洛贝林 | 90-69-7

• 物质功能分类: 原料药 - 神经系统用药 - 中枢兴奋药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 洛贝林
• 中文别名: 山梗菜碱
• 英文名称: lobeline
• 英文别名: Unilobin；cis-(-)-lobeline；lobelin；(−)-lobeline；2-[(2R,6S)-6-[(2S)-2-hydroxy-2-phenylethyl]-1-methylpiperidin-2-yl]-1-phenylethanone
• CAS: 90-69-7
• 化学式: C₂₂H₂₇NO₂
• 分子量: 337.462
• InChiKey: MXYUKLILVYORSK-HBMCJLEFSA-N

物化性质

• 熔点：
  130-131°
• 比旋光度：
  D15 -43° (alc)
• 沸点：
  473.76°C (rough estimate)
• 密度：
  1.0909 (rough estimate)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  T
• 安全说明：
  S36/37/39,S45
• 危险类别码：
  R23/24/25
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 1544
• 储存条件：
  库房应保持低温、通风和干燥，并与其他食品原料分开存放。

SDS

Date Updated: 13/FEB/2006
Version 1.2
Regulation (EC) No 1907/2006
________________________________________________________________________
1 - Product and Company Information
________________________________________________________________________
Product Name L-LOBELINE FREE BASE
Product Number L7149
Company
Century Ba-Shi Building 22A-B,
200020 Shanghai
Technical Phone # [phone]
Fax [phone]
E-mail Address
________________________________________________________________________
2 - Hazards Identification
________________________________________________________________________
SPECIAL INDICATION OF HAZARDS TO HUMANS AND THE ENVIRONMENT
Toxic by inhalation, in contact with skin and if swallowed.
________________________________________________________________________
3 - Composition/Information on Ingredients
________________________________________________________________________
Product Name CAS # EC no Annex I
Index Number
L-LOBELINE FREE BASE 90-69-7 202-012-3 None
Formula C22H27NO2
Molecular Weight 337,5000 AMU
Synonyms 8,10-Diphenyllobelionol *
2-(6-(beta-Hydroxy-phenethyl)-1-methyl-2-piperidy
l)acetophenone *
2-(6-(2-Hydroxy-2-phenylethyl)-1-methyl-2-piperid
inyl)-1-phenylethanone * Inflatine * Lobelin *
(-)-Lobeline * alpha-Lobeline * Lobnico
________________________________________________________________________
4 - First Aid Measures
________________________________________________________________________
AFTER INHALATION
If inhaled, remove to fresh air. If breathing becomes difficult,
call a physician.
AFTER SKIN CONTACT
In case of skin contact, flush with copious amounts of water for
at least 15 minutes. Remove contaminated clothing and shoes.
Call a physician.
AFTER EYE CONTACT
In case of contact with eyes, flush with copious amounts of
water for at least 15 minutes. Assure adequate flushing by
separating the eyelids with fingers. Call a physician.
AFTER INGESTION
If swallowed, wash out mouth with water provided person is
conscious. Call a physician.
________________________________________________________________________
5 - Fire Fighting Measures
________________________________________________________________________
EXTINGUISHING MEDIA
Suitable: Carbon dioxide, dry chemical powder, or appropriate
foam.
SPECIAL PROTECTIVE EQUIPMENT FOR FIREFIGHTERS
Wear self-contained breathing apparatus and protective clothing
to prevent contact with skin and eyes.
________________________________________________________________________
6 - Accidental Release Measures
________________________________________________________________________
PROCEDURE(S) OF PERSONAL PRECAUTION(S)
Wear respirator, chemical safety goggles, rubber boots, and
heavy rubber gloves.
METHODS FOR CLEANING UP
Sweep up, place in a bag and hold for waste disposal. Avoid
raising dust. Ventilate area and wash spill site after material
pickup is complete.
________________________________________________________________________
7 - Handling and Storage
________________________________________________________________________
________________________________________________________________________
8 - Exposure Controls / Personal Protection
________________________________________________________________________
ENGINEERING CONTROLS
Mechanical exhaust.
PERSONAL PROTECTIVE EQUIPMENT
Respiratory Protection: Use respirators and components tested and
approved under appropriate government standards such as NIOSH (US)
or CEN (EU). 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.
Hand Protection: Compatible chemical-resistant gloves.
