尼立达唑 | 61-57-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 尼立达唑
• 中文别名: 硝米达唑；硝唑咪；硝唑咪硝米达唑
• 英文名称: niridazole
• 英文别名: niridazol；1-(5-nitro-thiazol-2-yl)-imidazolidin-2-one；Ambilhar；1-<2-(5-Nitrothiazolyl)>-2-oxo-tetrahydroimidazol；1-(5-Nitro-2-thiazolyl)-2-oxo-tetrahydroimidazol；1-(5-nitro-1,3-thiazol-2-yl)imidazolidin-2-one
• CAS: 61-57-4
• 化学式: C₆H₆N₄O₃S
• mdl: MFCD00128262
• 分子量: 214.205
• InChiKey: RDXLYGJSWZYTFJ-UHFFFAOYSA-N

物化性质

• 熔点：
  260-262°
• 密度：
  1.561 (estimate)
• 颜色/状态：
  Yellow crystals from dimethylformamide/methanol
• 溶解度：
  In water, 1.3X10+2 mg/L at 25 °C
• 蒸汽压力：
  3.56X10-7 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  119
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

5-硝基-2-噻唑基-N'-羧甲基脲(NTCU)被确认为抗血吸虫病药物尼利达唑(1-(5-硝基-2-噻唑基)-2-咪唑烷酮)的尿液代谢物。当DBA/2J小鼠被处理(14)C尼利达唑时，24小时尿液样本中总放射活性的12-14%的代谢物可以通过HPLC解析。随后从接受尼利达唑治疗的患者的混合尿液中分离出该化合物。通过质谱鉴定为NTCU，并通过化学合成确认了推测的结构。在所有已知的尼利达唑代谢物中，NTCU是独一无二的，因为它缺乏完整的咪唑烷酮环。其结构允许发生酮烯醇互变异构，其中烯醇形式通过与硝基噻唑环共轭而稳定，这在吸收光谱中以pH依赖性的80纳米红移为证据。/它被/假设NTCU是通过5-羟基尼利达唑的环状醛互变异构体的氧化产生的，这是两种近氧化尼利达唑代谢物之一。环状醛互变异构体的间接证据包括5-羟基尼利达唑显示出与NTCU相同的pH依赖性光谱偏移，并且在388纳米处有一个等吸收点。当发现5-羟基尼利达唑在NAD(+)-依赖性醛脱氢酶(EC 1.2.1.3)的催化下形成NTCU时，提出的先驱-产物关系得到了确认。该活性与从小鼠肝脏细胞质中纯化出的苯甲醛脱氢酶活性一起。此外，苯甲醛是5-羟基尼利达唑脱氢酶活性的竞争性抑制剂。这些结果表明，5-羟基尼利达唑不是尼利达唑代谢的最终产物。因为尼利达唑向其4-和5-羟基衍生物的生物转化与药物的致癌性和中枢神经系统毒性有关，NTCU的形成似乎代表了一种哺乳动物的去毒途径。

N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea (NTCU) has been identified as a urinary metabolite of the antischistosomal drug niridazole (1-(5-nitro-2-thiazolyl)-2-imidazolidinone). When DBA/2J mice were treated with (14)C niridazole, a metabolite comprising 12-14% of the total radioactivity in 24-hr urine samples was resolved by HPLC. The compound was subsequently isolated from pooled urine of niridazole-treated patients. It was identified as NTCU by mass spectrometry, and the deduced structure was confirmed by chemical synthesis. NTCU is unique among known niridazole metabolites, because it lacks an intact imidazolidinone ring. Its structure allows for a ketoenol tautomerism in which the enolate is stabilized by conjugation with the nitrothiazole ring, as evidenced by a pH-dependent 80-nm red shift in the absorption spectrum. /It was/ hypothesized that NTCU arises via oxidation of an acyclic aldehyde tautomer of 5-hydroxyniridazole, one of two proximate oxidative niridazole metabolites. Indirect evidence for the aldehyde tautomer included the fact that 5-hydroxyniridazole displayed the same pH-dependent spectral shift as NTCU with a single isobestic point at 388 nm. The proposed precursor-product relationship was confirmed when /it was/ found that NTCU formation from 5-hydroxyniridazole was catalyzed by NAD(+)-dependent aldehyde dehydrogenase (EC 1.2.1.3). The activity copurified with benzaldehyde dehydrogenase activity from mouse liver cytosol. Furthermore, benzaldehyde was a competitive inhibitor of 5-hydroxyniridazole dehydrogenase activity. These results demonstrate that 5-hydroxyniridazole is not an end product of niridazole metabolism. Because biotransformation of niridazole to its 4- and 5-hydroxy derivatives has been implicated in the drug's carcinogenicity and central nervous system toxicity, NTCU formation appears to represent a detoxication pathway in mammals.

