地加瑞克杂质 | 934016-19-0

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 中文名称: 地加瑞克杂质
• 中文别名: 地加瑞克乙酸盐
• 英文名称: degarelix acetate
• 英文别名: (4S)-N-[4-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2R)-1-amino-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-6-(propan-2-ylamino)hexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[4-(carbamoylamino)phenyl]-1-oxopropan-2-yl]amino]-3-oxopropyl]phenyl]-2,6-dioxo-1,3-diazinane-4-carboxamide;acetic acid
• CAS: 934016-19-0
• 化学式: C₂H₄O₂*C₈₂H₁₀₃ClN₁₈O₁₆
• 分子量: 1692.34
• InChiKey: AUTFSFUMNFDPLH-KYMMNHPFSA-N

物化性质

• 溶解度：
  DMF：30mg/mL； DMSO：30mg/mL；乙醇：0.25mg/mL； PBS（pH 7.2）：10 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  -0.45
• 重原子数：
  121
• 可旋转键数：
  41
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  555
• 氢给体数：
  17
• 氢受体数：
  20

ADMET

代谢

Degarelix的稳定性在大鼠、豚鼠、家兔、狗、猴子和人源的肝微粒体中进行了研究，最长可达60分钟。在家兔、狗、猴子和人源的肝微粒体中未检测到Degarelix的降解。在豚鼠和大鼠的肝微粒体中，Degarelix表现出轻微降解的趋势。进一步在人的肝微粒体中对Degarelix的体外代谢进行了研究，最长可达60分钟。Degarelix的代谢模式在人及动物中相似。Degarelix几乎不是氧化代谢的底物，但可被肽酶降解，生成各种截短肽。在人的血浆中仅观察到一种代谢物低浓度存在，且在大鼠、狗和猴子中也观察到了这种代谢物。

The stability of degarelix was studied in liver microsomes from males in rat, guinea pig, rabbit, dog, monkey, and human, for up to 60 min. No degradation of degarelix was detected in liver microsomes from rabbit, dog, monkey, and human. Tendency to minor degradation of degarelix was seen in liver microsomes from guinea pig and rat. The in vitro metabolism of degarelix was further investigated in human liver microsomes for up to 60 min. The metabolism pattern of degarelix was reported to be similar in humans and animals. Degarelix was virtually no substrate for oxidative metabolism, but was degraded by peptidases with generation of various truncated peptides. Only low concentration of one metabolite was seen in human plasma, and this metabolite was also seen in rats, dogs and monkeys.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

Degarelix治疗已与高达三分之一的患者血清酶升高有关。然而，这些升高通常是轻微和自限性的，即使在不调整剂量的情况下也能解决。ALT值高于正常上限3倍的患者不到1%。偶尔有患者需要因血清酶升高而停药，但在degarelix的初步临床试验中没有报告出现黄疸或明显急性肝损伤的情况。自从它获得批准并更广泛使用以来，尽管它的使用范围有限，但还没有发表过归因于degarelix的明显临床肝损伤的报告。

Degarelix therapy has been associated with serum enzyme elevations in up to one-third of patients. The elevations, however, are generally mild and self-limited, resolving even without dose adjustment. ALT values above 3 times the ULN occur in less than 1% of patients. Occasional patients require drug discontinuation because of serum enzyme elevations, but no instances of liver injury with jaundice or clinically apparent acute liver injury were reported in the initial clinical trials of degarelix. Since its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to degarelix, although its general use has been limited.

来源:LiverTox

毒理性

• 相互作用

既然雄激素剥夺治疗可能会延长QTc间期，那么与已知能延长QTc间期的药物或能诱发尖端扭转型室速的药物（如IA类抗心律失常药物，例如奎尼丁、吡罗昔康；或III类抗心律失常药物，例如胺碘酮、索他洛尔、多非利特、伊布利特）联合使用时应仔细评估，以及甲氧酮、西沙必利、莫西沙星、抗精神病药物等。

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of degarelix with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, cisapride, moxifloxacine, antipsychotics, etc. should be carefully evaluated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

