cevimeline | 107233-08-9

• 物质功能分类: 原料药
• 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
• 英文名称: cevimeline
• 英文别名: Cevimeline [vandf]；(2S,5S)-2-methylspiro[1,3-oxathiolane-5,3'-1-azabicyclo[2.2.2]octane]
• CAS: 107233-08-9
• 化学式: C₁₀H₁₇NOS
• 分子量: 199.317
• InChiKey: WUTYZMFRCNBCHQ-WPRPVWTQSA-N

物化性质

• 熔点：
  195-197°C
• 沸点：
  308.5±42.0 °C(Predicted)
• 密度：
  1.19
• 溶解度：
  溶于二甲基亚砜
• 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

...。给药后24小时内，尿液中代谢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，还检测到两个未知代谢物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cevimeline的上市前试验中，血清酶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，cevimeline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。预期与 Cevimeline 同时使用的具有副交感神经拟似作用的药物会产生相加作用。Cevimeline 可能会干扰同时使用的药物的期望的抗胆碱能效果。抑制 CYP2D6 和 CYP3A3/4 的药物也会抑制 Cevimeline 的代谢。根据以往经验，Cevimeline 应谨慎用于已知或疑似 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）的病人中应谨慎使用，并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

在给予单次30毫克胶囊后，西维美林迅速被吸收，达到平均峰浓度的时间为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累积。与食物同服时，吸收速率降低，空腹时的T MAX为1.53小时，饭后为2.86小时；峰浓度降低了17.3%。在临床剂量范围内，单次口服剂量与剂量成正比。西维美林的分布容积约为6L/kg，并且不到20%与人血浆蛋白结合。这表明西维美林在组织中广泛结合，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毫克剂量的西维米林有84%通过尿液排出。经过七天，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)

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

概述

盐酸西维美林（cevimeline hydrochloride，商品名：Evoxac，简称西维美林）是一种选择性的毒蕈碱受体激动剂，能够显著促进动物和人类唾液的分泌。研究表明，在未去除涎腺的大鼠中，西维美林并无预防龋齿的作用；但在去除了全部涎腺或部分涎腺的大鼠中，它能显著减少龋齿的发生率。这表明西维美林可以刺激腮腺功能，弥补颌下腺和舌下腺分泌功能的缺失，从而起到防治龋齿的作用。有研究指出，在主要涎腺去除后，剩余涎腺的细胞体积和数量会代偿性增大，进而增加唾液及其成分的分泌。这可能是西维美林在实验中发挥预防龋齿作用的重要原因。

此外，临床上多种口腔疾病（如Sjögren综合征）、药源性问题、头颈部肿瘤放疗等均可导致涎腺损伤和唾液分泌不足，因此临床病例中涎腺分泌不足的情况较多。作为新型的治疗Sjögren综合征和放射引起的口干症药物，西维美林已上市多年；然而，其对于预防龋齿的具体疗效仍需进行更为系统的临床研究。

药理作用

西维美林是乙酰胆碱的一种奎宁环衍生物，是一种结合毒蕈碱受体的胆碱能激动药。在足够剂量下，它可以使外分泌腺（如唾液、汗液）分泌增加，并增强胃肠道和泌尿道平滑肌的张力。西维美林与泪腺和涎腺上皮上的毒蕈碱受体亲和力较高，而对心肌组织中毒蕈碱的亲和力较低。其结构不同于现有同类药物，但作用机制类似毛果芸香碱。西维美林通过P450 CYP2D6、3A3、3A4广泛代谢，并不对CYP1A2、2A6、2C9、2C19、2D6、2E1和3A4产生抑制作用。

生物活性

Cevimeline (AF-102B) 是一种乙酰胆碱的奎尼丁衍生物，也是一种选择性的和口服活性的毒蕈碱型 M1 和 M3 受体激动剂。它能够刺激唾液腺分泌，并可用作口干症的一种催涎剂。Cevimeline 还可以穿过血脑屏障。

靶点

• Muscarinic M1 and M3 receptor

体外研究

在消化的腮腺细胞中，Cevimeline (0.1-100 μM) 可以增加细胞内钙离子（Ca²⁺）浓度。

体内研究

对8周龄雄性Wistar大鼠注射Angiotensin-II后，给予西维美林（0.008 mg/kg或0.016 mg/kg；腹腔注射），结果显示逐渐且持续的唾液分泌增加、腮腺血流增加和血压升高。此外，在0.016 mg/kg剂量下，西维美林能抑制Angiotensin II引起的饮水摄入量及下丘脑室旁核的神经活动。

