诺米芬辛 | 24526-64-5

• 物质功能分类: 原料药 - 神经系统用药 - 抗抑郁、躁狂药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 中文名称: 诺米芬辛
• 中文别名: 苯异喹胺；2-甲基-4-苯基-8-氨基-1,2,3,4-四氢异喹啉
• 英文名称: nomifensine
• 英文别名: 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline；Merital；8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline；1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinamine；8-Amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisochinolin；2-methyl-4-phenyl-3,4-dihydro-1H-isoquinolin-8-amine
• CAS: 24526-64-5
• 化学式: C₁₆H₁₈N₂
• 分子量: 238.332
• InChiKey: XXPANQJNYNUNES-UHFFFAOYSA-N

物化性质

• 熔点：
  179-181°
• 沸点：
  370.93°C (rough estimate)
• 密度：
  0.9597 (rough estimate)
• 溶解度：
  DMF：25 mg/ml； DMSO：25 mg/ml；乙醇：10 mg/ml； PBS (pH 7.2)：部分溶解
• 蒸汽压力：
  7.61X10-7 mm Hg at 25 °C (est)
• 分解：
  When heated decomposition it emits toxic fumes of NOx.
• 保留指数：
  2108;2124;2122;2117.4

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  29.3
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

盐酸去甲替林 metabolism of nomifensine maleate was studied in 6 healthy subjects aged 22-41 yr, after single oral administration of two 50 mg capsules and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of the 3 main metabolites of nomifensine maleate in plasma and urine was performed by HPLC. The 3 principal metabolites reached maximum plasma concentrations rapidly (1-1.5 hr), less than 10% as a free, unconjugated form and were eliminated rapidly (elimination half life between 6.8 and 9.0 hr). Only very low concentrations of free metabolites were found in plasma after 24 hr. Two wk of dosing had no significant influence on the elimination of half life or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions and there were no changes in the conjugation reactions. Nomifensine had a very short half life and no tendency for accumulation after repeated doses. It was concluded that the clinical pharmacokinetic profile of nomifensine maleate is not significantly changed by the kinetic behavior of its 3 main metabolites after the usual maintenance doses. /Nomifensine maleate/

The metabolism of nomifensine maleate was studied in 6 healthy subjects aged 22-41 yr, after single oral administration of two 50 mg capsules and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of the 3 main metabolites of nomifensine maleate in plasma and urine was performed by HPLC. The 3 principal metabolites reached maximum plasma concentrations rapidly (1-1.5 hr), less than 10% as a free, unconjugated form and were eliminated rapidly (elimination half life between 6.8 and 9.0 hr). Only very low concentrations of free metabolites were found in plasma after 24 hr. Two wk of dosing had no significant influence on the elimination of half life or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions and there were no changes in the conjugation reactions. Nomifensine had a very short half life and no tendency for accumulation after repeated doses. It was concluded that the clinical pharmacokinetic profile of nomifensine maleate is not significantly changed by the kinetic behavior of its 3 main metabolites after the usual maintenance doses. /Nomifensine maleate/

来源:Hazardous Substances Data Bank (HSDB)

代谢

Nomifensine是一种抗抑郁药，但由于溶血性贫血发病率高而被停用。它含有一个N-甲基-8-氨基四氢异喹啉环，这个环有可能被氧化成四级二氢异喹啉和异喹啉离子，尽管这种转化以前未曾观察到。在这份报告中，展示了多种人类酶将Nomifensine转化为二氢异喹啉离子代谢物。补充了NADPH的人肝微粒体产生了二氢异喹啉离子代谢物以及其他羟基化代谢物，而当补充了t-丁基过氧化物时，只观察到了二氢异喹啉离子代谢物。单胺氧化酶A催化了这一反应，而单胺氧化酶B则没有，同样，补充了H2O2的人血红蛋白也催化了这一反应。在存在H2O2的情况下，人髓过氧化物酶催化了这一反应，并且在存在与人类测量浓度相关的对乙酰氨基酚的情况下，观察到反应的活化。整个血液中也观察到了这一反应。二氢异喹啉离子与卡宾醇胺之间的平衡显示出大约为11.7的pK值。

Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, ... the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes /is demonstrated/. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

