乌布吉泮 | 1374248-77-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 乌布吉泮
• 英文名称: ubrogepant
• 英文别名: (3S)-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide
• CAS: 1374248-77-7
• 化学式: C₂₉H₂₆F₃N₅O₃
• 分子量: 549.552
• InChiKey: DDOOFTLHJSMHLN-ZQHRPCGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  8

ADMET

代谢

Ubrogepant 主要通过代谢消除，其中大部分由 CYP3A4 介导。在人类血浆中，发现了两种循环的葡萄糖苷酸结合物以及未改变的母药，它们是最丰富的循环成分。据报道，葡萄糖苷酸代谢物在 CGRP 受体上的活性降低了 6000 倍，因此被认为是药理学上不活跃的。

Ubrogepant is eliminated primarily via metabolism, the majority of which is mediated by CYP3A4. Two circulating glucuronide conjugates, along with unchanged parent drug, were found to be the most abundant circulating components in human plasma. The glucuronide metabolites reportedly carry 6000-fold less activity at CGRP receptors and are therefore considered to be pharmacologically inert.

来源:DrugBank

毒理性

• 毒性总结

由于ubrogepant的临床经验有限，详细的毒性信息并不容易获得。ubrogepant的处方信息建议，基于其5到7小时的半衰期，在过量服用后至少监测24小时。

As clinical experience with ubrogepant is limited, detailed toxicity information is not readily available. Prescribing information for ubrogepant recommends a monitoring period of at least 24 hours following overdose based on its 5 to 7 hour half-life.

来源:DrugBank

毒理性

• 蛋白质结合

Ubrogepant 在体外实验中87%与蛋白质结合，尽管尚未阐明Ubrogepant具体结合的蛋白质种类。

Ubrogepant is 87% protein-bound _in vitro_, although the specific proteins to which ubrogepant binds have not been elucidated.

来源:DrugBank

吸收、分配和排泄

• 吸收

口服给药后，Tmax发生在0.7到1.5小时之间。与高脂肪餐同服时，Tmax延迟约2小时，Cmax降低了22%，AUC没有显著变化。Ubrogepant在整个推荐剂量范围内表现出剂量比例药代动力学。

Following oral administration, T_max occurs between 0.7 and 1.5 h. When administered with a high-fat meal, T_max is delayed by approximately 2 hours and C_max was reduced by 22% with no significant changes to the AUC. Ubrogepant exhibits dose-proportional pharmacokinetics throughout the entirety of its recommended dosing range.

来源:DrugBank

吸收、分配和排泄

• 消除途径

主要消除途径是粪便/胆汁，而肾排泄相对较少——在健康受试者口服单剂量后，大约42%的剂量在粪便中未变化地回收，6%在尿液中未变化地回收。

The main route of elimination is fecal/biliary, while renal excretion is comparatively minor - following administration of a single oral dose to healthy subjects, approximately 42% of the dose was recovered unchanged in the feces and 6% was recovered unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

口服给药后的表观中央分布体积大约为350升。

The apparent central volume of distribution following oral administration is approximately 350 L.

来源:DrugBank

吸收、分配和排泄

• 清除

乌布罗吉潘的表观口服清除率大约为87升/小时。

The apparent oral clearance of ubrogepant is approximately 87 L/h.

来源:DrugBank

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	(S)-1'-(tert-butyl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid	1455358-16-3	C19H19N3O3	337.378
  ——	(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid	1375541-21-1	C15H11N3O3	281.271
  ——	methyl (6S)-2'-oxo-1'-{[2-(trimethylsilyl)ethoxy]methyl}-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate	1375542-65-6	C22H27N3O4Si	425.56
  (3'S)-3-氯-1'-(1,1-二甲基乙基)-5,7-二氢螺[6H-环戊[B]吡啶-6,3'-[3H]吡咯并[2,3-B]吡啶]-2'(1'H)-酮	(S)-1'-(tert-butyl)-3-chloro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one	1455358-14-1	C18H18ClN3O	327.813
  ——	(6S)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one	1059186-43-4	C14H12N4O	252.275
  ——	1-(Tert-butyl)-3-((5-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)methyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one	1456804-09-3	C23H28ClN3O3	429.947
  ——	1-(tert-butyl)-3-((5-chloro-3-(chloromethyl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one	1455358-12-9	C18H19Cl2N3O	364.274
  ——	1-(tert-butyl)-3-((5-chloro-3-(hydroxymethyl)pyridin-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one	1455358-11-8	C18H20ClN3O2	345.829
  ——	tert-butyl [(3S,5S,6R)-5-(3-chlorophenyl)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate	1375477-14-7	C19H24ClF3N2O3	420.859
  1-叔丁基-2-氧代-1H,2H,3H-吡咯并[2,3-b]吡啶-3-羧酸甲酯	Methyl 1-tert-butyl-2-oxo-1H,2H,3H-pyrrolo[2,3-b]pyridine-3-carboxylate	1455358-36-7	C13H16N2O3	248.282

反应信息

• 作为产物：
  描述：

  4-溴苯基丙酮 在 盐酸 、 potassium phosphate 、 2-羟基吡啶-N-氧化物 、 palladium on activated charcoal 、 磷酸吡哆醛 、 transaminase ATA-426 、 potassium formate 、 potassium carbonate 、 caesium carbonate 、 异丙胺 、 sodium hydroxide 、 lithium tert-butoxide 作用下， 以 四氢呋喃 、 甲醇 、 甲基叔丁基醚 、 醋酸异丙酯 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 乌布吉泮
  参考文献：
  名称：

