4-氨基吡啶 | 504-24-5

• 物质功能分类: 医药中间体 - 吡啶类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 4-氨基吡啶
• 中文别名: 4-胺吡啶；鸟安定；达伐吡啶；4-吡啶胺；对氨基吡啶；4-氨基氮杂苯；氨吡啶
• 英文名称: 4-aminopyridine
• 英文别名: pyridin-4-ylamine；pyridin-4-amine；4-AP；pyridine-4-amine；p-aminopyridine；4‐aminopyridine；4-pyridylamine；dalfampridine
• CAS: 504-24-5；29212-32-6；916979-36-7
• 化学式: C₅H₆N₂
• mdl: MFCD00006439
• 分子量: 94.116
• InChiKey: NUKYPUAOHBNCPY-UHFFFAOYSA-N

物化性质

• 熔点：
  155-158 °C (lit.)
• 沸点：
  273 °C (lit.)
• 密度：
  1.26
• 闪点：
  156°C
• 溶解度：
  在水中的溶解度为50mg/mL，透明，无色
• LogP：
  -0.76 at pH7.4
• 物理描述：
  Pyridine, 4-amino- is a white crystalline material with no odor. Used as an avicide, an intermediate and as a fixer for some textile dyes. (EPA, 1998) It has been approved by the FDA for use as a treatment for multiple sclerosis.
• 颜色/状态：
  White crystals
• 气味：
  Odorless
• 蒸汽压力：
  2.09X10-4 mm Hg at 20 °C
• 稳定性/保质期：

  Stable under recommended storage conditions.

• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa = 9.17
• 碰撞截面：
  117.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 保留指数：
  1170

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  7
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  38.9
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

由于未广泛被肝脏代谢，因此预计与dalfampridine同时给药的影响细胞色素P450酶系统的药物不会相互影响。代谢物包括3-羟基-4-氨基吡啶和3-羟基-4-氨基吡啶硫酸盐，两者均无活性。CYP2E1是负责dalfampridine的3-羟基化的酶。

Not extensively metabolized by the liver therefore drugs effecting the cytochrome P450 enzyme system that are concomitantly administered with dalfampridine are not expected to interact with each other. Metabolites include 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate and both are inactive. CYP2E1 is the enzyme responsible for 3-hydroxylation of dalfampridine.

来源:DrugBank

代谢

fampridine的特定代谢酶在实验动物中未被识别，但根据人类微体研究；有人提出CYP2E1可能是人类羟基化的原因。在大鼠中，大约36%的母药通过肝脏首过代谢被去除。Fampridine主要通过羟基化代谢，然后进行硫酸盐结合。在鼠标、大鼠、家兔、犬和人类血浆中检测到两种循环代谢物：3-羟基-4-AP和3-羟基-4-AP硫酸盐。尽管这些代谢物在所有物种中都被鉴定出来，但在大鼠和犬中的代谢比人类更广泛。在鼠标和大鼠血浆中，还证明了4-AP-N-氧化物也是一种循环代谢物。在人类血浆中，有两种未识别的代谢物存在；然而，这些代谢物占放射性<2%。

The specific enzymes involved in the metabolism of fampridine were not identified in laboratory animals, but based on human microsome studies; it was suggested that CYP2E1 could be responsible for hydroxylation in man. In rat, approximately 36% of the parent drug was removed by hepatic first-pass metabolism. Fampridine was metabolized primarily by hydroxylation, followed by sulfate conjugation. Two circulating metabolites were detected in mouse, rat, rabbit, dog and human plasma: 3-hydroxy-4-AP and 3-hydroxy-4-AP sulfate. Although these metabolites were identified in all species, more extensive metabolism was determined in rats and dogs than in humans. In mouse and rat plasma, it was demonstrated that 4-AP-N-oxide was also a circulating metabolite. In human plasma, two unidentified metabolites were present; however, these metabolites accounted for <2% of the radioactivity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

