非那吡啶 | 94-78-0

• 物质功能分类: 原料药 - 泌尿系统用药 - 利尿药
• 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: 非那吡啶
• 中文别名: 3-苯氮杂-2,6-二氨基吡啶
• 英文名称: pyridium
• 英文别名: 2,6-diamino-3-(phenylazo)pyridine；3-phenylazo-2,6-diaminopyridine；3-phenylazopyridine-2,6-diamine；phenazopyridine；3-phenylazo-pyridine-2,6-diamine；3-Phenylazo-pyridin-2,6-diyldiamin；3-phenyldiazenylpyridine-2,6-diamine
• CAS: 94-78-0
• 化学式: C₁₁H₁₁N₅
• mdl: MFCD00035347
• 分子量: 213.242
• InChiKey: QPFYXYFORQJZEC-UHFFFAOYSA-N

物化性质

• 熔点：
  136-137°
• 沸点：
  343.23°C (rough estimate)
• 密度：
  1.2597 (rough estimate)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 颜色/状态：
  BROWNISH-YELLOW CRYSTALS
• 水溶性：
  3.83
• 稳定性/保质期：
  WILL PRECIPITATE OUT OF 2% SOLN AT 25 °C AFTER ABOUT 2 DAYS, & OUT OF 1% SOLN ONLY AFTER MONTHS /PHENAZOPYRIDINE HYDROCHLORIDE/
• 分解：
  When heated todecomposition it emits toxic fumes of /nitrogen oxides/.
• 保留指数：
  2345;2280;2290;2345;2346

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

酚氮唑嘧啶在肝脏中被代谢，已经发现对乙酰氨基酚是这种药物的代谢物之一。羟基化是这种药物代谢的途径。在人体中，5-羟基PAP是主要的代谢物（占剂量的48.3%），还产生了少量的其他羟基代谢物。酚氮唑嘧啶的代谢产生苯胺，这可能是某些患者出现高铁血红蛋白血症或在过量情况下出现的原因。这种染料在皮肤中积累，当服用高剂量的这种药物时，已经观察到皮肤出现黄色色素沉着。三氨吡啶也是酚氮唑嘧啶的代谢物。在药物代谢动力学研究中，苯胺约占尿液代谢物的6.9%，N-乙酰-p-氨基酚（对乙酰氨基酚）约占18%，P-氨基酚（PAP）占24%，最后，DPP（未改变的酚氮唑嘧啶）约占排出尿液代谢物的41%。

Phenazopyridine is metabolized in the liver, and acetaminophen has been discovered to be one metabolite of this drug. Hydroxylation is a pathway by which this drug is metabolized. In humans, 5-hydroxyl PAP is the major metabolite (48.3% of the dose) and small amounts of other hydroxy metabolites are produced. The metabolism of phenazopyridine produces aniline, which is likely associated with methemoglobinemia in some patients or in the case of an overdose. This dye accumulates in the skin, and yellow skin pigmentation has been observed when high doses of this drug have been taken. Triaminopyridine is also a metabolite of phenazopyridine. During a pharmacokinetic study, aniline contributed to approximately 6.9% of urinary metabolites. N acetyl-p-aminophenol (acetaminophen) contributes to about 18%, P-aminophenol (PAP) contributes 24%, and finally, DPP (unchanged phenazopyridine) contributes to about 41% of excreted urinary metabolites.

来源:DrugBank

代谢

在人体内给予600毫克盐酸非那吡啶口服剂量后，约80%在24小时内通过尿液排出：41-45%以结合型非那吡啶形式出现，24-27%为对氨基酚，18-20%为结合型N-乙酰对氨基酚，7-8%为苯胺，以及少量的邻氨基酚和2,3,6-三氨基吡啶。/盐酸非那吡啶/

AFTER ORAL DOSE OF 600 MG PHENAZOPYRIDINE HYDROCHLORIDE /IN MAN/, ABOUT 80% IS ELIMINATED IN URINE WITHIN 24 HR: 41-45% APPEARS AS CONJUGATED PHENAZOPYRIDINE, 24-27% AS PARA-AMINOPHENOL, 18-20% AS CONJUGATED N-ACETYL-PARA-AMINOPHENOL, 7-8% AS ANILINE & TRACES OF ORTHO-AMINOPHENOL & 2,3,6-TRIAMINOPYRIDINE. /PHENAZOPYRIDINE HYDROCHLORIDE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予家兔口服150毫克/千克体重的盐酸非那吡啶后...苯胺、对氨基酚（剂量中的50%）、N-乙酰对氨基酚、邻氨基酚（作为微量）、2,3,6-三氨基吡啶以及未改变的药物出现在尿液中。...除了还原代谢外，非那吡啶还经历氧化代谢：在给予50毫克/千克体重非那吡啶的大鼠尿液中，已检测到2,6-二氨基-3-((4-羟基苯基)偶氮)吡啶和2,6-二氨基-3-((2-羟基苯基)偶氮)吡啶。/盐酸非那吡啶/