  Ubrogepant. Calcitonin gene-related peptide (CGRP) receptor antagonist, Treatment of migraine

  摘要：

  Migraineis ranked as the sixth cause of years lost due to disability, with around 1.04 billion migraine sufferers globally. Triptans are considered the standard for acute migraine treatment, but an important number of migraineurs do not respond to them and these drugs are contraindicated in patients with cardiovascular disease. Migraine therapy is currently undergoing tremendous development, i.e., 5-HT1F receptor agonists (ditans), anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies, and small-molecule CGRP receptor antagonists (gepants). Ubrogepant (MK-1620) is a small-molecule, potent and selective CGRP receptor antagonist. In two phase III clinical trials (ACHIEVE I and II), ubrogepant showed, at 2 hours, significant percentages of pain freedom, and absence of the most bothersome symptoms in migraine patients. In a phase III study to assess the long-term (52-week) safety and tolerability, ubrogepant displayed good tolerability, and no signs of hepatic toxicity. In March 2019, the U.S. Food and Drug Administration accepted the new drug application (NDA) for ubrogepant for the acute treatment of migraine.

  DOI：

  10.1358/dof.2019.44.11.3035581

文献信息

• PIPERIDINONE CARBOXAMIDE AZAINDANE CGRP RECEPTOR ANTAGONISTS
  申请人：Bell Ian M.

  公开号：US20120122899A1

  公开（公告）日：2012-05-17

  The present invention is directed to piperidinone carboxamide azaindane derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the 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.

  本发明涉及哌啶酮羧酰胺吖啶衍生物，它们是CGRP受体拮抗剂，可用于治疗或预防CGRP参与的疾病，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CGRP参与的这类疾病中使用这些化合物和组合物。
• Process for Making CGRP Receptor Antagonists
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20160130273A1

  公开（公告）日：2016-05-12

  The invention encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine.

  这项发明涵盖了一种制备哌啶酮羧酰胺茚烷和氮杂茚衍生物的新工艺，这些衍生物是CGRP受体拮抗剂，可用于治疗偏头痛。
• Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant
  作者：Nobuyoshi Yasuda、Ed Cleator、Birgit Kosjek、Jianguo Yin、Bangping Xiang、Frank Chen、Shen-Chun Kuo、Kevin Belyk、Peter R. Mullens、Adrian Goodyear、John S. Edwards、Brian Bishop、Scott Ceglia、Justin Belardi、Lushi Tan、Zhiguo J. Song、Lisa DiMichele、Robert Reamer、Fabien L. Cabirol、Weng Lin Tang、Guiquan Liu

  DOI：10.1021/acs.oprd.7b00293

  日期：2017.11.17

  The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an

  描述了一种新的降钙素基因相关肽（CGRP）受体拮抗剂的可扩展的不对称路线的发展。重新定义了两个关键片段的合成，并通过新型化学方法访问了中间体。手性内酰胺2是通过同时介导两个立体中心的酶介导的动态动力学氨基转移反应制备的。酶的进化产生了优化的转氨酶，提供了大于60：1的syn / anti所需的构型。最终的手性中心是通过结晶诱导的非对映异构转变而设定的。不对称螺环化形成第二个片段，手性螺酸中间体3，由一种新型的双季铵化的相转移催化剂催化，并在分离时提供了光学纯的材料。有了这两个片段，描述了通过酰胺键形成以及随后的直接分离来发展其最终结合的过程。所描述的化学物质已用于递送超过100公斤的所需目标物，泛素。
• [EN] PIPERIDINONE CARBOXAMIDE AZAINDANE CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DU RÉCEPTEUR CGRP DE PIPÉRIDINONE CARBOXAMIDE AZAINDANE
  申请人：MERCK SHARP & DOHME

  公开号：WO2012064910A1

  公开（公告）日：2012-05-18

  The present invention is directed to piperidinone carboxamide azaindane derivatives of formula I which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the 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.

  本发明涉及公式I的哌啶酮羧酰胺氮杂吲哚衍生物，其是CGRP受体拮抗剂，用于治疗或预防CGRP参与的疾病，如偏头痛。本发明还涉及包含这些化合物的制药组合物以及使用这些化合物和组合物预防或治疗CGRP参与的疾病。
• [EN] PROCESS FOR MAKING CGRP RECEPTOR ANTAGONISTS<br/>[FR] PROCÉDÉ DE FABRICATION D'ANTAGONISTES DE RÉCEPTEURS DU CGRP
  申请人：MERCK SHARP & DOHME

  公开号：WO2013169348A1

  公开（公告）日：2013-11-14

  The disclosure encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, having less steps and improved yields as compared to previous synthetic methods for making these compounds, which are CGRP receptor antagonists, useful for the treatment of migrane. Conditions for an amide bond formation between an acid and amine include for example reacting the compounds of Formulae B (after salt break) and C with an amide coupling reagent and optionally an additive and an acid and/or a base in a non-reactive solvent.

  该披露涵盖了一种制备哌啶酮羧酰胺吲哌烷和氮杂吲哌烷衍生物的新工艺，与以前制备这些化合物的合成方法相比，步骤更少，产率更高，这些化合物是CGRP受体拮抗剂，可用于治疗偏头痛。酰胺键形成的条件包括例如用酰胺偶联试剂和可选的添加剂和酸和/或碱在非反应性溶剂中反应式B（盐断裂后）和C的化合物。