恶拉戈利 | 834153-87-6

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 促性激素类药
• 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: 恶拉戈利
• 中文别名: 4-[[(1R)-2-[5-(2-氟-3-甲氧基苯基)-3-[[2-氟-6-(三氟甲基)苯基]甲基]-3,6-二氢-4-甲基-2,6-二氧代-1(2H)-嘧啶基]-1-苯乙基]氨基]丁酸；噁拉戈利；4-[[(1R)-2-[5-(2-氟-3-甲氧基苯基)-3-[[2-氟-6-(三氟甲基)苯基]甲基]-4-甲基-2,6-二氧嘧啶-1-基-1-苯乙基]氨基]丁酸
• 英文名称: elagolix
• 英文别名: 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid；4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoic acid
• CAS: 834153-87-6
• 化学式: C₃₂H₃₀F₅N₃O₅
• 分子量: 631.599
• InChiKey: HEAUOKZIVMZVQL-VWLOTQADSA-N

物化性质

• 沸点：
  728.6±70.0 °C(Predicted)
• 密度：
  1.350
• 溶解度：
  二甲基亚砜：≥100 mg/ml（158.33mM）

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  45
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  99.2
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

代谢

Elagolix 主要通过 CYP3A 家族的同工酶代谢，尽管它也参与了与 CYP2D6、CYP2C8 和尿苷葡萄糖醛酸基转移酶 (UGTs) 酶的次要代谢途径。Elagolix 的主要代谢物，被称为 NBI-61962（R-(+)-4-{2-[5-(2-氟-3-羟基-苯基)-3-(2-氟-6-三氟甲基-苄基)-4-甲基-2,6-二氧代-3,6-二氢-2H-嘧啶-1-基]-1-苯基-乙氨基}-丁酸酯），由于其血浆暴露量低，并且观察到的效力远低于母体 Elagolix 化合物（Ki 值为 3.5，而 Elagolix 为 0.9 nM），因此认为它不具有显著的生物活性。

Elagolix is predominantly metabolized by the CYP3A family of isoenzymes despite participating in minor metabolic pathways with the CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) enzymes as well. The primary metabolite of elagolix, referred to as NBI-61962 (R-(+)-4-{2-[5-(2-fluoro-3-hydroxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino}-butyrate), is not believed to possess any significant biologic activity due to its low plasma exposure and an observed potency that is exceptionally less than the parent elagolix compound (Ki value of 3.5 compared to 0.9 nM).

来源:DrugBank

毒理性

• 肝毒性

Elagolix疗法在少数患者中与血清酶水平升高有关，使用150毫克每日一次时，ALT升高超过正常上限3倍的比例为0.2%，而使用200毫克每日两次时为1.1%。然而，这些升高通常是轻微和自限性的，即使不调整剂量也能自行解决。偶尔有患者因血清酶升高而需要停药，但在注册前的对照试验中没有出现黄疸或临床上明显的急性肝损伤的实例。自从其获得批准并更广泛使用以来，没有公开发表的报告将临床上明显的肝损伤归因于elagolix。

Elagolix therapy has been associated with serum enzyme elevations in a small proportion of patients, rates of ALT elevations above 3 times the upper limit of normal being 0.2% with 150 mg once daily and 1.1% with 200 mg twice daily. The elevations, however, are generally mild and self-limited, resolving even without dose adjustment. Occasional patients require drug discontinuation because of serum enzyme elevations, but there were no instances of liver injury with jaundice or clinically apparent acute liver injury in the preregistration-controlled trials. Since its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to elagolix.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概述：目前尚无关于哺乳期间使用艾拉戈利克斯（elagolix）的信息。艾拉戈利克斯80%与蛋白结合，半衰期为4到6小时，它是一种肽类物质，很可能在婴儿的胃肠道中被消化，因此不太可能达到婴儿血清中的临床重要水平。然而，由于缺乏关于哺乳期间使用艾拉戈利克斯的信息，应该谨慎使用，特别是在哺乳新生儿或早产儿时。 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:No information is available on the use of elagolix during breastfeeding. Elagolix is 80% protein bound, has a half-life of 4 to 6 hours, and it is a peptide that is likely digested in the infant's gastrointestinal tract, so it is unlikely to reach clinically important levels in infant serum. However, because no information is available on the use of elagolix during breastfeeding caution should be used, especially while nursing a newborn or preterm infant. ◉ 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

• 蛋白质结合

伊拉戈里克斯与人类血浆蛋白的结合率已记录为80%。

The percentage bound to human plasma proteins for elagolix has been documented as 80%.

