胆茶碱 | 4499-40-5

• 物质功能分类: 原料药 - 呼吸系统用药 - 平喘药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 胆茶碱
• 中文别名: 1,3-二甲基黄嘌呤胆碱盐；三羟甲基氨基甲烷
• 英文名称: 1,3-dimethyl-2-oxopurin-6-olate,2-hydroxyethyl(trimethyl)azanium
• 英文别名: choline theophyllinate；Oxtriphylline；(2-hydroxyethyl)trimethylazanium 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-ide；1,3-dimethyl-3,7-dihydro-purine-2,6-dione, theophylline; choline salt；1,3-Dimethyl-3,7-dihydro-purin-2,6-dion, Theophyllin; Cholin-Salz；choline theophylline
• CAS: 4499-40-5
• 化学式: C₅H₁₄NO*C₇H₇N₄O₂
• 分子量: 283.33
• InChiKey: RLANKEDHRWMNRO-UHFFFAOYSA-M

物化性质

• 熔点：
  176-178 °C
• 溶解度：
  PBS（pH 7.2）：10 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  -1.73
• 重原子数：
  20.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  91.22
• 氢给体数：
  1.0
• 氢受体数：
  6.0

安全信息

• 海关编码：
  2933990090
• 储存条件：
  -20°C，密闭保存，干燥条件

SDS

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Section 1. Chemical Product and Company Identification
Oxtriphylline
Common Name/
Trade Name
Oxtriphylline

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Section 3. Hazards Identification
Potential Acute Health Effects Slightly hazardous in case of skin contact (irritant), of eye contact (irritant), of ingestion, of inhalation.
Potential Chronic Health CARCINOGENIC EFFECTS: Not available.
Effects MUTAGENIC EFFECTS: Not available.
TERATOGENIC EFFECTS: Not available.
DEVELOPMENTAL TOXICITY: Not available.
Repeated or prolonged exposure is not known to aggravate medical condition.

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Section 4. First Aid Measures
Eye Contact Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at
least 15 minutes. Get medical attention if irritation occurs.
Skin Contact Wash with soap and water. Cover the irritated skin with an emollient. Get medical attention if irritation develops.
Serious Skin Contact Not available.
Inhalation If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get
medical attention.
Serious Inhalation Not available.
Ingestion Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an
unconscious person. If large quantities of this material are swallowed, call a physician immediately. Loosen tight
clothing such as a collar, tie, belt or waistband.
Serious Ingestion Not available.

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Section 5. Fire and Explosion Data
Flammability of the Product May be combustible at high temperature.
Auto-Ignition Temperature Not available.
Flash Points CLOSED CUP: Higher than 93.3°C (200°F).
Flammable Limits Not available.
These products are carbon oxides (CO, CO2), nitrogen oxides (NO, NO2...).
Products of Combustion
Fire Hazards in Presence of Slightly flammable to flammable in presence of heat.
Various Substances
Explosion Hazards in Presence Risks of explosion of the product in presence of mechanical impact: Not available.
of Various Substances Risks of explosion of the product in presence of static discharge: Not available.
Fire Fighting Media SMALL FIRE: Use DRY chemical powder.
and Instructions LARGE FIRE: Use water spray, fog or foam. Do not use water jet.
Special Remarks on As with most organic solids, fire is possible at elevated temperatures Material in powder form, capable of creating
Fire Hazards a dust explosion.
Special Remarks on Explosion Excess dust generation may create explosion hazard.
Hazards
Oxtriphylline

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Section 6. Accidental Release Measures
Small Spill Use appropriate tools to put the spilled solid in a convenient waste disposal container. Finish cleaning by
spreading water on the contaminated surface and dispose of according to local and regional authority
requirements.
Large Spill Use a shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water
on the contaminated surface and allow to evacuate through the sanitary system.

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Section 7. Handling and Storage
Precautions Keep away from heat. Keep away from sources of ignition. Empty containers pose a fire risk, evaporate the
residue under a fume hood. Ground all equipment containing material. Do not ingest. Do not breathe dust.
Wear suitable protective clothing. In case of insufficient ventilation, wear suitable respiratory equipment. If
ingested, seek medical advice immediately and show the container or the label.
Keep container tightly closed. Keep container in a cool, well-ventilated area. Do not store above 23°C (73.4°F).
Storage

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Section 8. Exposure Controls/Personal Protection
Engineering Controls Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below
recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to
airborne contaminants below the exposure limit.
Personal Protection Safety glasses. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Gloves.
Personal Protection in Case of Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used
a Large Spill to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist
BEFORE handling this product.
Exposure Limits Not available.