动物模型	8周龄雄性Wistar大鼠注射Angiotensin-II
剂量	0.008 mg/kg, 0.016 mg/kg
给药方式	腹腔注射
结果	逐渐且持续的唾液分泌增加、腮腺血流增加和血压升高，抑制Angiotensin II引起的饮水摄入量及下丘脑室旁核的神经活动。

反应信息

• 作为反应物：
  描述：

  cevimeline 在 sodium hydroxide 、 硫酸 作用下， 以 异丙醚 、 丙酮 为溶剂， 生成 cis-cevimeline sulfate
  参考文献：
  名称：

  PROCESS FOR THE PREPARATION OF CIS-2-METHYLSPIRO (1, 3-OXATHIOLANE 5-3') QUINUCLIDINE

  摘要：

  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。

  公开号：

  US20110301352A1
• 作为产物：
  描述：

  3-奎宁环酮盐酸盐 在 硫化氢 、 potassium tert-butylate 、 对甲苯磺酸 、 sodium hydroxide 作用下， 以 水 、 二甲基亚砜 、 异丙醇 为溶剂， 反应 14.0h， 生成 trans-cevimeline 、 cevimeline
  参考文献：
  名称：

  A new route to cevimeline

  摘要：

  The present work demonstrates a new route for the synthesis of cevimeline in which safe and odorless thiourea is utilized as a thiolating reagent. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2013.03.090

文献信息

• 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。
• NANO-SIZED PARTICLES COMPRISING MULTI-HEADED AMPHIPHILES FOR TARGETED DRUG DELIVERY
  申请人：Linder Charles

  公开号：US20120164072A1

  公开（公告）日：2012-06-28

  Nano-sized particles are provided comprising at least one multi-headed amphiphilic compound, in which at least one headgroup of said multi-headed amphiphilic compound is selectively cleavable or contains a selectively cleavable group, and at least one biologically active agent, which is both encapsulated within the nano-particle and non-covalently associated thereto.

  提供了一种纳米级颗粒，其中包含至少一种多头亲疏水化合物，其中至少一个头基团是可选择性断裂的或含有可选择性断裂基团，并且至少一种生物活性剂被封装在纳米粒子内并与其非共价结合。
• CIS-2-METHYLSPIRO 1, 3-OXATHIOLANE 5-3 QUINUCLIDINE
  申请人：APICORE, LLC

  公开号：US20130237707A1

  公开（公告）日：2013-09-12

  Pharmaceutical-grade compounds containing cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine having a purity >99.0% by HPLC with less than 0.5% of trans-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine are provided.

  提供含有cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine的药品级化合物，其纯度通过HPLC大于99.0％，且trans-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine含量不到0.5％。
• Optical isomers of a spiroquinuclidine derivative
  申请人：State of Israel Represented by the Prime Minister's Office The Israel Institute for Biological Research

  公开号：EP0303391A2

  公开（公告）日：1989-02-15

  The (+)-cis-, (-)-cis-, (+)-trans- and (-)-trans- forms of 2-methylspiro(1,3-oxathiolan-5,3′)quinuclidine are prepared by optical resolution of each of the (±)-cis- and (±)-trans-isomers. These compounds find application in treating diseases of the central nervous system in mammals, especially diseases due to a deficiency in the central cholinergic system. Biological tests indicate that the (-)-cis-form, as well as the (±)-cis-isomer, shows particular promise for treating senile dementia of Alzheimer's type.

  (+)-顺式、(-)-顺式、(+)-反式和(-)-反式形式的 2-甲基螺(1,3-氧硫杂环戊烷-5,3′)奎宁环是通过光学分解(±)-顺式和(±)-反式异构体制备的。这些化合物可用于治疗哺乳动物的中枢神经系统疾病，特别是由于中枢胆碱能系统缺乏引起的疾病。生物测试表明，(-)-顺式异构体和(±)-顺式异构体尤其有望治疗阿尔茨海默型老年痴呆症。