药物：诺米芬辛

Compound:nomifensine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

已撤回

Label Section:Withdrawn

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

盐酸诺米芬辛的药代动力学在6名23-41岁的受试者中进行研究，他们在单次口服两粒50毫克盐酸诺米芬辛胶囊（Nomival）和100毫克静脉注射后，以及在连续2周每天口服150毫克胶囊的给药后。通过高效液相色谱法（HPLC）测定血浆和尿液中游离和总诺米芬辛的浓度。诺米芬辛从胃肠道迅速吸收，游离诺米芬辛的峰浓度在1.13小时达到。单次给药后的消除半衰期约为4小时，与给药途径无关。诺米芬辛在体液和组织中广泛分布，表观分布容积为8.69升/千克。口服给药后游离诺米芬辛的药时曲线下面积（AUC）仅为静脉输注后的26.5%。从胃肠道的吸收是完全的，总诺米芬辛的AUC在所有治疗后均相等。在2周的给药期间后，游离诺米芬辛的AUC显著降低，消除半衰期缩短。结果表明，有限的生物利用度的主要原因是吸收过程中的广泛首过代谢，并且提示代谢酶的显著诱导；因此，某些患者可能需要增加诺米芬辛的剂量以维持充分的治疗效果。/盐酸诺米芬辛/

The pharmacokinetics of nomifensine were studied in 6 subjects aged 23-41 yr, after single oral administration of two 50 mg capsules of nomifensine maleate (Nomival) and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of free and total nomifensine in plasma and urine was performed by HPLC. Nomifensine was rapidly absorbed from the gastrointestinal tract and peak concentration of free nomifensine was reached at 1.13 hr. The elimination half life after single dose was about 4 hr regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The AUC of free nomifensine decreased substantially and the elimination half life was shortened after a 2-wk dosing period. It was concluded that the main reason for limited bioavailability seems to be extensive first-pass metabolism during the absorption process and that a marked induction of the metabolizing enzymes is suggested; therefore, an increase in nomifensine dosage may be needed in some patients to maintain a full therapeutic effect. /Nomifensine maleate/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

药物动力学的尼莫芬辛在12名健康男女服用单次100毫克尼莫芬辛马来酸盐（Merital）后进行了评估。未结合尼莫芬辛的平均血浆半衰期为1.9小时，总尼莫芬辛为4.1小时。未结合尼莫芬辛的平均峰值血浆浓度男性为130 + 或 - 36.5微克/升，女性为38 + 或 - 9.7微克/升，存在显著差异。在总尼莫芬辛血浆浓度峰值方面，男女之间没有观察到差异。... 口服清除率女性高于男性，分布体积也是如此。

The pharmacokinetics of nomifensine were assessed in 12 healthy men and women following single 100 mg oral doses of nomifensine maleate (Merital). Mean plasma half-life of unconjugated nomifensine was 1.9 hr and for total nomifensine was 4.1 hr. The mean peak plasma concentration of unconjugated nomifensine was 130 + or - 36.5 ug/L for men and 38 + or - 9.7 ug/L for women, a significant difference. No differences between males and females were observed for peak total nomifensine plasma concentrations. ... Oral clearance was higher in women than men as were the respective volumes of distribution.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

(14)C-诺米芬辛的放射性分布已在怀孕和非怀孕雌性大鼠中进行比较，通过检查血浆轮廓、放射性组织分布定性（全身放射性自显影）和放射性组织分布定量。怀孕和非怀孕大鼠血浆中(14)C-诺米芬辛的放射性清除是相似的，并且在口服和静脉给药后都表现出复杂的二次峰和平台期。最大血浆水平（平均值±标准差，分别为怀孕大鼠0.20±0.05和未怀孕大鼠0.22±0.02微克当量诺米芬辛/毫升血浆）在口服给药后30至45分钟出现。放射性在血浆中的生物半衰期在两种给药途径下均为4至5小时，尽管在静脉给药后还有一个快速的初始阶段（半衰期大约20分钟）。全身放射性自显影也显示怀孕和非怀孕大鼠之间的放射性组织分布模式非常相似，放射性从血液广泛分布到组织中。在15天怀孕大鼠的胎盘中，仅检测到少量来自(14)C-诺米芬辛的放射性穿过胎盘进入胎儿，并且这些放射性随时间迅速清除。在18天怀孕大鼠的胎儿中，穿过胎盘的放射性数量略高，并且在胎儿的大脑、心脏、肝脏和肺中检测到放射性。定量组织分布研究证实了这些定性发现。成人和胎儿组织中放射性的生物半衰期大约为5小时，除了成人肝脏中放射性的半衰期较长，大约为10小时。

