特非那定 | 50679-08-8

• 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 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 特非那定
• 中文别名: alpha-[4-叔丁基苯基]-4-(羟基二苯基甲基)-1-哌啶丁醇；叔哌丁醇；Α-[4-(1,1-二甲基乙基)苯基]-4-(羟基二苯甲基)-1-哌啶丁醇；Α-[4-叔丁基苯基]-4-(羟基二苯基甲基)-1-哌啶丁醇；特非那丁
• 英文名称: terfenadine
• 英文别名: ( ±)-1-(4-tert-butylphenyl)-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butan-1-ol；4-{4-[hydroxy(diphenyl)methyl]-1-piperidinyl}-1-[4-(2-methyl-2-propanyl)phenyl]-1-butanol；1-(4-(tert-butyl)phenyl)-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butan-1-ol；terfenadyna；terfenedine；1-(4-tert-butylphenyl)-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butan-1-ol
• CAS: 50679-08-8
• 化学式: C₃₂H₄₁NO₂
• mdl: MFCD00079622
• 分子量: 471.683
• InChiKey: GUGOEEXESWIERI-UHFFFAOYSA-N

物化性质

• 熔点：
  145-152 °C
• 沸点：
  572.76°C (rough estimate)
• 密度：
  1.0488 (rough estimate)
• 溶解度：
  可溶于250mg加5ml的氯仿溶液，清澈至非常轻微混浊，无色至淡黄色
• 物理描述：
  Solid
• 颜色/状态：
  White to off-white crystalline powder
• 蒸汽压力：
  9.4X10-15 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 8.91 (tertiary nitrogen) (EST)
• 碰撞截面：
  229.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 稳定性/保质期：
  如果按照规定使用和储存，则不会发生分解，也未发现有任何已知的危险反应。

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.437
• 拓扑面积：
  43.7
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

尽管特非那丁的确切代谢命运尚未明确建立，但该药物在肝脏中通过细胞色素P-450微粒体酶系统广泛代谢，包括CYP3A4，并且在较小程度上通过胃肠道粘膜的CYP3A代谢，主要是通过氧化末端的甲基组成为非索非那定，以及通过N-脱烷基化取代丁醇侧链成为哌啶甲醇衍生物（alpha,alpha-二苯基-4-哌啶甲醇）。也检测到少量其他羟基化代谢物，但它们的准确结构尚未阐明。

Although the exact metabolic fate of terfenadine is not clearly established, the drug is extensively metabolized in the liver by cytochrome P-450 microsomal enzyme system including CYP3A4 and to a lesser extent in the GI mucosa by CYP3A, principally via oxidation of the terminal methyl group to fexofenadine and via N-dealkylation of the substituted butanol side chain to a piperidine carbinol derivative (alpha,alpha-diphenyl-4-piperidinemethanol). Small amounts of other hydroxylated metabolites also have been detected, but their exact structures have not been elucidated.

来源:Hazardous Substances Data Bank (HSDB)

代谢

有人提出，特非那丁的主要代谢物非索非那定可能是特非那丁抗组胺作用的原因，因为在健康个体口服特非那丁后，血浆中通常只能检测到极少量（10 ng/mL 或更少）的未改变药物。这种哌啶甲醇衍生物在体内和体外均缺乏抗组胺活性。

It has been suggested that fexofenadine, the main metabolite of terfenadine, may be responsible for the antihistaminic effect of terfenadine since only minimal amounts (10 ng/mL or less) of unchanged drug usually are detected in plasma following oral administration of terfenadine in healthy individuals. The piperidine carbinol derivative lacks both in vivo and in vitro antihistaminic activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

