阿伐斯汀 | 87848-99-5

• 物质功能分类: 原料药 - 抗变态反应药 - 抗组胺药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 阿伐斯汀
• 中文别名: 阿伐司丁；(E)-3-[6-[(E)-1-(4-甲基苯基)-3-吡咯烷-1-基丙-1-烯基]吡啶-2-基]-2-丙烯酸
• 英文名称: acrivastine
• 英文别名: (E)-3-[6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-1-ium-1-ylprop-1-enyl]pyridin-2-yl]prop-2-enoate
• CAS: 87848-99-5
• 化学式: C₂₂H₂₄N₂O₂
• 分子量: 348.445
• InChiKey: PWACSDKDOHSSQD-IUTFFREVSA-N

物化性质

• 熔点：
  222° (dec)
• 沸点：
  555.1±50.0 °C(Predicted)
• 密度：
  1.170±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：>2mg/mL（加热）
• 碰撞截面：
  193.9 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  53.4
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

毒理性

• 肝毒性

阿昔伐司汀尚未与肝酶升高或临床明显的肝损伤病例相关联。其相对安全性可能与其快速代谢和低剂量使用有关。 可能性评分：E（不太可能是临床明显肝损伤的原因）。 关于抗组胺药的安全性和潜在肝毒性的参考文献，在抗组胺药概述部分之后一起给出。 药物类别：抗组胺药

Acrivastine has not been linked to liver enzyme elevations or to instances of clinically apparent liver injury. Its relative safety may relate to its rapid metabolism and use in low dosages. Likelihood score: E (unlikely cause of clinically apparent liver injury). References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines. Drug Class: Antihistamines

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：偶尔小剂量的阿克利瓦斯蒂尼不会预期对哺乳婴儿产生任何不良影响。较大剂量或更长时间的使用可能会导致婴儿出现嗜睡和其他效果，或者减少乳汁供应，特别是与伪麻黄碱等拟交感神经药合用时，或者在哺乳期尚未建立时。首选非镇静抗组胺药作为替代品。 对哺乳婴儿的影响：截至修订日期，没有找到关于阿克利瓦斯蒂尼的相关已发布信息。在一项电话随访研究中，母亲报告有10%的婴儿接触到各种抗组胺药后出现烦躁和肠绞痛症状，1.6%的婴儿出现嗜睡。所有反应均无需医疗关注。 对哺乳和乳汁的影响：在非哺乳期妇女和产后早期妇女中，相对高剂量的抗组胺药通过注射可以降低基础血清催乳素。然而，哺乳诱导的催乳素分泌不会受到产后母亲抗组胺药预处理的影响。尚未研究较低口服剂量的抗组胺药是否对血清催乳素有相同的影响，或者催乳素的影响是否对哺乳成功有任何后果。在已建立哺乳的母亲中，催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Small occasional doses of acrivastine would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use may cause drowsiness and other effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. The nonsedating antihistamines are preferred alternatives. ◉ Effects in Breastfed Infants:Relevant published information on acrivastine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention. ◉ Effects on Lactation and Breastmilk:Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

阿昔洛韦与人体血浆蛋白的结合率为50 ± 2.0%。

Acrivastine binding to human plasma proteins was 50 ± 2.0%.

来源:DrugBank

吸收、分配和排泄

• 吸收

阿昔伐司汀在口服给药后从复合胶囊中迅速吸收，并且与阿昔伐司汀溶液的生物利用度相当。在给予SEMPREX-D胶囊后，阿昔伐司汀的最大血浆浓度在1.14 ± 0.23小时内达到。

Acrivastine was absorbed rapidly from the combination capsule following oral administration and was as bioavailable as a solution of acrivastine. After administration of SEMPREX-D Capsules, maximum plasma acrivastine concentrations were achieved at 1.14 ± 0.23 hour.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在一项对7名健康志愿者的质量平衡研究中，发现阿克里瓦斯蒂主要是通过肾脏消除的。在72小时的收集期内，约84%的给药总放射性在尿液中回收，约13%在粪便中回收，总回收率约为97%。

A mass balance study in 7 healthy volunteers showed that acrivastine is primarily eliminated by the kidneys. Over a 72-hour collection period, about 84% of the administered total radioactivity was recovered in urine and about 13% in feces, for a combined recovery of about 97%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.46 ± 0.05 升/千克

0.46 ± 0.05 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

2.9 ± 0.7 毫升/分钟/千克

2.9 ± 0.7 mL/min/kg

来源:DrugBank

安全信息

• WGK Germany：
  3
• 安全说明：
  S37/39
• 危险品运输编号：
  NONH for all modes of transport
• 危险品标志：
  Xn,Xi
• 危险类别码：
  R22,R43
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8°C