来源:Hazardous Substances Data Bank (HSDB)

代谢

鼠肝微粒体将尼利达唑的主要代谢物转化为羟胺（N-羟基氨基噻咪达唑），这是通过尼利达唑的硝基还原形成的。这种还原作用也是由鼠肝黄嘌呤氧化酶介导的。

The principal metabolite of niridazole formed by rat liver microsomes was the hydroxylamine (N-hydroxyaminothiamidazol), formed by reduction of the nitro group of niridazole. This reduction was also mediated by rat liver xanthine oxidase.

来源:Hazardous Substances Data Bank (HSDB)

代谢

通过高效液相色谱分离出的4-酮基尼利达唑，经高分辨率电子冲击质谱分析确认为在大鼠和小鼠口服或腹腔注射尼利达唑后血清或血浆中的主要药物代谢物。这种代谢物具有5.8的pKa值，在生理pH下，大约有40%与接受尼利达唑治疗剂量的小鼠的血清蛋白结合。...

4-Keto niridazole, isolated by high-pressure liquid chromatography, was identified by high resolution electron impact mass spectral analysis as a major drug metabolite of niridazole in the serum or plasma of rats and mice treated orally or i.p. with niridazole. This metabolite has a pKa of 5.8 and is approximately 40% bound at physiologic pH to serum proteins of mice receiving therapeutic doses of niridazole. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

致癌性分类：1）人类无数据 2）动物中有足够证据。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。注意：总体评估仅基于致癌性专论中的证据（第13卷；1977年）。/来自表格/

Classification of carcinogenicity: 1) No data available in humans 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. NOTE: Overall evaluation based only on evidence of carcinogenicity in monograph (Volume 13; 1977). /From table/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：尼里达唑

IARC Carcinogenic Agent:Niridazole

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：2B组：可能对人类致癌

IARC Carcinogenic Classes:Group 2B: Possibly carcinogenic to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第13卷：（1977年）一些杂项药物物质

IARC Monographs:Volume 13: (1977) Some Miscellaneous Pharmaceutical Substances

来源:International Agency for Research on Cancer (IARC)

毒理性

• 相互作用

对铜中毒的大鼠给予尼利达唑，显著增加了金属通过尿液和胆汁的排泄。尽管药物增加了铁的尿液排泄，但在铜中毒后药物诱导的铜排泄期间，铁的排泄显著减少。在胆汁或尿液中排泄前形成铜-尼利达唑螯合物或螯合物可能解释这些发现。在体内形成的金属-药物螯合物的极性和分子量可能是选择螯合金属以及其尿液或胆汁排泄的指导力量。实验室制备两种铜-尼利达唑复合物支持这些结论。

Administration of niridazole to rats poisoned with copper caused a significant increase in both the urinary and biliary excretion of the metal. Although the urinary excretion of iron was increased by the drug, iron excretion was significantly decreased during the drug-induced excretion of copper after copper poisoning. Formation of a copper-niridazole chelate or chelates before excretion in the bile or urine may explain these findings. Polarity and molecular weights of the metal-drug chelates formed in vivo may be the directing forces not only in the selection of the metal for chelation, but also for its urinary or biliary excretion. The laboratory preparation of two copper-niridazole complexes lends support to these conclusions.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服尼立达唑吸收良好；它在肝脏中代谢，并几乎等量地大量通过尿液和粪便排出。

Orally administered niridazole is well absorbed; it is metabolized in the liver and eliminated largely and almost equally in the urine and feces.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠、兔子和狗中，口服给药的（14）C标记的咪唑啉酮环的尼利唑缓慢慢吸收，并在几天内通过尿液和粪便排出。在大鼠组织匀浆的实验中，尼利唑在肝脏和肾脏中降解最快，其次是在睾丸、脾脏、心脏、肺、大脑、肌肉和胸腺中降解较慢，这个顺序与这些组织中硝基还原酶的水平相对应。同样，尼利唑在体外实验中最快被小鼠肝脏代谢，然后依次是被大鼠、兔子、绵羊、猪和牛的肝脏代谢。在血液中，代谢物的水平高于母药。

In rats, rabbits and dogs, orally administered (14)C imidazinone ring-labeled niridazole is slowly but well absorbed and excreted in the urine and feces within a few days. In experiments involving rat tissue homogenates, it was degraded most rapidly by liver and kidney and to a lesser extent by testis, spleen, heart, lung, brain, muscle and thymus - this order corresponds to the levels of nitroreductase in these tissues. Similarly, it is metabolized most rapidly in vitro by mouse liver and then in descending order by the liver of rats, rabbits, sheep, pigs and bovines. In blood, the metabolites attain a higher level than the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2934999090

反应信息

• 作为反应物：
  描述：

  尼立达唑 、 聚合甲醛 生成 1-Morpholin-4-ylmethyl-3-(5-nitro-thiazol-2-yl)-imidazolidin-2-one
  参考文献：
  名称：

  AL-JOBOUR, NAZAR, N., J. IRAQI CHEM. SOC., 1980, 5, N 1-2, 37-44

  摘要：

  DOI：
• 作为产物：
  描述：

  2-(2-甲基硫烷基-4,5-二氢-咪唑-1-基)-5-硝基-噻唑 在 双氧水 、 溶剂黄146 作用下， 生成 尼立达唑
  参考文献：
  名称：

  Kutter; Machleidt; Reuter, Arzneimittel-Forschung/Drug Research, 1972, vol. 22, # 6, p. 1045 - 1054

  摘要：

  DOI：

文献信息

• ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
  申请人：Meng Charles Q.

