吡嘧司特 | 69372-19-6

• 物质功能分类: 原料药 - 抗变态反应药 - 过敏反应介质阻滞剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 中文名称: 吡嘧司特
• 中文别名: 哌罗司特；9-甲基-3-(1H-四唑-5-基)-4H-吡啶并[1,2-Α]嘧啶-4-酮
• 英文名称: pemirolast
• 英文别名: 3-(1H-tetrazol-5-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine；9-methyl-3-(1H-1,2,3,4-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one；9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one；9-methyl-3-(2H-tetrazol-5-yl)pyrido[1,2-a]pyrimidin-4-one
• CAS: 69372-19-6
• 化学式: C₁₀H₈N₆O
• 分子量: 228.213
• InChiKey: HIANJWSAHKJQTH-UHFFFAOYSA-N

物化性质

• 熔点：
  310-311° (dec)
• 沸点：
  454.8±55.0 °C(Predicted)
• 密度：
  1?+-.0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from dimethylformamide
• 溶解度：
  In water, 1.9X10+4 mg/L at 25 °C /Estimated/
• 蒸汽压力：
  3.3X10-6 mm Hg at 25 °C /Estimated/

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  87.1
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

肝脏的（眼部的）

Hepatic (Ophthalmic)

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：尽管关于哺乳期间使用培美罗司的已发表数据不存在，但使用眼药水后，母体乳汁中的水平可能非常低。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发表信息。

◉ Summary of Use during Lactation:Although no published data exist on the use of pemirolast during lactation, maternal milk levels are likely to be very low after the use eye drops. ◉ 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

• 相互作用

新开发的抗过敏药物富马酸贝前列腺素（TBX）对茶碱的药代动力学和代谢的影响在稳态条件下进行了研究，研究对象为七名健康的男性志愿者。首先给予茶碱缓释制剂（100毫克，每日两次，间隔12小时）作为单药治疗，并与TBX（10毫克，每日两次，间隔12小时）联合给药。比较了单独给予茶碱和与TBX联合给药后茶碱及其主要代谢物的血浆浓度-时间曲线和尿液排泄情况。本研究未观察到显著的不良反应。两种治疗方案在茶碱的总清除率、肾清除率和最大浓度方面没有显著差异，尽管与TBX联合给药显著延迟了达到茶碱最大浓度的时间。在尿液排泄方面，茶碱及其代谢物的尿液排泄分数没有显著变化。这些结果表明TBX对茶碱的药代动力学和代谢几乎没有影响，提示TBX对于接受茶碱治疗的慢性阻塞性气道疾病哮喘患者是安全的。