小鼠、大鼠、狗、猴子和人类的血浆蛋白结合使用(3)H- degarelix和超速离心技术进行了测量。动物和人类的血浆结合率约为90%。在大鼠、狗和猴子给药(3)H-degarelix后，研究了放射活性的分布，剂量分别为0.03 mg/kg、0.003 mg/kg和0.0082 mg/kg。在处死和解剖动物后，测量组织的放射性。高浓度主要出现在sc注射部位和排泄器官中。低于血浆的浓度，但在消除期仍高于血浆的浓度通常可见于一些含有LHRH特异性受体的内分泌和生殖器官以及富含网状内皮细胞的器官。没有组织滞留的迹象。

The protein binding in plasma of mouse, rat, dog, monkey, and humans was measured using the (3)H-degarelix and the ultracentrifugation technique. The plasma binding was approximately 90% in animals and humans. Distribution of radioactivity following administration of (3)H-degarelix was studied in rats, dogs and monkeys, doses were respectively 0.03 mg/kg, 0.003 mg/kg and 0.0082 mg/kg. Radioactivity of tissues was measured after sacrifice and necropsy of the animals. High concentrations were mainly seen at the s.c. injection site and in organs of excretion. Lower concentrations, but still higher than those in plasma were generally seen in some organs of the endocrine and reproductive systems most of which contain specific receptors for LHRH, and organs rich in reticuloendothelial cells during the elimination phase. There was no indication of tissue retention.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经皮下注射给药后，(3)H- degarelix的放射活性平衡在 rats、 dogs 和 monkeys 中进行了研究。Degarelix 主要通过尿液以原型排出，并且在动物和人体内通过肝胆途径消除时，会经历连续的肽链降解。

Balance of the radioactivity following SC administration of (3)H-degarelix was studied in rats, dogs and monkeys. Degarelix was mainly excreted unchanged via the urine and was subject to sequential peptidic degradation during its elimination via the hepato-biliary pathway in both animals and man.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

皮下给药后，地加瑞利形成了注射部位的局部储库，导致活性药物释放延缓和延长。从储库中的释放取决于剂量配方中的浓度和剂量体积。此外，在重复剂量研究中，剂量配方中增加的浓度导致了最大血浆浓度（Cmax）和给药间隔内血浆浓度与时间下的面积（AUC）的亚比例增加，低谷血浆浓度（Ctrough）的增加，终末半衰期（t1/2）的增加，从而增加了达到稳态的时间，以及最大血浆浓度时间（Tmax）的增加趋势。

After subcutaneous administration, degarelix forms a local depot at the injection site, leading to retarded and extended release of the active drug. The release from the depot is dependent on the concentration in the dose formulation and the dose volume. Furthermore, in repeat dose studies, increasing concentrations in the dose formulation resulted in sub-proportional increases in maximum plasma concentration (Cmax) and area under plasma concentration vs time in the dosing interval (AUC), an increase in trough plasma concentration (Ctrough), an increase in terminal half-life (t1/2), thus increasing the time to reach steady state, and a tendency of increase in time to maximum plasma concentration (Tmax).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Degarelix在注射部位形成储存库，从储存库中非常缓慢地释放到循环系统中。单次皮下注射240毫克剂量的Degarelix（浓度为40毫克/毫升）后，Degarelix的血浆峰浓度通常在2天内出现。Degarelix的药代动力学行为受到注射溶液中其浓度的影响。大约90%的药物与血浆蛋白结合。在皮下给药后，血浆中没有检测到数量上重要的代谢物。根据体外研究，Degarelix似乎不是细胞色素P-450（CYP）酶或P-糖蛋白转运系统的底物、诱导剂或抑制剂。Degarelix以双相方式消除，在中位终末半衰期约为53天的情况下，240毫克剂量（浓度为40毫克/毫升）的Degarelix在前列腺癌患者中给药后消除。Degarelix在通过肝胆系统时受到肽水解的影响，并主要以肽片段的形式在粪便中排出。大约20-30%的Degarelix剂量通过肾脏消除，这表明大约70-80%通过肝胆系统排出。

