(+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate | 153504-70-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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: (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate
• 英文别名: (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate；(+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride；(+/-)-cis-2-methylspiro[1,2-oxathiolane-5,3'-quinclidine] monohydrochloride；(+/-)-cis-2-methylspiro[1,3]oxathiolane-5,3'-quinuclidine monohydrochloride；(+/-)cis-2-methylspiro(1,3-oxathiolane-5,3')quinuclidine hydrochloride；cevimeline hydrochloride；(2S,5S)-2-methylspiro[1,3-oxathiolane-5,3'-1-azabicyclo[2.2.2]octane];hydrochloride
• CAS: 153504-70-2
• 化学式: C₁₀H₁₇NOS*ClH
• 分子量: 235.778
• InChiKey: SURWTGAXEIEOGY-GNAZCLTHSA-N

物化性质

• 溶解度：
  H2O：≥25mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.98
• 重原子数：
  14
• 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：
  1
• 氢受体数：
  3

安全信息

• 储存条件：
  -20°C

SDS

---

SECTION 1: Identification of the substance/mixture and of the company/undertaking
Product identifiers
Product name : Cevimeline hydrochloride hemihydrate
REACH No. : A registration number is not available for this substance as the substance
or its uses are exempted from registration, the annual tonnage does not
require a registration or the registration is envisaged for a later
registration deadline.
CAS-No. : 153504-70-2
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

---

SECTION 2: Hazards identification
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008
Acute toxicity, Oral (Category 3), H301
For the full text of the H-Statements mentioned in this Section, see Section 16.
Classification according to EU Directives 67/548/EEC or 1999/45/EC
T Toxic R25
For the full text of the R-phrases mentioned in this Section, see Section 16.
Label elements
Labelling according Regulation (EC) No 1272/2008
Pictogram
Signal word Danger
Hazard statement(s)
H301 Toxic if swallowed.
Precautionary statement(s)
P301 + P310 IF SWALLOWED: Immediately call a POISON CENTER or doctor/
physician.
Supplemental Hazard none
Statements
Other hazards - none

---

SECTION 3: Composition/information on ingredients
Substances
Synonyms : AF-102B
(2"R,3R)-rel-2"-Methylspiro[1-azabicyclo[2.2.2]octane-3,5"-
[1,3]oxathiolane]
SNI-2011
Formula : C10H17NOS · xHCl · yH2O
Molecular Weight : 199,31 g/mol
CAS-No. : 153504-70-2
Hazardous ingredients according to Regulation (EC) No 1272/2008
Component Classification Concentration
CEVIMELINE HYDROCHLORIDE
CAS-No. 107220-28-0 Acute Tox. 3; H301 <= 100 %
For the full text of the H-Statements and R-Phrases mentioned in this Section, see Section 16

---

SECTION 4: First aid measures
Description of first aid measures
General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician.
In case of skin contact
Wash off with soap and plenty of water. Take victim immediately to hospital. Consult a physician.
In case of eye contact
Flush eyes with water as a precaution.
If swallowed
Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician.
Most important symptoms and effects, both acute and delayed
The most important known symptoms and effects are described in the labelling (see section 2.2) and/or in
section 11
Indication of any immediate medical attention and special treatment needed
no data available

---

SECTION 5: Firefighting measures
Extinguishing media
Suitable extinguishing media
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx), Sulphur oxides, Hydrogen chloride gas
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

---

SECTION 6: Accidental release measures
Personal precautions, protective equipment and emergency procedures
Wear respiratory protection. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure
adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.
For personal protection see section 8.
Environmental precautions
Prevent further leakage or spillage if safe to do so. Do not let product enter drains.
Methods and materials for containment and cleaning up
Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed
containers for disposal.
Reference to other sections
For disposal see section 13.

---

SECTION 7: Handling and storage
Precautions for safe handling
Avoid contact with skin and eyes. Avoid formation of dust and aerosols.
Provide appropriate exhaust ventilation at places where dust is formed.
For precautions see section 2.2.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Recommended storage temperature: -20 °C
Specific end use(s)
A part from the uses mentioned in section 1.2 no other specific uses are stipulated

---

SECTION 8: Exposure controls/personal protection
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling
the product.
Personal protective equipment
Eye/face protection
Face shield and safety glasses Use equipment for eye protection tested and approved under
appropriate government standards such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Body Protection
Complete suit protecting against chemicals, The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Where risk assessment shows air-purifying respirators are appropriate use a full-face particle
respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering
controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use
respirators and components tested and approved under appropriate government standards such
as NIOSH (US) or CEN (EU).
Control of environmental exposure
Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

