非索芬那定 | 83799-24-0

• 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 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 非索芬那定
• 中文别名: 芬非那定；4-[4-[4-(羟基二苯基甲基)-1-哌啶基]-1-羟基丁基]-alpha,alpha-二甲基苯乙酸；非索非那定；Α,Α-二甲基-4-[1-羟基-4-[4-(羟基二苯基甲基)-1-哌啶基]丁基]苯乙酸
• 英文名称: fexofenadine
• 英文别名: terfenadine；terfenadine acid；2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoic acid；(±)-4-[1 hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetic acid；FEX；4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid；2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-ium-1-yl]butyl]phenyl]-2-methylpropanoate
• CAS: 83799-24-0
• 化学式: C₃₂H₃₉NO₄
• mdl: MFCD00871892
• 分子量: 501.666
• InChiKey: RWTNPBWLLIMQHL-UHFFFAOYSA-N

物化性质

• 熔点：
  218-220°C
• 沸点：
  697.3±55.0 °C(Predicted)
• 密度：
  1.171±0.06 g/cm3(Predicted)
• 溶解度：
  甲醇（微溶、加热、超声处理）
• LogP：
  2.81
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from methanol-butanone
• 稳定性/保质期：
  Commercially available fexofenadine hydrochloride capsules have an expiration date of 18 or 24 months after the date of manufacture when packaged in the manufacturer's unopened blister packages or high-density polyethylene bottles, respectively. Commercially available fexofenadine hydrochloride 30-mg conventional tablets have an expiration date of 18 months after the date of manufacture when packaged either in the manufacturer's unopened blister packages or high-density polyethylene bottles, whereas the commercially available fexofenadine hydrochloride 60-mg conventional tablets have an expiration date of 30 months after the date of manufacture when packaged either in the manufacturer's unopened blister packages or high-density polyethylene bottles. In addition, fexofenadine hydrochloride 180-mg conventional tablets have an expiration date of 18 or 30 months after the date of manufacture when packaged either in the manufacturer's unopened blister packages or high-density polyethylene bottles, respectively.
• 解离常数：
  pKa1 = 8.76 (tertiary nitrogen); pKa2 4.28 (carboxylic acid) (est)
• 碰撞截面：
  226.9 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.406
• 拓扑面积：
  81
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

非索非那定非常少量地被代谢，仅有5%的摄入剂量在肝脏进行代谢。唯一确定的代谢物是非索非那定的甲基酯（占总剂量的3.6%）和MDL 4829（占总剂量的1.5%）。负责这种代谢的酶尚未被阐明。

Fexofenadine is very minimally metabolized, with only 5% of an ingested dose undergoing hepatic metabolism. The only identified metabolites are a methyl ester of fexofenadine (3.6% of the total dose) and MDL 4829 (1.5% of the total dose). The enzymes responsible for this metabolism have not been elucidated.

来源:DrugBank

代谢

大约5%的单次口服剂量非索非那定会被代谢。

About 5% of a single oral dose of fexofenadine is metabolized.

来源:Hazardous Substances Data Bank (HSDB)

代谢

极少量非索非那定（大约占剂量的0.5-1.5%）通过细胞色素P-450微粒体酶系统在肝脏代谢为无活性代谢物，而大约3.5%的非索非那定剂量通过第二条代谢途径（与细胞色素P-450微粒体酶系统无关）代谢为非索非那定的甲基酯衍生物。非索非那定的甲基酯代谢物仅存在于粪便中，有人提出肠道菌群可能参与这一代谢过程。

Negligible amounts of fexofenadine (about 0.5-1.5% of a dose) are metabolized in the liver by the cytochrome P-450 microsomal enzyme system to an inactive metabolite, while about 3.5% of a fexofenadine dose is metabolized by a second metabolic pathway (unrelated to the cytochrome P-450 microsomal enzyme system) to the methyl ester derivative of fexofenadine. The methyl ester metabolite of fexofenadine is found only in feces, and it has been suggested that the intestinal flora probably are involved in this metabolism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大约5%的总剂量通过细胞色素P450 3A4和肠道微生物群进行代谢。 半衰期：14.4小时

Approximately 5% of the total dose is metabolized, by cytochrome P450 3A4 and by intestinal microflora. Half Life: 14.4 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

像其他H1受体拮抗剂一样，非索非那定与游离组胺竞争在胃肠道、大血管和支气管平滑肌上的H1受体结合位点。这阻断了内源性组胺的作用，从而随后导致暂时缓解由组胺引起的负面症状（例如鼻塞、流泪）。非索非那定不具有抗胆碱能、抗多巴胺能、α1-肾上腺素能或β-肾上腺素能受体阻断作用。

