2’-methylspiro{1-azabicyclo [2.2.2]octane-3,5'[1,3]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: 2’-methylspiro{1-azabicyclo [2.2.2]octane-3,5'[1,3]oxathiolane}
• 英文别名: cevimeline；AF102B；(2R,5R)-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-PSASIEDQSA-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)

代谢

塞维明iline已知的人类代谢物包括塞维明磺酰氧化物。

Cevimeline has known human metabolites that include Cevimeline Sulfoxide.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

在cevimeline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，cevimeline一直没有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

• 药物性肝损伤

化合物：西维美林

Compound:cevimeline

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

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，西维美林迅速吸收，平均达到峰值浓度的时间为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，吸收速率降低，空腹时T MAX为1.53小时，饭后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。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
• 储存条件：
  -20°C

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：

  2’-methylspiro{1-azabicyclo [2.2.2]octane-3,5'[1,3]oxathiolane} 在 盐酸 作用下， 以 1,4-二氧六环 、 乙醚 、 水 为溶剂， 生成 cevimeline hydrochloride
  参考文献：
  名称：

  OPHTHALMIC PERCUTANEOUSLY ABSORBED PREPARATION CONTAINING MUSCARINIC RECEPTOR AGONIST

  摘要：

  公开号：

  EP1754491B1

文献信息

• [EN] HETEROCYCLIC AMIDES USEFUL AS PROTEIN MODULATORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES UTILES EN TANT QUE MODULATEURS DE PROTÉINE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017175147A1

  公开（公告）日：2017-10-12

  Disclosed are compounds having the formula (I-N), wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.

  揭示了具有化学式（I-N）的化合物，其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐。
• [EN] MODULATORS OF STIMULATOR OF INTERFERON GENES (STING) USEFUL IN TREATING HIV<br/>[FR] MODULATEURS DE STIMULATEUR DES GÈNES (STING) D'INTERFÉRON UTILES DANS LE TRAITEMENT DU VIH
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019069269A1

  公开（公告）日：2019-04-11

  Disclosed are compounds having the formula: (I-N) wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, along with combinations thereof, all of which are useful in HIV therapies.

  揭示了具有以下式的化合物：(I-N)其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐，以及其组合物，所有这些在HIV疗法中是有用的。
• 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。