---

SECTION 9: Physical and chemical properties
Information on basic physical and chemical properties
a) Appearance Form: solid
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing no data available
point
f) Initial boiling point and no data available
boiling range
g) Flash point no data available
h) Evapouration rate no data available
i) Flammability (solid, gas) no data available
j) Upper/lower no data available
flammability or
explosive limits
k) Vapour pressure no data available
l) Vapour density no data available
m) Relative density no data available
n) Water solubility no data available
o) Partition coefficient: n- no data available
octanol/water
p) Auto-ignition no data available
temperature
q) Decomposition no data available
temperature
r) Viscosity no data available
s) Explosive properties no data available
t) Oxidizing properties no data available
Other safety information
no data available

---

SECTION 10: Stability and reactivity
Reactivity
no data available
Chemical stability
Stable under recommended storage conditions.
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
no data available
Hazardous decomposition products
Other decomposition products - no data available
In the event of fire: see section 5

---

SECTION 11: Toxicological information
Information on toxicological effects
Acute toxicity
LD50 Oral - rat - 92 mg/kg
LD50 Oral - mouse - 155 mg/kg
LD50 Intravenous - mouse - 33 mg/kg
LDLO Intraperitoneal - mouse - 80 mg/kg
LD50 Intraperitoneal - rat - 7,76 mg/kg
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitisation
no data available
Germ cell mutagenicity
no data available
Carcinogenicity
IARC: No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
no data available
Specific target organ toxicity - single exposure
no data available
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Additional Information
RTECS: Not available
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.

---

SECTION 12: Ecological information
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
PBT/vPvB assessment not available as chemical safety assessment not required/not conducted
Other adverse effects
no data available

---

SECTION 13: Disposal considerations
Waste treatment methods
Product
Offer surplus and non-recyclable solutions to a licensed disposal company. Dissolve or mix the material
with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.
Contaminated packaging
Dispose of as unused product.

---

SECTION 14: Transport information
UN number
ADR/RID: 2811 IMDG: 2811 IATA: 2811
UN proper shipping name
ADR/RID: TOXIC SOLID, ORGANIC, N.O.S. (CEVIMELINE HYDROCHLORIDE)
IMDG: TOXIC SOLID, ORGANIC, N.O.S. (CEVIMELINE HYDROCHLORIDE)
IATA: Toxic solid, organic, n.o.s. (CEVIMELINE HYDROCHLORIDE)
Transport hazard class(es)
ADR/RID: 6.1 IMDG: 6.1 IATA: 6.1
Packaging group
ADR/RID: III IMDG: III IATA: III
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

---

---

SECTION 15 - REGULATORY INFORMATION
N/A

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

盐酸西维美林概述

盐酸西维美林，药品名称为西维美林，是一种新型的选择性毒蕈碱受体激动剂。临床试验证明，它能显著促进动物和人类唾液的分泌，并可安全、有效地治疗舍格伦综合征患者的口干症状。三期临床实验显示，盐酸西维美林能够明显增加患者唾液含量，提高腺体的分泌功能。

作为一种胆碱能激动剂，盐酸西维美林与毒蕈碱受体结合后，可以促进唾液腺、汗腺等外分泌腺的分泌作用，并可增强胃肠道与尿道平滑肌的张力。

适应症

本品用于治疗舍格伦综合征导致的口干症状。舍格伦综合征是一种慢性进展性自身免疫性疾病，以外分泌腺（如涎腺和泪腺）的淋巴细胞浸润为特征。该病主要影响患者的唾液腺和泪腺，引起口干和眼睛干涩。

药理学作用

盐酸西维美林是乙酰胆碱的奎宁环衍生物，是一种结合毒蕈碱受体的胆碱能激动药。

1. 在适当剂量下，毒蕈碱激动剂能够增加外分泌腺（如唾液和汗腺）的分泌功能，并增强胃肠道与泌尿道平滑肌的张力。
2. 盐酸西维美林与泪腺和涎腺上皮上的毒蕈碱受体亲和性较高，而对心肌组织中受体的亲和性较低。
3. 西维美林结构不同于现用同类药物，其作用机制类似毛果芸香碱。
4. 该药广泛通过P450 CYP2D6、CYP3A3和CYP3A4代谢，并对CYP1A2、2A6、2C9、2C19、2E1和3A4均无抑制作用。

