耐法唑酮 | 83366-66-9

• 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 - 二嗪烷类
• 中文名称: 耐法唑酮
• 中文别名: 奈法唑酮；萘法唑酮；2-[3-[4-(3-氯苯基)-1-哌嗪基]丙基]-5-乙基-2,4-二氢-4-(2-苯氧基乙基)-3H-1,2,4-三唑-3-酮；2-[3-[4-(3-氯苯基)-1-哌嗪基]丙基]-5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮
• 英文名称: nefazadone
• 英文别名: 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]-propyl-]5-ethyl-2,4-dihydro-4-(2-phenoxy-ethyl)-3H-1,2,4-triazol-3-one；Nefazodone；2-<3-<4-(3-chlorophenyl)-1-piperazinyl>propyl>-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazolin-3-one；Serzone；2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one；2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazol-3-one
• CAS: 83366-66-9
• 化学式: C₂₅H₃₂ClN₅O₂
• 分子量: 470.014
• InChiKey: VRBKIVRKKCLPHA-UHFFFAOYSA-N

物化性质

• 熔点：
  180-182°C
• 沸点：
  599.6±60.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO: 11 mg/mL at 60 °C
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from 2-propanol/heptane
• 蒸汽压力：
  5.20X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：
  盐酸奈法唑酮（Nefazodone Hydrochloride）：化学式为C25H32ClN5O2·HCl， CAS号为82752-99-6。从异丙醇中缓慢冷却可得到熔点为186.0～187.0℃的多晶型结晶；快速冷却则得到熔点为181.0～182.0℃的多晶型结晶。也有报道称其从乙醇结晶时，熔点为175～177℃。
• 碰撞截面：
  211.7 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)：
  4.3
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  51.6
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

一名16岁的女性服用了2.4克的奈法唑酮。奈法唑酮的终末消除半衰期是8.3小时，其代谢物羟基（OH）-奈法唑酮的半衰期是14.6小时。血压-时间曲线显示了一个长达18小时的低血压期。收缩压与OH-奈法唑酮之间存在显著相关性（R2=0.602）。尽管存在低血压，心率保持在56至66次/分钟，持续了30小时。QT间期与奈法唑酮（R2=0.911）和OH-奈法唑酮（R2=0.797）显著相关，但QTc与药物浓度之间没有显著关系。

... A 16-year-old female took 2.4 g of nefazodone. ... The terminal elimination half-life for nefazodone was 8.3 hours, and its metabolite hydroxy(OH)-nefazodone was 14.6 hours. BP-time curves demonstrated an 18-hour period of hypotension. There was a significant correlation between systolic BP and OH-nefazodone (R2 = 0.602). HR remained between 56 and 66 bpm for 30 hours despite hypotension. QT was significantly correlated with nefazodone (R2 = 0.911) and OH-nefazodone (R2 = 0.797), but no significant relationship between QTc and drug concentrations. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究的目的是调查早产儿出现的不良反应是否可以归因于通过母乳接触奈法唑酮。这位35岁、体重60公斤的妇女每天服用300毫克奈法唑酮，她的哺乳期女儿（女性，体重2.1公斤，矫正胎龄36周）因为昏昏欲睡、乏力、无法维持正常体温且喂养困难而被送入医院。... 通过高效液相色谱法（HPLC）对奈法唑酮及其代谢物（三唑二酮、HO-奈法唑酮和m-氯苯基哌嗪）在母体血浆和乳汁中的浓度-时间曲线进行了量化。计算结果显示，通过母乳摄入的奈法唑酮及其活性代谢物（以奈法唑酮当量计算）的婴儿剂量仅相当于母亲体重调整后每日奈法唑酮剂量的0.45%。...