The disposition of radioactivity from (14)C-nomifensine has been compared in pregnant and non-pregnant female rats by examining plasma profiles, the qualitative tissue distribution (whole body autoradiography) and the quantitative tissue distribution of radioactivity. The clearance of radioactivity of (14)C-nomifensine from the plasma of pregnant and non-pregnant rats was similar and was complex with secondary peaks and plateaux after both oral and intravenous dosing. Maximum plasma levels (mean +/- S.D., 0.20 +/- 0.05 and 0.22 +/- 0.02 ug equivalents nomifensine/mL plasma for pregnant and non-pregnant rats respectively) occurred at 30 to 45 min after oral dosing. The biological half-life of radioactivity in plasma was between 4 and 5 hr for both routes of administration, although there was an additional rapid initial phase (half life approx. 20 min) after intravenous dosing. Whole body autoradiography also showed a very similar tissue distribution pattern of radioactivity between pregnant and non-pregnant rats with extensive distribution from blood into tissue. Only traces of radioactivity from (14)C-nomifensine were seen to cross the placenta into the fetuses of 15-day pregnant rats and these rapidly cleared with time. Slightly higher amounts were seen to cross the fetuses of 18-day pregnant rats and radioactivity was seen in the fetal brain, heart, liver and lung. Quantitative tissue distribution studies confirmed these qualitative findings. The biological half-life of radioactivity in both adult and fetal tissues was approximately 5 hr, except for adult livers where a longer half-life of radioactivity of approximately 10 hr was found.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Nomifensine（1和5毫克/千克）通过口服和静脉给药给狗。评估了该药的药代动力学。Nomifensine从胃肠道迅速吸收，在0.5-1小时达到最大浓度。峰值水平与给药剂量成正比。消除半衰期为6小时，给药后24小时在血液中仅发现极少量的药物。表观分布容积（Vd）为120-149升，表明药物在体液和组织中广泛分布。口服给药后获得的血清浓度-时间曲线下面积（AUC）明显小于静脉给药后的面积，表明口服形式的药物生物利用度不完全。还研究了两种不同给药途径后Nomifensine的结合反应：口服给药后15分钟结合反应达到平衡，而静脉给药后直到1-1.5小时才达到平衡。Nomifensine的代谢发生在吸收过程中的胃肠道膜和/或肝脏中；首过效应显著。

Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. The pharmacokinetics of the drug was evaluated. Nomifensine was rapidly absorbed from the gastro-intestinal tract reaching maximum concentration at 0.5-1 hr. The peak levels were directly proportional to the doses administered. The elimination half-life was 6 hr and only very small amounts were found in blood at 24 hr after administration. The apparent volume of distribution (Vd) was 120-149 1, suggesting an extensive distribution of the drug throughout body fluids and tissues. The area under the serum concentration-time curve (AUC) obtained after oral administration was significantly smaller than that after intravenous administration indicating incomplete bioavailability of the drug in oral form. The conjugation of nomifensine after the two different administration routes was also studied: the conjugation reaction was in equilibrium at 15 min after oral administration, while after intravenous administration, equilibrium was not reached until 1-1.5 hr. The metabolism of nomifensine occurred in the gastrointestinal membranes and or in the liver during the absorption process; the first-pass effect was marked.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Nomifensine口服吸收迅速，分布广泛。口服给药后，一至两小时内达到峰值。它的消除半衰期短，仅为两小时，主要通过尿液排出，其中60%至65%未经改变，其余以代谢物形式排出。Nomifensine也会分泌至母乳中。尽管半衰期短，但人类脑电图研究表明，在口服75或150毫克Nomifensine后，对中枢神经系统的影响可持续长达八小时。因此，尽管药物在血浆中的水平已经降低，但其中枢作用仍能持续很长时间。