特非那丁（塞尔丹）经过广泛的代谢，形成氮杂环醇和特非那丁醇。特非那丁醇随后被代谢为氮杂环醇和特非那丁酸。尽管已经证实睾酮6β-羟基化（CYP3A(4)）是特非那丁生物转化第一步（形成氮杂环醇和特非那丁醇）的主要酶，但催化特非那丁醇转化为氮杂环醇和特非那丁酸的后续代谢步骤的酶尚未被鉴定。这些研究的目的在于确定细胞色素P450同种物在特非那丁和特非那丁醇生物转化中的作用。为此，将特非那丁及其醇分别与10个已经对主要同种酶活性进行特征描述的个体人肝微粒体样本一起孵化。通过高效液相色谱（HPLC）定量分析代谢物和母药。确认特非那丁转化为氮杂环醇和特非那丁醇的过程主要是由CYP3A(4)同种酶催化的，特非那丁醇形成速率与氮杂环醇形成速率的比例为3:1。通过以下研究进一步证实了CYP3A(4)在特非那丁代谢中的作用：a) 通过酮康唑和三乙酰螺旋霉素这两种CYP3A(4)的特异性抑制剂抑制特非那丁醇的形成；b) 克隆人CYP3A(4)催化特非那丁醇形成的时间过程。当特非那丁醇作为底物时，特非那丁酸和氮杂环醇的形成同样由CYP3A(4)同种酶催化。然而，特非那丁酸代谢物形成的速率几乎比氮杂环醇快9倍。特非那丁酸与氮杂环醇的净比为2:1。

Terfenadine (Seldane) undergoes extensive metabolism to form azacyclonol and terfenadine alcohol. Terfenadine alcohol is subsequently metabolized to azacyclonol and terfenadine acid. Although testosterone 6 beta-hydroxylation (CYP3A(4)) has been shown to be the principal enzyme involved in the first step in terfenadine's biotransformation (formation of azacyclonol and terfenadine alcohol), the enzymes catalyzing the subsequent metabolic steps in the conversion of terfenadine alcohol to azacyclonol and terfenadine acid have not been identified. The purpose of these studies was to determine the role of cytochrome P450 isoforms in the biotransformation of terfenadine and terfenadine alcohol. To this end, both terfenadine and its alcohol were incubated with 10 individual human liver microsomal samples that have been characterized for major isozyme activities. The metabolites and parent drugs were quantified by HPLC. The formation of azacyclonol and terfenadine alcohol from terfenadine is confirmed to be catalyzed predominantly by CYP3A(4) isozyme, and the ratio of the rate of terfenadine alcohol formation to that of azacyclonol is 3:1. Involvement of the CYP3A(4) in terfenadine metabolism was further confirmed by the following studies: a) inhibition of terfenadine alcohol formation by ketoconazole and troleandomycin, two specific inhibitors of CYP3A(4), and b) time course of terfenadine alcohol formation by cloned human CYP3A(4). When terfenadine alcohol was used as substrate, both the terfenadine acid and azacyclonol formation were also catalyzed by CYP3A(4) isozyme. However, the rate of formation of the terfenadine acid metabolite is almost 9 times faster than that of azacyclonol. The net ratio of terfenadine acid to azacyclonol is 2:1.

来源:Hazardous Substances Data Bank (HSDB)

代谢

特非那丁是一种前药，通常在肝脏通过细胞色素P450 CYP3A4同型酶完全代谢为其活性形式非索非那定。由于它在离开肠道后立即被肝脏几乎完全代谢，特非那丁在血浆中通常无法测量到。（维基百科） 半衰期：3.5小时

Terfenadine is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 CYP3A4 isoform. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. (Wikipedia) Half Life: 3.5 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

特非那丁与组胺竞争在胃肠道、子宫、大血管和支气管肌肉的H1受体结合位点。特非那丁与H1受体的可逆结合抑制了由于组胺活性导致的浮肿、红斑和瘙痒的形成。由于该药物不易穿过血脑屏障，对中枢神经系统的影响最小。

Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

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

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

在高剂量时对心脏有毒。在较高的血浆浓度下，可能导致对心脏节律的有毒影响（例如心室心动过速和尖端扭转型室速）。(维基百科)