来源:DrugBank

吸收、分配和排泄

• 吸收

艾拉戈利克斯的Tmax报告为1.0小时。高脂肪餐（相对于空腹）的影响可能导致AUC和Cmax分别减少多达24%和36%。

The Tmax of elagolix is reported as being 1.0 hours. The effect of a high-fat meal (relative to fasting) can result in a reduction of the AUC and Cmax by as much as 24% and 36%, respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

艾拉戈利克斯主要通过肝脏代谢消除。

The primary route of elimination of elagolix is via hepatic metabolism.

来源:DrugBank

吸收、分配和排泄

• 分布容积

Elagolix 在稳态下的表观分布容积 (Vdss/F) 对于每日150毫克的方案报告为1674，而对于每日两次200毫克的方案报告为881。

The apparent volume of distribution at steady state (Vdss/F) of elagolix is reported to be 1674 for a 150 mg daily regimen and 881 for a 200 mg twice daily regimen.

来源:DrugBank

吸收、分配和排泄

• 清除

Elagolix的口服清除率（CL/F）为123 L/小时，对于每日一次150毫克的方案，以及144 L/小时，对于每日两次200毫克的方案。

The oral clearance (CL/F) of elagolix is 123 L/hr for a 150 mg once daily regimen and 144 L/hr for a 200 mg twice daily regimen.

来源:DrugBank

安全信息

• 储存条件：
  2-8℃

制备方法与用途

理化性质

恶拉戈利（elagolix）是由艾伯维（AbbVie）与合作伙伴Neurocrine Biosciences 共同研发的一种口服GnRH拮抗剂。它通过抑制脑垂体促性腺释放激素受体，从而降低血循环中的性腺激素水平。

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
  ——	methyl (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate	1092070-97-7	C33H32F5N3O5	645.626
  (R)-4-((2-(5-(2-氟-3-甲氧苯基)-3-(2-氟-6-(三氟甲基)苯甲基)-4-甲基-2,6-二氧代-2,3-二氢嘧啶-1(6H)–基)-1-苯乙基)氨基)正丁酸乙酯	ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)butanoate	832720-84-0	C34H34F5N3O5	659.653
  ——	(R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione	830346-50-4	C28H24F5N3O3	545.509
  5-(2-氟-3-甲氧基苯基)-1-[[2-氟-6-(三氟甲基)苯基]甲基]-6-甲基-2,4(1H,3H)-嘧啶二酮	5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione	1150560-59-0	C20H15F5N2O3	426.343
  5-溴-1-(2-氟-6-(三氟甲基)苄基)-4-羟基-6-甲基嘧啶-2(1H)-酮	5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione	830346-48-0	C13H9BrF4N2O2	381.124
  1-[2-氟-6-(三氟甲基)苄基]-5-碘-6-甲基嘧啶-2,4(1h,3h)-二酮	1-[2-fluoro-6-(trifluoromethyl)benzyl]-5-iodo-6-methyl-3H-pyrimidine-2,4-dione	1150560-54-5	C13H9F4IN2O2	428.125

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	(R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethyl-N-methylamino}butyric acid	——	C33H32F5N3O5	645.626

反应信息

• 作为反应物：
  描述：

  恶拉戈利 在 磷酸 作用下， 以 乙酸乙酯 为溶剂， 以93.6%的产率得到elagolix phosphoric acid salt
  参考文献：
  名称：

