2'-甲基螺[4-氮杂双环[2.2.2]辛烷-2,5'-[1,3]恶噻戊环] | 124620-88-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 中文名称: 2'-甲基螺[4-氮杂双环[2.2.2]辛烷-2,5'-[1,3]恶噻戊环]
• 英文名称: 2-methylspiro(1,3-oxathiolane-5,3'-quinuclidine)
• 英文别名: 2-methylspiro(1,3-oxathiolan-5,3')quinuclidine；2-methylspiro(1,3-oxathiolane-5,3')quiniclidin；2-Methylspiro[1,3-oxathiolane-5,3'-1-azabicyclo[2.2.2]octane]
• CAS: 124620-88-8
• 化学式: C₁₀H₁₇NOS
• 分子量: 199.317
• InChiKey: WUTYZMFRCNBCHQ-UHFFFAOYSA-N

物化性质

• 沸点：
  308.5±42.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 溶解度：
  In water, 4.1X10+4 mg/L at 25 °C /Estimated/
• 解离常数：
  pKa= 9.78 /Estimated/

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  37.8
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

药代动力学和代谢对cevimeline进行了研究，在对6名健康志愿者单次口服给药14(C)-cevimeline后进行了研究。...在给药后24小时内，尿液中毒物代谢产物的平均回收率分别为cevimeline 16.0%，cevimeline trans-sulfoxide 35.8%，cevimeline cis-sulfoxide 8.7%，cevimeline N-oxide 4.1%，另外，还检测到两种未知代谢物UK-1和UK-2，分别为14.6%和7.7%。LC/MS分析和水解研究揭示，UK-1和UK-2分别是cevimeline和cevimeline trans-sulfoxide的葡萄糖醛酸苷结合物。

The pharmacokinetics and metabolism cevimeline were investigated in six healthy volunteers after a single oral administration of 14(C)-cevimeline. ... The mean recoveries of the metabolites in urine at 24 hr after administration were 16.0% for cevimeline, 35.8% for cevimeline trans-sulfoxide, 8.7% for cevimeline cis-sulfoxide, 4.1% for cevimeline N-oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6% and 7.7%, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of cevimeline and cevimeline trans-sulfoxide, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

同工酶CYP2D6和CYP3A3/4负责代谢西维美林。24小时后，86.7%的剂量被回收（16.0%未改变，44.5%为顺式和反式亚砜，22.3%的剂量作为葡萄糖醛酸苷和4%的剂量作为西维美林的N-氧化物）。大约8%的反式亚砜代谢物随后转化为相应的葡萄糖醛酸苷并被排出。西维美林未抑制细胞色素P450同工酶1A2、2A6、2C9、2C19、2D6、2E1和3A4。

Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline. After 24 hours, 86.7% of the dose was recovered (16.0% unchanged, 44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate and 4% of the dose as N-oxide of cevimeline). Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在赛维米林的上市前试验中，血清酶水平升高的情况并不比安慰剂更常见，并且没有急性肝损伤的报告。自从获得许可并更广泛使用以来，赛维米林一直未与临床上明显的肝损伤案例有关联。

In prelicensure trials of cevimeline, serum enzyme elevations were no more frequent than with placebo and there were no reports of acute liver injury. Since licensure and more wide scale use, cevimeline has remained free of association with instances of clinically apparent liver injury.

来源:LiverTox

毒理性

• 相互作用

Cevimeline 应谨慎给予正在服用β-肾上腺素能拮抗剂的患者，因为可能会出现传导障碍。与 Cevimeline 同时使用的具有副交感神经刺激效应的药物可能会产生相加效应。Cevimeline 可能会干扰同时使用的药物所期望的 antimuscarinic 效应。抑制 CYP2D6 和 CYP3A3/4 的药物也会抑制 Cevimeline 的代谢。根据以往的经验，应谨慎使用 Cevimeline 于已知或疑似 CYP2D6 活性缺乏的个体，因为他们可能会有更高的不良事件风险。

Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevimeline can be expected to have additive effects. Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly. Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

治疗过量：注意：尚不清楚cevimeline是否可通过透析清除。特定治疗：治疗cevimeline中毒的症状和体征应与其他毒蕈碱型、胆碱能激动剂指示的治疗方式一致。如果医学上有指征，可以使用抗胆碱能药物阿托品作为紧急用途的解毒剂。如果医学上有指征，在出现严重心血管抑制或支气管收缩的情况下，肾上腺素也可能有价值。支持性护理：应启动一般支持性措施。确认或怀疑故意过量的患者应转诊进行精神科咨询。