一小部分达伐拉米定剂量通过细胞色素P-450（CYP）同工酶代谢为3-羟基-4-氨基吡啶和3-羟基-4-氨基吡啶硫酸盐。这些代谢物对钾通道没有药理活性。体外研究表明CYP2E1是主要负责达伐拉米定3-羟基化的酶；其他未识别的CYP酶在药物的3-羟基化中发挥较小作用。

A small portion of dalfampridine dose is metabolized by cytochrome P-450 (CYP) isoenzymes to 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate. These metabolites have no pharmacologic activity on potassium channels. In vitro studies indicate CYP2E1 is the major enzyme responsible for 3-hydroxylation of dalfampridine; other unidentified CYP enzymes play a minor role in 3-hydroxylation of the drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

由肝脏代谢但不广泛，因此预计与达夫氨吡啶同时使用的会影响细胞色素P450酶系统的药物之间不会相互作用。4-氨基吡啶从胃肠道快速吸收进入血液循环。它在肝脏中被迅速分解或代谢成可排出的化合物，并通过尿液排出。静脉和口服吸收后，代谢物几乎全部通过尿液排出。它不会在皮肤中浓缩或积累。4-氨基吡啶通过尿液排出，并在肝脏中迅速解毒（T48, L1090）。代谢物包括3-羟基-4-氨基吡啶和3-羟基-4-氨基吡啶硫酸盐，两者均无活性。CYP2E1是负责达夫氨吡啶3-羟基化的酶。 消除途径：几乎所有的剂量及其代谢物在24小时内通过肾脏完全排出。 尿液（96%；总剂量的90%为未改变的药物）； 粪便（0.5%） 半衰期：立即释放型= 3.5小时； 缓释型= 5.47小时；

Not extensively metabolized by the liver therefore drugs effecting the cytochrome P450 enzyme system that are concomitantly administered with dalfampridine are not expected to interact with each other. 4-Aminopyridine is rapidly absorbed into the bloodstream from the gastrointestinal tract. It is readily broken down, or metabolized, in the liver into removable compounds excreted in urine. After intravenous and oral absoprtion, the metabolites were almost all excreted in the urine. It does not to concentrate or accumulate in skin. 4-Aminopyridine is excreted in urine and rapidly detoxified in the liver (T48, L1090). Metabolites include 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate and both are inactive. CYP2E1 is the enzyme responsible for 3-hydroxylation of dalfampridine. Route of Elimination: Almost all of the dose and its metabolites are completely eliminated by the kidneys after 24 hours. Urine (96%; 90% of total dose as unchanged drug); Feces (0.5%) Half Life: Immediate release form = 3.5 hours; Extended release form = 5.47 hours;

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

4-氨基吡啶可以阻断钾通道，从而增加神经末梢乙酰胆碱和可能还有去甲肾上腺素的释放（A316）。在多发性硬化症（MS）中，轴突逐渐脱髓鞘，暴露出钾通道。因此，钾离子泄漏导致细胞复极化，降低神经元兴奋性。总体影响是神经肌肉传递受损，因为触发动作电位变得更加困难。 地夫木辛在中枢神经系统抑制电压门控钾通道，以维持跨膜电位并延长动作电位。换句话说，地夫木辛的作用是确保可用的电流足够高，以刺激MS患者暴露的脱髓鞘轴突的传导。此外，它通过解除脱髓鞘轴突中的传导阻塞，促进神经肌肉和突触传递。

4-Aminopyridine blocks potassium channels and thereby increases acetylcholine, and possibly noradrenaline, release at nerve terminals (A316). In MS, axons are progressively demyelinated which exposes potassium channels. As a result, there is a leak of potassium ions which results in the repolarization of cells and a decrease in neuronal excitability. The overall impact is the impairment of neuromuscular transmission as it is harder to trigger an action potential. Dalfampridine inhibits voltage-gated potassium channels in the CNS to maintain the transmembrane potential and prolong action potential. In other words, dalfampridine works to make sure that the current available is high enough to stimulate conduction in demyelinated axons that are exposed in MS patients. Furthermore, it facilitates neuromuscular and synaptic transmission by relieving conduction blocks in demyelinated axons.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

