氮卓斯汀 | 58581-89-8

• 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 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 氮卓斯汀
• 中文别名: 氮卓司丁；盐酸氮卓斯汀；4-[(4-氯苯基)甲基]-2-(六氢-1-甲基-1H-氮杂卓-4-基)二氮杂萘酮；4-[(4-氯苯基)甲基]-2-(六氢-1-甲基-1H-氮杂卓-4-基)-1(2H)-酞嗪酮；4-[(4-氯苯基)甲基]-2-(六氢-1-甲基-1H-氮杂卓)二氮杂萘酮
• 英文名称: azelastine
• 英文别名: azelastine hydrochloride；4-[(4-chlorophenyl)methyl]-2-(1-methylazepan-4-yl)phthalazin-1-one
• CAS: 58581-89-8
• 化学式: C₂₂H₂₄ClN₃O
• 分子量: 381.905
• InChiKey: MBUVEWMHONZEQD-UHFFFAOYSA-N

物化性质

• 熔点：
  111 - 115°C
• 沸点：
  533.9±60.0 °C(Predicted)
• 密度：
  1.1505 (rough estimate)
• 溶解度：
  可溶于氯仿（轻微）、DMSO（轻微、加热）、甲醇（轻微）
• 物理描述：
  Solid
• 颜色/状态：
  Oil
• 蒸汽压力：
  5.51X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：
  单水合物：从乙醇-水结晶中获得，可鉴定出两种不同的晶型。 盐酸氮革斯汀（Azelastine Hydrochloride）的化学式为C22H24ClN3O·HCl，其CAS号为79307-93-0。这是一种白色结晶性粉末，无臭、味苦。它溶于氯仿和二氯甲烷或冰醋酸，略溶于甲醇，微溶于无水乙醇或水，不溶于丙酮或乙醚。其熔点为225～229℃。 急性毒性实验显示： - 雄性小鼠口服：124 mg/kg - 雌性小鼠口服：139 mg/kg - 雄性大鼠口服：310 mg/kg - 雌性大鼠口服：417 mg/kg - 雄性豚鼠口服：126 mg/kg - 雌性豚鼠口服：130 mg/kg 静脉注射： - 雄性小鼠：597.0 mg/kg - 雌性小鼠：57.2 mg/kg - 雄性大鼠：143.0 mg/kg - 雌性大鼠：115.0 mg/kg - 雄性豚鼠：46.2 mg/kg - 雌性豚鼠：52.2 mg/kg 肌肉注射： - 雄性小鼠：63.0 mg/kg - 雌性小鼠：54.2 mg/kg - 雄性大鼠：66.5 mg/kg - 雌性大鼠：59.6 mg/kg 雄性小鼠皮下注射剂量为41.0 mg/kg，雌性小鼠为37.3 mg/kg。

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  35.9
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

盐酸氮卓斯汀通过细胞色素P450酶系统被氧化代谢为其主要且具有生物活性的代谢物去甲基氮卓斯汀。尽管氮卓斯汀的标签说明尚未明确特定的CYP酶参与，但有人提出氮卓斯汀的N-脱甲基化主要是由CYP3A4、CYP2D6和CYP1A2催化的。

Azelastine hydrochloride is oxidatively metabolized to its main, and biologically active, metabolite desmethylazelastine by the cytochrome P450 enzyme system. Though labels for azelastine state that specific CYP enzyme involvement has not been elucidated, it has been suggested that the N-demethylation of azelastine is primarily catalyzed by CYP3A4, CYP2D6, and CYP1A2.

来源:DrugBank

代谢

azelastine被细胞色素P450酶系统氧化代谢为其主要活性代谢物，去甲基azelastine。负责azelastine生物转化的特定P450同工酶尚未被识别。

Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified

来源:Hazardous Substances Data Bank (HSDB)

代谢

氢氯化阿扎司丁单次鼻腔给药后，其主要活性代谢物去甲基阿扎司丁无法测量（低于检测限）。在氢氯化阿扎司丁鼻腔给药达到稳态后，去甲基阿扎司丁的血浆浓度范围为阿扎司丁浓度的20-50%。