The purpose of this study was/ to investigate whether adverse effects in a premature neonate could be attributed to nefazodone exposure via breast milk. The breast-fed white infant (female, 2.1 kg, 36 weeks corrected gestational age) of a 35-year-old woman (60 kg) taking nefazodone 300 mg/day was admitted to the hospital because she was drowsy, lethargic, unable to maintain normal body temperature, and was feeding poorly. ... The maternal plasma and milk concentration-time profiles for nefazodone and its metabolites, triazoledione, HO-nefazodone, and m-chlorphenylpiperazine, were quantified by HPLC. The calculated infant dose for nefazodone and its active metabolites (as nefazodone equivalents) via the milk was only 0.45% of the weight-adjusted maternal nefazodone daily dose. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

多元分析在体外代谢物鉴定研究中的实用性通过研究奈法唑酮这种具有明确代谢轮廓的抗抑郁药物进行了检验。色谱条件是有意选择的，以反映高通量筛选新化学实体的微粒体稳定性的条件。通过主成分分析（PCA）评估了有人类肝微粒体样本（有或无奈法唑酮）的分子离子和保留时间信息。PCA得出的得分和载荷图揭示了药物及其相应代谢物的分离和感兴趣的离子。随后对靶向离子的串联质谱（MS/MS）光谱的获取，使得可以查询和解释光谱以识别奈法唑酮及其代谢物。当使用类似的分析方法时，通过PCA识别的奈法唑酮代谢物与通过传统代谢物鉴定方法发现的代谢物之间具有良好的相关性。在补充了β-烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的人类肝微粒体培养中，鉴定出15种奈法唑酮的代谢物，几乎包括了之前报告的所有主要代谢物。在这15种代谢物中，有8种来自奈法唑酮中N-取代的3-氯苯基哌嗪基团的N-脱烷基化和N-脱苯基化，6种来自单羟基化和双羟基化，1种来自奈法唑酮中乙基三唑酮基团的拜耳-维利格氧化。

The utility of multivariate analysis in in vitro metabolite identification studies was examined with nefazodone, an antidepressant drug with a well-established metabolic profile. The chromatographic conditions were purposefully chosen to reflect those utilized in high-throughput screening for microsomal stability of new chemical entities. Molecular ion, retention time information on groups of human liver microsomal samples with/without nefazodone was evaluated by principal component analysis (PCA). Resultant scores and loadings plots from the PCA revealed the segregation and the ions of interest that designated the drug and its corresponding metabolites. Subsequent acquisition of tandem mass spectrometry (MS/MS) spectra for targeted ions permitted the interrogation and interpretation of spectra to identify nefazodone and its metabolites. A comparison of nefazodone metabolites identified by PCA versus those found by traditional metabolite identification approaches resulted in very good correlation when utilizing similar analytical methods. Fifteen metabolites of nefazodone were identified in beta-nicotinamide adenine dinucleotide phosphate (NADPH)-supplemented human liver microsomal incubations, representing nearly all primary metabolites previously reported. Of the 15 metabolites, eight were derived from the N-dealkylation and N-dephenylation of the N-substituted 3-chlorophenylpiperazine motif in nefazodone, six were derived from mono- and bis-hydroxylation, and one was derived from the Baeyer Villiger oxidation of the ethyltriazolone moiety in nefazodone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在口服给药后，奈法唑酮通过N-脱烷基化和脂肪族及芳香族羟基化被广泛代谢，小于1%的给药奈法唑酮以原形在尿液中排泄。已经进行了尝试以表征在血浆中识别出的三种代谢物，包括羟基奈法唑酮（HO-NEF）、甲基氯苯基哌嗪（mCPP）和一个三唑-二酮代谢物。

Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和用途：奈法唑酮是一种固体。它被用作抗抑郁药。人类研究：在上市后经验中，报告了单独使用奈法唑酮以及与酒精和/或其他物质联合使用的过量情况。尽管有罕见报告称患者在服用奈法唑酮过量后死亡，主要与酒精和/或其他物质联合使用有关，但尚未建立与奈法唑酮的因果关系。在上市前临床研究中，有七份报告称单独或与其他药物联合使用奈法唑酮过量。这些患者中没有人死亡。摄入的奈法唑酮量从1000毫克到11200毫克不等。奈法唑酮过量常见报告的症状包括恶心、呕吐和嗜睡。一名患者服用了2000到3000毫克的奈法唑酮，同时服用了美索巴莫和酒精，据报告此人经历了抽搐。奈法唑酮治疗与肝脏异常有关，从无症状可逆的血清转氨酶升高到导致移植和/或死亡的肝衰竭病例。目前，无法预测谁可能会发展成肝衰竭。通常，活动性肝病患者不应接受奈法唑酮治疗。该药物在妊娠期间并未将重大人类畸形率增加到1%至3%的基线率以上。动物研究：没有证据表明奈法唑酮具有致癌性。将奈法唑酮通过饮食途径给予大鼠和小鼠，每日剂量分别为200毫克/千克和800毫克/千克，持续2年，并未增加肿瘤的发生。在怀孕兔和大鼠中进行了生殖研究，每日剂量分别高达200毫克和300毫克/千克（分别大约是6倍和5倍）。由于奈法唑酮治疗，后代中没有观察到畸形。然而，在大鼠中看到了早期幼崽死亡率的增加和幼崽体重的下降。在大鼠中进行的一项生育研究显示，每日剂量为200毫克/千克时，生育能力略有下降。基于以下检测，奈法唑酮已被证实不具有遗传毒性：细菌突变检测、大鼠肝细胞培养中的DNA修复检测、中国仓鼠卵巢细胞中的哺乳动物突变检测、大鼠骨髓细胞中的体内细胞遗传学检测和大鼠显性致死研究。

IDENTIFICATION AND USE: Nefazodone is a solid. It is used as an antidepressive agent. HUMAN STUDIES: In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established. In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. None of these patients died. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One patient took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol, and this person reportedly experienced a convulsion. Nefazodone therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with nefazodone. The drug does not increase the rates of major human malformations during pregnancy above the baseline rate of 1% to 3%. ANIMAL STUDIES: There is no evidence of carcinogenicity with nefazodone. The dietary administration of nefazodone to rats and mice for 2 years at daily doses of up to 200 mg/kg and 800 mg/kg, respectively, produced no increase in tumors. Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively. No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality, and decreased pup weights were seen in rats. A fertility study in rats showed a slight decrease in fertility at 200 mg/kg/day. Nefazodone has been shown to have no genotoxic effects based on the following assays: bacterial mutation assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, an in vivo cytogenetics assay in rat bone marrow cells, and a rat dominant lethal study.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

在血清素能系统中，奈法唑酮作为5-HT2型血清素（5-HT2）突触后受体的拮抗剂，并且像氟西汀类抗抑郁药一样，抑制突触前血清素（5-HT）的重摄取。这些机制增加了可用于与5-HT受体相互作用的血清素的数量。在去甲肾上腺素能系统中，奈法唑酮对去甲肾上腺素的重摄取抑制最小。奈法唑酮还拮抗α1-肾上腺素能受体，产生镇静、肌肉放松和多种心血管效应。奈法唑酮对苯二氮卓类、胆碱能、多巴胺能、组胺能以及β或α2-肾上腺素能受体的亲和力并不显著。

Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT₂) post-synaptic receptors and, like fluoxetine-type antidepressants, inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha(1)-adrenergic receptors, producing sedation, muscle relaxation, and a variety of cardiovascular effects. Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha(2)-adrenergic receptors is not significant.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在使用奈法唑酮的患者中，有一定比例的人会出现肝功能测试异常，但升高通常是轻微的，通常不需要调整剂量或停药。在奈法唑酮普遍可用后不久，它就被联系到几例急性、临床上明显的肝损伤，其中一些是致命的。损伤的发生时间从6周到8个月不等，血清酶升高的模式通常是肝细胞型的。自身免疫（自身抗体）和免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）并不常见。肝脏活检通常显示急性肝炎伴胆汁淤积和不同程度的中央区（第3区）坏死。系统评价表明，由于奈法唑酮导致的肝衰竭的发生率是每250,000到300,000患者暴露年1例。由于这种并发症，奈法唑酮在许多国家被停用。然而，奈法唑酮对于其他抗抑郁药无效的严重抑郁症患者可能有效。因此，它在美国仍然可用，但建议只有当其他抗抑郁药被发现无效，并在充分披露和讨论风险后才能使用。它有一个关于肝毒性的“黑盒”警告。

