[(7R)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate | 115956-12-2

• 物质功能分类: 原料药 - 消化系统用药 - 止吐催吐药
• 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
• 英文名称: [(7R)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate
• 英文别名: (3R)-10-oxo-8-azatricyclo[5.3.1.03,8]undec-5-yl 1H-indole-3-carboxylate
• CAS: 115956-12-2
• 化学式: C₁₉H₂₀N₂O₃
• 分子量: 324.4
• InChiKey: UKTAZPQNNNJVKR-DBBXXEFVSA-N

物化性质

• 熔点：
  278 ºC
• 沸点：
  535.1±50.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少量）、DMSO（少量）、甲醇（少量）
• 物理描述：
  Solid
• 蒸汽压力：
  1.7X10-9 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  62.4
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

生物转化是肝脏介导的，并且是完整的，主要转化为活性代谢物氢多拉赛吨（通过普遍存在的酶，羰基还原酶）。进一步的羟基化由细胞色素P450 CYP2D6介导，而进一步的N-氧化则由CYP3A和黄素单加氧酶共同介导。

Biotransformation /is/ hepatic and complete, mainly to the active metabolite hydrodolasetron (by means of the ubiquitous enzyme, carbonyl reductase). Further hydroxylation is mediated by cytochrome P450 CYP2D6 and further N-oxidation by both CYP3A and flavin monooxygenase.

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸多拉司琼的代谢在六名健康男性志愿者中进行研究，这些志愿者单次口服了300毫克的[14C]多拉司琼盐酸。平均来看，总放射活性的59%在尿液中回收，25%在粪便中。在给药后长达36小时内收集的尿样中定量了代谢物。还原型多拉司琼（RD）在尿液中的剂量占17-54%。RD的羟基代谢物在尿液中的剂量不超过9%。剩余的大部分尿液中放射性活性是由RD和羟基RD的缀合代谢物组成。对选定的尿液样本进行水解显示，RD的葡萄糖苷酸是尿液中含量最丰富的缀合物。尿液中有一小部分剂量（<1%）被确认为RD的N-氧化物。通过手性HPLC分析尿液样本表明，RD的R(+):S(-)比例大约为9:1。

The metabolism of dolasetron mesylate was studied in six healthy male volunteers who were given a single 300 mg oral dose of [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in the urine and 25% in the feces. Metabolites were quantitated in urine samples taken up to 36 hr post-dose. Reduced dolasetron (RD) accounted for 17-54% of the dose in urine. Hydroxylated metabolites of RD made up no more than 9% of the dose in urine. Most of the remaining urinary radioactivity consisted of conjugated metabolites of RD and hydroxy RD. Hydrolysis of selected urine samples showed that the glucuronide of RD was the most abundant conjugate in urine. A small percentage of the dose (< 1%) in urine was identified as the N-oxide of RD. Analysis of urine samples by chiral HPLC indicated that the R(+):S(-) ratio of RD was approximately 9:1.

来源:Hazardous Substances Data Bank (HSDB)

代谢

多拉塞曲恩（dolasetron）或MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-八氢-3-氧代-2,6-亚甲基-2H-喹诺里嗪-8-基-1H-吲哚-3-羧酸甲烷磺酸盐]的代谢初始步骤是还原前手性羰基，产生手性二级醇“还原多拉塞曲恩”。已经开发并使用了一种高效液相色谱法（HPLC），使用手性柱来分离还原多拉塞曲恩对映体，并用于测量在大鼠、狗和人体内给予多拉塞曲恩后尿液中的对映体。在所有情况下，还原对(+)-(R)-对映体具有对映选择性，尽管狗在静脉给药后显示出较低的对映选择性。在大鼠和人体尿液中，大约找到90:10的对映体比率(+/-)。由于初步研究表明，人肝微粒体对对映体醇的氧化只表现出轻微的对映选择性，因此进一步代谢对此对映体比率的影响被认为很小。通过体外研究进一步证实了立体选择性还原在人体内的作用，其中多拉塞曲恩与人全血一起孵化。在人全血中形成的还原多拉塞曲恩的对映体组成与给予多拉塞曲恩后在人尿液中发现的相同。对映选择性不是由于对映体在吸收、分布、代谢或排泄方面的差异，因为静脉或口服给予大鼠和狗消旋还原多拉塞曲恩后，在尿液中回收的基本上与给药剂量的对映体组成相同。幸运的是，(+)-(R)-对映体主要通过羰基还原酶形成，因为它是最活跃的化合物。