Eye Protection: Chemical safety goggles.
________________________________________________________________________
9 - Physical and Chemical Properties
________________________________________________________________________
Appearance Physical State: Solid
Property Value At Temperature or Pressure
pH N/A
BP/BP Range N/A
MP/MP Range N/A
Flash Point N/A
Flammability N/A
Autoignition Temp N/A
Oxidizing Properties N/A
Explosive Properties N/A
Explosion Limits N/A
Vapor Pressure N/A
Partition Coefficient N/A
Viscosity N/A
Vapor Density N/A
Saturated Vapor Conc. N/A
Evaporation Rate N/A
Bulk Density N/A
Decomposition Temp. N/A
Solvent Content N/A
Water Content N/A
Surface Tension N/A
Conductivity N/A
Miscellaneous Data N/A
Solubility N/A
________________________________________________________________________
10 - Stability and Reactivity
________________________________________________________________________
STABILITY
Stable: Stable.
HAZARDOUS DECOMPOSITION PRODUCTS
Hazardous Decomposition Products: Carbon monoxide, Carbon dioxide,
Nitrogen oxides.
HAZARDOUS POLYMERIZATION
Hazardous Polymerization: Will not occur
________________________________________________________________________
11 - Toxicological Information
________________________________________________________________________
RTECS NUMBER: OJ8480000
ACUTE TOXICITY
LD50
Intraperitoneal
Mouse
43500 UG/KG
LD50
Intravenous
Mouse
6300 UG/KG
LD50
Subcutaneous
Rabbit
35 MG/KG
SIGNS AND SYMPTOMS OF EXPOSURE
Stomach pains, vomiting, diarrhea. Exposure can cause:
ROUTE OF EXPOSURE
Multiple Routes: Harmful if swallowed, inhaled, or absorbed
through skin. May cause irritation.
TARGET ORGAN INFORMATION
Central nervous system. Peripheral nervous system.
________________________________________________________________________
12 - Ecological Information
________________________________________________________________________
No data available.
________________________________________________________________________
13 - Disposal Considerations
________________________________________________________________________
SUBSTANCE DISPOSAL
Dissolve or mix the material with a combustible solvent and burn
in a chemical incinerator equipped with an afterburner and
scrubber. Observe all federal, state, and local environmental
regulations.
________________________________________________________________________
14 - Transport Information
________________________________________________________________________
RID/ADR
UN#: 1544
Class: 6.1
PG: III
Proper Shipping Name: Alkaloids, solid, n.o.s.
IMDG
UN#: 1544
Class: 6.1
PG: III
Proper Shipping Name: Alkaloids, solid, n.o.s.
Marine Pollutant: No
Severe Marine Pollutant: No
Technical Name: Required
IATA
UN#: 1544
Class: 6.1
PG: III
Proper Shipping Name: Alkaloids, solid, n.o.s.
Inhalation Packing Group I: No
Technical Name: Required
________________________________________________________________________
15 - Regulatory Information
________________________________________________________________________
CLASSIFICATION AND LABELING ACCORDING TO EU DIRECTIVES
INDICATION OF DANGER: T
Toxic.
R-PHRASES: 23/24/25
Toxic by inhalation, in contact with skin and if swallowed.
S-PHRASES: 36/37/39-45
Wear suitable protective clothing, gloves, and eye/face
protection. In case of accident or if you feel unwell, seek
medical advice immediately (show the label where possible).
COUNTRY SPECIFIC INFORMATION
Germany
WGK: 3
Self-Classification
________________________________________________________________________
16 - Other Information
________________________________________________________________________
WARRANTY
The above information is believed to be correct but does not
purport to be all inclusive and shall be used only as a guide. The
information in this document is based on the present state of our
knowledge and is applicable to the product with regard to
appropriate safety precautions. It does not represent any
shall not be held liable for any damage resulting from handling or
from contact with the above product. See reverse side of invoice
or packing slip for additional terms and conditions of sale.
unlimitedpaper copies for internal use only.
DISCLAIMER
For R&D use only. Not for drug, household or other uses.

