3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-酮 | 718635-93-9

• 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: 3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-酮
• 中文别名: 丁苯那嗪外消旋体
• 英文名称: (3RS,11bRS)-tetrabenazine
• 英文别名: Tetrabenazine；9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one
• CAS: 718635-93-9
• 化学式: C₁₉H₂₇NO₃
• mdl: MFCD00042740
• 分子量: 317.428
• InChiKey: MKJIEFSOBYUXJB-UHFFFAOYSA-N

物化性质

• 熔点：
  125 °C
• 沸点：
  448.9±45.0 °C(Predicted)
• 密度：
  1.12±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥3.2 mg/ml（10.08mM）
• 物理描述：
  Solid
• 颜色/状态：
  Prisms from methanol
• 蒸汽压力：
  5.31X10-7 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa = 6.51
• 碰撞截面：
  182.6 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)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

Tetrabenazine 在肝脏中被代谢。肝脏中的羰基还原酶负责形成两种主要活性代谢物：α-二氢四苯并嗪（α-HTBZ）和β-二氢四苯并嗪（β-HTBZ）。α-HTBZ 进一步通过 CYP2D6 代谢成一种次要代谢物 9-去甲基-α-DHTBZ，CYP1A2 也有所贡献。β-HTBZ 通过 CYP2D6 代谢成另一种主要循环代谢物，9-去甲基-β-DHTBZ。这种代谢物的 Tmax 是在服用四苯并嗪后 2 小时。

Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.

来源:DrugBank

代谢

在一项针对6名健康志愿者的质量平衡研究中，大约75%的剂量通过尿液排出，粪便中回收的剂量约占7%到16%。在人类尿液中未发现未改变的丁苯那嗪。尿液排出的α-二氢丁苯那嗪（a-HTBZ）或β-二氢丁苯那嗪（b-HTBZ）占给药剂量的不到10%。循环中的代谢物，包括HTBZ代谢物的硫酸盐和葡萄糖醛酸苷结合物以及氧化代谢产物，占尿液中代谢物的大部分。

In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine, and fecal recovery accounted for approximately 7 to 16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of alpha-dihydrotetrabenazine (a-HTBZ) or beta-dihydrotetrabenazine (b-HTBZ) accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

口服给药后，四苯喹嗪在肝脏广泛代谢，代谢物主要通过肾脏排出。

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外研究的结果并不表明四苯喹嗪、alpha-二氢四苯喹嗪（a-HTBZ）、beta-二氢四苯喹嗪（b-HTBZ）或9-去甲基-beta-二氢四苯喹嗪可能导致临床意义上的CYP2D6、CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2E1或CYP3A的抑制作用。体外研究还表明，四苯喹嗪及其a-或b-HTBZ或9-去甲基-beta-二氢四苯喹嗪代谢物不太可能导致临床意义上的CYP1A2、CYP3A4、CYP2B6、CYP2C8、CYP2C9或CYP2C19的诱导作用。

The results of in vitro studies do not suggest that tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) or 9-desmethyl-beta-dihydrotetrabenazine are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its a- or b-HTBZ or 9-desmethyl-beta-dihydrotetrabenazine metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在人体口服给药后，已经识别出至少19种四苯并嗪的代谢物。α-二氢四苯并嗪（a-HTBZ）、β-二氢四苯并嗪（b-HTBZ）和9-去甲基-β-二氢四苯并嗪是主要的循环代谢物，随后被代谢为硫酸盐或葡萄糖醛酸苷结合物。a-HTBZ和b-HTBZ是由主要发生在肝脏的羰基还原酶形成的。a-HTBZ通过CYP450酶，主要是CYP2D6，以及CYP1A2的一些贡献，进行O-脱烷基化，形成9-去甲基-α-二氢四苯并嗪，这是一个次要的代谢物。b-HTBZ主要通过CYP2D6进行O-脱烷基化，形成9-去甲基-β-二氢四苯并嗪。