与其它药物的相互作用

1. β-阻断药可能会与西维美林产生药理学上的相互作用，引起心脏传导阻滞。
2. 合用抗毒蕈碱药会产生拮抗效果。
3. 对CYP2D6、3A4或3A3产生抑制作用的药物会减少西维美林的代谢；而产生诱导作用的药物则增加其代谢。

不良反应

1. 常见不良反应包括多汗、头痛、恶心、鼻窦炎、上呼吸道感染、鼻炎、腹泻、消化不良、腹痛、泌尿道感染、咳嗽、咽炎、呕吐、腰痛、皮疹、结膜炎、头晕、支气管炎、关节痛和乏力。
2. 可能发生流泪、呼吸窘迫、视力障碍、胃肠痉挛、心动过速、心动过缓、房室传导阻滞、低血压、高血压、休克、精神错乱、心律失常和震颤。
3. 由于胆道平滑肌收缩，可能导致胆囊炎、胆管炎和胆道梗阻。
4. 肾结石史患者因尿道平滑肌张力增强可能引发肾绞痛或输尿管反流。
5. 出汗过多可能导致失水。CYP2D6缺乏的患者可能会因为代谢减少而使不良反应加重。

参考文献

1. 百度百科
2. 维基8
3. 华红. 干燥综合征西医、中医治疗研究进展[J]. 中国实用口腔科杂志, 2012, 05(3):142-145.
4. 王利珍. 如何预防放射性口干燥症及治疗对策[J]. 科技与创新, 2016(20):87-87.
5. 周伟, 李冬. 西维美林对部分去涎腺大鼠龋齿的预防作用[J]. 中国药学杂志, 2009, 44(18):1384-1386.

反应信息

• 作为反应物：
  描述：

  (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate 在 sodium hydroxide 、 硫酸 作用下， 以 异丙醚 、 丙酮 为溶剂， 反应 3.0h， 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：

  trans-cevimeline 在 四氯化钛 、 盐酸 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 生成 (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate
  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

文献信息

• 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。
• Dry skin remedies
  申请人：——

  公开号：US20020004056A1

  公开（公告）日：2002-01-10

  Novel dry skin remedies useful for treatment dry skin, containing as the active ingredient spiro [oxathiolane-quinuclidine] derivatives represented by general formula (I) or acid addition salts thereof, desirably cis-2-methylspiro [1,3-oxathiolane-5,3′-quinuclidine] hydrochloride. The remedies promote the secretion of sebaceous and sweat glands through oral or parenteral administration to treat dry skin, thus being useful as drugs. 1

  治疗干燥皮肤的小说干燥皮肤疗法，其活性成分为一般式（I）或其酸加成盐所代表的螺环氧硫烷-喹诺啉衍生物，最好是顺式-2-甲基螺环氧硫烷-5,3'-喹诺啉盐酸盐。该疗法通过口服或经肌肉注射促进皮脂腺和汗腺的分泌，治疗干燥皮肤，因此可用作药物。
• Tablets and methods for modified release of hydrophilic and other active agents
  申请人：Yamanouchi Pharma Technologies, Inc.

  公开号：US20030108602A1

  公开（公告）日：2003-06-12

  The invention provides a tablet and methods for making the tablet comprising a gel-forming material and at least one particle comprising an active agent in contact with a coating material to modify release of the active agent.

  本发明提供了一种片剂和制作片剂的方法，该片剂由凝胶形成材料和至少一种包含活性剂的颗粒组成，颗粒与包衣材料接触以改变活性剂的释放。
• Tablets and methods for modified release of hydrophylic and other active agents
  申请人：Chu Shunnan James

  公开号：US20050042289A1

  公开（公告）日：2005-02-24

  A novel tablet and methods for making the tablet are provided. The tablet comprises at least one particle containing a pharmaceutically active agent and a gel-forming material comprising a first polymer, a second polymer, and a gelation facilitator agent, and has a sustained release profile for the active agent.

  本文提供了一种新型片剂和片剂的制造方法。该片剂包括至少一种含有药物活性剂的颗粒和凝胶形成材料，凝胶形成材料包括第一聚合物、第二聚合物和凝胶促进剂，并具有活性剂的持续释放特性。
• A new route to cevimeline
  作者：Chinmoy Pramanik、Pradip Patil、Sandeep Kotharkar、Narendra K. Tripathy、Mukund K. Gurjar

  DOI：10.1016/j.tetlet.2013.03.090

  日期：2013.6

  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.