The effect of a newly developed anti-allergic drug, pemirolast potassium (TBX), on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in seven healthy male volunteers. A sustained-release theophylline formulation (100 mg twice daily at 12 h intervals) was given as monotherapy and coadministered with TBX (10 mg twice daily at 12 h). Plasma concentration-time curves and the urinary excretion of theophylline and its major metabolites after administration of theophylline alone and after coadministration with TBX were compared. No significant adverse effects from this study were observed. There were no significant differences in the total body clearance, renal clearance and maximum concentration of theophylline between the two treatments, although coadministration of TBX significantly delayed the time to reach maximum concentration of theophylline. In the case of urinary excretion, no significant changes in the fraction of urinary excretion of theophylline and its metabolites were observed. These results indicate that TBX has little or no effect on the pharmacokinetics and metabolism of theophylline and suggest that TBX is safe for asthma patients receiving theophylline therapy for treatment of chronic obstructive airway diseases.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：发育或生殖毒性/给予兔子的口服剂量高达150 mg/kg的培美洛司特钾并未显示出致畸性.../培美洛司特钾/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pemirolast potassium was not teratogenic in rabbits given oral doses up to 150 mg/kg ... /Pemirolast potassium/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：发育或生殖毒性/培美洛司特钾在器官形成期间给予大鼠口服剂量>/=250 mg/kg时，会导致颈部胸腺残留增加、心室间隔缺损、胎儿波状肋骨、胸椎体分裂以及骨化胸骨、骶骨和尾椎以及跖骨数量减少的情况。在大鼠口服400 mg/kg培美洛司特钾时，胎儿和新生儿肾盂/输尿管扩张的发生率也有所增加。/培美洛司特钾/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pemirolast potassium caused an increased incidence of thymic remnant in the neck, interventricular septal defect, fetuses with wavy rib, splitting of thoracic vertebral body, and reduced numbers of ossified sternebrae, sacral and caudal vertebrae, and metatarsi when rats were given oral doses >/= 250 mg/kg during organogenesis. Increased incidence of dilation of renal pelvis/ureter in the fetuses and neonates was also noted when rats were given an oral dose of 400 mg/kg pemirolast potassium. /Pemirolast potassium/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：发育或生殖毒性/培美洛司特钾在给予大鼠口服剂量400毫克/千克时，会导致着床前和着床后损失增加，胚胎/胎儿和新生儿存活率降低，新生儿体重减轻，以及新生儿发育延迟。当F0代母鼠在妊娠晚期和哺乳期间口服剂量大于或等于250毫克/千克时，培美洛司特钾还会减少F1代大鼠的 corpus lutea（黄体）数量、着床数量和活胎儿数量。/培美洛司特钾/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pemirolast potassium produced increased pre- and post-implantation losses, reduced embryo/fetal and neonatal survival, decreased neonatal body weight, and delayed neonatal development in rats receiving an oral dose at 400 mg/kg. Pemirolast potassium also caused a reduction in the number of corpus lutea, the number of implantations, and number of live fetuses in the F1 generation in rats when F0 dams were given oral doses >/= 250 mg/kg during late gestation and the lactation period. /Pemirolast potassium/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 消除途径

大约10-15%的剂量在尿液中原样排出。

Following topical administration, about 10-15% of the dose was excreted unchanged in the urine.

来源:DrugBank

吸收、分配和排泄

经过2周给药后，平均血浆峰浓度为4.7 ng/mL。/培美洛司坦钾/

A mean peak plasma level of 4.7 ng/mL occurred after 2 weeks of administration. /Pemirolast potassium/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：肾脏，84%至90%的剂量在24小时内消除，约10%至15%的剂量以原形排泄。/培美罗硫酸钾/

Elimination: Renal, 84 to 90% of dose eliminated within 24 hours, about 10 to 15% of the dose was excreted unchanged. /Pemirolast potassium/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

哺育期大鼠的乳汁中排出的泼米罗酸钾浓度高于血浆中的浓度。目前尚不清楚泼米罗酸钾是否会在人类乳汁中排出。

Pemirolast potassium is excreted in the milk of lactating rats at concentrations higher than those in plasma. It is not known whether pemirolast potassium is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

16名健康志愿者每天四次，每次每只眼滴入一到两滴Alamast眼药水，持续两周，通过眼结膜给药后，药物在血浆中可检测到。平均（+/-标准误）血浆峰浓度为4.7 +/- 0.8 ng/mL，发生在0.42 +/- 0.05小时，平均半衰期为4.5 +/- 0.2小时。/培美洛司特钾/

Topical ocular administration of one to two drops of Alamast ophthalmic solution in each eye four times daily in 16 healthy volunteers for two weeks resulted in detectable concentrations in the plasma. The mean (+/- SE) peak plasma level of 4.7 +/- 0.8 ng/mL occurred at 0.42 +/- 0.05 hours and the mean half-life was 4.5 +/- 0.2 hours. /Pemirolast potassium/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  C
• WGK Germany：
  3
• 危险类别：
  8
• 安全说明：
  S16,S26,S36/37/39,S37/39
• 危险类别码：
  R34
• 包装等级：
  II
• 危险品运输编号：
  UN 1993 3/PG 2

制备方法与用途

概述

吡嘧司特能强效抑制细胞外钙内流和细胞内钙的释放，同时抑制磷酸二酯酶活性，从而升高细胞内的cAMP水平，并且还能抑制花生四烯酸的释放和代谢。它对由抗原-抗体反应引起的组胺、白三烯及前列腺素等物质的释放具有显著的抑制作用，能够减轻被动皮肤过敏反应和实验性哮喘。临床主要用于预防或减轻支气管哮喘发作，但不能迅速缓解急性哮喘发作。