Liver test abnormalities occur in a proportion of patients on nefazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. Soon after its general availability, nefazodone was linked to several instances of acute, clinically apparent liver injury, some of which were fatal. The onset of injury varied from 6 weeks to 8 months and the pattern of serum enzyme elevations was typically hepatocellular. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were uncommon. Liver biopsy usually demonstrated an acute hepatitis with cholestasis and variable degrees of centrolobular (zone 3) necrosis. Systematic reviews suggested that the incidence of hepatic failure due to nefazodone is 1 per 250,000 to 300,000 patient-years of exposure. Because of this complication, nefazodone was withdrawn from use in many countries. Nefazodone, however, can be effective in patients with otherwise resistant forms of severe depression. For this reason, it remains available in the United States with the recommendation that it be used only if other antidepressants have been found to be ineffective and after full disclosure and discussion of the risks. It has a “black box” warning for hepatotoxicity.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：奈法唑酮

Compound:nefazodone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：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

吸收、分配和排泄

• 吸收

Nefazodone is rapidly and completely absorbed. Its absolute bioavailability is low (about 20%). 纳伏唑酮（Nefazodone）是一种抗抑郁药，属于三环类抗抑郁药。

Nefazodone is rapidly and completely absorbed. Its absolute bioavailability is low (about 20%).

来源:DrugBank

吸收、分配和排泄

• 消除途径

Nefazodone 口服给药后通过 n-脱烷基化、脂肪族和芳香族羟基化广泛代谢，小于 1% 的给药 Nefazodone 以原形从尿液中排出。

Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.22到0.87升/千克

0.22 to 0.87 L/kg

来源:DrugBank

吸收、分配和排泄

/MILK/ 在两个...受试者中，一个每天两次服用50毫克，另一个早上服用50毫克，晚上服用100毫克，低谷血浆水平低于50纳克/毫升，而配对的乳汁浓度分别为687和213纳克/毫升。

/MILK/ In two ... subjects, one taking 50 mg twice daily and the other 50 mg in the morning and 100 mg in the evening, the trough plasma levels were <50 ng/mL, whereas the paired milk concentrations were 687 and 213 ng/mL, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

/MILK/ ... 在一名妇女每天两次服用200毫克/奈法唑酮/的情况下，奈法唑酮在乳汁和血浆（低谷）中的配对浓度分别为57和617 ng/mL。乳汁：血浆比率为0.09。

/MILK/ ... In one woman taking 200 mg twice daily /of nefazodone/, the paired concentrations of nefazodone in milk and plasma (trough) were 57 and 617 ng/mL, respectively. the milk:plasma ratio was 0.09.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 安全说明：
  S22,S24/25

制备方法与用途

化学性质

盐酸奈法唑酮（Nefazodone Hydrochloride）的化学式为C25H32ClN5O2·HCl。其从异丙醇结晶后，在缓慢冷却条件下形成多晶型结晶，熔点在186.0～187.0℃之间；快速冷却时，则形成另一多晶型结晶，熔点为181.0～182.0℃。也有报道称，其从乙醇结晶后的熔点约为175～177℃。

用途

盐酸奈法唑酮是一种抗抑郁剂，属于苯基哌嗪类衍生物，具有对5-HT的双重作用。它主要用于治疗抑郁症。

生产方法

生产过程如下：

1. 化合物(I)与1-溴-3-氯丙烷反应进行N-烷化得到化合物(Ⅱ)，收率约为66%。
2. 使用肼处理化合物(Ⅱ)以获得92%收率的化合物(Ⅲ)。
3. 在乙醇中，将化合物(Ⅲ)与（硫代丙酰氨基）甲酸乙酯反应生成三唑(Ⅳ)，收率为72%。
4. 最后，在氢氧化钠的作用下，用苯氧基乙基溴对三唑(Ⅳ)进行N-烷化反应，得到奈法唑酮，收率约为53%。

