降解杂质，其中，酸性条件下还添加了试剂一。本发明的创新点在于：首次公开琥珀酸呋罗曲坦酰胺降解杂质的合成方法；该合成方法环境友好、收率高，收率为90%以上，大幅降低了制备该杂质的研发成本。

  公开号：

  CN117402103A
• 作为产物：
  描述：

  (R)-3-[benzyl(methyl)amino]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以71%的产率得到夫罗曲坦
  参考文献：
  名称：

  血清素受体激动剂 (R)-Frovatriptan 的化学酶促不对称合成

  摘要：

  已经开发了一种简单的化学酶促不对称途径来生产抗偏头痛药 (R)-Frovatriptan。脂肪酶和氧化还原酶已被确定为在安全和环境友好的条件下生产对映体纯的合成中间体的理想生物催化剂。(S)-3-Hydroxy-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile 是该药物合成的最佳结构单元，已通过 Candida antarctica 脂肪酶 B 型催化酰化其相应的外消旋混合物或醇脱氢酶A介导相应酮的生物还原。手性中心的反转已被确定为关键步骤，优化过程以避免部分外消旋化。最后，

  DOI：

  10.1002/ejoc.201300114

文献信息

• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：UNIV EMORY

  公开号：WO2013181135A1

  公开（公告）日：2013-12-05

  The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

  该披露涉及喹唑啉衍生物、组合物以及相关方法。在某些实施例中，该披露涉及NADPH-氧化酶（Nox酶）和/或髓过氧化物酶的抑制剂。
• [EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
  申请人：MERCK SHARP & DOHME

  公开号：WO2013169567A1

  公开（公告）日：2013-11-14

  The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

  本发明涉及螺内酰胺类似物，其为CGRP受体拮抗剂，可用于治疗或预防涉及CGRP的疾病，如偏头痛。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗涉及CGRP的这类疾病中使用这些化合物和组合物。
• [EN] PYRROLE COMPOUNDS FOR THE TREATMENT OF PROSTAGLANDIN MEDIATED DISEASES<br/>[FR] COMPOSES PYRROLIQUES DESTINES AU TRAITEMENT DE MALADIES INDUITES PAR PROSTAGLANDINE
  申请人：GLAXO GROUP LTD

  公开号：WO2003101959A1

  公开（公告）日：2003-12-11

  Compounds of formula (I) or a pharmaceutically acceptable derivative thereof: wherein A, R1, R2a, R2b, Rx, R8, and R9 are as defined in the specification, a process for the preparation of such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in medicine, in particular their use in the treatment of prostaglandin mediated diseases such as pain, inflammatory, immunological, bone, neurodegenerative or renal disorder.

  式(I)的化合物或其药学上可接受的衍生物：其中A、R1、R2a、R2b、Rx、R8和R9如规范中所定义，一种制备这种化合物的方法，包括这种化合物的药物组合物以及这种化合物在医学中的用途，特别是它们在治疗前列腺素介导的疾病，如疼痛、炎症、免疫、骨骼、神经退行性或肾脏疾病中的用途。
• [EN] INDANE DERIVATIVES AS MGLUR7 MODULATORS<br/>[FR] DÉRIVÉS D'INDANE UTILISÉS COMME MODULATEURS DE MGLUR7
  申请人：TAKEDA PHARMACEUTICALS CO

  公开号：WO2017131221A1

  公开（公告）日：2017-08-03

  The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4a and R4b are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds of formula (I) are mGluR7 modulators.

  本发明提供了式（I）的化合物及其药学上可接受的盐，其中R1、R2、R3、R4a和R4b如规范中定义，其制备方法，含有它们的药物组合物以及它们在治疗中的用途。式（I）的化合物是mGluR7调节剂。