达伐拉滨与治疗期间偶尔出现的血清转氨酶升高有关，但并未明确与临床上明显的肝损伤病例相关联。在1922名多发性硬化症患者进行的达伐拉滨上市前控制性试验的安全性分析中，没有报告肝损伤或实验室证据显示有肝毒性信号。然而，已发表的文献中出现了几例接受达伐拉滨治疗的患者出现临床上明显的肝损伤的情况。但在每一例中，将损伤归因于达伐拉滨的论据并不确凿。

Dalfampridine has been associated with infrequent serum aminotransferase elevations during therapy and has not been convincingly linked to instances of clinically apparent liver injury. In analyses of safety of dalfampridine in pre-registration controlled trials with 1922 patients with multiple sclerosis, there were no reports of hepatic injury or laboratory evidence of a hepatotoxicity signal. Nevertheless, a few instances of clinically apparent liver injury in patients receiving dalfampridine have appeared in the published literature. In each instance, however, attribution to dalfampridine was not convincing.

来源:LiverTox

毒理性

• 致癌性证据

癌症分类：D组 不可归类为人类致癌性

Cancer Classification: Group D Not Classifiable as to Human Carcinogenicity

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

分类：D；无法归类为人类致癌性。分类依据：无人类数据，也无动物数据。人类致癌性数据：无。

CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: No human data and no animal data available. HUMAN CARCINOGENICITY DATA: None.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

口服达伐米丁从胃肠道快速且完全吸收。立即释放形式的Tmax（达峰时间）为1小时；延长释放形式的Tmax为3.5小时；10毫克延长释放的Cmax（峰浓度）为17.3 - 21.6纳克/毫升；与水溶性口服溶液相比，10毫克延长释放片的相对生物利用度为96%。

Orally-administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Tmax, immediate release form = 1 hour; Tmax, extended release form = 3.5 hours; Cmax, 10 mg extended release = 17.3 - 21.6 ng/mL; Relative bioavailability of 10 mg extended-release tablets compared to aqueous oral solution = 96%

来源:DrugBank

吸收、分配和排泄

• 消除途径

几乎所有的剂量及其代谢物在24小时后都通过肾脏完全消除。尿液（96%；总剂量的90%以未改变药物的形态）；粪便（0.5%）

Almost all of the dose and its metabolites are completely eliminated by the kidneys after 24 hours. Urine (96%; 90% of total dose as unchanged drug); Feces (0.5%)

来源:DrugBank

吸收、分配和排泄

• 分布容积

10毫克缓释 = 2.6升/千克

10 mg extended release = 2.6 L/kg

来源:DrugBank

吸收、分配和排泄

与其他氨基吡啶类药物一样，4-氨基吡啶能迅速从胃肠道吸收进入血液循环。该化合物在肝脏中容易代谢，代谢物通过尿液排出。大约90%的给药剂量，无论是静脉注射还是口服，都会通过尿液排出。

Like other aminopyridines, 4-aminopyridine is rapidly absorbed from the gastrointestinal tract into circulation. The compound is readily metabolized in the liver and metabolites are excreted in urine. About 90% of the administered dose, following IV or oral administration, excretes in the urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

达尔巴米普利啶能从胃肠道快速且完全吸收。

Dalfampridine is rapidly and completely absorbed from the GI tract.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险等级：
  6.1
• 危险品标志：
  T+
• 安全说明：
  S1,S26,S28A,S36/37/39,S37/39,S45,S60,S61
• 危险类别码：
  R36/37/38,R28
• WGK Germany：
  3
• 海关编码：
  2933399090
• 危险品运输编号：
  UN 2671 6.1/PG 2
• 危险类别：
  6.1
• RTECS号：
  US1750000
• 包装等级：
  II
• 危险标志：
  GHS06
• 危险性描述：
  H300,H315,H319,H335
• 危险性防范说明：
  P261,P264,P301 + P310,P305 + P351 + P338