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Section 9. Physical and Chemical Properties
Physical state and appearance Solid. (Powdered solid.) Odor Amino like.
Not available.
Taste
Molecular Weight 283.33 g/mole
White.
Color
Not applicable.
pH (1% soln/water)
Boiling Point Not available.
185°C (365°F) - 189 C.
Melting Point
Critical Temperature Not available.
Specific Gravity 0.5 (Water = 1)
Not applicable.
Vapor Pressure
Vapor Density Not available.
Not available.
Volatility
Odor Threshold Not available.
Water/Oil Dist. Coeff. Not available.
Ionicity (in Water) Not available.
Dispersion Properties Not available.
Solubility Insoluble in cold water, hot water.
Oxtriphylline

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Section 10. Stability and Reactivity Data
The product is stable.
Stability
Instability Temperature Not available.
Excess heat, excess dust generation, incompatible materials.
Conditions of Instability
Not available.
Incompatibility with various
substances
Corrosivity Not available.
Special Remarks on Not available.
Reactivity
Special Remarks on Not available.
Corrosivity
Polymerization Will not occur.

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Section 11. Toxicological Information
Routes of Entry Inhalation. Ingestion.
Toxicity to Animals Acute oral toxicity (LD50): 210 mg/kg [Guinea pig].
Chronic Effects on Humans Not available.
Other Toxic Effects on Slightly hazardous in case of skin contact (irritant), of ingestion, of inhalation.
Humans
Special Remarks on Not available.
Toxicity to Animals
Special Remarks on Not available.
Chronic Effects on Humans
Special Remarks on other Acute Potential Health Effects:
Toxic Effects on Humans Skin: May cause skin irritaiton.
Eyes: May cause eye irritation.
Inhalation: May cause respiratory tract and mucous membrane irritation.
Ingestion: May be harmful if swallowed. May cause gastrointestinal tract irritation with nausea and vomiting. May
affect behavior/central nervous system (tremor, excitement), metabolism (metabolic acidosis), endocrine system
(pancreas - hyperglycemia), and urinary system.
Chronic Potential Health Effects: no information found.

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Section 12. Ecological Information
Ecotoxicity Not available.
BOD5 and COD Not available.
Products of Biodegradation Possibly hazardous short term degradation products are not likely. However, long term degradation products may
arise.
Toxicity of the Products The products of degradation are less toxic than the product itself.
of Biodegradation
Special Remarks on the Not available.
Products of Biodegradation
Oxtriphylline

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Section 13. Disposal Considerations
Waste Disposal Waste must be disposed of in accordance with federal, state and local environmental
control regulations.

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Section 14. Transport Information
DOT Classification Not a DOT controlled material (United States).
Not applicable.
Identification
Not applicable.
Special Provisions for
Transport
DOT (Pictograms)

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Section 15. Other Regulatory Information and Pictograms
No products were found.
Federal and State
Regulations
California California prop. 65: This product contains the following ingredients for which the State of California has found
to cause cancer which would require a warning under the statute: No products were found.
Proposition 65
Warnings
California prop. 65: This product contains the following ingredients for which the State of California has found
to cause birth defects which would require a warning under the statute: No products were found.
Other Regulations EINECS: This product is on the European Inventory of Existing Commercial Chemical Substances (EINECS No.
224-798-7).
Canada: Listed on Canadian Domestic Substance List (DSL).
China: Not listed on National Inventory.
Japan: Not listed on National Inventory (ENCS).
Korea: Listed on National Inventory (KECI).
Philippines: Not listed on National Inventory (PICCS).
Australia: Listed on AICS.
WHMIS (Canada) Not controlled under WHMIS (Canada).
Other Classifications
DSCL (EEC) R22- Harmful if swallowed. S46- If swallowed, seek medical advice
immediately and show this container or label.
Health Hazard
HMIS (U.S.A.) 1 National Fire Protection
1 Flammability
1 Association (U.S.A.)
Fire Hazard
1 0 Reactivity
Health
Reactivity
0
Specific hazard
Personal Protection
E
WHMIS (Canada)
(Pictograms)
DSCL (Europe)
(Pictograms)
Oxtriphylline
TDG (Canada)
(Pictograms)
ADR (Europe)
(Pictograms)
Protective Equipment
Gloves.
Lab coat.
Dust respirator. Be sure to use an
approved/certified respirator or
equivalent.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