Cardiotoxic at higher doses. In larger plasma concentrations, it may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia and torsades de pointes). (Wikipedia)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服。根据使用14C标记的特非那丁进行的质量平衡研究，估计特非那丁的口服吸收率至少为70%。

Oral. On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70%

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

温和（例如，头痛，恶心，混乱），但已报告有心脏事件，包括心脏骤停，室性心律失常，包括尖端扭转型室速和QT间期延长。

Mild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

在用14C标记的特非那丁进行质量平衡研究中，估计特非那丁的口服吸收率至少为70%。

On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70%

来源:DrugBank

吸收、分配和排泄

尽管口服给药后，至少70%的特非那丁剂量会从胃肠道快速吸收，但该药物在肝脏和胃肠道经历了广泛的首过代谢（99%），在健康个体中，通常只有极少量的（10纳克/毫升或更少）口服给药剂量以未改变的形式出现在系统循环中。在某些情况下，报告了在表面上健康的个体中口服给药后特非那丁血药浓度增加（超过10纳克/毫升），这些个体没有可识别的未改变药物系统性积累的风险；... 同样剂量的特非那丁在个体间峰值血药浓度有相当大的差异（高达五倍），可能是由于个体间首过代谢和/或药物肠肝循环的差异造成的。

Although at least 70% of an oral dose of terfenadine is rapidly absorbed from the GI tract following oral administration, the drug undergoes extensive (99%) first-pass metabolism in the liver and GI tract, with minimal (10 ng/mL or less)amounts of an orally administered dose of the drug generally appearing to reach systemic circulation unchanged in healthy individuals. In some cases, increased plasma terfenadine concentrations (exceeding 10 ng/mL) following oral administration of the drug were reported in apparently healthy individuals with no identifiable risk for systemic accumulation of unchanged drug; ... Considerable interindividual variations (up to five-fold) in peak plasma concentrations have been reported with the same oral dose of terfenadine, possibly resulting from interindividual differences in first-pass metabolism and/or enterohepatic circulation of the drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服特非那丁的绝对生物利用度尚不清楚。当口服给药时，特非那丁在180毫克剂量内表现出线性药代动力学。

The absolute bioavailability of oral terfenadine is not known. When administered orally, terfenadine exhibits linear pharmacokinetics up to doses of 180 mg.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

食物可能会略微影响速率，但似乎不会影响特非那丁的胃肠道吸收程度。

Food may effect the rate slightly but does not appear to effect the extent of GI absorption of terfenadine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服单剂60毫克特非那定的剂量（作为片剂或悬浮液）后，药物在血液中的峰值浓度大约在1-2小时内出现。

Following oral administration of a single 60-mg terfenadine dose (as tablet or suspension, peak plasma concentrations of the drug occur at about 1-2 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  2
• 海关编码：
  2933399090
• RTECS号：
  TM4969000
• 危险性描述：
  H413
• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P201,P264,P280,P301+P330+P331,P312
• 危险品运输编号：
  3077
• 储存条件：
  密封，在2°C至-8°C下保存

SDS

Name:	Terfenadine Material Safety Data Sheet
Synonym:
CAS:	50679-08-8

Section 1 - Chemical Product MSDS Name:Terfenadine Material Safety Data Sheet
Synonym:

---

Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
50679-08-8	Terfenadine		256-710-8

Hazard Symbols: None Listed.
Risk Phrases: None Listed.

---

Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Not available.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation. May be harmful if absorbed through the skin.
Ingestion:
May cause irritation of the digestive tract. May be harmful if swallowed.
Inhalation:
May cause respiratory tract irritation. May be harmful if inhaled.
Chronic:
Not available.

---

Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes.
Ingestion:
Get medical aid. Wash mouth out with water.
Inhalation:
Remove from exposure and move to fresh air immediately.
Notes to Physician:
Treat symptomatically and supportively.