制备方法与用途

4-氨基吡啶 性质与用途

从苯中析出的4-氨基吡啶为无色针状结晶，带有氨气味。它可用作农药、医药及染料中间体，也可作为化学试剂。

合成方法

微波辅助脱保护反应将10 mmol基质、10 mmol甲酸铵和2 mmol锌粉悬浮于15 mL乙二醇中，在锥形烧瓶中进行。用160 W微波辐射加热，同时在锥形烧瓶上放置过滤漏斗以防溢出。维持“散热器”以控制输入反应混合物中的微波能量。冷却后，将反应混合物过滤，并用水稀释滤液，然后用乙醚或乙酸乙酯萃取有机层两次，再使用饱和盐水溶液和水洗涤。干燥有机层并过滤蒸发，通过制备TLC或柱色谱纯化得到4-氨基吡啶，产率为95%，熔点158-159℃。

生物活性

4-氨基吡啶（4-AP、Fampridine、Dalfampridine）是一种有效的非选择性电压门控钾通道(Kv)抑制剂，在CHO细胞中对Kv1.1和Kv1.2的IC50分别为170 μM和230 μM。

靶点

Target	Value
Kv1.4	13 μM
Kv3.1	29 μM
Kv3.2	100 μM
Kv1.3	195 μM
Kv1.1	290 μM

化学性质

4-氨基吡啶为无色针状晶体，熔点158-159℃，沸点273℃（180℃时沸点为1.73kPa）。它溶于水和乙醇，略溶于乙醚和苯，难溶于轻油和石油类。

用途

用于有机合成，并可作为医药中间体。此外，4-氨基吡啶还用作合成抗生素类药物的中间体。

生产方法

将1 g N-氧化-4-硝基吡啶（熔点159℃）溶于30 mL乙酸中，加入2.2 g铁粉反应，保温1 h。冷却后，用水稀释并用30%氢氧化钠溶液调整为强碱性，再用乙醚提取三次，每次100 mL。合并乙醚提取液，并使用无水碳酸钾干燥。蒸发乙醚并减压蒸馏获得4-氨基吡啶粗品。将该粗品从苯或甲苯-石油醚混合溶剂中重结晶可得0.6 g白色针状结晶的4-氨基吡啶，产率为90%。

类别

农药

毒性分级

剧毒

急性毒性

口服 - 大鼠 LD50: 21 毫克/公斤；小鼠 LD50: 42 毫克/公斤

可燃性危险特性

明火可燃，高热时释放有毒氮氧化物气体。

储运特性

库房应通风、低温干燥。与氧化剂、酸类和食品添加剂分开存放。

灭火剂

干粉、泡沫、二氧化碳、砂土

反应信息

• 作为反应物：
  描述：

  4-氨基吡啶 在 亚硝酸特丁酯 、 copper dichloride 作用下， 以 乙腈 、 乙二醇 为溶剂， 以47%的产率得到4-氯吡啶
  参考文献：
  名称：

  沙梅尔反应从间歇到连续过程的高效换位

  摘要：

  研究了桑德迈尔氯化法从批次到安全连续流过程的转换。我们最初的方法是开发一种使用流化学的级联方法，该方法涉及重氮盐的生成并用氯化铜淬灭。为了实现这种安全的连续过程重氮化，使用了化学计量方法（Simplex方法）并外推以建立完全连续流方法。还通过合成几种（杂）芳基氯来检查反应范围。还对过程进行了验证和放大。在提高安全性的同时获得了更高的生产率。

  DOI：

  10.1021/acs.oprd.6b00318
• 作为产物：
  描述：

  4-氰基吡啶