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模块 15 - 法规信息
N/A

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模块16 - 其他信息
N/A

制备方法与用途

洛贝林是什么

洛贝林（Lobeline），又称山梗菜碱、祛痰菜碱，是从山梗菜中提取的生物碱，是一种中枢兴奋药。它选择性地刺激颈动脉体化学感受器，反射性地引起呼吸中枢、迷走神经中枢和血管运动中枢的兴奋。洛贝林用于治疗新生儿窒息、一氧化碳引起的窒息、吸入麻醉剂及其它中枢抑制药（如阿片、巴比妥类）的中毒以及肺炎、白喉等传染病导致的呼吸衰竭。其不良反应和毒性轻微，安全范围大，不易引起惊厥。使用时应严格控制剂量和用药间隔时间，并密切观察机体反应。

用途

洛贝林用于治疗新生儿窒息、一氧化碳引起的窒息、吸入麻醉剂及其它中枢抑制药（如阿片、巴比妥类）的中毒以及肺炎、白喉等传染病导致的呼吸衰竭。

制备

1. 在搅拌条件下，于室温下依次向反应器中加入左旋洛贝林、无水乙醇和甲基叔丁基醚，混合均匀以制成混合物a；其中，左旋洛贝林与无水乙醇及甲基叔丁基醚的重量比为1:(2~4):(6~12)。

2. 继续搅拌，在混合物a中逐步加入质量百分比浓度为10%~25%氯化氢-乙醇溶液，加入量为左旋洛贝林重量的0.7~1.4倍。随后以2~4°C/min的速率缓慢加热，当出现回流时停止升温，并保温反应0.5~2小时后停止搅拌。

3. 降温至0~5°C后进行析晶4~6小时，过滤得滤饼；

4. 将步骤2得到的滤饼用甲基叔丁基醚及无水乙醇各洗一次，收料。于45-60℃下鼓风干燥，最终获得白色结晶性粉末即为洛贝林。

类别

有毒物质
毒性分级 高度
急性毒性 皮下-大鼠 LD₅₀: 80 毫克/公斤；腹腔-小鼠 LD₅₀: 43.5 毫克/公斤
可燃性危险特性 山梗菜叶含山梗菜碱，不可做茶叶饮用；热分解排出有毒氮氧化物烟雾
储运特性 库房低温通风干燥，与食品原料分开存放
灭火剂 水、二氧化碳、泡沫、干粉

反应信息

• 作为反应物：
  描述：

  洛贝林 在 sodium tetrahydroborate 、 磷酸 作用下， 以 乙醇 为溶剂， 生成 8R-hydroxylobel-9-ene
  参考文献：
  名称：

  Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters

  摘要：

  A series of des-keto lobeline analogs has been synthesized and evaluated for their ability to inhibit the dopamine transporter (DAT) and serotonin transporter (SERT) function and for their affinity for the synaptic vesicle monoamine transporter (VMAT2), as well as for alpha 4 beta 2* and alpha 7* neuronal nicotinic acetylcholine receptors (nAChRs). The enantiomers 8R-hydroxylobel-9-ene (3a) and 10S-hydroxylobel-7-ene (3c) exhibited high potency and selectivity at SERT and DAT, respectively. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.07.070
• 作为产物：
  描述：

  Lobelanine 在 甲酸铵 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 1.0h， 以91%的产率得到洛贝林
  参考文献：
  名称：

  2-[(2R ,6S)-6-[(2S)-2-羟基-2-苯乙基]-1- 甲基哌啶]-1-苯乙酮的合成方法

  摘要：

  本发明公开了2‑[(2R，6S)‑6‑[(2S)‑2‑羟基‑2‑苯乙基]‑1‑甲基哌啶]‑1‑苯乙酮的合成方法，属于有机合成领域。本发明先采用(1S，2S)‑1，2‑二苯基乙二胺为原料经过酰化、取代等三步制备手性胺催化剂；主路线总共两步，采用戊二醛、苯甲酰乙酸、甲胺盐酸盐合成出顺式山梗烷酮，在催化剂的作用下，通过温和的反应条件进行不对称选择性还原合成2‑[(2R，6S)‑6‑[(2S)‑2‑羟基‑2‑苯乙基]‑1‑甲基哌啶]‑1‑苯乙酮。整个工艺路线原料便宜易得，催化剂可以回收继续利用，成本低，工艺简单，反应条件温和，操作方便，总收率高。

  公开号：

  CN106496099B
• 作为试剂：
  描述：

  、 氯化钠 、 氯化钾 、 potassium dihydrogenphosphate 、 magnesium sulfate 、 无水氯化钙 、 葡萄糖 、 抗坏血酸 、 4-羟乙基哌嗪乙磺酸 、 乙二胺四乙酸 、 优降宁 在 洛贝林 、 ice 、 邻苯二酚 作用下， 以 ice 为溶剂， 反应 1.0h， 以to yield true inhibition constants (Ki=IC50/[1+c/Km]), where c的产率得到3H-dopamine
  参考文献：
  名称：

  2,6-disubstituted piperidines and piperazine compounds

  摘要：

  本发明针对具有以下一般式的2,6-二取代哌啶和哌嗪类似物，用于治疗中枢神经系统疾病、药物滥用及其戒断，以及治疗进食障碍。

  公开号：

  US20040266824A1

文献信息

• CONJUGATE-BASED ANTIFUNGAL AND ANTIBACTERIAL PRODRUGS
  申请人：Bapat Abhijit S.