Degarelix forms a depot at the injection site following subcutaneous administration from which the drug is very slowly released into circulation. Peak plasma concentrations of degarelix generally occur within 2 days following subcutaneous administration of a single 240 mg dose at a concentration of 40 mg/mL.. The pharmacokinetic behavior of degarelix is strongly influenced by its concentration in the injection solution. Approximately 90% of the drug is bound to plasma proteins. No quantitatively substantial metabolites have been detected in plasma following subcutaneous adminstration. Degarelix does not appear to be a substrate, inducer, or inhibitor of the cytochrome P-450 (CYP) enzyme or P-glycoprotein transport systems based on in vitro studies. Degarelix is eliminated in a biphasic manner, with a median terminal half-life of about 53 days following subcutaneous administration of a 240 mg dose at a concentration of 40 mg/mL in prostate cancer patients. Degarelix is subject to peptide hydrolysis during its passage through the hepatobiliary system and is mainly excreted as peptide fragments in feces. Approximately 20-30% of a given dose of degarelix is renally eliminated, suggesting that approximately 70-80% is excreted via the hepatobiliary system.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  -20°C，密闭保存，干燥环境

制备方法与用途

Degarelix是一种合成的gonadotropin-releasing hormone受体(GNRHR)拮抗剂，在表达人类受体的HEK293细胞中其IC50值为3纳摩尔。

反应信息

• 作为产物：
  描述：

  Fmoc-L-亮氨酸 、 N-FMOC-N’-BOC-N’-异丙基-L-赖氨酸 、 N-[芴甲氧羰基]-4-[[[(4S)-六氢-2,6-二氧代-4-嘧啶基]羰基]氨基]-L-苯丙氨酸 、 Fmoc-D-Aph(tBu-Cbm)-OH 、 Fmoc-L-脯氨酸 、 FMOC-O-叔丁基-L-丝氨酸 、 9-fluorenylmethyloxycarbonyl-D-2-naphthylalanine 、 乙酸酐 、 Fmoc-D-丙氨酸 、 FMOC-D-4-氯苯丙氨酸 、 N-(9-芴甲氧羰基)-3-吡啶基-D-丙氨酸 在 1-羟基苯并三唑 、 N,N'-二异丙基碳二亚胺 、 二乙烯三胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 地加瑞克杂质
  参考文献：
  名称：

  Process for the preparation of Degarelix acetate and Degarelix acetate-mannitol premix

  摘要：

  提供了制备地加雷利司醋酸盐的方法，包括以下步骤：提供适当的树脂；用二乙二胺溶液去保护树脂；依次用不同的Fmoc保护氨基酸与去保护的树脂反应；以逐步方式用二乙二胺溶液去保护每个序列中的氨基酸，得到地加雷利司粗化合物；并纯化地加雷利司粗化合物，得到药用可接受的地加雷利司醋酸盐。还提供了制备地加雷利司醋酸盐-甘露醇预混物及由此得到的地加雷利司醋酸盐-甘露醇预混物的方法。

  公开号：

  US20210094984A1

文献信息

• Process for the preparation of Degarelix acetate and Degarelix acetate-mannitol premix
  申请人：RK Pharma Solutions LLC

  公开号：US20210094984A1

  公开（公告）日：2021-04-01

  Methods for preparing degarelix acetate are provided that include the steps of providing a suitable resin; deprotecting the resin with a diethylenetriamine solution; reacting sequentially the deprotected resin with different Fmoc protected amino acids ;deprotecting the amino acid in each sequence with a diethylenetriamine solution in a stepwise fashion to yield a degarelix crude compound; and purifying the degarelix crude compound to yield pharmaceutically acceptable degarelix acetate. Methods of preparing degarelix acetate-mannitol premix and the resulting degarelix acetate-mannitol premix are also provided

  提供了制备地加雷利司醋酸盐的方法，包括以下步骤：提供适当的树脂；用二乙二胺溶液去保护树脂；依次用不同的Fmoc保护氨基酸与去保护的树脂反应；以逐步方式用二乙二胺溶液去保护每个序列中的氨基酸，得到地加雷利司粗化合物；并纯化地加雷利司粗化合物，得到药用可接受的地加雷利司醋酸盐。还提供了制备地加雷利司醋酸盐-甘露醇预混物及由此得到的地加雷利司醋酸盐-甘露醇预混物的方法。