The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. It is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概述：关于哺乳期间使用多拉赛曲林的资料很少。在获得更多数据之前，哺乳期间应谨慎使用多拉赛曲林。可能更倾向于使用另一种药物。 对哺乳婴儿的影响：一项双盲研究随机选取了160名在脊髓麻醉下接受选择性剖宫产的妇女，分别接受患者控制静脉镇痛的舒芬太尼（标准治疗）或标准治疗加上右美托咪定。右美托咪定以5微克/公斤给药，随后以0.5微克/公斤/小时的速度持续输注至手术结束。后一组患者在术后2天内接受右美托咪定加舒芬太尼的患者控制静脉镇痛。两组都将25毫克的多拉赛曲林添加到患者控制静脉镇痛溶液中，所有母亲都给婴儿哺乳。两组在分娩后第1天和第2天的婴儿行为神经学评估都良好。[1] 对泌乳和母乳的影响：一项双盲研究随机选取了160名在脊髓麻醉下接受选择性剖宫产的妇女，分别接受患者控制静脉镇痛的舒芬太尼（标准治疗）或标准治疗加上右美托咪定。右美托咪定以5微克/公斤给药，随后以0.5微克/公斤/小时的速度持续输注至手术结束。后一组患者在术后2天内接受右美托咪定加舒芬太尼的患者控制静脉镇痛。两组都将25毫克的多拉赛曲林添加到患者控制静脉镇痛溶液中。接受右美托咪定的患者第一次泌乳的时间更短（28小时对34小时），更快实现纯母乳喂养（8天对11天），且在分娩后第二天有更多的乳汁。[1]

◉ Summary of Use during Lactation:Little information is available on the use of dolasetron during breastfeeding. Until more data become available, dolasetron should be used with caution during breastfeeding. An alternate drug may be preferred. ◉ Effects in Breastfed Infants:A double-blind study randomized 160 women receiving an elective cesarean section under spinal anesthesia to receive either sufentanil for patient-controlled intravenous analgesia (standard care) or standard care plus dexmedetomidine. Dexmedetomidine was given as 5 mcg/kg, followed by a continuous infusion of 0.5 mcg/kg per hour until the end of surgery. Patient in this latter group received dexmedetomidine plus sufentanil for patient-controlled intravenous analgesia postoperatively for 2 days. Both groups had 25 mg of dolasetron added to the patient-controlled intravenous analgesia solution and all mothers breastfed their infants. Both groups had good neonatal behavioral neurological assessments on days 1 and 2 postpartum.[1] ◉ Effects on Lactation and Breastmilk:A double-blind study randomized 160 women receiving an elective cesarean section under spinal anesthesia to receive either sufentanil for patient-controlled intravenous analgesia (standard care) or standard care plus dexmedetomidine. Dexmedetomidine was given as 5 mcg/kg, followed by a continuous infusion of 0.5 mcg/kg per hour until the end of surgery. Patient in this latter group received dexmedetomidine plus sufentanil for patient-controlled intravenous analgesia postoperatively for 2 days. Both groups had 25 mg of dolasetron added to the patient-controlled intravenous analgesia solution. Patients who received dexmedetomidine had a shorter time to the first lactation (28 vs 34 hours), achieved exclusive breastfeeding sooner (8 vs 11 days) and had a greater amount of milk on the second day postpartum.[1]

