甲磺酸雷沙吉兰 | 161735-79-1

• 物质功能分类: 生物化工 - 抑制剂 - 代谢(Metabolism)
• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 中文名称: 甲磺酸雷沙吉兰
• 中文别名: 雷沙吉兰甲磺酸盐；(R)-N-2-丙炔基-1-氢化茚胺甲磺酸盐
• 英文名称: rasagiline mesylate
• 英文别名: methanesulfonic acid;(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine
• CAS: 161735-79-1
• 化学式: CH₄O₃S*C₁₂H₁₃N
• mdl: MFCD08460604
• 分子量: 267.349
• InChiKey: JDBJJCWRXSVHOQ-UTONKHPSSA-N

物化性质

• 熔点：
  155-158°C
• 溶解度：
  H2O：≥20mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.384
• 拓扑面积：
  74.8
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S37/39
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  3
• 海关编码：
  2921499090
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20°C freezer

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : Rasagiline mesylate
: SML0124
CAS-No. : 161735-79-1

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008 [EU-GHS/CLP]
Acute toxicity, Oral (Category 4)
Classification according to EU Directives 67/548/EEC or 1999/45/EC
Harmful if swallowed.
Label elements
Labelling according Regulation (EC) No 1272/2008 [CLP]
Pictogram
Signal word Warning
Hazard statement(s)
Harmful if swallowed.
Precautionary statement(s) none
Supplemental Hazard none
Statements
According to European Directive 67/548/EEC as amended.
Hazard symbol(s)
R-phrase(s)
R22 Harmful if swallowed.
S-phrase(s) none
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
Synonyms : N-Propargyl-1(R)-aminoindan methanesulfonate
(1R)-2,3-Dihydro-N-2-propynl-1H-inden-1-amine methanesulfonate
Formula : C12H13N · CH4O3S
Molecular Weight : 267,34 g/mol
Component Concentration
(1R)-2,3-Dihydro-N-2-propynl-1H-inden-1-amine methanesulfonate
CAS-No. 161735-79-1 -

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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. 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
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.
Indication of any immediate medical attention and special treatment needed
no data available

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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
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

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Section 6. ACCIDENTAL RELEASE MEASURES
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure
adequate ventilation. Avoid breathing dust.
Environmental precautions
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.

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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.
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: 2 - 8 °C
Store with desiccant.
Specific end uses
no data available

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Section 8. EXPOSURE CONTROLS/PERSONAL PROTECTION
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and
at the end of workday.
Personal protective equipment
Eye/face protection
Safety glasses with side-shields conforming to EN166 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
For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher
level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges.
Use respirators and components tested and approved under appropriate government standards
such as NIOSH (US) or CEN (EU).

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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) Evaporation 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) Autoignition 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

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Section 10. STABILITY AND REACTIVITY
Reactivity
no data available
Chemical stability
no data available
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available

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Section 11. TOXICOLOGICAL INFORMATION
Information on toxicological effects
Acute toxicity
no data available
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitization
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
Potential health effects
Inhalation
May be harmful if inhaled. May cause respiratory tract irritation.
Ingestion Harmful if swallowed.
Skin May be harmful if absorbed through skin. May cause skin irritation.
Eyes May cause eye irritation.
Signs and Symptoms of Exposure
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.
Additional Information
RTECS: Not available

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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
no data available
Other adverse effects
no data available

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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.

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Section 14. TRANSPORT INFORMATION
UN number
ADR/RID: - IMDG: - IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA: Not dangerous goods
Transport hazard class(es)
ADR/RID: - IMDG: - IATA: -
Packaging group
ADR/RID: - IMDG: - IATA: -
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

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Section 15. REGULATORY INFORMATION
This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006.
Safety, health and environmental regulations/legislation specific for the substance or mixture
no data available
Chemical Safety Assessment

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

帕金森病药物

甲磺酸雷沙吉兰由以色列梯瓦制药工业公司研发，并于2005年2月21日获得欧洲药物管理局（EMA）批准上市，2006年5月16日获美国食品药品管理局（FDA）批准。该药适用于原发性帕金森病患者的单一治疗（不用左旋多巴），以及作为左旋多巴的辅助用药用于有剂末波动现象的患者。

甲磺酸雷沙吉兰是一种不可逆性单胺氧化酶抑制剂，通过选择性抑制单胺氧化酶减少多巴胺的分解，提高大脑高纹状体内多巴胺细胞外水平，增加后的多巴胺水平可以减轻帕金森病症状。与第一代单胺氧化酶抑制剂司来吉兰（包括思吉宁、咪哆吡、金思平等）相比，甲磺酸雷沙吉兰的抑制作用强5～10倍，并对长期应用多巴制剂药效出现衰退的患者也有改善的作用。此外，其代谢产物为一种无活性的非苯丙胺物质，副作用较小。更重要的是，与其它抗帕金森病药物不同，甲磺酸雷沙吉兰还具有神经保护作用。在联合治疗时，可优化左旋多巴治疗效应，进一步有效控制症状，减少运动并发症。