After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine are the major circulating metabolites and are subsequently metabolized to sulfate or glucuronide conjugates. a-HTBZ and b-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. a-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-alpha-dihydrotetrabenazine, a minor metabolite. b-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-beta-dihydrotetrabenazine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定与使用：四苯并嗪是一种固体。它被用作肾上腺素摄取抑制剂，用于治疗亨廷顿病相关的舞蹈病。药理学研究表明，四苯并嗪可逆地抑制囊泡单胺转运蛋白2的活性，导致中枢多巴胺的耗竭。人体研究：不良反应与剂量和年龄相关，包括抑郁、疲劳、震颤麻痹和嗜睡。在接受四苯并嗪和其他减少多巴胺传递药物的患者中报告了神经阻滞恶性综合征（NMS），这是一种可能致命的综合征。在支持注册的开放标签试验中发生了三起过量用药事件。文献中报告了8起过量用药病例。这些患者药物剂量范围从100毫克到1克。过量用药的副作用包括急性肌张力障碍、眼球震颤危机、恶心和呕吐、出汗、镇静、低血压、混乱、腹泻、幻觉、潮红和震颤。在接受四苯并嗪的187人中，报告了自杀成功、自杀未遂和6起自杀意念。主要人体代谢物9-去甲基-β-二氢四苯并嗪在体外人类外周血单核细胞染色体畸变试验中，无论是否存在代谢激活，均未表现出断裂作用。 动物研究：在口服给予主要人体代谢物9-去甲基-β-二氢四苯并嗪（20、100和200 mg/kg/天）的转基因小鼠中，连续治疗26周未观察到肿瘤增加。在交配前和整个交配期间以及妊娠第7天之前，给雌性大鼠口服四苯并嗪（5、15或30 mg/kg/天）会导致剂量大于5 mg/kg/天的动情周期中断。当雄性大鼠口服四苯并嗪（5、15或30 mg/kg/天）时，对交配和生育指数或精子参数（活动力、计数、密度）没有观察到影响。然而，由于用四苯并嗪处理的大鼠不产生9-去甲基-β-二氢四苯并嗪，这是主要的人体代谢物，因此这项研究可能没有充分评估药物对人类生育能力的影响潜力。在器官形成期口服给予9-去甲基-β-二氢四苯并嗪（8、15和40 mg/kg/天）的怀孕和哺乳大鼠，在15和40 mg/kg/天剂量下胚胎胎儿死亡率增加，在40 mg/kg/天剂量下胎儿体重减轻，同时也对母体有毒。当从器官形成期开始通过哺乳期口服给予9-去甲基-β-二氢四苯并嗪（8、15和40 mg/kg/天）的大鼠，观察到妊娠期延长、死产和后代出生后死亡率增加（40 mg/kg/天）；幼崽体重减轻（40 mg/kg/天）；神经行为（活动增加、学习和记忆缺陷）和生殖（窝仔数减少）损害（15和40 mg/kg/天）；最高剂量下观察到母体毒性。四苯并嗪及其代谢物α-二氢四苯并嗪（a-HTBZ）、β-二氢四苯并嗪（b-HTBZ）和9-去甲基-β-二氢四苯并嗪在体外细菌回复突变试验中呈阴性。四苯并嗪在存在代谢激活的情况下，在中国仓鼠卵巢细胞的体外染色体畸变试验中表现出断裂作用。a-HTBZ和b-HTBZ在中国仓鼠肺细胞的体外染色体畸变试验中，无论是否存在代谢激活，均表现出断裂作用。在雄性和雌性大鼠以及雄性小鼠中进行了体内微核试验。四苯并嗪在雄性小鼠和大鼠中呈阴性，但在雌性大鼠中产生了不确定的反应。