Treatment of overdose: Note: It is not known whether cevimeline is dialyzable. Specific treatment: Treatment of signs and symptoms of cevimeline toxicity should occur in a manner consistent with that indicated for other muscarinic, cholinergic agonists. If medically indicated, atropine, an anti-cholinergic agent, may be of value as an antidote for emergency use. If medically indicated, epinephrine may also be of value in the presence of severe cardiovascular depression or bronchoconstriction. Supportive care: General supportive measures should be initiated. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

毒性表现为副交感神经刺激效应的加剧。这些可能包括头痛、视觉障碍、流泪、出汗、呼吸困难、胃肠道痉挛、恶心、呕吐、腹泻、房室传导阻滞、心动过速、心动过缓、低血压、休克、精神混乱、心律失常和震颤。

/SIGNS AND SYMPTOMS/ Toxicity is characterized by exaggeration of parasympathomimetic effects. These may include headache, visual disturbance, lacrimation, sweating, respiratory distress, GI spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, shock, mental confusion, cardiac arrhythmias, and tremors.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

体征和症状：心脏传导和/或心率改变的风险。患有临床重要心血管疾病的病人可能无法补偿cevimeline引起的血流动力学或心率的短暂变化。在有心血管疾病史（例如，心绞痛、心肌梗死）的病人中谨慎使用，并应在密切的医疗监督下使用。

/SIGNS AND SYMPTOMS/ Risk of altered cardiac conduction and/or heart rate. Patients with clinically important cardiovascular disease may be unable to compensate for transient changes in hemodynamics or heart rhythm induced by cevimeline. Use with caution and under close medical supervision in patients with a history of cardiovascular disease (e.g., angina pectoris, myocardial infarction).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：尿液：97%。粪便：0.5%。

Elimination: Urine: 97%. Feces: 0.5%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这种药物是否会在人类乳汁中分泌尚不清楚。

It is not known whether this drug is secreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在服用单个30毫克胶囊后，cevimeline迅速被吸收，达到平均峰值浓度的时间为1.5到2小时。在多次给药后，未观察到活性药物或其代谢物的积累。与食物同服时，吸收速率会降低，空腹时T MAX为1.53小时，餐后T MAX为2.86小时；峰值浓度降低17.3%。在临床剂量范围内的单次口服剂量与剂量成正比。Cevimeline的分布体积约为6L/kg，并且不到20%与人血浆蛋白结合。这表明cevimeline广泛地与组织结合；然而，具体的结合位点尚不清楚。

After administration of a single 30 mg capsule, cevimeline was rapidly absorbed with a mean time to peak concentration of 1.5 to 2 hours. No accumulation of active drug or its metabolites was observed following multiple dose administration. When administered with food, there is a decrease in the rate of absorption, with a fasting T MAX of 1.53 hours and a T MAX of 2.86 hours after a meal; the peak concentration is reduced by 17.3%. Single oral doses across the clinical dose range are dose proportional. Cevimeline has a volume of distribution of approximately 6L/kg and is <20% bound to human plasma proteins. This suggests that cevimeline is extensively bound to tissues; however, the specific binding sites are unknown.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在24小时后，30毫克剂量西维美林中有84%通过尿液排出。在七天之后，剂量的97%在尿液中回收，0.5%在粪便中回收。

After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. After seven days, 97% of the dose was recovered in the urine and 0.5% was recovered in the feces.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  2'-甲基螺[4-氮杂双环[2.2.2]辛烷-2,5'-[1,3]恶噻戊环] 生成 正己烷
  参考文献：
  名称：

  Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine

  摘要：

  一种制备2-甲基螺(1,3-噁硫烷-5,3')喹胺的方法，包括在至少选自锡卤化物、氧化磷酸、磷氧卤化物和有机磺酸的群体中选择至少一种成员制备催化剂，然后在该催化剂的存在下，将3-羟基-3-巯基甲基喹啉或其盐和一个羰基化合物反应，以制备顺式形式的2-甲基螺(1,3-噁硫烷-5,3')喹胺或其盐。

  公开号：

  US05571918A1
• 作为产物：
  描述：

  3-(疏基甲基)-1-阿杂环[2.2.2]辛烷-3-醇 、 乙醛 在 sodium hydroxide 、 硫酸 、 sodium sulfate 作用下， 以 氯仿 为溶剂， 生成 2'-甲基螺[4-氮杂双环[2.2.2]辛烷-2,5'-[1,3]恶噻戊环]
  参考文献：
  名称：

  Method for producing 2-methylspiro(1,3-oxathiolane-5,3')quinuclidine

  摘要：

  一种制备2-甲基螺(1,3-噁硫烷-5,3')喹胺的方法，包括在至少选自锡卤化物、氧化磷酸、磷氧卤化物和有机磺酸的群体中选择至少一种成员制备催化剂，然后在该催化剂的存在下，将3-羟基-3-巯基甲基喹啉或其盐和一个羰基化合物反应，以制备顺式形式的2-甲基螺(1,3-噁硫烷-5,3')喹胺或其盐。

  公开号：

  US05571918A1

文献信息

• 1,3-OXATHIOLANE DERIVATIVES, PROCESS FOR THE PREPARATION OF 1,3-OXATHIOLANE DERIVATIVES AND INTERMEDIATES THEREOF
  申请人：APOTEX PHARMACHEM INC.