反应信息

• 作为反应物：
  描述：

  耐法唑酮 在 乙二醇二甲醚溴化镍 、 potassium phosphate 、 1,10-菲罗啉 、 氯(2-二环己基膦基-2',4′,6′-三异丙基-1,1′-联苯基)[2-(2-氨基乙基)苯基)]钯(II) 、 potassium acetate 、 sodium t-butanolate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 19.0h， 生成 5-ethyl-4-(2-phenoxyethyl)-2-(3-(4-(3-((1-phenylethyl)amino)phenyl)piperazin-1-yl)propyl)-2,4-dihydro-3H-1,2,4-triazol-3-one
  参考文献：
  名称：

  通过双功能 N-氨基吡啶中间体进行无痕苯甲基 C−H 胺化

  摘要：

  据报道，通过无痕双功能氮活化进行 C−H 胺化化学。依次进行 CH 氨基吡啶化，然后进行镍催化与芳基硼酸的交叉偶联，得到芳基氮烯插入 CH 键的产物。由于芳基氮烯固有的不稳定性，这些产品无法通过直接氮烯插入获得。所描述的方法可以应用于药理学活性分子的背景下。

  DOI：

  10.1002/anie.202200665
• 作为产物：
  描述：

  N-(2-phenoxyethyl)propionamide 在 咪唑 、 光气 、 sodium hydroxide 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 反应 28.0h， 生成 耐法唑酮
  参考文献：
  名称：

  2,4,5-三取代的1,2,4-三唑啉-3-酮的合成及X射线晶体结构

  摘要：

  描述了BMY 13754（一种1,2,4-三唑啉-3-酮）在临床上作为抗抑郁药的合成和X射线晶体结构。讨论了几种综合策略。

  DOI：

  10.1002/jhet.5570220440
• 作为试剂：
  描述：

  耐法唑酮 、 sodium hydroxide 在 ice 、 耐法唑酮 、 水 、 氯离子 、 异丙醇 作用下， 以 水 为溶剂， 生成 萘法唑酮盐酸盐
  参考文献：
  名称：

  Salt form of nefazodone for use in extended release formulations

  摘要：

  甲磺酸内法唑酮的结晶稳定盐在水和THAM缓冲液（pH7.5）中显示出比其他内法唑酮盐更高的本征溶解度。这种盐在中性pH下更快的溶解速率表明在肠道中更好的溶解和吸收，从而允许内法唑酮口服制剂的控制释放。

  公开号：

  US06034085A1

文献信息

• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [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。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• Novel Compounds
  申请人：Chhipa Laxmikant

  公开号：US20100168110A1

  公开（公告）日：2010-07-01

  The present invention discloses a novel thyroid like compounds of formula (I), wherein R 1 R 2 , R 3 , R 4 and Z are as defined in the specification, method for its preparation, composition containing such compounds and use of such compounds and composition as medicament. Further, compounds of formula (I) has significantly low binding affinity to thyroid receptors and thus considerably devoid of thyrotoxic effects. The invention also relates to the use of the compound of formula (I) for the preparation of a medicament for treating various disease conditions such as obesity, dyslipidemia, metabolic syndrome and co-morbidities associated with metabolic syndrome.

  本发明公开了一种新型的甲状腺类似化合物，其化学式为（I），其中R1、R2、R3、R4和Z如规范中所定义，以及其制备方法、含有这种化合物的组合物和这种化合物及组合物作为药物的用途。此外，化合物的化学式（I）具有与甲状腺受体显著低的结合亲和力，因此在很大程度上缺乏甲状腺毒性作用。该发明还涉及将化学式（I）的化合物用于制备用于治疗肥胖、血脂异常、代谢综合征以及与代谢综合征相关的合并症等各种疾病状况的药物。