Like other H1-blockers, Fexofenadine competes with free histamine for binding at H1-receptors in the GI tract, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. Fexofenadine exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic or beta-adrenergic-receptor blocking effects.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

非索非那定使用通常不与肝酶升高有关联，但是特非那定，一种部分代谢为非索非那定的第二代抗组胺药，被认为是导致一些报告中的临床明显肝损伤的原因。特非那定还与心率和QTc间期延长有关，因此于1997年被撤出使用，而非索非那定正是那时被引入的。特非那定引起的肝损伤通常出现在1到5个月之后，并且与肝细胞模式的肝酶异常有关，没有免疫性或自身免疫特征。非索非那定没有与类似的心率失常或肝损伤案例有关联。 可能性评分：E（不太可能是临床明显肝损伤的原因）。 关于抗组胺药的安全性和潜在肝毒性的参考文献在抗组胺药概述部分之后给出。 药物类别：抗组胺药

Fexofenadine use is not generally associated with liver enzyme elevations but terfenadine, a second generation antihistamine that is metabolized in part to fexofenadine, was the attributed cause of several reported cases of clinically apparent liver injury. Terfenadine was also linked to cardiac arrhythmias and prolongation of the QTc interval for which reason it was withdrawn from use in 1997, just as fexofenadine was introduced. Liver injury from terfenadine typically arose after 1 to 5 months and was associated with a hepatocellular pattern of liver enzyme abnormalities without immunoallergic or autoimmune features. Fexofenadine has not been linked to similar cases of cardiac arrhythmias or liver injury. Likelihood score: E (unlikely cause of clinically apparent liver injury). References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines. Drug Class: Antihistamines

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：非索非那定

Compound:fexofenadine

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：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

非索非那定口服给药后迅速吸收，其绝对生物利用度大约为33%。口服给药后的Tmax大约为1-3小时。每日两次给药60mg的稳态AUCss(0-12h)和Cmax分别为1367 ng/mL.h和299 ng/mL。非索非那定的AUC在与水果汁（如苹果、橙子、葡萄柚）联合给药时会减少超过20%，这是由于这些果汁对OATP转运体的抑制作用——因此，处方信息建议仅用水服用非索非那定。同样，非索非那定与高脂肪餐联合给药似乎也会使AUC和Cmax降低超过20%。

Fexofenadine is rapidly absorbed following oral administration and its absolute bioavailability is approximately 33%. The Tmax following oral administration is approximately 1-3 hours. The steady-state AUCss(0-12h) and Cmax following twice daily dosing of 60mg are 1367 ng/mL.h and 299 ng/mL, respectively. Fexofenadine AUC is decreased by >20% when coadministered with fruit juices (e.g. apple, orange, grapefruit) due to their inhibition of OATP transporters - for this reason, prescribing information recommends administering fexofenadine only with water. Similarly, coadministration of fexofenadine with a high-fat meal appears to decrease AUC and Cmax by >20%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约80%的摄入剂量通过粪便排出，由于非索非那定的代谢有限，很可能是大部分未发生改变，11%通过尿液排出。非索非那定的主要排泄途径是胆汁和肾脏。

Approximately 80% of an ingested dose is eliminated in the feces, likely largely unchanged due to fexofenadine's limited metabolism, and 11% is eliminated in the urine. The principal pathways of fexofenadine elimination are biliary and renal.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积大约为5.4-5.8 L/kg。

The volume of distribution is approximately 5.4-5.8 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

非索非那定的口服清除率大约为50.6升/小时，肾清除率大约为4.32升/小时。

The oral clearance of fexofenadine is approximately 50.6 L/h and the renal clearance is approximately 4.32 L/h.