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

同时使用西咪替丁（一种非选择性细胞色素P450酶抑制剂）和度洛赛琼7天，被发现会使羟度洛赛琼血药浓度增加24%。

Concurrent use of cimetidine, which is a nonselective cytochrome P450 enzyme inhibitor, with dolasetron for 7 days has been found to result in a 24% increase in hydrodolasetron blood concentrations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

静脉注射多拉塞曲林和阿替洛尔同时使用已被发现会使多拉塞曲林的清除率降低27%。

Concurrent use of intravenous dolasetron and atenolol has been found to result in a 27% decrease in clearance hydrodolasetron.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道（如需要，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，协助通气。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）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的呕吐反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干性无菌敷料覆盖皮肤烧伤……。/毒物A和B/

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

高级治疗：对于昏迷、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受体激动剂，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）或乳酸钠林格氏液。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……。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……。/毒物A和B/

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

口服多拉塞曲酮吸收良好，但由于迅速且完全代谢为羟基多拉塞曲酮，母药在血浆中很少被检测到。

Orally-administered dolasetron is well absorbed, but the parent drug is rarely detected in plasma due to rapid and complete metabolism to hydrodolasetron.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服多拉赛曲静脉注射溶液和片剂具有生物等效性。

Orally-administered dolasetron intravenous solution and tablets are bioequivalent.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服多拉赛龙的明显绝对生物利用度大约为75%。食物不会影响口服多拉赛龙的生物利用度。

The apparent absolute bioavailability of oral dolasetron is approximately 75%. Food does not affect the bioavailability of dolasetron taken by mouth.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服给药后达峰时间约为1小时，静脉注射后达峰时间为0.6小时。

Time to peak plasma concentration /for hydrodolasetron/ following oral administration /was/ approximately 1 hour and following intravenous injection /was/ 0.6 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• WGK Germany：
  3
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  Refrigerator

制备方法与用途

理化性质

多拉司琼是一种选择性5-HT3受体拮抗剂，其作用类似于昂丹司琼和格拉司琼。该药物口服或静脉注射均可有效防止癌症化疗后引起的恶心。其具体理化参数如下：

• 密度：1.37 g/cm³
• 熔点：278 ºC
• 沸点：535.1ºC（在760 mmHg下）
• 闪点：277.4ºC
• 折射率：1.76
• 水溶解性：可溶
• 蒸汽压：4.08E-10mmHg（在25°C时）

生产方法

多拉司琼的合成过程包括以下几个步骤：

1. 以环戊烯羧酸乙酯(Ⅰ)为原料，在四氧化锇催化下用N-甲基吗啉-N-氧化物进行氧化，生成二醇(Ⅱ)。
2. 再在过碘酸钠作用下分裂为二醛(Ⅲ)，其水溶液在pH值4时通过Robinson-Schoepf反应转化为双环化物(Ⅳ)。
3. (Ⅳ)再用硼氢化钠还原为醇(Ⅴ)，与二氢吡喃反应形成四氢呋喃醚(Ⅵ)，以保护形成的羟基。
4. 然后转化为三环化物(Ⅶ)，接着在四氟硼银存在下，和酰氯(Ⅷ)反应，最终酰化得到多拉司琼。

应用及发展前景

作为5-HT3受体拮抗剂，多拉司琼主要应用于治疗由化疗、放疗引起的术后恶心及呕吐。其止吐作用较盐酸阿扎司琼（azasetron hydrochloride）和盐酸格拉司琼（granisetron hydrochloride）等其他5-HT3受体拮抗剂更强。

生物活性

多拉司琼(Dolasetron，MDL-73147)是一种有效的5-HT3受体拮抗剂，具有用于化疗引起的恶心和呕吐治疗的潜力。

靶点

多拉司琼主要作用于5-HT₃受体。

反应信息

• 作为反应物：
  描述：

  [(7R)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate 在 甲醇 、 sodium methylate 作用下， 生成 methyl 2,3-anhydro-β-D-ribopyranoside
  参考文献：
  名称：