FOLLOWING ORAL ADMIN OF 150 MG/KG BODY WT PHENAZOPYRIDINE HYDROCHLORIDE TO RABBITS ... ANILINE, PARA-AMINOPHENOL (AS 50% OF DOSE), N-ACETYL-PARA-AMINOPHENOL, ORTHO-AMINOPHENOL (AS TRACES), 2,3,6-TRIAMINOPYRIDINE & UNCHANGED DRUG APPEAR IN URINE. ... IN ADDN TO REDUCTIVE METABOLISM, PHENAZOPYRIDINE ALSO UNDERGOES OXIDATIVE METABOLISM: IN URINE OF RATS TREATED WITH 50 MG/KG BODY WT PHENAZOPYRIDINE, 2,6-DIAMINO-3-((4-HYDROXYPHENYL)AZO)PYRIDINE & 2,6-DIAMINO-3-((2-HYDROXYPHENYL)AZO)PYRIDINE HAVE BEEN DETECTED. /PHENAZOPYRIDINE HYDROCHLORIDE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予大鼠口服50毫克/千克非那吡啶后，提取尿液水样，分离出4-乙酰氨基酚、2,6-二氨基吡啶-3-亚硝基氧苯以及一种未确定的水杨酸型吡啶亚硝基衍生物。在哺乳动物中，从偶氮化合物形成亚硝基衍生物是不同寻常的，并且具有重大的毒理学意义。

FOLLOWING ORAL ADMIN OF 50 MG/KG PHENAZOPYRIDINE TO RATS & EXTRACTION OF URINE AQ SAMPLES, 4-ACETAMIDOPHENOL, 2,6-DIAMINOPYRIDINE-3-NNO-AZOXYBENZENE & AN UNIDENTIFIED AZOXY DERIV OF HYDROXYPYRIDINE WERE ISOLATED. FORMATION OF AZOXY DERIV FROM AZO-COMPD IS UNUSUAL IN MAMMALS & HAS GREAT TOXICOLOGICAL IMPORTANCE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给大鼠口服苯氮吡啶（100毫克/千克）后，通过质谱鉴定出尿液中出现了一种新的代谢物，即2,6-二氨基-5-羟基-3-(苯基偶氮)吡啶。根据质谱的裂解情况，很明显是杂环环而非苯环发生了选择性的代谢氧化。

FOLLOWING THE ORAL ADMIN OF PHENAZOPYRIDINE (100 MG/KG) TO RATS, 2,6-DIAMINO-5-HYDROXY-3-(PHENYLAZO)PYRIDINE WAS IDENTIFIED AS A NEW METABOLITE IN URINE BY MASS SPECTRA. BASED ON THE FRAGMENTATION OF THE MASS SPECTRUM, A SELECTIVE METABOLIC OXIDN OF THE HETEROCYCLIC RING, RATHER THAN OF THE BENZENE RING, WAS EVIDENT.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

致癌性分类：1）人类证据：不足；2）动物证据：充分。对人类致癌风险的总体评估为2B组：该物质可能对人类致癌。/盐酸非那吡啶；来自表格/

Classification of carcinogenicity: 1) evidence in humans: Insufficient; 2) evidence in animals: Sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /Phenazopyridine hydrochloride; From table/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

盐酸非那吡啶：合理预期为人类致癌物。/盐酸非那吡啶/

Phenazopyridine hydrochloride: reasonably anticipated to be a human carcinogen. /Phenazopyridine hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：尚未确立苯吡啶在婴儿或母乳喂养期间的安全性。因为它可能导致高铁血红蛋白血症、磺血红蛋白血症和溶血性贫血，所以在母乳喂养期间应避免使用，特别是在一个月以下的婴儿或患有葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症的婴儿中。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:The safety of phenazopyridine is not established in infants or during breastfeeding. Because it can cause methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia, it should be avoided while breastfeeding, especially with an infant under 1 month of age or with glucose-6-phosphate dehydrogenase (G6PD) deficiency. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 解毒与急救

在盐酸非那吡啶急性过量时，应立即通过催吐或洗胃来清空胃部。如果患者昏迷、有癫痫发作或缺乏咳嗽反射，可以在放置了充气气囊的气管内管的情况下进行洗胃，以防止胃内容物的吸入。应启动支持和对症治疗。静脉注射亚甲蓝1-2 mg/kg或口服维生素C 100-200 mg应迅速减少高铁血红蛋白血症并消除发绀。在婴儿中，已经成功使用交换输血来处理急性非那吡啶过量。在非那吡啶引起的急性肾衰竭中，腹膜透析可能有助于管理液体和电解质紊乱。/盐酸非那吡啶/