药性与应用

胆茶碱

胆茶碱是一种由茶碱与胆碱按等分子比例组成的化合物，具有较高的溶解度和较小的刺激性。它口服吸收迅速且维持时间较长，作用类似于氨茶碱，能够松弛支气管和平滑肌、强心及利尿。虽然其支气管扩张作用较弱，对心脏和神经系统的副作用较少，但依然适用于治疗支气管哮喘、心源性哮喘、心绞痛、胆绞痛以及心脏性水肿等疾病。不过，它不适用于哮喘持续状态或急性支气管痉挛发作的情况。

茶碱

茶碱（theophylline）已有超过五十年的使用历史，在全球范围内广泛应用于治疗哮喘，仍然是许多国家和地区首选的平喘药物。尽管对慢性哮喘的疗效仍有争议，一些发达国家将其列为第三线用药。近年来的研究发现小剂量茶碱具有抗炎和免疫调节作用，再次引起了人们对茶碱的兴趣。

茶碱类药物的药理作用非常广泛，除了舒张支气管平滑肌外，还能兴奋呼吸中枢、增强膈肌收缩力、强心利尿，并降低肺血管压力及减少肺部液体渗出。此外，研究表明它还有抗炎、免疫调节和支气管保护作用，如抑制炎症细胞（包括T淋巴细胞、嗜酸性粒细胞、肥大细胞和巨噬细胞等）的活化；阻止外周血中T淋巴细胞向气道内转移；干扰肿瘤坏死因子（TNF-α）活性，减少由其引发的高反应性及诱导人外周血B细胞凋亡。

目前临床应用的茶碱主要分为四类：

1. 与不同盐或碱基结合的茶碱，如氨茶碱和胆茶碱。
2. 茶碱N-7位上以不同基团取代的衍生物，这类药物虽然水溶性增加但半衰期缩短、作用强度不如茶碱，主要针对对茶碱或氨茶碱不耐受的患者。
3. 恩丙茶碱（enprophylline），为一种由3-丙基取代茶碱3-甲基的新开发黄嘌呤衍生物。
4. 茶碱缓释剂或控释剂，能够提供较为稳定的血药浓度。

单纯使用茶碱制剂的吸收迅速，会导致明显波动的血药浓度、短暂的支气管扩张作用及较多不良反应；而缓释剂或控释剂则能提供较稳定的血药浓度。

生物活性

Choline theophyllinate（Oxtriphylline） 是茶碱与胆碱形成的盐，具有抗哮喘的作用。

化学性质

白色结晶性粉末，熔点为187-192℃。易溶于水、乙醇，微溶于乙醚和氯仿，略带胺味且有咸苦感。

用途

与茶碱相同，用于治疗心脏性和支气管性哮喘以及心脏性肾脏性水肿等症。

生产方法

由茶碱与胆碱缩合得到。

反应信息

• 作为反应物：
  描述：

  二正丁基氧化锡 、 胆茶碱 以 甲醇 、 苯 为溶剂， 反应 4.0h， 以68%的产率得到
  参考文献：
  名称：

  Synthesis, characterization and biological activity of diorgano and triorganotin (IV) complexes of Chlordiazepoxide, Choline theophyllinate and Phenobarbitone sodium