来源:DrugBank

吸收、分配和排泄

盐酸非索非那定口服给药后能迅速从胃肠道吸收。口服两粒60毫克盐酸非索非那定胶囊后，大约在2.6小时内达到血浆峰浓度。在健康个体中，单次口服一粒60毫克胶囊或60毫克或180毫克常规片剂后，平均血浆峰浓度分别为131、142和494纳克/毫升。在健康男性中，每隔12小时口服一次60毫克盐酸非索非那定，连续9次后，血浆峰浓度在1.42小时内达到167纳克/毫升。

Fexofenadine hydrochloride is rapidly absorbed from the GI tract following oral administration. Following oral administration of two 60-mg fexofenadine hydrochloride capsules, peak plasma concentrations are achieved in about 2.6 hours. Following oral administration of a single 60-mg capsule or 60- or 180-mg conventional tablet in healthy individuals, mean peak plasma concentrations were 131, 142, and 494 ng/mL, respectively. In healthy men, peak plasma concentrations of 167 ng/mL were achieved within 1.42 hours following oral administration of 60-mg fexofenadine hydrochloride doses every 12 hours for 9 doses.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933399090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20°C 冰箱

制备方法与用途

简介

非索非那定是特非那定的体内代谢产物。早期研究发现，特非那定不仅本身具有药理作用，其代谢产物仍具有药理活性，如直接用于治疗过敏反应，可避免药酶代谢而消除对人体的心脏毒性。正是基于这一特性，在1995年德国Hoechst Marion Roussel药厂最先研发了特非那定的活性代谢产物——非索非那定，并于1997年获得FDA批准。由于该药物没有心脏毒副作用，被认为是一种高效、长效、低毒特点的第三代抗组胺药物。

化学性质

从甲醇中可得到白色结晶，熔点为142～143℃。

用途

非索非那定是组胺H1受体拮抗剂，用于治疗过敏性鼻炎。此外，还适用于呼吸系统及抗过敏用药，如季节性过敏性鼻炎、慢性突发性风疹等。

生产方法

化合物(I)(20.0g, 0.093mol)溶解于240ml甲醇中，在搅拌下滴加三甲基氯化硅(26.0ml, 0.205mol)，在室温及氮气保护条件下搅拌15小时。减压浓缩，得到21.4g微黄色油状物的化合物(Ⅱ)，收率100%，直接用于下一步反应。

• 化合物(Ⅱ)(21.3g, 93.0mmol)溶解于100ml干燥四氢呋喃中，在搅拌下，将其加入到350ml干燥四氢呋喃溶液中的8.37g(80%悬浮液, 0.279mol)的氢化钠。再滴加碘甲烷(13.9ml, 0.223mol)，在室温及氮气保护条件下搅拌15小时。加入10g Florisil，过滤。滤液减压浓缩，剩下的黄色固体用戊烷(3×250mL)提取。提取液减压浓缩，残液用硅胶层析，己烷-乙酸乙酯(10:1至8:1)洗脱, 得到16.9g化合物(Ⅲ)，收率71%。

• 化合物(Ⅲ)(933mg, 1.18mmol)溶解于2ml甲醇中，加入氧化汞的硫酸溶液(含75mg氧化汞和12ml 4%W/V硫酸混合液的10ml)，在55℃下加热3小时。加入50ml饱和碳酸氢钠溶液，再用二氯甲烷(4×50mL)提取。提取液用饱和盐水洗，无水硫酸钠干燥，减压浓缩。残物用硅胶层析，以1:2至3:1的乙酸乙酯-己烷，再用15:1的二氯甲烷-甲醇洗脱, 得到456mg化合物(Ⅷ)，收率75%。

• 化合物(Ⅷ)(350mg, 0.681mmol)溶解于5ml甲醇中，在搅拌下缓慢加入38mg硼氢化钠(1.0mmol)，在室温及氮气条件下搅拌20小时。加入10ml 3%硫酸水溶液，以破坏过量的硼氢化钠。然后加入饱和碳酸氢钠水溶液，用二氯甲烷(3×75mL)提取。提取液用饱和盐水洗，无水硫酸钠干燥，减压浓缩。残物用硅胶层析，以1:5的己烷-丙酮洗脱，得到342mg白色固体化合物(Ⅸ)，收率95%。