---

Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear.
Extinguishing Media:
Use water spray, dry chemical, carbon dioxide, or chemical foam.

---

Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container.

---

Section 7 - HANDLING and STORAGE
Handling:
Avoid breathing dust, vapor, mist, or gas. Avoid contact with skin and eyes.
Storage:
Store in a cool, dry place. Store in a tightly closed container.

---

Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 50679-08-8: Personal Protective Equipment Eyes: Not available.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to prevent skin exposure.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

---

Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Crystalline powder
Color: white
Odor: Not available.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 146-148 deg C
Autoignition Temperature: Not available.
Flash Point: Not available.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water: 0.001 g/100 ml H2O (30C)
Specific Gravity/Density:
Molecular Formula: C32H41NO2
Molecular Weight: 471.2925

---

Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable.
Conditions to Avoid:
Incompatible materials.
Incompatibilities with Other Materials:
Strong oxidizing agents.
Hazardous Decomposition Products:
Nitrogen oxides, carbon monoxide, carbon dioxide.
Hazardous Polymerization: Will not occur.

---

Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 50679-08-8: TM4969000 LD50/LC50:
CAS# 50679-08-8: Oral, mouse: LD50 = 5 gm/kg; Oral, rat: LD50 = 5 gm/kg.
Carcinogenicity:
Terfenadine - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

---

Section 12 - ECOLOGICAL INFORMATION

---

Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

---

Section 14 - TRANSPORT INFORMATION

IATA
No information available.
IMO
No information available.
RID/ADR
No information available.

---

Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: Not available.
Risk Phrases:
Safety Phrases:
S 24/25 Avoid contact with skin and eyes.
WGK (Water Danger/Protection)
CAS# 50679-08-8: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 50679-08-8 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 50679-08-8 is not listed on the TSCA inventory.
It is for research and development use only.

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

药物概况

特非那定（商品名：敏迪）是一种从抗精神病药物筛选中发现的哌啶类抗组胺药。它主要用于治疗过敏性疾病，特别是用于过敏性鼻炎和荨麻疹，也可用于过敏性皮肤病和花粉症。与其他传统抗组胺药相比，其最大优点是不产生中枢神经系统镇静作用，因此不会引起嗜睡、困倦等副作用，迅速成为广受欢迎的药物之一。

特非那定于1982年首次在英、法、西德上市，并于1985年在美国获准上市。此后，它在全球范围内广泛使用。我国扬州制药厂自1989年起以试字号上市后，该药因安全性好、性价比高，在临床上得到了广泛应用。

化学性质

特非那定是从丙酮结晶制备的化合物，熔点为146.5～148.5℃。其在不同溶剂中的溶解度各异：30℃时水中的溶解度为0.001g/100ml，乙醇中为3.780g/100ml，甲醇中为3.750g/100ml，己烷中为0.034g/100ml。其最大紫外吸收波长分别为260nm（甲醇），260nm（乙醇）和260nm（二氯甲烷）。急性毒性实验表明，特非那定大鼠、小鼠、豚鼠口服LD₅₀均大于2000mg/kg。

用途

• 新型抗组胺药：具有外周H₁受体拮抗作用，适用于季节性过敏性鼻炎（花粉症）、常年性过敏性鼻炎、急慢性荨麻疹等的治疗。
• 抗组胺药：用于过敏性鼻炎、荨麻疹及过敏性皮肤病。

生产方法

特非那定的合成过程涉及多个步骤。首先，将α, α-二苯基-4-哌啶基甲醇（107g）、1-[4-(1, 1-二甲基乙基)苯基]-4-氯-1-丁酮（105g）和碳酸氢钾（70g）与碘化钾一起溶解在600ml的甲苯中，回流搅拌60小时。过滤后，将滤液与过量的氯化氢乙醚溶液反应，并收集沉淀物，用甲醇-异丙醇重结晶得化合物(I)。

