氟硝西泮 | 1622-62-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: 氟硝西泮
• 中文别名: 氟硝基安定；氟硝安定
• 英文名称: flunitrazepam
• 英文别名: 1-methyl-5-(2'-fluoro-phenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one；5-(2-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one；[³H]flunitrazepam；(+/-)-flunitrazepam；[3H]-flunitrazepam；5-(2-fluorophenyl)-1-methyl-7-nitro-3H-1,4-benzodiazepin-2-one
• CAS: 1622-62-4
• 化学式: C₁₆H₁₂FN₃O₃
• 分子量: 313.288
• InChiKey: PPTYJKAXVCCBDU-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  常温常压下稳定，避免氧化物接触。

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  78.5
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

作者们确定了CYP2C19和CYP3A4是主要的细胞色素P450酶，参与氟硝西泮代谢为其主要代谢物去甲基氟硝西泮和3-羟基氟硝西泮。人CYP2C19和CYP3A4介导去甲基氟硝西泮的形成，其Km值分别为11.1和108微米，分别对应3-羟基氟硝西泮的Km值为642和34.0微米。在人类肝脏微粒体（n=4）中，两种代谢物的形成遵循双相动力学。去甲基氟硝西泮的形成被S-美芬妥因抑制了31%，被酮康唑抑制了78%，表明CYP2C19和CYP3A4都有参与。3-羟基氟硝西泮的形成也显著被酮康唑（94%）和S-美芬妥因（18%）抑制。为了支持这些化学抑制数据，针对CYP2C19和CYP3A4的抗体分别选择性抑制去甲基氟硝西泮的形成，分别为26%和45%，而抗CYP3A4抗体减少了3-羟基氟硝西泮的形成80%。我们的数据还表明CYP1A2、-2B6、-2C8、-2C9、-2D6和-2E1都不参与这些代谢途径中的任何一个。作者们估计，在治疗性氟硝西泮浓度（0.03微米）下，CYP2C19和CYP3A4对去甲基氟硝西泮形成的相对贡献分别为63%和37%。作者们得出结论，多态性酶CYP2C19在介导氟硝西泮去甲基化方面起着重要作用，这可能会改变药物的疗效和安全性，而CYP3A4催化3-羟基氟硝西泮的形成。

/The authors/ have identified CYP2C19 & CYP3A4 as the principal cytochrome P450s involved in the metab of flunitrazepam to its major metabolites desmethylflunitrazepam & 3-hydroxyflunitrazepam. Human CYP2C19 & CYP3A4 mediated the formation of desmethylflunitrazepam with Km values of 11.1 & 108 microM, respectively, & 3-hydroxyflunitrazepam with Km values of 642 & 34.0 microM, respectively. In human liver microsomes (n=4) formation of both metabolites followed biphasic kinetics. Desmethylflunitrazepam formation was inhibited 31% by S-mephenytoin & 78% by ketoconazole, suggesting involvement of both CYP2C19 & CYP3A4. Formation of 3-hydroxyflunitrazepam was also significantly inhibited by ketoconazole (94%) & S-mephenytoin (18%). In support of these chemical inhibition data, antibodies directed against CYP2C19 & CYP3A4 selectively inhibited formation of desmethylflunitrazepam by 26 & 45%, respectively, while anti-CYP3A4 antibodies reduced 3-hydroxyflunitrazepam formation by 80%. Our data also suggest that CYP1A2, -2B6, -2C8, -2C9, -2D6, & -2E1 are not involved in either of these metabolic pathways. /The authors/ estimate that the relative contributions of CYP2C19 & CYP3A4 to the formation of desmethylflunitrazepam in vivo are 63 & 37%, respectively, at therapeutic flunitrazepam concns (0.03 microM). /The authors/ conclude that the polymorphic enzyme CYP2C19 importantly mediates flunitrazepam demethylation, which may alter the efficacy & safety of the drug, while CYP3A4 catalyzes the formation of 3-hydroxyflunitrazepam.

来源:Hazardous Substances Data Bank (HSDB)

代谢

该研究的目的是在体外条件下，当氟硝西泮溶于二甲基甲酰胺和乙腈时，考察其氧化代谢的动力学，并确定涉及哪种细胞色素P450同型物。形成3'-羟基氟硝西泮和去甲基氟硝西泮的动力学是非线性的，最好使用Hill方程进行估计。使用特定的化学抑制剂、表达酶系统和特异性抗体来研究它们形成的抑制。当二甲基甲酰胺是有机溶剂时，形成3'-羟基氟硝西泮和去甲基氟硝西泮的Ks、Vmax、Clmax和n（斜率因子）的范围分别为165-338和179-391微米，22-81和3-10纳米摩尔/毫克蛋白/小时，6-17和0.9-1.9微升/毫克蛋白/小时，以及2.3-3.6和1.6-2.6。当乙腈是溶剂时，形成3'-羟基氟硝西泮和去甲基氟硝西泮的Ks、Vmax、Clmax和n（斜率因子）的范围分别为173-231和74-597微米，35-198和2.7-48纳米摩尔/毫克蛋白/小时，1347和0.7-6.3微升/毫克蛋白/小时，以及1.5-3.6和1.1-2.7。CYP2C19、CYP3A4和CYP1A2介导了3'-羟基氟硝西泮和去甲基氟硝西泮的形成。研究人员需要仔细考虑有机溶剂的选择，以避免错误的CYP鉴定。

