(2R)-5'-methyl-4-azaspiro[bicyclo[2.2.2]octane-2,2'-[1,4]oxathiolane] | 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: (2R)-5'-methyl-4-azaspiro[bicyclo[2.2.2]octane-2,2'-[1,4]oxathiolane]
• 英文别名: (5R)-2-methylspiro[1,3-oxathiolane-5,3'-1-azabicyclo[2.2.2]octane]
• CAS: 107233-08-9；112425-76-0
• 化学式: C₁₀H₁₇NOS
• 分子量: 199.32
• InChiKey: WUTYZMFRCNBCHQ-LHIURRSHSA-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
• 物理描述：
  Solid
• 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

主要在肝脏进行，细胞色素P450同工酶CYP2D6和CYP3A4负责代谢西维美林。大约44.5%的药物转化为顺式和反式亚砜，22.3%转化为葡萄糖醛酸苷结合物，4%转化为西维美林的N-氧化物。然后，大约8%的反式亚砜代谢物转化为相应的葡萄糖醛酸苷结合物。

Primarily hepatic, isozymes CYP2D6 and CYP3A4 are responsible for the metabolism of cevimeline. Approximately 44.5% of the drug is converted to cis and trans-sulfoxide, 22.3% to glucuronic acid conjugate, and 4% to N-oxide of cevimeline. Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate.

来源:DrugBank

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

在塞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，塞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

西维米林应谨慎给予正在服用β-肾上腺素能拮抗剂的患者，因为有传导干扰的可能性。与西维米林同时使用的具有副交感神经拟似作用的药物可能会产生叠加效果。西维米林可能会干扰同时使用的药物所需的抗胆碱能效果。抑制CYP2D6和CYP3A3/4的药物也会抑制西维米林的代谢。根据以往经验，西维米林应在已知或疑似CYP2D6活性缺陷的个体中谨慎使用，因为他们可能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、胆碱能激动剂所指示的方式一致。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。这可能包括头痛、视觉障碍、流泪、出汗、呼吸困难、胃肠痉挛、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

• 吸收

1.5到2小时后达到高峰浓度，迅速吸收

Rapidly absorbed with peak concentration after 1.5 to 2 hours

来源:DrugBank

吸收、分配和排泄

• 消除途径

在24小时后，30毫克剂量的西维米林有84%通过尿液排出。

After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

6 升/千克

6 L/kg

来源:DrugBank

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

目前尚不清楚这种药物是否会在人类乳汁中分泌。

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

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。

文献信息

• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• Piperazine-piperidine antagonists and agonists of the 5-HT1A receptor
  申请人：Asselin Magda

  公开号：US20070027160A1

  公开（公告）日：2007-02-01

  The present invention relates to novel piperazine-piperidine compounds. The compounds are useful as 5-HT 1A binding agents, particularly as 5-HT 1A receptor antagonists and agonists. These compounds are useful in treating central nervous system disorders, such as cognition disorders, anxiety disorders, depression and sexual dysfunction.

  本发明涉及新型哌嗪-哌啶化合物。这些化合物可用作5-HT1A结合剂，特别是作为5-HT1A受体拮抗剂和激动剂。这些化合物在治疗中枢神经系统疾病方面很有用，如认知障碍、焦虑症、抑郁症和性功能障碍。
• NEPRILYSIN INHIBITORS
  申请人：Hughes Adam D.

  公开号：US20130330366A1

  公开（公告）日：2013-12-12

  In one aspect, the invention relates to compounds having the formula XII: where R a , R b , R 2 , R 7 , and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds described herein are prodrugs of compounds having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

  在一方面，本发明涉及具有公式XII的化合物： 其中R a ，R b ，R 2 ，R 7 和X如说明书中所定义，或其药用可接受的盐。所述的化合物是具有中性粒细胞弹性蛋白酶抑制活性的化合物的前药。在另一方面，本发明涉及包含这些化合物的药物组合物；使用这些化合物的方法；以及制备这些化合物的过程和中间体。
• [EN] COMPOUNDS WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE<br/>[FR] COMPOSÉS PRÉSENTANT UNE ACTIVITÉ AU NIVEAU DU RÉCEPTEUR M1 ET LEURS UTILISATIONS EN MÉDECINE
  申请人：GLAXO GROUP LTD

  公开号：WO2009037294A1

  公开（公告）日：2009-03-26

  Compounds of formula (I) or a salt thereof are provided: wherein R4, R5, R6, Q, A, Y and R are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders, cognitive impairments and Alzheimer's Disease are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.

  提供具有公式(I)或其盐的化合物：其中R4、R5、R6、Q、A、Y和R按描述定义。披露了这些化合物作为药物的使用和在制造用于治疗精神病性障碍、认知障碍和阿尔茨海默病药物中的应用。本发明还公开了包含这些化合物的药物组合物。
• [EN] HETEROCYCLIC COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES ET LEURS UTILISATIONS
  申请人：INFINITY PHARMACEUTICALS INC

  公开号：WO2015051241A1

  公开（公告）日：2015-04-09

  Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

  本发明描述了调节激酶活性的化合物和药物组合物，包括PI3激酶活性，以及用于治疗与激酶活性相关的疾病和状况的化合物、药物组合物和方法，包括PI3激酶活性。