The major active metabolite, desmethylazelastine, was not measurable (below assay limits) after single-dose intranasal administration of azelastine hydrochloride. After intranasal dosing of azelastine hydrochloride to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸氮䓬斯汀单次和多次给药（4.4毫克片剂，tau = 12小时）的药代动力学在14名65岁以上志愿者（6名女性，8名男性，年龄70 +/- 5岁，平均值 +/- 标准差）中进行研究。RIA同时检测到除了氮䓬斯汀之外的药代动力学活性代谢物N-去甲基氮䓬斯汀，因此，这些参数描述了这两种化合物的药代动力学行为，即“有效成分”。已知N-去甲基化代谢物通常比其母化合物的半衰期更长，因此在多次给药过程中会以更高程度累积。

The ... pharmacokinetics of azelastine hydrochloride after single and multiple dosing (4.4 mg as tablet, tau = 12 hr) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). ... The RIA co-detects besides azelastine the pharmacodynamically active metabolite N-demethyl-azelastine and thus, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds, i.e. the "active principle". N-Demethylated metabolites are known to have longer half-lives usually than their parent compounds and thus, accumulate in a higher degree during multiple dosing.

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸氮卓斯汀被细胞色素P450酶系统氧化代谢为其主要代谢物，N-去甲基氮卓斯汀，然而具体涉及的细胞色素P450同工酶尚未确定。主要代谢物，去甲基氮卓斯汀，也具有H1受体拮抗剂的活性。 消除途径：大约75%的口服放射性标记的盐酸氮卓斯汀剂量在粪便中排出，不到10%以未改变的氮卓斯汀形式存在。盐酸氮卓斯汀被细胞色素P450酶系统氧化代谢为其主要代谢物，N-去甲基氮卓斯汀。 半衰期：消除半衰期（基于静脉注射和口服给药）为22小时。活性代谢物，去甲基氮卓斯汀的消除半衰期为54小时（口服给药氮卓斯汀后）。

Azelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system, however the exact cytochrome P450 isoenzyme involved has not been determined. The major metabolite, desmethylazelastine, also has H1-receptor antagonist activity. Route of Elimination: Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Azelastine hydrochloride is oxidatively metabolized to the principal metabolite, N-desmethylazelastine, by the cytochrome P450 enzyme system. Half Life: Elimination half-life (based on intravenous and oral administration) is 22 hours. Elimination half-life of the active metabolite, desmethylazelastine, is 54 hours (after oral administration of azelastine).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

azelastine竞争组胺H1受体位点并作为拮抗剂，抑制组胺和其他参与过敏性反应的介质的释放。

Azelastine competes with histamine for the H1-receptor sites on effector cells and acts as an antagonist by inhibiting the release of histamine and other mediators involved in the allergic response.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类无致癌性（未列入国际癌症研究机构名录）。

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

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：偶尔小剂量使用氮䓬斯汀鼻喷剂预计不会对哺乳婴儿产生任何不良反应。较大剂量或更长时间使用鼻喷剂可能会导致婴儿出现嗜睡和其他效应，或者减少乳汁供应，尤其是在与伪麻黄碱等拟交感神经药联合使用或哺乳尚未建立良好时。由于药物的苦味，婴儿可能会拒绝哺乳。首选的替代品是非镇静性口服抗组胺药。 由于眼部吸收有限，氮䓬斯汀预计不会对哺乳婴儿产生任何不良反应。为了显著减少使用眼药水后到达母乳中的药物量，可以在眼角按压泪囊1分钟或更长时间，然后用吸收性纸巾去除多余的溶液。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到关于氮䓬斯汀的相关已发布信息。在一项电话随访研究中，母亲报告有10%的婴儿接触各种抗组胺药后出现烦躁和腹痛症状，1.6%的婴儿出现嗜睡。所有反应均未需要医疗关注。 ◉ 对泌乳和母乳的影响：在非哺乳期妇女和产后早期妇女中，通过注射给予相对高剂量的抗组胺药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使用抗组胺药预处理的影响。尚未研究口服较低剂量的抗组胺药是否对血清催乳素有相同的影响，或者对催乳素的影响是否对哺乳成功有任何影响。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 azelastine nasal spray would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use of the nasal spray 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. Infant rejection of the breast might occur because of the bitter taste of the drug. The oral, nonsedating antihistamines are preferred alternatives. Because absorption from the eye is limited, azelastine would not be expected to cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ Effects in Breastfed Infants:Relevant published information on azelastine 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