  公开号：US20140142114A1

  公开（公告）日：2014-05-22

  The present invention relates to novel anthelmintic compounds of formula (I) below: wherein Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.

  本发明涉及以下式（I）的新型驱虫化合物： 其中 Y和Z分别是双环碳环或双环杂环基团，或者Y或Z中的一个是双环碳环或双环杂环基团，另一个是烷基，烯基，炔基，环烷基，苯基，杂环基或杂芳基，以及变量X 1 ，X 2 ，X 3 ，X 4 ，X 5 ，X 6 ，X 7 和X 8 如本文所定义。本发明还提供了包含本发明的驱虫化合物的兽药组合物，以及它们用于治疗和预防动物寄生虫感染的用途。
• [EN] ANTHELMINTIC DEPSIPEPTIDE COMPOUNDS<br/>[FR] COMPOSÉS DEPSIPEPTIDIQUES ANTHELMINTHIQUES
  申请人：MERIAL INC

  公开号：WO2018093920A1

  公开（公告）日：2018-05-24

  The present invention provides cyclic depsipeptide compounds of formula (I) wherein the stereochemical configuration of at least one carbon atom bearing the groups Cy1, Cy2, R1, R2, R3, R4, Ra and Rb is inverted compared with the naturally occurring cyclic depsipeptide PF1022A. The invention also provides compositions comprising the compounds that are effective against parasites that harm animals. The compounds and compositions may be used for combating parasites in or on mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in birds and mammals.

  本发明提供了公式（I）的环状脱氨肽化合物，其中至少一个碳原子的立体化学构型与自然存在的环状脱氨肽PF1022A的基团Cy1、Cy2、R1、R2、R3、R4、Ra和Rb相比发生了倒置。该发明还提供了包含这些化合物的组合物，对危害动物的寄生虫具有有效性。这些化合物和组合物可用于对抗哺乳动物和鸟类体内或体表的寄生虫。该发明还提供了一种改进的方法，用于根除、控制和预防鸟类和哺乳动物的寄生虫感染。
• FUSED BICYCLIC HETEROCYCLE DERIVATIVES AS PESTICIDES
  申请人：Bayer Aktiengesellschaft

  公开号：US20200383334A1

  公开（公告）日：2020-12-10

  The invention relates to novel compounds of the formula (I) in which Aa, Ab, Ac, Ad, Q, R 1 and n have the definitions given above, to their use as acaricides and/or insecticides for controlling animal pests and to processes and intermediates for their preparation.

  这项发明涉及公式（I）的新化合物， 其中Aa、Ab、Ac、Ad、Q、R1和n具有上述给定的定义， 以及它们作为杀螨剂和/或杀虫剂用于控制动物害虫的用途，以及用于它们制备的工艺和中间体。
• [EN] ANTI PARASITIC DIHYDROAZOLE COMPOUNDS AND COMPOSITIONS COMPRISING SAME<br/>[FR] DIHYDROAZOLES ANTIPARASITAIRES ET COMPOSITIONS LES INCLUANT
  申请人：MERIAL LTD

  公开号：WO2011075591A1

  公开（公告）日：2011-06-23

  The present invention relates to novel dihydroazole of formula (I) and salts thereof: Wherein R1, A1, A2, G, X and Y are as defined in the description, compositions thereof, processes for their preparation and their uses to prevent or treat parasitic infections or infestations in animals and as pesticides.

  本发明涉及式(I)的新型二氢咪唑及其盐：其中R1、A1、A2、G、X和Y如描述中所定义，以及它们的组合物、制备方法以及它们用于预防或治疗动物寄生虫感染或寄生虫侵袭以及作为杀虫剂的用途。
• SUBSTITUTED SULFONYL AMIDES FOR CONTROLLING ANIMAL PESTS
  申请人：Bayer Aktiengesellschaft

  公开号：US20190269134A1

  公开（公告）日：2019-09-05

  The present invention relates to the use of a compound of the general formula (I) in which M and D have the meanings given in the description for controlling animal pests, in particular nematodes.

  本发明涉及使用一种具有一般式(I)的化合物，其中M和D具有描述中给出的含义，用于控制动物害虫，特别是线虫。