The aims were to examine the kinetics of the oxidative metabolism of flunitrazepam in vitro when flunitrazepam was dissolved in dimethylformamide and acetonitrile, and to determine which cytochrome P450 isoform(s) are involved. The kinetics of the formations of 3'-hydroxyflunitrazepam and desmethyl-flunitrazepam were non-linear and best estimated using the Hill equation. Inhibition of their formation was studied using specific chemical inhibitors, expressed enzyme systems and specific antibodies. Ks, Vmax, Clmax and n (slope factor) for the formation of 3'-hydroxyflunitrazepam and desmethylflunitrazepam had ranges of 165-338 and 179-391 microM, 22-81 and 3-10 nmol x mg protein(-1) x h(-1), 6-17 and 0.9-1.9 microl x mg protein(-1) x h(-1), and 2.3-3.6 and 1.6-2.6 respectively when dimethylformamide was the organic solvent. When acetonitrile was the solvent, Ks, Vmax, Clmax and n (slope factor) for the formation of 3'-hydroxyflunitrazepam and desmethylflunitrazepam had ranges of 173-231 and 74-597 microM, 35-198 and 2.7-48 nmol.mg protein(-1) x h(-1), 1347 and 0.7-6.3 microl.mg protein(-1) x h(-1), and 1.5-3.6 and 1.1-2.7 respectively. CYP2C19, CYP3A4 and CYP1A2 mediated the formation of both 3'-hydroxyflunitrazepam and desmethylflunitrazepam. Investigators need carefully to consider the choice of organic solvent to avoid false CYP identification.

来源:Hazardous Substances Data Bank (HSDB)

代谢

近年来，关于药物辅助性侵犯的报告数量显著增加。苯二氮卓类药物是最常见的所谓“约会强奸”药物，其中氟硝西泮（Rohypnol）是最常被提及的。本研究的目的是确定在接受单次2毫克Rohypnol剂量后，是否可以在10名健康志愿者的头发中检测到氟硝西泮及其主要代谢物7-氨氟硝西泮，使用固相萃取和NCI-GC-MS。这样的数据对于执法机构确定从药物辅助性侵犯受害者身上采集头发的最佳时间间隔以揭示药物使用将非常重要。10名健康志愿者（8名女性和2名男性，年龄21至49岁）参与了这项研究。从每位志愿者那里收集了以下头发样本：一次在氟硝西泮给药前，以及给药后1、3、5、14、21和28天。在5名志愿者中，给药后24小时检测到7-氨氟硝西泮，并在整个28天的研究期间持续存在于头发中（0.6-8.0 pg/mg）。在2例中，7-氨氟硝西泮在药物摄入后21天出现在头发中（0.5-2.7 pg/mg），在两个受试者中14天后出现（0.5-5.4 pg/mg）。在一名志愿者中，7-氨氟硝西泮在第14天和第21天被检测到，但浓度低于定量限。在一些样本中检测到了氟硝西泮，但所有浓度都低于定量限（0.5-2.3 pg/mg）。

In recent years, there has been a notable increase in the number of reports on drug-facilitated sexual assault. Benzodiazepines are the most common so-called "date-rape" drugs, with flunitrazepam (Rohypnol) being one of the most frequently mentioned. The aim of this study was to determine whether flunitrazepam & its major metabolite 7-aminoflunitrazepam could be detected in hair collected from 10 healthy volunteers after receiving a single 2 mg dose of Rohypnol using solid phase extraction & NCI-GC-MS. Such data would be of great importance to law enforcement agencies trying to determine the best time interval for hair collection from a victim of drug-facilitated sexual assault in order to reveal drug use. Ten healthy volunteers (8 women & 2 men, 21 to 49 yr old) participated in the study. The following hair samples were collected from each volunteer: one before flunitrazepam admin, & 1, 3, 5, 14, 21, & 28 days after. In 5 volunteers, 7-aminoflunitrazepam was detected 24 hr after flunitrazepam admin & remained in hair throughout the entire 28-day study period (0.6-8.0 pg/mg). In 2 cases, 7-aminoflunitrazepam appeared in hair 21 days after drug intake (0.5-2.7 pg/mg), & in two subjects 14 days later (0.5-5.4 pg/mg). In one volunteer, 7-aminoflunitrazepam was detected on day 14 & 21 but concns were below the quantitation limit. Flunitrazepam was detected in some samples but all concns were below the quantitation limit (0.5-2.3 pg/mg).