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : Acrivastine
CAS-No. : 87848-99-5
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Not a hazardous substance or mixture according to Regulation (EC) No. 1272/2008.
This substance is not classified as dangerous according to Directive 67/548/EEC.
Label elements
The product does not need to be labelled in accordance with EC directives or respective national laws.
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
Synonyms : (E)-6-((E)-3-(1-Pyrrolidinyl)-1-p-tolylpropenyl)-2-pyridineacrylic acid
Formula : C22H24N2O2
Molecular Weight : 348,44 g/mol

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Section 4. FIRST AID MEASURES
Description of first aid measures
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration.
In case of skin contact
Wash off with soap and plenty of water.
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.
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)
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
Avoid dust formation. Avoid breathing vapors, mist or gas.
Environmental precautions
Do not let product enter drains.
Methods and materials for containment and cleaning up
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
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
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
General industrial hygiene practice.
Personal protective equipment
Eye/face protection
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
Choose body protection in relation to its type, to the concentration and amount of dangerous
substances, and to the specific work-place., The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Respiratory protection is not required. Where protection from nuisance levels of dusts are desired,
use type N95 (US) or type P1 (EN 143) dust masks. 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- log Pow: 4,243
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 May be 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: UD3474000

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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.
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
N/A

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

第二代抗组胺药物

阿伐斯汀是一种吡咯胺类结构的第二代抗组胺药物，是竞争性组织胺H1受体拮抗剂。它由英国Glaxo-Wellcome公司研发，作为曲谱利定的衍生物，能与组胺竞争结合效应细胞上的H1受体，从而抑制组胺引起的过敏反应。

阿伐斯汀不易通过血一脑脊液屏障，因此一般不会引起嗜睡或其他不良反应。其治疗慢性荨麻疹疗效观察报告指出，阿伐斯汀的血浆半衰期短，药物不容易积蓄，且副作用较轻，无口干现象，患者易接受，有利于长期服药。

临床研究显示，阿伐斯汀治疗慢性荨麻疹效果显著，临床效果优于氯雷他定，并能更好改善患者的症状。

药理作用

阿伐斯汀是一种中等强度的竞争性组织胺H1受体拮抗剂，属于20世纪80年代末由葛兰素威康公司推出的酚嗪类抗组胺药物。它具有选择性地阻断组胺H1受体的作用，没有明显抗胆碱作用，并且对中枢神经系统的穿透能力低。

阿伐斯汀可通过完全或部分阻止组织胺释放而缓解相关症状，不易通过血脑屏障，无镇静作用。口服吸收良好，1.5小时达到血药峰值，大部分原形药物经肾排泄，少部分经肝代谢，代谢产物仍具活性，由尿排出。阿伐斯汀适用于治疗过敏性鼻炎、枯草热、荨麻疹、湿疹及皮肤瘙痒症等。

适应症

阿伐斯汀用于治疗以下疾病：

• 过敏性鼻炎
• 过敏性皮肤疾病
• 慢性自发性荨麻疹
• 症状性皮肤划痕症
• 胆碱性荨麻疹
• 自发的后日性寒冷感冒荨麻疹
• 湿疹瘙痒

生物活性

Acrivastine (BW825C) 是一种用于研究过敏性鼻炎的短效histamine 1受体拮抗剂。

体内研究

阿伐斯汀在治疗慢性荨麻疹和过敏性鼻炎方面表现出良好的疗效，效果优于安慰剂，并与氯雷他定相当。在治疗由组胺引起的皮肤病时，其疗效优于安慰剂，并类似通常剂量的氯苯那敏、异丙嗪、盐酸赛庚啶或特非那丁的效果。

阿伐斯汀比氯苯那敏引起的嗜睡少得多，不良反应的发生率与安慰剂或特非那丁相当。4毫克和8毫克的阿伐斯汀均能显著缓解季节性过敏性鼻炎的症状，并改善打喷嚏、流鼻涕等症状，同时减少流泪和喉咙痒的症状。

化学性质

从异丙醇结晶，熔点222℃（分解）。

用途

竞争性H1受体拮抗剂。适用于治疗：

• 过敏性鼻炎
• 花粉病
• 慢性原发性荨麻疹
• 皮肤划痕症
• 拟副交感神经性荨麻疹
• 特异性风冷型荨麻疹

生产方法

从2，6-二溴吡啶、4-甲基苯甲腈、EtO2CH2P(O)(Oet)2和(2-吡咯烷基乙基)三苯基膦溴化物经过五步反应得到。

反应信息

• 作为反应物：
  描述：

  阿伐斯汀 在 水 、 碘 、 碳酸氢钠 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成
  参考文献：
  名称：