IDENTIFICATION AND USE: Tetrabenazine is a solid. It is used as adrenergic uptake inhibitor for the treatment of chorea associated with Huntington's disease. Pharmacology studies demonstrate that betrabenzaine reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. HUMAN STUDIES: Adverse effects are dose and age related and include depression, fatigue, parkinsonism, and somnolence. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving tetrabenazine and other drugs that reduce dopaminergic transmission. Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose have been reported in the literature. The dose of the drug in these patients ranged from 100 mg to 1 g. Adverse reactions associated with overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Completed suicide, attempted suicide, and 6 cases of suicidal ideation were reported in 187 tetrabenazine recipients. Major human metabolite 9-Desmethyl-beta-dihydrotetrabenazine was not clastogenic in an in vitro chromosomal aberration assay in human peripheral blood mononuclear cells in the presence or absence of metabolic activation. ANIMAL STUDIES: No increase in tumors was observed in transgenic mice treated orally with a major human metabolite, 9-desmethyl-beta-dihydrotetrabenazine (20, 100, and 200 mg/kg/day), for 26 weeks. Oral administration of tetrabenazine (5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when male rats were treated orally with tetrabenazine (5, 15, or 30 mg/kg/day. However, because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-dihydrotetrabenazine, a major human metabolite, this study may not have adequately assessed the potential of the drug to impair fertility in humans. Oral administration of 9-desmethyl-beta-dihydrotetrabenazine (8, 15, and 40 mg/kg/day) to pregnant and lactating rats throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-beta-dihydrotetrabenazine (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. Tetrabenazine and metabolites alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ), and 9-desmethyl-beta-dihydrotetrabenazine were negative in an in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. a-HTBZ and b-HTBZ were clastogenic in an in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus assays were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

四苯喹嗪尚未与安慰剂治疗相比出现血清酶升高率增加的情况，但在治疗期间关于肝脏测试结果的信息有限，并且赞助商报告了偶尔无症状ALT升高导致药物停用或剂量调整的情况。在数百名患者的上市前关键注册试验中，四苯喹嗪并未与黄疸或肝炎的病例相关。自从获得许可以来，没有公开发表的报告将临床明显的肝损伤、黄疸或肝炎归因于四苯喹嗪。因此，如果四苯喹嗪导致的临床明显肝损伤伴有黄疸，这种情况一定是罕见的，甚至可能根本不会发生。

Tetrabenazine has not been associated with rates of serum enzyme elevations greater than occur with placebo therapy, but information on liver test results during therapy is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation or dose modification have been reported by the sponsor. In prelicensure pivotal registration trials in several hundred patients, tetrabenazine was not associated with cases of jaundice or hepatitis. Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to tetrabenazine. Thus, clinically apparent liver injury with jaundice due to tetrabenazine must be rare, if it occurs at all.

来源:LiverTox

毒理性

• 药物性肝损伤

四苯喹嗪

Compound:tetrabenazine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

经口服给药后，四苯喹嗪的吸收率至少为75%。在单次口服剂量从12.5到50毫克范围内，由于四苯喹嗪的快速和广泛肝脏代谢，血浆中四苯喹嗪的浓度通常低于检测限。食物不会影响四苯喹嗪的吸收。亨廷顿病或迟发性运动障碍患者的Cmax,口服为4.8 ng/mL；Tmax, 口服为69分钟。

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients

来源:DrugBank

吸收、分配和排泄

• 消除途径

经口服给药后，四苯喹嗪会在肝脏广泛代谢，代谢物主要通过肾脏消除（75%）。四苯喹嗪也会通过粪便清除（7%至16%）。在人类尿液中未发现未改变的四苯喹嗪。尿液中的α-HTBZ或β-HTBZ（主要代谢物）的排泄量不到给药剂量的10%。

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose.

来源:DrugBank

吸收、分配和排泄

• 分布容积

稳态，静脉注射，在亨廷顿病或迟发性运动障碍患者中：385L。静脉注射后，四苯喹啉迅速分布到大脑。结合最高的部位是纹状体，而结合最低的在大脑皮层被观察到。

Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.