In acute overdosage of phenazopyridine hydrochloride, the stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and sympotmatic treatment should be initiated. IV administration of methylene blue 1-2 mg/kg or oral administration of ascorbic acid 100-200 mg should cause prompt reduction of methemoglobinemia and disappearance of cyanosis. Exchange transfusions have been used successfully in acute phenazopyridine overdosage in infants. Peritoneal dialysis may be useful for managing fluid and electrolyte disturbances in phenazopyridine-induced acute renal failure. /Phenazopyridine hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

高铁血红蛋白血症，无论是否伴有海因茨体溶血成分，在至少7起人类中毒事件中构成了关键特征。/盐酸非那吡啶/

METHEMOGLOBINEMIA WITH OR WITHOUT HEINZ BODY HEMOLYTIC COMPONENT CONSTITUTED KEY FEATURE IN AT LEAST 7 HUMAN INTOXICATIONS. /PHENAZOPYRIDINE HYDROCHLORIDE/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

酚氮嘧啶在胃肠道被吸收。平均Cmax为65.00 ± 29.23 ng/mL，平均Tmax为2.48 ± 0.50小时，平均AUC(0 – ∞)为431.77 ± 87.82 ng·h/mL。

Phenazopyridine is absorbed in the gastrointestinal tract. The mean Cmax is 65.00 ± 29.23 ng/mL, the mean Tmax is 2.48 ± 0.50 h, and the mean AUC(0 – ∞)is 431.77 ± 87.82 ng.h/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

高达65%的口服苯氮卓吡啶剂量会迅速由肾脏以未改变的药物形式排出，在尿液中可以测量到。这种药物在人体内的药代动力学尚未进行深入评估。在一小组健康研究志愿者中，发现90%的每日600毫克苯氮卓吡啶盐酸盐口服剂量在1天内排出，其中41%为未改变的药物，49%为苯氮卓吡啶代谢物。另一项针对人类的研究确定，在给药后48小时内，80.07 ± 4.54%的剂量通过尿液清除。在大鼠中，胆汁排泄量很高，8小时内就有40.7%的剂量被排出。

Up to 65% of an oral phenazopyridine dose is quickly excreted by the kidneys as unchanged drug measured in the urine. The pharmacokinetics of this drug have not been evaluated in depth in man. In a small group of healthy research volunteers, 90% of a daily 600 mg oral dose of phenazopyridine hydrochloride was found to be excreted within 1 day, with 41% as unchanged drug and 49% as phenazopyridine metabolites. Another study in humans determined that 80.07 ± 4.54 percent of the dose was cleared in the urine within 48 hours of administration. In rats, biliary excretion was high, with 40.7% of a dose excreted in 8 hours.

来源:DrugBank

吸收、分配和排泄

• 分布容积

少量（小）的苯吡唑啉被认为能够穿过胎盘和血脑屏障，到达脑脊液。在大鼠中的药代动力学研究发现，苯吡唑啉的代谢物在肾脏和肝脏中含量很高。

Small, trace quantities of phenazopyridine are thought to cross the placenta and the blood-brain barrier, reaching cerebrospinal fluid. A pharmacokinetic study in rats determined that phenazopyridine metabolites were present in high levels in the kidney and liver.

来源:DrugBank

吸收、分配和排泄

• 清除

这种药物由肾脏迅速排泄，口服给药的剂量中多达65%可能以未改变的药物形式随尿液排出。当肾功能或肝功能受损时，非那吡啶的清除率可能会降低，在这些情况下是禁忌的。

This drug is rapidly excreted by the kidneys, up to 65% of a dose administered orally may be excreted as unchanged drug in the urine. The clearance of phenazopyridine may be decreased with impaired renal or hepatic function and is contraindicated in these conditions.

来源:DrugBank

吸收、分配和排泄

在人类中，口服200毫克吡啶ium……在14-48小时内排出，主要在尿液中，但部分在粪便中：大约80%的口服600毫克剂量在24小时内通过尿液排出。/盐酸非那吡啶/

IN HUMANS, ORALLY ADMIN DOSES OF 200 MG PYRIDIUM ... EXCRETED WITHIN 14-48 HR, MAINLY IN URINE BUT PARTLY IN FECES: ABOUT 80% OF ORALLY ADMIN DOSE OF 600 MG IS ELIMINATED IN URINE WITHIN 24 HR. /PHENAZOPYRIDINE HYDROCHLORIDE/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品运输编号：
  25kgs
• 海关编码：
  2933399090
• 储存条件：
  | 20°C，惰性气体 |