  公开号：US20130274474A1

  公开（公告）日：2013-10-17

  This invention relates to 1,3-oxathiolane derivatives (I), processes for the preparation of 1,3-oxathiolane derivatives and intermediate compounds thereof.

  这项发明涉及1,3-氧硫杂环戊烷衍生物(I)，以及制备1,3-氧硫杂环戊烷衍生物和其中间化合物的方法。
• Process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3')quiniclidine
  申请人：Bratovanov Svetoslav S.

  公开号：US20080249312A1

  公开（公告）日：2008-10-09

  An industrially acceptable process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine. The cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine is known generally as Cevimeline.

  一种工业上可接受的制备2-甲基螺(1,3-氧硫杂环己烷-5,3′)喹啉啶的过程。2-甲基螺(1,3-氧硫杂环己烷-5,3′)喹啉啶的顺式异构体通常被称为赛维明。
• Process for the preparation and purification of cis-2-methylspiro(1,3-oxathiolane-5,3')quiniclidine hydrochloride
  申请人：Bratovanov Svetoslav S.

  公开号：US20090182146A1

  公开（公告）日：2009-07-16

  An industrially acceptable process for the preparation and purification of cis-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine from a cisitrans mixture of isomers. Treatment of the mixture with an organic sulfonice acid generates a less soluble acid addition salt that is enriched in the cis-isomer. Recrystallization or pulping using various organic solvents allows for enrichment of the cis-isomer by filtration. These new sulfonic acid salts of the cis-isomer of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine prepared according to the present invention could be further converted into the hydrochloride salt by any known procedures such as treatment with a base and then hydrochloric acid salt formation or exchange of the sulfonic acid salt with hydrochloric acid.

  一种工业上可接受的过程，用于从顺式/反式异构体的混合物中制备和纯化cis-2-甲基螺(1,3-噻吩环-5,3′)喹诺啉。用有机磺酸处理混合物会产生一种溶解性较低的酸加合盐，其中富集了顺式异构体。通过结晶再结晶或使用各种有机溶剂进行过滤，可以实现对顺式异构体的富集。根据本发明制备的cis-异构体2-甲基螺(1,3-噻吩环-5,3′)喹诺啉的这些新磺酸盐可以通过任何已知的程序进一步转化为盐酸盐，例如用碱处理然后形成盐酸盐，或者用盐酸交换磺酸盐。
• PROCESS FOR THE PREPARATION OF CIS-2-METHYLSPIRO (1, 3-OXATHIOLANE 5-3') QUINUCLIDINE
  申请人：Kovi Ravishanker

  公开号：US20110301352A1

  公开（公告）日：2011-12-08

  Methods are provided for making pharmaceutical-grade cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine and pharmaceutically acceptable salts thereof by isomerizing racemic 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine to cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine and subsequent purification of the C-MSOQ by salt formation with inexpensive and commercially available material such as sulfuric acid. Purification methods are disclosed which employ an organic solvent/water system and recrystallization with an organic solvent such as acetone.

  提供了一种制备医药级顺式-2-甲基螺(1,3-噁唑烷-5,3')喹啉及其药学上可接受的盐的方法，包括将外消旋的2-甲基螺(1,3-噁唑烷-5,3')喹啉异构化为顺式-2-甲基螺(1,3-噁唑烷-5,3')喹啉，并通过与廉价和商业化的材料（如硫酸）形成盐来纯化C-MSOQ。还揭示了采用有机溶剂/水系统和有机溶剂（如丙酮）再结晶的纯化方法。
• Compounds with activity on muscarinic receptors
  申请人：——

  公开号：US20030144285A1

  公开（公告）日：2003-07-31

  Compounds and methods are provided for the alleviation or treatment of diseases or conditions in which modification of muscarinic m1 receptor activity has a beneficial effect. In the method, a therapeutically effective amount of a selective muscarinic m1 agonist compound is administered to a patient in need of such treatment.

  本发明提供了化合物和方法，用于减轻或治疗通过改变毒蕈碱受体m1的活性具有益处的疾病或病症。在该方法中，向需要此类治疗的患者施用选择性毒蕈碱受体m1激动剂化合物的治疗有效量。