据2017年美国IMS数据显示，在全球500强畅销药物市场中，抗帕金森治疗市场的规模为20.56亿美元，同比增长3.73%。

药理作用

雷沙吉兰是一种强效、高选择性、不可逆性单胺氧化酶-B抑制剂，能够抑制多巴胺降解，增加多巴胺蓄积，并促进多巴胺的释放。这种新化学结构旨在改进初代MAO-B抑制剂治疗中出现的问题。司来吉兰是第一代MAO-B抑制剂，其代谢产物包括苯丙胺衍生物，可能导致不良反应如影响患者睡眠。相比之下，雷沙吉兰的代谢产物不含苯丙胺衍生物。

雷沙吉兰与MAO-B结合具有高度选择性，结构中的芳香环和N-炔丙基末端之间保持两个碳单位的距离，且有效基团N-炔丙胺三键对于其不可逆性至关重要。不可逆作用意味着持续效果，因此可能提供持续的多巴胺能刺激（continuous dopaminergic stimulation, CDS），这为每日一次给药方式提供了基础；数据显示雷沙吉兰的药代动力学半衰期与药效学半衰期无关，临床疗效可持续24小时。

生物活性

Rasagiline Mesylate (TVP-1012) 是一种新型MAO-B抑制剂，用于治疗突发性帕金森病。

靶点

Target	Value
MAO-B	4.43 nM
MAO-A	412 nM

体外研究

Rasagiline 抑制大鼠脑组织MAO A型和B型，IC50分别为4.43 nM 和412 nM。在急性和慢性给药后，Rasagiline 对大鼠脑和肝的MAO-B抑制作用是selegiline的3至15倍，在体外效力相似。 在SH-SY5Y细胞中，Rasagiline 防止N-甲基（R）salsolinol诱导的GAPDH 的核积累，并防止线粒体膜电位衰减，伴随凋亡过程。在部分神经分化的PC12 细胞中，Rasagiline 对应血清和生长因子撤出具有强效的抗凋亡和神经保护活性。

体内研究

Rasagiline 抑制离体脑和肝中MAO，ED50分别为4.43 nM 和412 nM。在小鼠中的研究显示，Rasagiline（剂量为 0.2 毫克/千克 和1毫克/千克）加速了运动功能和空间记忆的恢复，并减少了约40-50％脑水肿。

反应信息

• 作为反应物：
  描述：

  甲磺酸雷沙吉兰 以 水 为溶剂， 反应 0.6h， 生成 雷沙吉兰
  参考文献：
  名称：

  Dosage forms with an enterically coated core tablet

  摘要：

  本发明提供了一种口服制剂给患者使用，包括一种经肠包被的核心片剂，套在压缩粉末或颗粒材料的环状体内。本发明还提供了一种联合使用两种或多种活性药物成分的药物剂型。本发明还提供了一种方法，包括将本发明的药物剂型用于患有胃动力障碍的患者，例如帕金森病患者。

  公开号：

  US20060153918A1
• 作为产物：
  描述：

  1-茚酮肟 在 Candida antarctica lipase B 、 三乙醇胺 、 palladium 10% on activated carbon 、 Pd/AlO(OH) 、 氢气 、 potassium carbonate 、 sodium hydroxide 作用下， 以 乙醇 、 水 、 异丙醇 、 甲苯 、 乙腈 为溶剂， 反应 34.75h， 生成 甲磺酸雷沙吉兰
  参考文献：
  名称：

  化学动力学动态拆分合成雷沙吉兰的新方法

  摘要：

  以南极假丝酵母脂肪酶B（CALB）和Pd纳米催化剂为催化剂，以动态动力学拆分（DKR）为关键步骤，提出了制备雷沙吉兰甲磺酸雷沙吉兰的新方法。通过外消旋氨基茚满rac -1的DKR获得手性中间体（R）-2，3-二氢-1-茚满胺，产率高（＞ 90％），对映选择性优异（ee＞ 99％）。该过程可以在200克/升的73克规模下进行。甲磺酸雷沙吉兰在7个步骤中以25％的总收率和出色的对映选择性（99.9％ee）合成。

  DOI：

  10.1021/op500152g

文献信息

• RASAGILINE CITRAMIDE
  申请人：TEVA PHARMACEUTICAL INDUSTRIES, LTD.