  依拉戈利及其钠盐的中间体及其盐的制备方法和应用

  摘要：

  本发明申请依拉戈利及其钠盐的中间体及其盐的制备方法和应用，涉及医药品中间体及其制备方法和应用。本发明提供所提供工艺内容该盐型制备工艺简单，成本低廉，环境友好。对于依拉戈利及其中间体的纯化提供了新的方法可以有效控制药物活性成分中的杂质含量，所得成盐后的化合物，稳定性更好，便于保存。

  公开号：

  CN109651171A
• 作为产物：
  描述：

  methyl (R)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate 在 水 、 lithium hydroxide 作用下， 以 甲醇 为溶剂， 生成 恶拉戈利
  参考文献：
  名称：

  Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

  摘要：

  The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

  DOI：

  10.1021/jm8006454

文献信息

• [EN] PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES<br/>[FR] PROCÉDÉS DE PRÉPARATION DE DÉRIVÉS D'URACILE
  申请人：NEUROCRINE BIOSCIENCES INC

  公开号：WO2009062087A1

  公开（公告）日：2009-05-14

  The present invention relates to processes and intermediates for preparing Gonadotropin-Releasing Hormone (GnRH) receptor antagonists of structure (VI); and stereoisomers and pharmaceutically acceptable salts thereof.

  本发明涉及制备促性腺激素释放激素（GnRH）受体拮抗剂结构（VI）的过程和中间体，以及其立体异构体和药用盐。
• Tetrazolones as a Carboxylic Acid Bioisosteres
  申请人：RIGEL PHARMACEUTICALS, INC.

  公开号：US20160213648A1

  公开（公告）日：2016-07-28

  The present disclosure provides compounds that include a tetrazolone derivative of a carboxyl group of an active agent. This disclosure also relates to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, and processes for preparing these compounds.

  本公开提供了包括活性剂羧基的四唑酮衍生物的化合物。本公开还涉及包括这些化合物的药物组合物，使用这些化合物治疗各种疾病和疾病的方法，以及制备这些化合物的过程。
• [EN] PYRIMIDINE-2, 4-DIONE DERIVATIVES AS GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS<br/>[FR] DERIVES DE PYRIMIDINE-2, 4-DIONE UTILISES COMME ANTAGONISTES DU RECEPTEUR D'HORMONE LIBERANT DE LA GONADOTROPHINE
  申请人：NEUROCRINE BIOSCIENCES INC

  公开号：WO2005007165A1

  公开（公告）日：2005-01-27

  GnRH receptor antagonists are disclosed that have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein R1a, R1b, R1c, R2a, R2b, R3, R4, R5, R6 and X are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

  GnRH受体拮抗剂被披露，对男性和女性的各种与性激素相关的疾病具有治疗作用。本发明的化合物具有以下结构：其中R1a、R1b、R1c、R2a、R2b、R3、R4、R5、R6和X的定义如本文所述，包括立体异构体、前药和其药用可接受盐。还披露了含有本发明化合物的组合物与药用可接受载体的组合物，以及与在需要时对抗性腺激素释放激素的使用方法。
• 一种制备恶拉戈利的中间体的方法
  申请人：上海医药工业研究院

  公开号：CN110498771B

  公开（公告）日：2023-02-17

  本发明涉及一种制备恶拉戈利的中间体和方法。具体地，本发明公开了一种制备恶拉戈利关键中间体化合物E8的制备方法，以及用于制备该中间体化合物E8的化合物E4等化合物，该方法操作简便、条件温和，非常适合工业化生产。
• 氘代噁拉戈利衍生物及其用途
  申请人：安帝康（无锡）生物科技有限公司

  公开号：CN108129400B

  公开（公告）日：2021-10-15

  本发明公开了一组氘代噁拉戈利衍生物的方法，作为GnRH受体拮抗剂，其具有治疗男性与女性的性激素相关疾病状态的用途。本发明还公开了包含与药物可接受的载体组合的本发明化合物的组合物，以及使用该组合物来拮抗个体内的促性腺激素释放激素的方法。