Nomifensine is rapidly absorbed and is widely distributed. After oral administration, peak levels are obtained within one to two hours. It has a rapid elimination half life of two hours and is primarily excreted in the urine, 60% to 65% unchanged, the remainder as metabolites. Nomifensine is excreted in breast milk. Despite the short half life, electroencephalographic studies in humans reveal that maximal central nervous system effects are sustained up to eight hours after the oral administration of 75 or 150 mg of nomifensine. Thus, central effects persist long after the plasma levels of the drug have diminished.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xn
• 安全说明：
  S26,S36
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  3
• 海关编码：
  2933499090
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 3249
• 储存条件：
  2-8℃

制备方法与用途

概述

甲基苯丙胺（methamphetamine, MA），俗称冰毒，进入21世纪以来其滥用人数已经超过海洛因，成为21世纪的毒品之王。多巴胺（DA）是儿茶酚胺类神经递质，研究表明，甲基苯丙胺对人体的影响主要是通过其对多巴胺能神经元的毒性作用产生的。具体机制是：MA能够通过多巴胺转运体进入神经元和神经末梢，置换出多巴胺（DA），使其大量外流到突触间隙，进而通过作用于多巴胺受体导致神经毒性的发生。多巴胺生物合成调控的核心在于酪氨酸羟化酶（tyrosine hydroxylase, TH）的活性变化。

药理作用

诺米芬辛（nomifensine）是一种新型抗抑郁药，适用于治疗内源性抑郁症、躁狂抑郁症及焦虑抑郁症。它通过选择性地抑制中枢神经元对去甲肾上腺素（NA）、多巴胺（DA）和5-羟色胺（5-HT）的再摄取而产生抗抑郁作用。与丙米嗪相比，诺米芬辛起效快、作用强且毒副作用较少，并具有轻微的抗胆碱作用。

口服吸收迅速完全， Tmax 为1小时，半衰期约为1～2小时，代谢产物全部经肾脏排泄。

不良反应

诺米芬辛的不良反应较少且较轻，主要表现为外周抗胆碱作用引起的症状，如失眠、头痛、口干和便秘等。这些症状常见于再次给药时，并可以通过减少用药次数来避免。少数患者可能会出现疲劳、嗜睡、震颤或眩晕等神经系统症状，但治疗剂量下一般不会引起心血管毒性。

用途及用法

诺米芬辛主要用于治疗内源性抑郁症，尤其适用于老年患者。其初始剂量为25毫克，每日分2-3次服用，在7-10天内逐步调整至最佳剂量范围，大多数患者的每日平均剂量在75-500毫克之间。达到最佳剂量后，应持续用药直至症状缓解减轻，之后可逐渐停药或以较低维持剂量继续治疗。

对于老年人，建议初始剂量不超过25毫克/日两次（bid），而儿童用药经验不足，但已知以1至2毫克/(kg·d)早晨一次性给药或早晨给予全天剂量的三分之二、晚上给予三分之一的方式，安全用于5-14岁儿童。

反应信息

• 作为反应物：
  描述：

  诺米芬辛 在 Hg(II)-EDTA 、 hydroxide 作用下， 反应 6.0h， 生成 N-(1-hydroxy-2-methyl-4-phenyl-3,4-dihydro-1H-isoquinolin-8-yl)acetamide
  参考文献：
  名称：

  来自取代四氢异喹啉的甲醇胺

  摘要：

  使用一种脱氢方法无法从各种取代模式的四氢异喹啉中提取甲醇胺，而这需要有区别地使用汞 (II) EDTA、乙酸汞 (II) 和 N-溴代琥珀酰亚胺。

  DOI：

  10.1002/ardp.19883211015
• 作为产物：
  描述：

  (2-amino-benzylidene)-methyl-amine 在 sodium tetrahydroborate 、 硫酸 、 三乙胺 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 22.33h， 生成 诺米芬辛
  参考文献：
  名称：

  4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors

  摘要：

  Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.050
• 作为试剂：
  描述：

  DL-去甲肾上腺素 、 氯化钠 、 氯化钾 、 氯化镁 、 、 无水氯化钙 、 a-无水葡萄糖酯 、 碳酸氢钠 、 维生素 C 、 disodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate 、 氧气 、 、 在 优降宁 、 诺米芬辛 、 地昔帕明 、 S(−) nicotine 作用下， 反应 3.58h， 生成 3H-dopamine
  参考文献：
  名称：