• 在妊娠和哺乳期间的影响

◈ 什么是氮䓬斯汀？ 氮䓬斯汀是一种抗组胺药。它通常用于治疗过敏症状。它以鼻喷剂（鼻腔内用）形式出现，用于治疗流鼻涕、鼻痒、鼻塞和打喷嚏等症状。这种药物的品牌名为Astelin®。氮䓬斯汀还以眼药水形式出现，用于治疗因过敏引起的眼睛痒。其品牌名为Optivar®。有时人们发现自己怀孕了，会考虑改变用药方式，或者完全停止用药。然而，在做出任何改变之前，与您的医疗保健提供者交谈是非常重要的。您的医疗保健提供者可以与您讨论治疗您的疾病的好处以及怀孕期间未治疗疾病的风险。 ◈ 我服用氮䓬斯汀。它会让我更难怀孕吗？ 尚未在人类中进行研究，以观察氮䓬斯汀是否会使人更难怀孕。在对大鼠进行的动物研究中，当氮䓬斯汀以口服方式使用，剂量达到成人推荐的最大每日鼻腔内剂量的150倍时，并未对雌性大鼠的生育能力产生影响。 ◈ 服用氮䓬斯汀会增加流产的风险吗？ 流产可能因多种不同原因发生在任何怀孕中。尚未进行研究以观察氮䓬斯汀是否会增加流产的风险。 ◈ 服用氮䓬斯汀会增加出生缺陷的风险吗？ 每怀孕都有3-5%的出生缺陷风险。这被称为背景风险。尚未在人类中进行研究，以观察氮䓬斯汀是否会增加怀孕时出现出生缺陷的风险。在动物研究中，使用与人类使用剂量相似的氮䓬斯汀剂量，并未显示出生缺陷的风险增加。 ◈ 孕期服用氮䓬斯汀会增加其他与怀孕相关问题的风险吗？ 尚未进行研究，以观察氮䓬斯汀是否会增加与怀孕相关问题的风险，如早产（出生在37周之前）或低出生体重（出生时体重低于5磅8盎司[2500克]）。 ◈ 孕期服用氮䓬斯汀会影响孩子的未来行为或学习能力吗？ 尚未进行研究，以观察氮䓬斯汀是否会对孩子的行为或学习能力造成影响。 ◈ 服用氮䓬斯汀时哺乳： 尚未对氮䓬斯汀在哺乳期使用的安全性进行研究。当以眼药水形式使用时，氮䓬斯汀的吸收量可能很小，预计不会对哺乳婴儿造成问题。按照指示使用几天的氮䓬斯汀鼻喷剂也不预期会对哺乳婴儿产生任何不良反应。因为氮䓬斯汀味道苦涩，婴儿可能会拒绝哺乳。如果鼻喷剂使用剂量较大或超过几天，可能会导致婴儿嗜睡。如果与伪麻黄碱类药物联合使用，或者在使用母乳供应良好建立之前开始使用，它也可能降低乳汁供应。如果您怀疑婴儿有任何症状（如嗜睡），请联系孩子的医疗保健提供者。请务必与您的医疗保健提供者讨论所有关于哺乳的问题。 ◈ 如果男性服用氮䓬斯汀，会影响生育能力（使伴侣怀孕的能力）或增加出生缺陷的风险吗？ 尚未进行研究，以观察氮䓬斯汀是否会影响人类的生育能力或增加伴侣出生缺陷的风险。在对大鼠进行的动物研究中，当氮䓬斯汀以口服方式使用，剂量达到成人推荐的最大每日鼻腔内剂量的150倍时，并未对雄性大鼠的生育能力产生影响。一般来说，父亲或精子捐赠者的暴露不太可能增加怀孕的风险。更多信息，请参阅MotherToBaby关于父亲暴露的小册子，网址为https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/。