  公开号：US20140364595A1

  公开（公告）日：2014-12-11

  The invention provides conjugate-based antifungal or antibacterial prodrugs formed by coupling at least one anti-fungal agent or antibacterial agent with at least one linker and/or carrier. The prodrugs are of formula: (i) (AFA) m -X-(L) n ; (ii) [(AFA) m′ -X] p -L; (iii) AFA-[X-(L) n′ ] q ; or (iv) (AFA) m″ -X, wherein: AFA is an antifungal agent or an antibacterial agent; L is a carrier; X is a linker; m ranges from 1 to 10; n ranges from 2 to 10; m′ is 1 to 10; p is 1 to 10; n′ is 1 to 10; and q is 1 to 10, provided that q′ and n are not both 1; and m″ is 1 to 10. The invention also provides nanoparticles comprising the conjugate-based prodrugs. Additionally, the invention also provides non-conjugated antifungal and antibacterial agents in the form of nanoparticles.

  该发明提供了由至少一种抗真菌剂或抗菌剂与至少一种连接剂和/或载体偶联形成的基于共轭的抗真菌或抗菌前药。这些前药的公式为：(i) (AFA) m -X-(L) n ; (ii) [(AFA) m′ -X] p -L; (iii) AFA-[X-(L) n′ ] q ; 或 (iv) (AFA) m″ -X，其中：AFA是抗真菌剂或抗菌剂；L是载体；X是连接剂；m范围从1到10；n范围从2到10；m′为1到10；p为1到10；n′为1到10；q为1到10，前提是q'和n不同时为1；m″为1到10。该发明还提供了包含基于共轭的前药的纳米粒子。此外，该发明还提供了以纳米粒子形式的非共轭抗真菌和抗菌剂。
• AZAINDOLE DERIVATIVES WITH A COMBINATION OF PARTIAL NICOTINIC ACETYL-CHOLINE RECEPTOR AGONISM AND DOPAMINE REUPTAKE INHIBITION
  申请人：STOIT Axel

  公开号：US20080009514A1

  公开（公告）日：2008-01-10

  Azaindole derivatives of formula (I): wherein the symbols have the meanings given in the specification, are described. These compounds have a combination of partial nicotinic acetylcholine receptor agonism and dopamine reuptake inhibition. The invention also relates to pharmaceutical compositions containing these compounds, to methods for preparing them, methods for preparing novel intermediates useful for their synthesis, methods for preparing compositions, and uses of such compounds and compositions, for example, their use in administering them to patients to achieve a therapeutic effect in disorders in which nicotinic receptors and/or dopamine transporters are involved, or that can be treated via manipulation of those receptors

  阿扎因多ール衍生物的公式（I）如下： 其中符号的含义如说明书中所给。这些化合物具有部分尼古丁乙酰胆碱受体激动作用和去甲肾上腺素再摄取抑制作用。本发明还涉及包含这些化合物的药物组合物，制造它们的方法，制造用于其合成的新的中间体的方法，制造组合物的方法以及这些化合物和组合物的用途，例如，用于将它们施用于患者以在尼古丁受体和/或去甲肾上腺素转运体涉及的疾病中实现治疗效果，或者可以通过操纵这些受体来治疗的疾病。
• [EN] COMPOSITIONS AND METHODS THEREOF<br/>[FR] COMPOSITIONS ET PROCÉDÉS ASSOCIÉS
  申请人：EXCIVA UG HAFTUNGSBESCHRAENKT

  公开号：WO2018039642A1

  公开（公告）日：2018-03-01

  Compounds of formula I, (I) or enantiomers thereof, metabolites thereof, derivatives thereof, deuterated derivatives thereof, halogenated derivatives thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, N- oxides thereof, or a combination thereof, processes and intermediates for preparation thereof, compositions thereof, and uses thereof, are provided. Pharmaceutical compositions comprising a compound of formula I and a compound of Formula II: (IIa) (IIb) or enantiomers thereof, metabolites thereof, derivatives thereof, deuterated derivatives thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination thereof. Compositions and methods for improving the efficacy of DEX, or providing beneficial pharmacokinetic effects to DEX, comprising co-administering a compound of formula I or SARPO, and a compound of Formula II or DEX to a subject in need thereof, and dosage forms, drug delivery systems, methods of treatment thereof.