  无过渡金属的胺氧化：内酰胺后期形成的化学选择性策略

  摘要：

  描述了通过选择性氧化环状仲和叔胺形成内酰胺的无金属策略。分子碘促进与环胺直接相邻的C–H键的化学选择性和区域选择性氧化。使用包括临床批准的药物支架在内的各种多样的小分子环胺，证明了其温和的条件，官能团耐受性和底物范围。

  DOI：

  10.1021/acs.orglett.7b00021
• 作为产物：
  描述：

  2-溴-6-[2-(4-甲基苯基)-1,3-二氧戊环-2-基]吡啶 在 盐酸 、 sodium hydroxide 、 正丁基锂 、 sodium hydride 作用下， 以 乙醚 、 正己烷 为溶剂， 反应 8.33h， 生成 阿伐斯汀
  参考文献：
  名称：

  Triprolidine放射免疫分析：在动物和人类中的配置。

  摘要：

  合成了三吡咯烷的半抗原衍生物，其在吡啶环氮原子旁带有丙烯酸侧链，并与牛血清白蛋白偶联。用所得的药物-蛋白质缀合物免疫新西兰白兔导致产生抗血清，该抗血清能够以高抗血清稀释度（1：70,000-1：150,000）结合雷公藤半抗原衍生物的放射性碘化酪胺缀合物。这些抗血清用于开发人类血浆中曲普利定的放射免疫分析（RIA），灵敏度极限为0.1 ng / mL（实际质量为0.01 ng）。已知的三氢吡啶的羟甲基和羧基代谢产物与该抗血清的交叉反应较弱（分别小于2％和小于0.05％）。RIA可以用于人和兔血浆中曲普利定的直接分析，但不适用于大鼠或狗血浆，大概是由于存在其他干扰物质（可能是代谢物）。通过定量TLC（r = 0.985，斜率= 1.076）对许多样品进行比较分析，证明了RIA方法在人血浆中的有效性。该测定法用于描述曲普利定在兔中的药代动力学（t 1/2，β= 1.7 h）。该测定具有足够的灵

  DOI：

  10.1002/jps.2600731003

文献信息

• [EN] 3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS 3,5-DIAMINO -6-CHLORO-N-(N- (4-PHÉNYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2-CARBOXAMIDE
  申请人：PARION SCIENCES INC

  公开号：WO2014099673A1

  公开（公告）日：2014-06-26

  The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

  本发明涉及以下化合物的公式：或其药学上可接受的盐，用作钠通道阻滞剂，以及含有这些化合物的组合物，制备这些化合物的方法，以及在促进粘膜表面水合和治疗包括囊性纤维化、慢性阻塞性肺病、哮喘、支气管扩张、急性和慢性支气管炎、肺气肿和肺炎等疾病的治疗方法。
• CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
  申请人：Parion Sciences, Inc.

  公开号：US20140171447A1

  公开（公告）日：2014-06-19

  This invention provides compounds of the formula I: and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.

  这项发明提供了式I的化合物及其药用盐，可用作钠通道阻滞剂，包含这些化合物的组合物，以及用于这些化合物的治疗方法和用途，以及制备这些化合物的方法。
• Dual Pharmacophores - PDE4-Muscarinic Antagonistics
  申请人：Callahan James Francis

  公开号：US20090203657A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.

  本发明涉及具有式（I）的新化合物及其药用盐，药物组合物及其用作对PDE4和肌胆碱受体（mAChRs）具有抑制活性的双色素，因此可用于治疗呼吸道疾病。
• [EN] DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS<br/>[FR] PHARMACOPHORES DUALS, ANTAGONISTES DES RÉCEPTEURS MUSCARINIQUES ET INHIBITEURS DE L'ACTIVITÉ PDE4
  申请人：GLAXO GROUP LTD

  公开号：WO2009100169A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.

  本发明涉及式(I) - (VI)的新化合物，以及其药学上可接受的盐、药物组合物及其在治疗中的应用，例如作为磷酸二酯酶IV (PDE4)的抑制剂和肌碱乙酰胆碱受体 (mAChRs)的拮抗剂，用于治疗和/或预防呼吸道疾病，包括炎症性和/或过敏性疾病，如慢性阻塞性肺病（COPD）、哮喘、鼻炎（例如过敏性鼻炎）、特应性皮炎或银屑病。
• [EN] PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS<br/>[FR] DÉRIVÉS DE PYRROLOTRIAZINONE EN TANT QU'INHIBITEURS DES PI3K
  申请人：ALMIRALL SA

  公开号：WO2014060432A1

  公开（公告）日：2014-04-24

  New pyrrolotriazinone derivatives having the chemical structure of formula (I), are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks)

  新的吡咯三唑酮衍生物具有化学结构式（I），公开；以及它们的制备方法，包括它们的药物组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的应用。