制备方法与用途

非那吡啶具有局部镇痛作用，主要用于缓解因泌尿道感染、手术或损伤引起的相关症状，如疼痛、刺激、不适或紧迫感。

反应信息

• 作为反应物：
  描述：

  非那吡啶 在 乙酸酐 、 镍 作用下， 生成 N,N',N''-pyridine-2,3,6-triyl-tris-acetamide
  参考文献：
  名称：

  Tchitchibabine; Hoffmann, Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1937, vol. 205, p. 153

  摘要：

  DOI：
• 作为产物：
  描述：

  alkaline earth salt of/the/ methylsulfuric acid 在 水 作用下， 生成 非那吡啶
  参考文献：
  名称：

  Note on Bacteriostatic Azo Compounds

  摘要：

  DOI：

  10.1021/ja01323a019

文献信息

• [EN] PHENAZOPYRIDINE COMPOUNDS<br/>[FR] COMPOSÉS DE PHÉNAZOPYRIDINE
  申请人：PINNACLE PHARMACEUTICALS INC

  公开号：WO2010071878A1

  公开（公告）日：2010-06-24

  The present invention is directed to substituted phenazopyridines represented by Formula I. The present invention also relates to the discovery that compounds of Formula I have increased bioavailability as compared to unconjugated phenazopyridine.

  本发明涉及由式I表示的取代苯偏氨基吡啶。本发明还涉及发现，与未结合的苯偏氨基吡啶相比，式I化合物具有增加的生物利用度。
• Polymorphic Forms of a Molecular Salt of Phenazopyridine with 3,5-Dihydroxybenzoic Acid: Crystal Structures, Theoretical Calculations, Thermodynamic Stability, and Solubility Aspects
  作者：Qian Tao、Qian-Qian Hao、Alexander P. Voronin、Xia-Lin Dai、Yu Huang、German L. Perlovich、Tong-Bu Lu、Jia-Mei Chen

  DOI：10.1021/acs.cgd.9b00618

  日期：2019.10.2

  of multicomponent crystals has not been studied as widely as that of single-component crystals. In this work, two polymorphic forms of a pharmaceutical salt of phenazopyridine with 3,5-dihydroxybenzoic acid in a 1:1 stoichiometry were successfully obtained and fully characterized by X-ray diffraction, thermal analysis, and dynamic vapor sorption measurement. The crystal structure study exhibited similarities

  尚未像单组分晶体那样广泛地研究多组分晶体的多态性。在这项工作中，成功地获得了1：1的化学计量比的吩唑吡啶与3,5-二羟基苯甲酸药用盐的两种多晶型形式，并通过X射线衍射，热分析和动态蒸气吸附测量对其进行了全面表征。晶体结构研究在两个多晶型物的氢键合成子，分子构象和堆积排列方面表现出相似之处和不同之处。进行了固态密度泛函理论计算，并辅以对周期性电子密度的Bader分析和Hirshfeld表面分析，以量化两种形式的分子间相互作用的模式和晶格的能量。实验和理论相结合的方法表明这两个多晶型是对映相关的。它们表现出不同但明显改善的水溶性。
• Phenazopyridine compounds
  申请人：Pinnacle Pharmaceuticals, Inc.

  公开号：US08288365B2

  公开（公告）日：2012-10-16

  The present invention is directed to substituted phenazopyridines represented by Formula I. The present invention also relates to the discovery that compounds of Formula I have increased bioavailability as compared to unconjugated phenazopyridine.

  本发明涉及由公式I所表示的取代苯偶氮吡啶。本发明还涉及发现公式I化合物与未结合的苯偶氮吡啶相比具有增加的生物利用度。
• Phenazopyridine Cocrystal and Salts That Exhibit Enhanced Solubility and Stability
  作者：Qian Tao、Jia-Mei Chen、Lei Ma、Tong-Bu Lu

  DOI：10.1021/cg300327x

  日期：2012.6.6

  One phenazopyridine monohydrate (1 center dot H2O), one cocrystal of phenazopyridine with phthalimide (2), and three salts of phenazopyridine with benzoic acid (3), 4-hydroxyphenylacetic acid (4), and scaaharin (5) were synthesized, and their structures were determined by single crystal X-ray diffraction. The results of dissolution experiments indicate that the solubility of phenazopyridine can be enhanced after the formations of cocrystal and salts, in which the apparent solubility value of 5 is approximately 9 times as large as that of phenazopyridine in water, and the apparent solubility value of 4 is approximately 10 times as large as that of phenazopyridine hydrochloride (1 center dot HCl) in 0.1 M HCl aqueous solution. The results of the stability study demonstrate that 2-5 are less hygroscopic than 1 center dot H2O and 1 center dot HCl at both 85% and 98% RH.
• Charrier; Jorio, Gazzetta Chimica Italiana, 1938, vol. 68, p. 640,647
  作者：Charrier、Jorio

  DOI：——

  日期：——

表征谱图