• 化合物(Ⅸ)(256mg, 0.496mmol)溶解于3.0ml乙醇中，在搅拌下缓慢加入3.0ml 1mol/L氢氧化钾水溶液，加热至80℃并在该温度下搅拌16小时。冷却后小心加入1mol/L盐酸至pH=7.0，并用超声波使固体分散，放置过夜。过滤收集固体，用甲醇重结晶，得到189mg白色结晶的非索非那定，收率76%，熔点为142～143℃。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  非索非那定甲酯	fexofenadine methyl ester	154825-96-4	C33H41NO4	515.693
  非索非那定杂质9	ethyl 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate	174483-06-8	C34H43NO4	529.72
  4-((4-(4-羟基二苯甲基)-1-哌啶基)-1-氧代丁基)-a,a-二甲基苯乙酸	4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid	76811-98-8	C32H37NO4	499.65
  4-(4-羟基联苯甲基)哌啶-1-氧代丁基-2,2-二甲基苯乙酸甲酯	methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate	154477-55-1	C33H39NO4	513.677
  ——	4-<4-<4-(Hydroxydiphenylmethyl)-1-piperidinyl>-1-butynyl>-α,α-dimethylbenzeneacetic acid methyl ester	154825-95-3	C33H37NO3	495.662
  特非那定	terfenadine	50679-08-8	C32H41NO2	471.683
  ——	2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methyl-propanoic acid	1451149-73-7	C34H43NO5	545.719
  非索非那定杂质C	4-(4'-(hydroxy(diphenyl)methyl)piperidin-1-yl)-1-(4-isopropylphenyl)butan-1-ol	185066-37-9	C31H39NO2	457.656
  ——	methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methyl-propanoate	1451149-72-6	C35H45NO5	559.746
  ——	4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyraldehyde	105955-84-8	C22H27NO2	337.462
• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	2-[4-[(1R)-1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-ium-1-yl]butyl]phenyl]-2-methylpropanoate	——	C32H39NO4	501.7

反应信息

• 作为反应物：
  描述：

  非索芬那定 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 生成 盐酸非索非那定
  参考文献：
  名称：

  [EN] POLYMORPHIC FORM XVI OF FEXOFENADINE HYDROCHLORIDE
  [FR] FORME POLYMORPHE XVI DE L'HYDROCHLORURE DE FEXOFENADINE

  摘要：

  提供的是一种晶体（多形）形式的盐酸费托芬啶，命名为盐酸费托芬啶XVI型。

  公开号：

  WO2003104197A1
• 作为产物：
  描述：

  特非那定 在 Absidia corymbifera LCP 62 1800 、 YM medium cultured with soybean peptones 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 120.0h， 以92%的产率得到非索芬那定
  参考文献：
  名称：

  Microbial oxidation of terfenadine and ebastine into fexofenadine and carebastine

  摘要：

  The oxidation of tert-butyl-phenyl group of title compounds by some microorganisms was studied. We have optimized the conditions of culture to increase the formation of acid metabolites and to avoid the formation of side products. We showed that an oxidative activity is induced by soybean peptones in Streptomyces platensis. The biologically active compounds, fexofenadine and carebastine, are produced in good yield (86-95%) by Absidia corymbifera. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.07.076
• 作为试剂：
  描述：

  盐酸非索非那定 、 sodium hydroxide 、 在 非索芬那定 作用下， 生成 非索芬那定
  参考文献：
  名称：

  Tasteless, directly compressible, fast-dissolving complexes and pharmaceutical formulations thereof

  摘要：

  本发明揭示了一种无味、颗粒状、可直接压缩、稳定、快速溶解的苦味基药物的复合物，以及包含基药物无味复合物的制药配方和剂型。基药物可以是费索巴丹，而基药物的复合物可以是费索巴丹-聚丙烯酸复合物。本发明还揭示了制备、分离和表征苦味基药物无味复合物的过程以及制备制药配方的过程。

  公开号：

  US20030170310A1

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。
• [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。
• 3-Aminocyclopentanecarboxamides as modulators of chemokine receptors
  申请人：Xue Chu-Biao

  公开号：US20060004018A1

  公开（公告）日：2006-01-05

  The present invention is directed to compounds of Formula I: which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.

  本发明涉及以下式的化合物： 这些化合物是趋化因子受体的调节剂。本发明的化合物及其组合物在治疗与趋化因子受体表达和/或活性相关的疾病方面是有用的。
• [EN] PYRIMIDINE JAK INHIBITORS FOR THE TREATMENT OF SKIN DISEASES<br/>[FR] INHIBITEURS DE JAK À BASE DE PYRIMIDINE POUR LE TRAITEMENT DE MALADIES DE LA PEAU
  申请人：THERAVANCE BIOPHARMA R&D IP LLC

  公开号：WO2020219640A1

  公开（公告）日：2020-10-29

  The invention provides compounds of formula (I): or pharmaceutically-acceptable salts thereof, that are inhibitors of Janus kinases. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat inflammatory and autoimmune skin diseases.

  该发明提供了式(I)的化合物或其药用可接受盐，这些化合物是Janus激酶的抑制剂。该发明还提供了包含这些化合物的药物组合物，以及使用这些化合物治疗炎症性和自身免疫性皮肤疾病的方法。