  摘要：

  In an attempt to develop novel metal-based drugs with a different therapeutic profile to cisplatin, a new series of diorganotin (IV) and triorganotin (IV) complexes of R(2)SnA(2) (R = Me, n-Bu, n-Oct and Phenyl) and R(3)SnA(2) (R = n-Bu) where A is the anion of Chlordiazepoxide ((LH)-H-1) {(2Z)-7-chloro-2-(methylimino)-5-phenyl-3,4-dihydro-2H-1,4-benzodiazepin-4-ol}, Choline theophyllinate ((LH)-H-2) {(2-hydroxyethyl)trimethylazanium; 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-ide} and Phenobarbitone sodium ((LH)-H-3) {5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione} have been synthesized. These resulting complexes were characterized by elemental analysis, UV, IR, NMR (H-1, C-13 and Sn-119) studies. On the basis of these spectroscopic studies, it was proposed that diorganotin (IV) complexes of Chlordiazepoxide, Choline theophyllinate and Phenobarbitone sodium having 1: 2 stoichiometry show tetrahedral geometry. Triorganotin (IV) complexes of Chlordiazepoxide and Choline theophyllinate having 1: 2 stoichiometry show trigonal bipyramidal geometry. The ligand molecules in these complexes appear to be bound to the tin atom through the hydroxyl oxygen in Chlordiazepoxide, Choline theophyllinate and Phenobarbitone sodium. The biological activity of all these complexes was screened against six indicator strains: Bacteriodes fragilis, Salmonella enterica, Listeria monocytogenes, Pseudomonas aeruginosa, Escherichia coli and Vibrio cholerae. The antibacterial activity is found maximum for n-Bu2Sn(L-2)(2) which is most effective against all indicator strains used. n-Bu2Sn(L-1)(2) is effective against Pseudomonas aeruginosa and Vibrio cholerae while Me2Sn(L-3)(2) and Ph2Sn(L-3)(2) show good inhibitions against Bacteriodes fragilis and Salmonella enterica. (C) 2014 Elsevier B. V. All rights reserved.

  DOI：

  10.1016/j.jorganchem.2013.12.020

文献信息

• [EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017197240A1

  公开（公告）日：2017-11-16

  Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

  本文提供了ASH1L活性的小分子抑制剂，促进ASH1L降解的小分子以及它们的使用方法，用于治疗疾病，包括急性白血病、实体肿瘤和其他依赖于ASH1L活性的疾病。
• CONJUGATES OF CEREBLON BINDING COMPOUNDS AND G12C MUTANT KRAS, HRAS OR NRAS PROTEIN MODULATING COMPOUNDS AND METHODS OF USE THEREOF
  申请人：Araxes Pharma LLC

  公开号：US20180015087A1

  公开（公告）日：2018-01-18

  Conjugates of a cereblon-binding compound and compounds having modulatory activity against G12C mutant KRAS, HRAS or NRAS G12C proteins are provided. Methods associated with preparation and use of such conjugates, pharmaceutical compositions comprising such conjugates and methods to modulate the activity of G12C mutant KRAS, HRAS or NRAS G12C proteins for treatment of disorders, such as cancer, are also provided.

  提供了与谷氨酰脑结合化合物和具有调节活性对抗G12C突变KRAS、HRAS或NRAS G12C蛋白的化合物的共轭物。还提供了与制备和使用这种共轭物相关的方法，包括含有这种共轭物的药物组合物以及调节G12C突变KRAS、HRAS或NRAS G12C蛋白活性的方法，用于治疗癌症等疾病。
• [EN] METHODS AND COMPOSITIONS FOR INHIBITION OF RAS<br/>[FR] MÉTHODES ET COMPOSITIONS PERMETTANT L'INHIBITION DE LA RAS
  申请人：ARAXES PHARMA LLC

  公开号：WO2016049568A1

  公开（公告）日：2016-03-31

  Inhibitors of Ras protein, methods to modulate the activity of Ras protein, and methods of treatment of disorders mediated by Ras protein are provided. A method for regulating activity of a K-Ras, H-Ras or N-Ras mutant protein with a compound is described. Disorders that can be treated include cancer, such as hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer, or lung cancer.

  提供了Ras蛋白的抑制剂，调节Ras蛋白活性的方法，以及通过Ras蛋白介导的疾病治疗方法。描述了一种使用化合物调节K-Ras、H-Ras或N-Ras突变蛋白活性的方法。可治疗的疾病包括癌症，如血液癌症、胰腺癌、MYH相关性息肉症、结直肠癌或肺癌。
• [EN] INHIBITORS OF KRAS G12C<br/>[FR] INHIBITEURS DE K-RAS G12C
  申请人：ARAXES PHARMA LLC

  公开号：WO2015054572A1

  公开（公告）日：2015-04-16

  Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

  提供了作为G12C突变KRAS蛋白抑制剂活性的化合物。这些化合物具有以下结构（I）：或其药用可接受的盐、互变异构体、前药或立体异构体，其中R1、R2a、R3a、R3b、R4a、R4b、G1、G2、L1、L2、m1、m2、A、B、W、X、Y、Z和E如本文所定义。还提供了与制备和使用这些化合物相关的方法，包括含有这些化合物的药物组合物以及调节G12C突变KRAS蛋白活性以治疗癌症等疾病的方法。
• [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。