  2,6-disubstituted piperidines as modulators of nicotinic acetylcholine receptor mediated neurotransmitter release, uptake and storage

  摘要：

  用于治疗药物滥用的依赖或戒断、饮食障碍或中枢神经系统疾病或病理的化合物，具有以下公式：

  公开号：

  US06703406B2

文献信息

• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• [EN] 3-ARYLOXY/ THIO-2, 3-SUBSTITUTED PROPANAMINES AND THEIR USE IN INHIBITING SEROTONIN AND NOREPINEPHRINE REUPTAKE<br/>[FR] 3-ARYLOXY/THIO-2, 3-SUBSTITUE PROPANAMINES ET LEUR UTILISATION POUR INHIBER LE RECAPTAGE DE LA SEROTONINE ET DE LA NOREPINEPHRINE
  申请人：LILLY CO ELI

  公开号：WO2004043903A1

  公开（公告）日：2004-05-27

  There is provided a compound of formula (I) wherein A is selected from -O- and -S-; X is selected from phenyl optionally substituted with up to 5 substituents each independently selected from halo, C1-C4 alkyl and C1-C4 alkoxy, thienyl optionally substituted with up to 3 substituents each independently selected from halo and C1-C4 alkyl, and C2-C8 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl and C4-C8 cycloalkylalkyl, each of which may be optionally substituted with up to 3 substituents each independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-S(O)n- where n is 0, 1 or 2, -CF3, -CN and -CONH2; Y is selected from phenyl, naphthyl, dihydrobenzothienyl, benzothiazolyl, benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, thienopyridyl, indanyl, 1,3-benzodioxolyl, benzothienyl, indolyl and benzofuranyl, each of which may be optionally substituted with up to 4 or, where possible, up to 5 substituents each independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-S(O)n- where n is 0, 1 or 2, nitro, acetyl, -CF3, -SCF3 and cyano; and when Y is indolyl it may be substituted or further substituted by an N-substituent selected from C1-C4 alkyl; Z is selected from OR3 or F, wherein R3 is selected from H, C1-C6 alkyl and phenyl C1-C6 alkyl; R1 and R2 are each independently H or C1-C4 alkyl; and pharmaceutically acceptable salts thereofwith the proviso that when Y is optionally substituted phenyl or optionally substituted 1,3-benzodioxolyl and Z is OR3 and X is optionally substituted phenyl then A is -S-.

  提供一种化合物，其化学式为（I），其中A从-O-和-S-中选择；X从苯基选项地取代，每个取代基可独立地从卤素、C1-C4烷基和C1-C4烷氧基中选择最多5个取代基，噻吩基选项地取代，每个取代基可独立地从卤素和C1-C4烷基中选择最多3个取代基，以及C2-C8烷基、C2-C8烯基、C3-C8环烷基和C4-C8环烷基烷基，每个基可选地取代，每个取代基可独立地从卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷基-S(O)n-（其中n为0、1或2）、-CF3、-CN和-CONH2中选择；Y从苯基、萘基、二氢苯并噻吩基、苯并噻唑基、苯并异噻唑基、喹啉基、异喹啉基、萘啉基、噻吩吡啉基、茚基、1,3-苯并二氧杂环戊基、苯并噻吩基、吲哚基和苯并呋喃基中选择，每个基可选地取代，最多可独立地从卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷基-S(O)n-（其中n为0、1或2）、硝基、乙酰基、-CF3、-SCF3和氰基中选择最多4个或在可能的情况下最多5个取代基；当Y为吲哚基时，它可以被取代或进一步被N-取代基取代，N-取代基从C1-C4烷基中选择；Z从OR3或F中选择，其中R3从H、C1-C6烷基和苯基C1-C6烷基中选择；R1和R2各自独立地为H或C1-C4烷基；以及其药学上可接受的盐，但有一个条件，即当Y为可选地取代的苯基或可选地取代的1,3-苯并二氧杂环戊基，Z为OR3且X为可选地取代的苯基时，A为-S-。
• [EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：UNIV EMORY