其次，以化合物(I)(60g)为原料，在甲醇中溶解并加入氢氧化钾的甲醇溶液调至碱性。冷至-1℃后分批加入硼氢化钾（5g），在蒸汽浴上减压浓缩得到固体，并用水洗涤后用丙酮重结晶2次，最终获得特非那定。

该合成路线表明了特非那定从起始原料到成品的完整制备过程。

反应信息

• 作为反应物：
  描述：

  特非那定 在 Streptomyces platensis NRRL 2364 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 以51%的产率得到2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl)-phenyl)-2-methyl-propanol
  参考文献：
  名称：

  甲基的生物氧化：在特非那定，依巴斯汀及其类似物的醇和酸代谢产物的制备中的应用

  摘要：

  这项研究的目的是找到制备特非那定，依巴斯汀及其类似物代谢物的最佳条件。为此，我们研究了氧化全细胞活性所需的结构底物要求，并选择了获得每种化合物的最有效条件。我们的结果表明，由甲基氧化产生的醇或酸衍生物是主要产物，其比例取决于所用微生物和细胞培养条件。氧化代谢产物以制备规模进行合成，并在表征之前以35–88％的产率分离。

  DOI：

  10.1016/j.tet.2008.09.098
• 作为产物：
  描述：

  O-trimethylsilyl Terfenadine 在 苄基三甲基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 72.0h， 生成 特非那定
  参考文献：
  名称：

  [EN] HYDROAMINOMETHYLATION OF OLEFINS
  [FR] HYDROAMINOMETHYLATION D'OLEFINES

  摘要：

  公开号：

  WO2005077884A3
• 作为试剂：
  描述：

  依巴斯汀 、 、 卡瑞斯汀 在 特非那定 作用下， 以 二甲基亚砜 为溶剂， 以To obtain the 50 mM terfenadine stock solution 1.5 mg of terfenadine having a molecular weight of 471.7的产率得到特非那定
  参考文献：
  名称：

  BMP-2 upregulating compounds for healing bone tissue and screening methods for selecting such compounds

  摘要：

  本公开涉及一种刺激受试者内源性BMP-2上调的方法，该方法包括向受试者施用有效量的H1受体拮抗剂，从而刺激受试者内源性BMP-2上调。还提供了一种包括有效量H1受体拮抗剂的制药配方，用于刺激受试者内源性BMP-2上调，以及一个工具包。

  公开号：

  US09216181B2

文献信息

• [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。
• CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
  申请人：Parion Sciences, Inc.

  公开号：US20140171447A1

  公开（公告）日：2014-06-19

  This invention provides compounds of the formula I: and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.

  这项发明提供了式I的化合物及其药用盐，可用作钠通道阻滞剂，包含这些化合物的组合物，以及用于这些化合物的治疗方法和用途，以及制备这些化合物的方法。
• Dual Pharmacophores - PDE4-Muscarinic Antagonistics
  申请人：Callahan James Francis

  公开号：US20090203657A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.

  本发明涉及具有式（I）的新化合物及其药用盐，药物组合物及其用作对PDE4和肌胆碱受体（mAChRs）具有抑制活性的双色素，因此可用于治疗呼吸道疾病。
• [EN] DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS<br/>[FR] PHARMACOPHORES DUALS, ANTAGONISTES DES RÉCEPTEURS MUSCARINIQUES ET INHIBITEURS DE L'ACTIVITÉ PDE4
  申请人：GLAXO GROUP LTD

  公开号：WO2009100169A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.

  本发明涉及式(I) - (VI)的新化合物，以及其药学上可接受的盐、药物组合物及其在治疗中的应用，例如作为磷酸二酯酶IV (PDE4)的抑制剂和肌碱乙酰胆碱受体 (mAChRs)的拮抗剂，用于治疗和/或预防呼吸道疾病，包括炎症性和/或过敏性疾病，如慢性阻塞性肺病（COPD）、哮喘、鼻炎（例如过敏性鼻炎）、特应性皮炎或银屑病。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。

表征谱图