来源:DrugBank

吸收、分配和排泄

• 清除

IV, 1.67 L/min 在血液透析或迟发性运动障碍患者中

IV, 1.67 L/min in HD or tardive dyskinesia patients

来源:DrugBank

吸收、分配和排泄

四苯喹嗪、α-二氢四苯喹嗪（a-HTBZ）和β-二氢四苯喹嗪（b-HTBZ）在人体血浆中的体外蛋白结合情况进行了检测，浓度范围为50至200 ng/mL。四苯喹嗪的结合率在82%至85%之间，a-HTBZ的结合率在60%至68%之间，b-HTBZ的结合率在59%至63%之间。

The in vitro protein binding of tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), and beta-dihydrotetrabenazine (b-HTBZ) was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, a-HTBZ binding ranged from 60% to 68%, and b-HTBZ binding ranged from 59% to 63%.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

生物活性方面，四苯肼外消旋体（罗1-9569外消旋体）是一种具有选择性且可逆的多巴胺转运蛋白VMAT-2抑制剂。

反应信息

• 作为反应物：
  描述：

  3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-酮 在 水 、 potassium hydroxide 作用下， 以 乙酸乙酯 为溶剂， 反应 0.5h， 生成 丁苯那嗪
  参考文献：
  名称：

  一种苯并喹嗪类衍生物的制备方法

  摘要：

  本发明涉及一种苯并喹嗪类衍生物的制备方法，属于药物化学技术领域，具体涉及一种丁苯那嗪的手性拆分方法。以丁苯那嗪消旋体为原料，通过与手性酸成盐、打浆、解离等步骤简便有效地制得高光学纯度的(3R,11bR)‑丁苯那嗪或(3S,11bS)‑丁苯那嗪。该方法和现有工艺相比，优势在于各步反应条件温和，收率高，操作简便，工艺稳定，适于大规模工业化生产。

  公开号：

  CN111285867B
• 作为产物：
  描述：

  5-甲基-2-己酮 以 乙醇 、 水 为溶剂， 反应 90.0h， 生成 3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-酮
  参考文献：
  名称：

  Synthesis of 3H-labeled Tetrabenazine (TBZ)

  摘要：

  四氟苯胺（TBZ）（1,3,4,6,7,11b-六氢-9,10-二甲氧基-3-(2-甲基丙基)-2H-苯并[a]喹啉-2-酮），是一种囊泡单胺转运体 2 抑制剂，作为一种具有高特异性活性和放射化学纯度的氚标记化合物进行制备。通过催化氢化带有末端双键的前体来引入氚。这种方法提供了高特异性活性和放射化学纯度的氚标记 TBZ，使其在神经领域的进一步研究成为可能。版权 © 2011 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.1881

文献信息

• [EN] COMPOUNDS FOR THE TREATMENT OF AMYLOID-ASSOCIATED DISEASES<br/>[FR] COMPOSÉS POUR LE TRAITEMENT DE MALADIES ASSOCIÉES À LA SUBSTANCE AMYLOÏDE
  申请人：REMYND NV

  公开号：WO2016083490A1

  公开（公告）日：2016-06-02

  This invention provides novel compounds of formulae (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof, (I) (II) wherein the substituents are as defined in the specification. The present invention also relates to the novel compounds for use as a medicine, more in particular for the prevention or treatment of amyloid-related diseases, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such amyloid-related diseases. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.

  这项发明提供了式(I)或(II)或其立体异构体、对映异构体、消旋体或互变异构体的新化合物，其中取代基如规范中所定义。本发明还涉及用作药物的这些新化合物，更具体地用于预防或治疗与淀粉样蛋白相关的疾病，更具体地说是某些神经系统疾病，如被统称为tau病变的疾病，以及由细胞毒性α-突触核蛋白淀粉生成所特征化的疾病。本发明还涉及利用这些新化合物制备对治疗此类淀粉样蛋白相关疾病有用的药物。本发明还涉及包括这些新化合物的药物组合物以及这些新化合物的制备方法。
• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）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。

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