  公开号：WO2013181135A1

  公开（公告）日：2013-12-05

  The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

  该披露涉及喹唑啉衍生物、组合物以及相关方法。在某些实施例中，该披露涉及NADPH-氧化酶（Nox酶）和/或髓过氧化物酶的抑制剂。
• Carbon-linked substituted piperidines and derivatives thereof useful as histamine H3 antagonists
  申请人：Aslanian G. Robert

  公开号：US20070010513A1

  公开（公告）日：2007-01-11

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt thereof, wherein: M 1 and M 3 are CH or N; M 2 is CH, CF or N; Y is —C(═O)—, —C(═S)—, —(CH 2 ) q —, —C(═NOR 7 )— or —SO 1-2 —; Z is a bond or optionally substituted alkylene or alkenylene; R 1 is H, alkyl, alkenyl, or optionally substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl or a group of the formula: where ring A is a monoheteroaryl ring; R 1 is optionally substituted alkyl, alkenyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and the remaining variables are as defined in the specification; compositions and methods of treating allergy-induced airway responses, congestion, obesity, metabolic syndrome nonalcoholic fatty liver disease, hepatic steatosis, nonalcoholic steatohepatitis, cirrhosis, hepatacellular carcinoma or cognition deficit disorders using said compounds, alone or in combination with other agents.

  揭示了以下化合物的结构式或其药学上可接受的盐，其中： M1和M3为CH或N； M2为CH、CF或N； Y为—C(═O)—、—C(═S)—、—(CH2)q—、—C(═NOR7)—或—SO1-2—；Z为键或可选择地取代的烷基或烯基； R1为H、烷基、烯基，或可选择地取代的环烷基、芳基、杂芳基、杂环烷基或下式的基团： 其中环A为单杂芳基环； R1为可选择地取代的烷基、烯基、芳基、杂芳基、环烷基或杂环烷基；其余变量如规范中所定义；使用这些化合物，单独或与其他药剂结合，治疗过敏引起的气道反应、充血、肥胖、代谢综合征、非酒精性脂肪肝病、肝脂肪变性、非酒精性脂肪性肝炎、肝硬化、肝细胞癌或认知缺陷症状的组合物和治疗方法。
• Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists
  申请人：Mutahi W. Mwangi

  公开号：US20070167435A1

  公开（公告）日：2007-07-19

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein: M is CH or N; U and W are each CH, or one of U and W is CH and the other is N; X is a bond, alkylene, —C(O)—, —C(N—OR 5 )—, —C(N—OR 5 )—CH(R 6 )—, —CH(R 6 )—C(N—OR 5 )—, —O—, —OCH 2 —, —CH 2 O— or —S(O) 0-2 —; Y is —O—, —(CH 2 ) 2 —, —C(═O)—, —C(═NOR 7 )— or —SO 0-2 —; Z is a bond, optionally substituted alkylene or alkylene interrupted by a heteroatom or heterocyclic group; R 1 is optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, or benzimidazolyl or a derivative thereof; R 2 is optionally substituted alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and the remaining variables are as defined in the specification; compositions and methods for treating an allergy-induced airway response, congestion, diabetes, obesity, an obesity-related disorder, metabolic syndrome and a cognition deficit disorder using said compounds, alone or in combination with other agents.

  揭示了以下化合物的结构式或其药学上可接受的盐或溶剂，其中：M为CH或N；U和W分别为CH，或者U和W中的一个为CH，另一个为N；X为键，烷基，—C(O)—，—C(N—OR5)—，—C(N—OR5)—CH(R6)—，—CH(R6)—C(N—OR5)—，—O—，—OCH2—，—CH2O—或—S(O)0-2—；Y为—O—，—(CH2)2—，—C(═O)—，—C(═NOR7)—或—SO0-2—；Z为键，可选择地取代的烷基或被杂原子或杂环基中断的烷基；R1为可选择地取代的烷基，环烷基，芳基，芳基烷基，杂芳基，杂环烷基或苯并咪唑基或其衍生物；R2为可选择地取代的烷基，烯基，芳基，芳基烷基，杂芳基，杂芳基烷基，环烷基或杂环烷基；其余变量如规范中所定义；使用这些化合物，单独或与其他药剂联合使用，治疗由过敏引起的气道反应、充血、糖尿病、肥胖症、与肥胖有关的疾病、代谢综合征和认知缺陷障碍的组合物和方法。

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