  公开号：US20130089611A1

  公开（公告）日：2013-04-11

  The subject invention provides rasagiline citramide and a composition containing N-propargyl-1(R)-aminoindan or a pharmaceutically acceptable salt thereof, and a compound of rasagiline citramide or a salt thereof.

  该发明提供了拉沙吉林柠檬酰胺和含有N-丙炔基-1(R)-氨基茚或其药用可接受盐的组合物，以及拉沙吉林柠檬酰胺化合物或其盐。
• Process for preparation of Rasagiline and salts thereof
  申请人：Sathe Dhananjay Govind

  公开号：US08741962B2

  公开（公告）日：2014-06-03

  The present invention relates to an improved process for the preparation of Rasagiline or pharmaceutically acceptable salts thereof. The present invention also relates to Rasagiline salts, polymorphs thereof and process for preparation thereof.

  本发明涉及一种改进的用于制备Rasagiline或其药用可接受盐的方法。本发明还涉及Rasagiline盐、其多晶形态以及制备方法。
• NOVEL COMPOUND AND MEDICAL USE THEREOF
  申请人：Kokubo Masaya

  公开号：US20130245074A1

  公开（公告）日：2013-09-19

  Provided is a levodopa prodrug that overcomes the problems attributed to the blood kinetics of levodopa such as large number of doses and the incidence of side effects due to frequent dosing. (2S)-2-Amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid, a salt thereof, or a solvate thereof is a levodopa prodrug, and provides a flat blood concentration-time profile of levodopa through oral administration, and therefore is useful as a preventive and/or therapeutic agent for Parkinson's disease and/or Parkinson's syndrome that overcomes the problems associated with pharmaceutical preparations of levodopa.

  提供了一种左多巴前药，它克服了左多巴的血液动力学问题，例如需要大量剂量和频繁给药导致的副作用。其化学名为(2S)-2-氨基-3-(3,4-双((2-(苯甲酰氧基)-2-甲基丙酰氧)苯基)丙酸，其盐或溶剂化合物是左多巴前药，通过口服给药提供了左多巴平稳的血药浓度时间曲线，因此可用作克服左多巴药物制剂相关问题的帕金森病和/或帕金森综合征的预防和/或治疗药物。
• [EN] PROCESS FOR THE PREPARATION OF ENATIOMERICALLY PURE 1-AMINOINDAN<br/>[FR] PROCÉDÉ DE PRÉPARATION DE 1-AMINOINDANE ÉNANTIOMÉRIQUEMENT PUR
  申请人：FARMA GRS D O O

  公开号：WO2015070995A1

  公开（公告）日：2015-05-21

  The present invention relates to a process for the preparation of optically pure ( R) -1-aminoindan by a diastereomeric resolution of 1-aminoindan using N-acetyl-L-glutamic acid as a resolving agent. In another aspect, the invention relates to diastereomeric salts of (R) -1-aminoindan with N-acetyl-L-glutamic acid, and their use in the process for the preparation of rasagiline.

  本发明涉及一种通过使用N-乙酰-L-谷氨酸作为分离剂对1-氨基茚进行对映异构分离，制备光学纯（R）-1-氨基茚的方法。另一方面，本发明涉及（R）-1-氨基茚与N-乙酰-L-谷氨酸的对映异构盐，以及它们在制备拉沙吉林的过程中的应用。
• Chemoenzymatic synthesis of rasagiline mesylate using lipases
  作者：Thiago de Sousa Fonseca、Marcos Reinaldo da Silva、Maria da Conceição Ferreira de Oliveira、Telma Leda Gomes de Lemos、Ricardo de Araújo Marques、Marcos Carlos de Mattos

  DOI：10.1016/j.apcata.2014.12.015

  日期：2015.2

  A straightforward chemoenzymatic synthesis of rasagiline mesylate has been developed. The key steps for the introduction of chirality involved kinetic enzymatic resolution with lipases via acetylation of rac-indanol and an inversion configuration Mitsunobu reaction of the produced (S)-indanol. Immobilized lipase from Thermomyces lanuginosus proved to be a robust biocatalyst in the kinetic resolution

  已经开发了雷沙吉兰甲磺酸盐的直接化学酶法合成。引入手性的关键步骤包括通过外消旋茚满醇的乙酰化作用用脂肪酶进行动力学酶促拆分，以及所产生的（S）-茚满醇的转化构型Mitsunobu反应。事实证明，固定化的嗜热单胞菌脂肪酶是一种动力学分辨率强的生物催化剂 ，在35°C的正己烷中，仅需15分钟即可产生（S）-茚满醇，选择性高（ee  > 99％，E > 200）。可重复使用十次，而不会显着降低活性和选择性。