  提供具有公式I的化合物(I)或其对应异构体、代谢物、衍生物、氘化衍生物、卤化衍生物、前药、药用可接受盐、N-氧化物或其组合，以及它们的制备过程和中间体、组合物和使用方法。包含公式I化合物的药物组合物以及公式II的化合物(IIa) (IIb)或其对应异构体、代谢物、衍生物、氘化衍生物、前药、药用可接受盐、N-氧化物或其组合。包含共给予需要该物质的受试者公式I化合物或SARPO和公式II化合物或DEX的DEX效能改进或提供DEX有益药代动力学效果的组合物和方法，以及剂量形式、药物传递系统、治疗方法。
• Hydroxylated nebivolol metabolites
  申请人：O'Donnell P. John

  公开号：US20070014733A1

  公开（公告）日：2007-01-18

  Hydroxylated nebivolol metabolites increase NO release from human endothelial cell preparations in a concentration dependent fashion following acute administration. In addition, hydroxylated nebivolol metabolites, including but not limited to 4-hydroxy-6,6′difluoro-, 4-hydroxy-5-phenol-6,6′difluoro-, and 4-hydroxy-8-pheno-6,6′difluoro-, have the ability to increase the capacity for NO release in human endothelial cells following chronic administration. This invention provides hydroxylated nebivolol metabolites and compositions comprising nebivolol and/or at least one hydroxylated metabolite of nebivolol and/or at least one additional compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof. In addition, this invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol that is capable of releasing a therapeutically effective amount of nitric oxide to a targeted site affected by the vascular disease. Also, this invention is directed to the treatment and/or prevention of migraine headaches administering at least one hydroxylated metabolite of nebivolol. This invention may also be used in conjunction with or as a single treatment of metabolic syndrome disorders.

  羟基化奈必洛尔代谢物在急性给药后以浓度依赖性方式增加人内皮细胞制剂的一氧化氮释放。此外，羟基化奈必洛尔代谢物，包括但不限于4-羟基-6,6'-二氟代-、4-羟基-5-苯酚-6,6'-二氟代-和4-羟基-8-苯并-6,6'-二氟代-，在慢性给药后能够增加人内皮细胞的一氧化氮释放能力。本发明提供了羟基化奈必洛尔代谢物和包含奈必洛尔和/或至少一种羟基化奈必洛尔代谢物和/或至少一种用于治疗心血管疾病的附加化合物的组合物，以及可药用的盐。此外，本发明还提供了通过给药至少一种能够释放治疗有效量的一氧化氮到受血管疾病影响的靶向部位的羟基化奈必洛尔代谢物来治疗和/或预防血管疾病的方法。本发明还涉及通过给药至少一种羟基化奈必洛尔代谢物来治疗和/或预防偏头痛。本发明还可以与治疗代谢综合征障碍的其他治疗联合使用，或作为单一治疗。
• Nitric Oxide Releasing Prodrugs of Therapeutic Agents
  申请人：SATYAM Apparao

  公开号：US20110263526A1

  公开（公告）日：2011-10-27

  The present invention relates to nitric oxide releasing prodrugs of known drugs or therapeutic agents which are represented herein as compounds of formula (I) wherein the drugs or therapeutic agents contain one or more functional groups independently selected from a carboxylic acid, an amino, a hydroxyl and a sulfhydryl group. The invention also relates to processes for the preparation of the nitric oxide releasing prodrugs (the compounds of formula (I)), to pharmaceutical compositions containing them and to methods of using the prodrugs.

  本发明涉及已知药物或治疗剂的一氧化氮释放前药，其在此处表示为式(I)的化合物，其中药物或治疗剂包含一个或多个功能基团，独立地选自羧酸、氨基、羟基和巯基。该发明还涉及制备一氧化氮释放前药（式(I)的化合物）的方法，含有它们的药物组合物以及使用这些前药的方法。