用法

口服，每次10毫克，每日2次，建议在早、午或临睡前服用。

不良反应及注意事项

偶见头痛、胃不适、便秘、口干、皮疹和瘙痒等症状，也有报道显示血小板计数增加以及肝、肾功能损害等不良反应。哺乳妇女及幼儿应慎用。

化学性质

吡嘧司特从二甲基甲酰胺中结晶，熔点为310-311℃（分解）。吡嘧司特钾（Pemirolast Potassium）是一种淡黄色的结晶性粉末，无臭且味道苦涩。它易溶于水，难溶于甲醇或乙醇，并几乎不溶于乙醚。其熔点超过320℃。

用途

主要用于治疗支气管哮喘。

生产方法

吡嘧司特由2-氨基-3-甲基吡啶、叠氮钠、三氯化铝及3-乙氧基-2-氰基丙烯酸乙酯在四氢呋喃中回流制得。

反应信息

• 作为反应物：
  描述：

  吡嘧司特 在 氢氧化钾 作用下， 以 甲醇 为溶剂， 生成 Pemirolast potassium
  参考文献：
  名称：

  Process for the preparation of high purity pemirolast

  摘要：

  本发明揭示了一种用于纯化Pemirolast的新工艺，其钾盐是一种抗过敏药物产品。

  公开号：

  US20030032805A1
• 作为产物：
  描述：

  4-imino-9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido<1,2-a>pyrimidine 在 盐酸 作用下， 反应 1.0h， 以84.6%的产率得到吡嘧司特
  参考文献：
  名称：

  A Facile and Practical Synthesis of 9-Methyl-3-(1H-tetrazol-5-yl)-4H-pyrido(1,2-a)pyrimidin-4-one.

  摘要：

  9-甲基-3-(1H-四唑-5-基)-4H-吡啶并[1, 2-α]嘧啶-4-酮(4)的简便实用合成，其钾盐在临床上用作描述了一种抗哮喘剂。用叠氮化钠在 N,N-二甲基甲酰胺中处理由 2-氨基-3-甲基吡啶 (1) 和 2-乙氧基亚甲基-1, 3-丙二腈制备的关键中间体 (6b)，主要得到氰基四唑 (7a)，同时在乙酸中仅生成亚胺四唑 (7b)，很容易通过酸水解转化为 4。建立了从6b开始得到4的一锅法，避免使用爆炸性叠氮化铝。

  DOI：

  10.1248/cpb.43.683

文献信息

• [EN] BORON-CONTAINING RHO KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA RHO KINASE CONTENANT DU BORE
  申请人：PERCIPIAD INC

  公开号：WO2021011873A1

  公开（公告）日：2021-01-21

  The present invention provides boron-containing isoquinoline compounds as protein kinase-modulating compounds. These compounds are useful as neuroprotective and neuro-regenerative agents for the amelioration of glaucoma and other ocular neuropathies.

  本发明提供了含硼的异喹啉化合物作为蛋白激酶调节化合物。这些化合物可用作神经保护和神经再生剂，用于改善青光眼和其他眼神经病变。
• [EN] HETEROCYCLIC PROLINAMIDE DERIVATIVES<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES DE PROLINAMIDE
  申请人：INCEPTION 4 INC

  公开号：WO2017222915A1

  公开（公告）日：2017-12-28

  This invention is directed to novel heterocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRAl. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRAl. The compounds of the invention are also useful for inhibiting HTRAl protease activity in an eye or locus of an arthritis or related condition.

