左布地奈德 | 51333-22-3

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 肾上腺皮质激素类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 左布地奈德
• 中文别名: S-丙基亚甲基二氧-孕甾-1,4-二烯-11beta,21-二羟基-3,20二酮；16alpha,17alpha-22R,S-丙基亚甲基二氧-孕甾-1,4-二烯-11beta,21-二羟基-3,20二酮；布地奈德
• 英文名称: budesonide
• 英文别名: (1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one
• CAS: 51333-22-3
• 化学式: C₂₅H₃₄O₆
• 分子量: 430.541
• InChiKey: VOVIALXJUBGFJZ-KWVAZRHASA-N

物化性质

• 熔点：
  221-232°C (dec.)
• 比旋光度：
  D25 +98.9° (c = 0.28 in methylene chloride)
• 沸点：
  464.79°C (rough estimate)
• 密度：
  1.1046 (rough estimate)
• 溶解度：
  几乎不溶于水，易溶于二氯甲烷，微溶于乙醇（96%）。
• 物理描述：
  Solid
• 颜色/状态：
  Crystals
• 蒸汽压力：
  8.81X10-15 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Chemical stability: Stable under recommended storage conditions.
• 旋光度：
  Specific optical rotation: +98.9 deg at 25 °C/D (c = 0.28 in methylene chloride)
• 碰撞截面：
  204.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  93.1
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

布地奈德在首次通过肝脏时，有80-90%被代谢。布地奈德通过CYP3A酶代谢为其两个主要代谢物，6beta-羟基布地奈德和16alpha-羟基泼尼松龙。这些代谢物的糖皮质激素活性与母化合物相比可以忽略不计（<1/100）。CYP3A4是布地奈德最强的代谢酶，其次是CYP3A5和CYP3A7。

Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7.

来源:DrugBank

代谢

布地奈德在肝脏中被细胞色素P-450（CYP）同工酶3A4代谢；主要代谢物的糖皮质激素受体亲和力不到母化合物的1%。布地奈德以代谢物的形式通过尿液和粪便排出体外。

Budesonide is metabolized in the liver by the cytochrome P-450 (CYP) isoenzyme 3A4; the 2 main metabolites have less than 1% of affinity for glucocorticoid receptors than the parent compound. Budesonide is excreted in urine and feces as metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

哮喘是世界上最常见的疾病之一，其主要治疗方法是吸入糖皮质激素（GCs）。尽管这些药物被广泛使用，但大约30%的哮喘患者表现出一定程度的激素不敏感或对吸入GCs无效。解释这种现象的一个假设是患者之间这些化合物清除率的差异。本研究的目的是确定CYP3A家族酶对GCs的代谢如何影响哮喘患者的疗效。在这项工作中，研究了四种经常处方吸入的GCs，即丙酸倍氯米松、氟尼缩松、布地奈德和丙酸氟替卡松，通过CYP3A家族酶的代谢，以确定它们清除率的差异并识别它们的代谢物。观察到了代谢率和代谢命运的酶间和药物间的变异性。CYP3A4是所有化合物的最有效代谢催化剂，而CYP3A7的速率最慢。CYP3A5，特别是在肺部GC代谢方面具有相关性，也被证明有效地代谢了丙酸倍氯米松、布地奈德和丙酸氟替卡松。相比之下，氟尼缩松仅通过CYP3A4代谢，CYP3A5或CYP3A7没有显著转化。常见的代谢物包括对丙酸倍氯米松、布地奈德和氟尼缩松的6 Beta-羟基化和Delta (6)-脱氢化。通过NMR分析明确确立了Delta (6)-氟尼缩松的结构。代谢也发生在D环取代基上，包括丙酸倍氯米松和氟尼缩松的21-羧基代谢物。通过液相色谱-质谱和NMR分析还鉴定出了新的代谢物21-去甲丙酸倍氯米松。

Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6 Beta-hydroxylation and Delta (6)-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Delta (6)-flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴别人和使用：布地奈德（商品名：Rhinocort，MMX）是一种处方药，用于治疗过敏性鼻炎（Rhinocort鼻喷剂）和轻度至中度克罗恩病（MMX，肠溶胶囊）。人类暴露和毒性：贴片测试表明布地奈德可能引起迟发型过敏反应和特应性皮炎。在吸入暴露的情况下，报告了口周皮炎。在口服给药的情况下，报告了念珠菌性食管炎、吞咽困难、血压升高、下肢水肿和体重增加，尽管其中一些不良事件可能是与伏立康唑药物相互作用的结果。流行病学研究发现了与吸入布地奈德使用相关肺炎、心脏心律失常、白内障和骨折的风险增加。额外的流行病学研究发现，怀孕期间吸入布地奈德可能是后代内分泌和代谢紊乱的危险因素。还报告了低出生体重。在接受布地奈德治疗持续性哮喘的儿童中，也观察到了生长速度放缓、体重增长缓慢和骨骼成熟迟缓。在鼻腔布地奈德治疗期间，报告了鼻和喉咙的局部念珠菌感染。患者可能增加某些感染的风险，例如水痘。在儿童和青少年中，布地奈德给药可能导致生长抑制。它还可能引起急性或迟发型超敏反应。在母亲怀孕期间接受皮质类固醇治疗的婴儿中，可能会出现低肾上腺功能。动物研究：在致癌性研究中，口服布地奈德的大鼠中观察到了肝细胞肿瘤和神经胶质瘤。在皮下接受布地奈德的雌性大鼠中，观察到了孕期和哺乳期大鼠的存活率和幼崽存活率下降。在接受口服布地奈德的小鼠中检测到了幽门透明变性。

IDENTIFICATION AND USE: Budesonide (trade names: Rhinocort, MMX) is a prescription medication approved for the treatment of allergic rhinitis (Rhinocort nasal spray) and mild to moderate Crohn's disease (MMX, enteric coated capsules). HUMAN EXPOSURE AND TOXICITY: Patch tests have indicated that budesonide can produce delayed allergic reactions, and atopic dermatitis. In cases of inhalational exposure, periorificial dermatitis has been reported. In cases of oral administration, Candida albicans esophagitis, dysphagia, elevated blood pressure, lower extremity edema, and weight gain have been reported, although some of these adverse events may have been the result of a drug interaction with voriconazole. Epidemiological studies have found an increased risk of pneumonia, cardiac dysrhythmias, cataracts, and fractures associated with inhaled budesonide use. Additional epidemiological studies have found that budesonide inhalation during pregnancy may be a risk factor for offspring endocrine and metabolic disturbances. Low birth weight has also been reported. In children taking budesonide for persistent asthma, slower linear growth, slow weight gain, and slow skeletal maturation have also been observed. Localized Candidal infections of the nose and pharynx has been reported during intranasal budesonide therapy. Patients may be at an increased risk for certain infections, such as Varicella (chickenpox). In children and adolescents, administration of budesonide may cause growth suppression. It may also cause acute or delayed hypersensitivity reactions. Hypoadrenalism may occur in infants of mothers receiving corticosteroid therapy during pregnancy. ANIMAL STUDIES: In carcinogenicity studies, hepatocellular tumors and gliomas have been observed in rats that received oral budesonide. In female rats that received budesonide subcutaneously, a decrease in prenatal viability and viability of pups during pregnancy and lactation was observed. Pyloric hyalinization was detected in mice that received budesonide orally.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

长期使用布地奈德治疗并未与血清酶水平升高有关联，在临床试验中，与安慰剂治疗相比，ALT升高的比率相似。在有对照的试验中，没有报告与使用布地奈德相关的临床上明显的肝损伤病例。与传统的系统性给予的皮质类固醇不同，布地奈德并未与乙型肝炎再激活的发作有关联。布地奈德已用于治疗严重的自身免疫性肝病，没有证据表明它会加剧中肝脏损伤。由于它能够改善自身免疫性肝炎患者的血清转氨酶升高，因此停药后可能会出现反弹升高，这也发生在传统皮质类固醇治疗中。此外，曾有个别病例报告在布地奈德治疗期间出现急性血清转氨酶升高，但在停药后缓解，但相关记录有限，且患者同时使用了多种其他可能对肝脏有毒性的药物。