◈ What is azelastine? Azelastine is an antihistamine. It is commonly used to treat allergy symptoms. It comes as a nasal spray (intranasal) to treat symptoms such as runny, itchy, and stuffy nose and sneezing. This is sold under the brand name Astelin®. Azelastine also comes in eye drop form to treat itchy eyes due to allergies. It is sold under the brand name Optivar®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy. ◈ I take azelastine. Can it make it harder for me to get pregnant? Studies have not been done in humans to see if azelastine can make it harder to get pregnant. Animal studies have shown no impact on female fertility in rats when azelastine was used by mouth (orally) at levels up to 150 times the maximum recommended human daily intranasal (by nose) dose in adults. ◈ Does taking azelastine increase the chance for miscarriage? Miscarriage can occur in any pregnancy for many different reasons. Studies have not been done to see if azelastine increases the chance of miscarriage. ◈ Does taking azelastine increase the chance of birth defects? Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have not been done in humans to see if azelastine could increase the chance of having a pregnancy with a birth defect.Animal studies that used doses of azelastine that would be similar to doses used in humans have not shown an increased chance for birth defects. ◈ Does taking azelastine in pregnancy increase the chance of other pregnancy related problems? Studies have not been done to see if azelastine increases the chance for pregnancy related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). ◈ Does taking azelastine in pregnancy affect future behavior or learning for the child? Studies have not been done to see if azelastine can cause behavior or learning issues for the child. ◈ Breastfeeding while taking azelastine: Azelastine has not been studied for use with breastfeeding.When used in eye drop form, the amount of the azelastine absorbed is likely small, and is not expected to cause problems in breastfed infants.When used as directed for a few days, azelastine nasal spray would also not be expected to cause any adverse effects in breastfed infants. Because azelastine tastes bitter, the baby may reject breastfeeding. If the nasal spray is used in larger doses or for more than a few days, it may cause drowsiness in the infant. It might also lower milk supply, especially when used with a medication called pseudoephedrine or if started before breastmilk supply is well established. If you suspect the baby has any symptoms (such as drowsiness), contact the child’s healthcare provider.Be sure to talk to your healthcare provider about all of your breastfeeding questions. ◈ If a male takes azelastine, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects? Studies have not been done to see if azelastine could affect human fertility or increase the chance of birth defects in a partner. Animal studies have shown no change on male fertility in rats when azelastine was used by mouth (orally) at levels up to 150 times the maximum recommended human daily intranasal dose in adults. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

来源:Mother To Baby Fact Sheets

毒理性

• 暴露途径

奥扎拉斯特ine经眼给药后的吸收相对较低。经鼻给药后，系统的生物利用度大约是40%。

Absorption of azelastine following ocular administration was relatively low. Systemic bioavailability is approximately 40% after nasal administration.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

盐酸氮䓬斯汀经鼻内给药的系统性生物利用度大约为40%，在2-3小时内达到Cmax。当给药剂量超过推荐的最大剂量时，观察到Cmax和AUC的增幅大于剂量比例。

Systemic bioavailability of azelastine hydrochloride following intranasal administration is approximately 40%, reaching Cmax within 2-3 hours. When administered at doses greater than the recommended maximum, greater than proportional increases in both Cmax and AUC were observed.

来源:DrugBank

吸收、分配和排泄

• 消除途径

口服标记的盐酸氮䓬斯汀后，大约75%通过粪便排出，其中不到10%为未改变的盐酸氮䓬斯汀。

After an oral dose of radio-labeled azelastine hydrochloride, approximately 75% was excreted in the feces, with less than 10% as unchanged azelastine hydrochloride.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉和口服给药后，稳态分布容积为14.5 L/kg。

After intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

根据静脉和口服给药，阿伐斯汀表现出0.5 L/h/kg的血浆清除率。

Based on intravenous and oral administration, azelastine demonstrated a plasma clearance of 0.5 L/h/kg.

来源:DrugBank

吸收、分配和排泄

经鼻内给药后，盐酸氮䓬斯的系统生物利用度大约为40%。在2-3小时内达到最大血浆浓度（Cmax）。

After intranasal administration, the systemic bioavailability of azelastine hydrochloride is approximately 40%. Maximum plasma concentrations (Cmax) are achieved in 2-3 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T,N
• RTECS号：
  CY5950000
• 海关编码：
  2933990090
• 危险类别：
  6.1(b)
• 安全说明：
  S20/21,S28,S28A,S45,S60,S61
• 危险类别码：
  R23/25,R50/53
• 包装等级：
  III
• 危险品运输编号：
  1557
• 储存条件：
  贮存于密封容器中，并置于干燥、阴凉的地方保存。