  212.β-甲基阿拉伯糖苷的反应。第二部分 3：4-丙酮β-甲基阿拉伯糖基吡喃糖苷。3：4-二甲基阿拉伯糖。阿拉伯糖向木糖的转化

  摘要：

  DOI：

  10.1039/jr9460000990
• 作为产物：
  描述：

  methyl 3,4-O-isopropylidene-β-L-arabinopyranoside 在 吡啶 、 盐酸 作用下， 生成 [(7R)-10-oxo-8-azatricyclo[5.3.1.03,8]undecan-5-yl] 1H-indole-3-carboxylate
  参考文献：
  名称：

  212.β-甲基阿拉伯糖苷的反应。第二部分 3：4-丙酮β-甲基阿拉伯糖基吡喃糖苷。3：4-二甲基阿拉伯糖。阿拉伯糖向木糖的转化

  摘要：

  DOI：

  10.1039/jr9460000990

文献信息

• Muscarinic combinations and their use for combating hypocholinergic disorders of the central nervous system
  申请人：Chase Pharmaceuticals Corporation

  公开号：US10307409B2

  公开（公告）日：2019-06-04

  A combination of a muscarinic cholinergic receptor agonist, a non-anticholinergic antiemetic agent and a non-selective, peripheral anticholinergic agent for the treatment of hypocholinergic disorders of the central nervous system.

  一种毒蕈碱胆碱能受体激动剂、一种非抗胆碱能止吐药和一种非选择性外周抗胆碱能药的复方制剂，用于治疗中枢神经系统的低胆碱能紊乱。
• Memantine combinations and use
  申请人：CHASE PHARMACEUTICALS CORPORATION

  公开号：US10548855B2

  公开（公告）日：2020-02-04

  A pharmaceutical combination of memantine and a non-anticholinergic antiemetic agent for the treatment of hypocholinergic disorders in further combination with high doses of donepezil and with solifenacin, and kits comprising said combination. A pharmaceutical combination of memantine and solifenacin for the treatment of hypocholinergic disorders, including Alzheimer type dementia, in further combination with high doses of donepezil, and kits comprising said combination.

  一种治疗低胆碱能紊乱的美金刚和非抗胆碱能止吐药的药物组合，进一步与大剂量多奈哌齐和索利芬那新组合，以及包含所述组合的试剂盒。一种美金刚和索利芬那新的药物组合，用于治疗低胆碱能疾病，包括阿尔茨海默型痴呆，进一步与大剂量多奈哌齐组合，以及包含所述组合的试剂盒。
• Compositions and methods for treating synucleinopathies
  申请人：CHASE THERAPEUTICS CORPORATION

  公开号：US10799484B2

  公开（公告）日：2020-10-13

  The present invention describes the use of a 5HT3-antagonist, in combination with a 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, to reduce adverse effects and to facilitate the neuroprotective treatment of a patient suffering from a synucleinopathic disorder to enable a therapeutically effective 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine daily dose without the dose-limiting adverse effects caused by pramipexole when administered alone.

  本发明描述了5HT3-拮抗剂与6-丙基氨基-4,5,6,7-四氢-1,3-苯并噻唑-2-胺的联合使用、以减少不良反应，促进对患有突触素病症的患者进行神经保护性治疗，从而使 6-丙基氨基-4,5,6,7-四氢-1,3-苯并噻唑-2-胺的每日剂量具有治疗效果，而不会产生普拉克索单独给药时的剂量限制性不良反应。
• MUSCARINIC COMBINATION AND ITS USE FOR COMBATING HYPOCHOLINERGIC DISORDERS OF THE CENTRAL NERVOUS SYSTEM
  申请人：Chase Pharmaceuticals Corporation

  公开号：EP3347011A1

  公开（公告）日：2018-07-18
• MUSCARINIC COMBINATIONS AND THEIR USE FOR COMBATING HYPOCHOLINERGIC DISORDERS OF THE CENTRAL NERVOUS SYSTEM
  申请人：Chase Pharmaceuticals Corporation

  公开号：EP3347012A1

  公开（公告）日：2018-07-18