  这项发明涉及一种新颖的Formula (I)异环脯氨酰胺衍生物，以及在预防（例如，延缓或减少发展风险）和治疗（例如，控制、缓解或减缓进展）与眼睛相关的年龄相关性黄斑变性（AMD）和相关疾病中有用的药用盐、溶剂化合物、盐的溶剂化合物和其前药。这些疾病包括干性AMD、湿性AMD、地理性萎缩、糖尿病视网膜病变、早产儿视网膜病变、多发性脉络膜血管病变以及视网膜或光感受细胞的退化。本公开的发明还涉及预防、减缓进展和治疗干性AMD、湿性AMD、地理性萎缩、糖尿病视网膜病变、早产儿视网膜病变、多发性脉络膜血管病变以及视网膜或光感受细胞的退化的方法，包括：给予所述发明化合物的治疗有效量。本发明的化合物是HTRAl的抑制剂。因此，本发明的化合物在预防和治疗一系列（全部或部分）由HTRAl介导的疾病中有用。本发明的化合物还可用于抑制眼睛或关节炎或相关疾病部位中的HTRAl蛋白酶活性。
• Nitrogen-containing tricyclic compounds
  申请人：Yamada Rintaro

  公开号：US20060247266A1

  公开（公告）日：2006-11-02

  A novel compound represented by the following formula (1) or a salt thereof [wherein R 1 , R 5 , R 6 , R 7 , and R 8 represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, an alkenyl group and the like; X 1 . . . X 2 represents —CH(R 2 )—CH(R 3 )—, —CH(R 2 )—CH(R 3 )—CH(R 4 )—, —C(R 2 )═C(R 3 )—, or —C(R 2 )═C(R 3 )—CH(R 4 )—(R 2 , R 3 , and R 4 represent hydrogen atom, or an alkyl group); A 1 , A 11 , A 2 , and A 21 represent hydrogen atom, or an alkyl group; Y represents —CH(A 3 )-, —CH(A 3 )-C(A 4 )(A 41 )-, —CH(A 3 )-C(A 4 )(A 41 )-C(A 5 )(A 51 )-, or a single bond (A 3 , A 4 , A 41 , A 5 , and A 51 represent hydrogen atom, or an alkyl group), and Z represents hydroxyl group, or —N(A 6 )(A 61 )(A 6 represents hydrogen atom, or an alkyl group, and A 61 represents hydrogen atom, an alkyl group, a substituted alkyl group and the like)], having an action of potently inhibiting phosphorylation of myosin regulatory light chain.

  以下式（1）表示的新化合物或其盐[其中R1、R5、R6、R7和R8代表氢原子、卤素原子、羟基、烷基、烯基等；X1...X2代表—CH(R2)—CH(R3)—、—CH(R2)—CH(R3)—CH(R4)—、—C(R2)=C(R3)—或—C(R2)=C(R3)—CH(R4)—(R2、R3和R4代表氢原子或烷基)；A1、A11、A2和A21代表氢原子或烷基；Y代表—CH(A3)-、—CH(A3)-C(A4)(A41)-、—CH(A3)-C(A4)(A41)-C(A5)(A51)-或单一键（A3、A4、A41、A5和A51代表氢原子或烷基），Z代表羟基或—N(A6)(A61)(A6代表氢原子或烷基，A61代表氢原子、烷基、取代烷基等)]具有强烈抑制肌球蛋白调节轻链磷酸化的作用。
• TREATMENT FOR DISCOID LUPUS
  申请人：Magilavy Daniel

  公开号：US20120232106A1

  公开（公告）日：2012-09-13

  Compounds I and II as well as salts and pharmaceutical compositions containing them are useful for treating diseases and/or disorders of the skin, such as cutaneous lupus, for example acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, or discoid lupus erythematosus. In certain embodiments, the compounds are provided in topical compositions.

  I和II以及含有它们的盐和药物组合物可用于治疗皮肤疾病和/或障碍，例如皮肤红斑狼疮，例如急性皮肤红斑狼疮、亚急性皮肤红斑狼疮或盘状红斑狼疮。在某些实施例中，化合物以局部组合物形式提供。
• COMPOSITION FOR OPHTHALMIC ADMINISTRATION
  申请人：Rigel Pharmaceuticals, Inc.

  公开号：US20140206708A1

  公开（公告）日：2014-07-24

  Disclosed herein are embodiments of a composition useful for treating and/or preventing dry eye disorders. The disclosed composition comprises components that maintain the composition's chemical and/or physical properties thereby providing a composition suitable for use.

  披露的是用于治疗和/或预防干眼病的组合物的实施例。所述组合物包含维持其化学和/或物理性质的成分，从而提供适合使用的组合物。