Long term therapy with budesonide has not been linked to elevations in serum enzyme levels, and in clinical trials rates of ALT elevations were similar with budesonide as with placebo treatment. In controlled trials, there were no reported cases of clinically apparent liver injury associated with its use. Unlike conventional systemically administered corticosteroids, budesonide has not been linked to episodes of reactivation of hepatitis B. Budesonide has been used in severe autoimmune liver diseases without evidence that it causes worsening of liver injury. Because it can improve serum aminotransferase elevations in patients with autoimmune hepatitis, its withdrawal may be followed by rebound elevations as also occurs with conventional corticosteroid therapy. In addition, there has been a single case report of acute serum aminotransferase elevations during budesonide therapy that resolved when the drug was stopped, but documentation was limited and the patient was on multiple other potentially hepatotoxic drugs.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：布地奈德

Compound:budesonide

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

缓释口服胶囊的生物利用度为9-21%。9毫克剂量的Cmax为1.50±0.79ng/mL，Tmax为2-8小时，AUC为7.33ng*hr/mL。高脂肪餐会增加Tmax 2.3小时，但除此之外不影响布地奈德的药代动力学。180-360微克定量吸入剂量的布地奈德有34%沉积在肺部，39%的生物利用度，Cmax为0.6-1.6nmol/L，Tmax为10分钟。1毫克雾化剂量的生物利用度为6%，Cmax为2.6nmol/L，Tmax为20分钟。9毫克口服缓释片的Cmax为1.35±0.96ng/mL，Tmax为13.3±5.9小时，AUC为16.43±10.52ng*hr/mL。布地奈德直肠泡沫2毫克每日两次的AUC为4.31ng*hr/mL。

Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a Cmax of 1.50±0.79ng/mL with a Tmax of 2-8h and an AUC of 7.33ng\*hr/mL. A high fat meal increases the Tmax by 2.3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a Cmax of 0.6-1.6nmol/L with a Tmax of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a Cmax of 2.6nmol/L with a Tmax of 20 minutes. A 9mg oral extended release tablet reaches a Cmax of 1.35±0.96ng/mL with a Tmax of 13.3±5.9h and an AUC of 16.43±10.52ng\*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4.31ng\*hr/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约60%的布地奈德剂量以主要代谢物6beta-羟基布地奈德、16alpha-羟基泼尼松龙及其结合物形式在尿液中回收。尿液中没有未改变的布地奈德被回收。

Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

布地奈德的分布容积为2.2-3.9L/kg。

The volume of distribution of budesonide is 2.2-3.9L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

丁酸氢化可的松的血浆清除率为0.9-1.8L/分钟。22R形式的清除率为1.4L/分钟，而22S形式的清除率为1.0L/分钟。哮喘儿童（4-6岁）的清除率为0.5L/分钟。

Budesonide has a plasma clearance of 0.9-1.8L/min. The 22R form has a clearance of 1.4L/min while the 22S form has a clearance of 1.0L/min. The clearance in asthmatic children 4-6 years old is 0.5L/min.

来源:DrugBank

吸收、分配和排泄

/MILK/ 尚不清楚布地奈德是否分布到牛奶中。

/MILK/ Not known whether budesonide is distributed in milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S36
• 危险类别码：
  R40
• WGK Germany：
  3
• 海关编码：
  29372900
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  TU3723000

制备方法与用途

布地奈德是一种糖皮质激素类药物，用于治疗哮喘和非传染性鼻炎。它通过抑制炎症反应和免疫反应来减轻症状。

作用机制

• 靶点: 主要是糖皮质激素受体。
• 生物活性:
  • 在人支气管上皮细胞系BEAS-2B和原代人支气管上皮细胞中，布地奈德有效地抑制eotaxin和RANTES蛋白质的产生。
  • 减少趋化因子和MCP-4的mRNA的衰变。
  • 抑制VEGF的分泌和VEGF mRNA表达。