制备方法与用途

生物活性

Azelastine是第二代H1受体拮抗剂。

化学性质

Azelastine为油状物，易溶于二氯甲烷。其单水合物是从乙醇-水结晶中结晶而来，并可鉴定出两种不同的晶型。盐酸氮革斯汀（化学名：C22H24ClN3O·HCl，CAS号：79307-93-0）为白色结晶性粉末，无臭、味苦。该化合物溶于氯仿、二氯甲烷或冰醋酸，略溶于甲醇，微溶于无水乙醇或水，不溶于丙酮或乙醚。熔点范围为225～229℃。

用途

Azelastine用于支气管哮喘和鼻变态反应的治疗，并作为基础抗组胺药使用。

生产方法

生产过程包括两个主要步骤：

1. 首先，30.6克对氯苄基苯乙酮-邻-羧酸与16克硫酸肼及9.4克氢氧化钠溶于250毫升水中并加热。洗涤和干燥后得到27克4-(4-氯苄基)-1-(2H)-酞嗪酮（化合物Ⅱ）。
2. 然后，将20克2-(2-氯乙基)-N-甲基四氢吡咯盐酸盐加入到4.4克氢氧化钠的20毫升水溶液中并加热至70℃。随后滴入已经加热至相同温度的含有27克化合物Ⅱ和40毫升50%氢氧化钠水溶液的反应混合物，继续在该温度下加热1小时。冷却后用清水稀释，过滤除去不溶物，并将滤液溶于二氯甲烷中。使用稀盐酸进行萃取，提取后的液体再用氢氧化钾水溶液碱化并析出油状物。再次溶解于二氯甲烷后干燥和浓缩以获得粗品，其收率超过90%。最后将其转化为盐酸盐并通过重结晶提纯得到熔点为225～229℃的盐酸氮革斯汀。

反应信息

• 作为反应物：
  描述：

  氮卓斯汀 在 水 作用下， 以 乙醇 为溶剂， 生成 Azelastine monohydrate
  参考文献：
  名称：

  Crystalline form of azelastine

  摘要：

  阿齐拉斯汀的多形态I的化学式(I)，其制备过程包括以下步骤：a)从异丁基甲基酮溶液中结晶化阿齐拉斯汀；b)分离出在上一步骤中出现的阿齐拉斯汀的多形态I；c)从所得的阿齐拉斯汀多形态I中去除有机溶剂，并将其用作抗组胺药。

  公开号：

  EP2072510A1
• 作为产物：
  描述：

  1-甲基六氢-4H-氮杂卓-4-酮 在 盐酸 、 氢氧化钾 、 sodium tetrahydroborate 作用下， 反应 5.0h， 生成 氮卓斯汀
  参考文献：
  名称：

  氮卓斯汀的合成及晶体结构分析

  摘要：

  氮卓斯汀盐酸盐（ASTA A 5610），4-（对氯苄基）-2-（六氢-1-甲基-1H-azepin-4-yl）-1（2H）-酞嗪酮盐酸盐（2）是一种新型口服溶液长- 持久的抗过敏和预防哮喘。从邻苯二甲酸酐开始，描述了盐酸氮卓斯汀的两种替代合成路线。氮卓斯汀一水合物的 X 射线结构分析显示两个独立的分子 A 和 B，具有显着的构象差异。根据结构-活性关系讨论结构差异。

  DOI：

  10.1002/ardp.19883210406

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20150231142A1

  公开（公告）日：2015-08-20

  The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

  本发明涉及含有上皮钠通道活性抑制剂与至少一种ABC转运蛋白调节剂化合物（A式、B式、C式或D式）的药物组合物。该发明还涉及这些药物配方，以及使用这些组合物治疗CFTR介导的疾病，特别是囊性纤维化的方法。
• [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。
• [EN] FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE CONDENSÉS UTILISÉS EN TANT QU'INHIBITEURS DE JAK
  申请人：ALMIRALL SA

  公开号：WO2017220431A1

  公开（公告）日：2017-12-28

  Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

  公开了式（I）的新型融合吡唑衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为Janus激酶（JAK）抑制剂在治疗中的用途。
• [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。