体内研究

在大鼠实验中，布地奈德可以完全抑制LPS诱导产生的TNF-α、白细胞介素（IL）1beta、IL-6和单核细胞趋化蛋白（MCP）-1。此外，在A/J小鼠中，它还发挥化学预防作用。

临床应用

• 哮喘: 布地奈德气雾剂可用于轻症支气管哮喘。
• 非传染性鼻炎：适用于治疗这类病症。

注意事项与禁忌

• 慎用于肺结核、气道真菌感染或病毒感染患者。
• 孕妇应避免使用。
• 对依赖口服激素的病人，应在并用本品10天后逐渐减少口服激素剂量。

安全性

虽然布地奈德对大多数患者的副作用较小，但仍需注意其可能引起的咽痛、白色念珠菌感染等问题。此外，在严重应激状态或痰液变稠导致气道堵塞时，建议补充使用其他治疗方法如较大剂量水溶性皮质激素等。

急性毒性

• 腹腔 - 大鼠：LD50 (半数致死剂量) 为138毫克/公斤。
• 口服 - 小鼠：LD50 为4750毫克/公斤。

火灾危险与灭火方法

布地奈德在热分解过程中可能会排出有毒的辛辣刺激性烟雾。因此，在储存和运输时需要库房通风、低温干燥，并配备适当的消防设备如水、干粉、二氧化碳等灭火剂。

综上所述，布地奈德是一种有效的治疗哮喘和非传染性鼻炎的药物，但需注意其使用条件与潜在副作用。

反应信息

• 作为反应物：
  描述：

  左布地奈德 在 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 以78.2%的产率得到(6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7,10-Dihydroxy-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[2,1-b]furan-4,9(10H)-dione (Dexamethasone Impurity
  参考文献：
  名称：

  17-脱氧泼尼松龙的16，21-环状半缩醛的合成方法

  摘要：

  本发明提供了一种使用布地奈德制备17‑脱氧泼尼松龙的16，21‑环状半缩醛的方法。所述合成方法工艺路线简单、操作方便、收率较高；合成的布地奈德杂质17‑脱氧泼尼松龙的16，21‑环状半缩醛可作为布地奈德的检测及研究用对照品，应用于布地奈德及其相关制剂的质量控制，控制布地奈德原料药或者其制剂的纯度。

  公开号：

  CN113444137B
• 作为产物：
  描述：

  2-((10S,13S)-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15-octahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate 在 盐酸 、 potassium permanganate 、 N-溴代丁二酰亚胺(NBS) 、 甲酸 、 高氯酸 、 chromium(III) chloride hexahydrate 、 巯基乙酸 、 sodium hydroxide 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 为溶剂， 反应 7.0h， 生成 左布地奈德
  参考文献：
  名称：

  一种布地奈德工业化制备方法

  摘要：

  本发明涉及一种布地奈德工业化制备方法。具体而言，本发明涉及在盐酸水溶液、二氯甲烷和乙腈中，16α‑羟基泼尼松龙与正丁醛反应制得布地奈德。本发明的方法具有在工业上可实施、重现性好等优势。

  公开号：

  CN109384827A
• 作为试剂：
  描述：

  左布地奈德 在 左布地奈德 作用下， 以 乙醇 、 水 为溶剂， 反应 72.0h， 生成 Budesonide ethanol
  参考文献：
  名称：

  Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid

  摘要：

  提供了一种含有SAE-γ-CD和皮质类固醇的可吸入制剂。该制剂适用于通过任何已知的雾化器雾化给予受试者。该制剂可以包含在套装中。该制剂以水溶液形式给予，但可以作为干粉、即用溶液或浓缩组合物储存。该制剂用于改进的雾化系统，通过吸入给予皮质类固醇。制剂中存在的SAE-γ-CD显著增强了布地奈德的化学稳定性。提供了一种通过吸入给予制剂的方法。该制剂也可以通过传统的鼻腔给药装置给予。该制剂可以包含一个或多个额外的治疗剂，用于与皮质类固醇联合使用。SAE-γ-CD特别适用于溶解酯化皮质类固醇。

  公开号：

  US20070020298A1

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [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] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。
• [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。