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟硝西泮已知的人类代谢物包括去甲基氟硝西泮和3-羟基氟硝西泮。

Flunitrazepam has known human metabolites that include desmethylflunitrazepam and 3-hydroxyflunitrazepam.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

苯二氮卓类药物非特异性地与苯二氮卓受体BNZ1结合，后者介导睡眠，以及与BNZ2结合，影响肌肉松弛、抗惊厥活性、运动协调和记忆。由于认为苯二氮卓受体与γ-氨基丁酸-A (GABAA) 受体相耦合，这通过增加GABA对GABA受体的亲和力来增强GABA的效果。抑制性神经递质GABA与该位点的结合打开了氯离子通道，导致细胞膜超极化，阻止细胞进一步兴奋。

Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

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

它们会导致说话含糊不清、迷失方向和“醉酒”行为。它们在身体和心理上都具有成瘾性。

They cause slurred speech, disorientation and "drunken" behavior. They are physically and psychologically addictive.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：氟硝西泮在美国尚未获得美国食品药品监督管理局的市场批准。它会排入母乳中，并且由于其大约20小时的长半衰期，它可能会在重复剂量的情况下在哺乳婴儿的血清中积聚。在哺乳新生儿或早产儿时，首选其他药物。如果长期使用氟硝西泮，需监测婴儿是否有镇静、进食不良和体重增长不良的情况。在单次剂量的氟硝西泮后，例如在程序前的镇静，通常不需要等待就可以恢复哺乳，尽管对于新生儿或早产儿，谨慎的做法是在恢复哺乳前等待6到8小时。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Flunitrazepam is not approved for marketing in the United States by the U.S. Food and Drug Administration. It is excreted into breastmilk and, because of its long half-life of about 20 hours, it may accumulate in the serum of breastfed infants with repeated doses. Other agents are preferred, especially while nursing a newborn or preterm infant. If flunitrazepam is used long-term, monitor the infant for sedation, poor feeding and poor weight gain. After a single dose of flunitrazepam, as for sedation before a procedure, there is usually no need to wait to resume breastfeeding, although with a newborn or preterm infant, a cautious approach would be to wait a period of 6 to 8 hours before resuming nursing. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 暴露途径

50%（栓剂）和64-77%（口服）

50% (suppository) and 64-77% (oral)

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

50%（栓剂）和64-77%（口服）

50% (suppository) and 64-77% (oral)

来源:DrugBank

吸收、分配和排泄

... 氟硝西泮缓慢通过胎盘。在早期和晚期妊娠中，口服1毫克剂量后大约12小时，脐带血与母体血液的比例分别约为0.5和0.22。羊水与母体血清的比例在两种情况下都在0.02-0.07范围内。在重复剂量后，胎儿中可能会发生蓄积。

... Flunitrazepam crosses the placenta slowly. About 12 hr after a 1 mg oral dose cord:maternal blood ratios in early and late pregnancy were about 0.5 and 0.22, respectively. Amniotic fluid:maternal serum ratios were in the 0.02-0.07 range in both cases. accumulation in the fetus may occur after repeated doses.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氟硝西泮可排入乳汁中。在五名患者单次口服2毫克剂量后，11、15、27和39小时的平均乳汁:血浆比分别为0.61、0.68、0.9和0.75。

Flunitrazepam is excreted into breast milk. Following a single 2 mg oral dose in five patients, mean milk:plasma ratios at 11, 15, 27, and 39 hr were 0.61, 0.68, 0.9, and 0.75, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

本文的目的是研究在10名健康志愿者服用单次2毫克 Rohypnol（罗眠痛）口服剂量后，收集尿液中的氟硝西泮和7-氨基氟硝西泮的消除情况，以确定药物给药后多久可以在尿液中检测到7-氨基氟硝西泮。开发了一种高度灵敏的NCI-GC-MS方法，用于同时定量尿液中氟硝西泮（LOQ 100 pg/mL）和7-氨基氟硝西泮（LOQ 10 pg/mL）。所有样本都使用优化的微板酶免疫分析筛选苯二氮卓类药物。在9名受试者中，给药后6小时观察到7-氨基氟硝西泮（70-518 ng/mL）和氟硝西泮（0.7-2.8 ng/mL）在尿液中的最高浓度，在一名受试者给药后24小时观察到。在6名受试者中，氟硝西泮给药后可检测到7-氨基氟硝西泮长达14天，一名受试者长达21天，3名受试者长达28天。在从6名志愿者收集的尿液中，3天后检测到氟硝西泮，3名受试者24小时后，一名受试者5天后。苯二氮卓微板酶免疫分析试剂盒允许在药物给药后5到21天检测到氟硝西泮及其代谢物。

... The objective of this paper was to study elimination of flunitrazepam and 7-aminoflunitrazepam in urine collected from 10 healthy volunteers who received a single 2 mg oral dose of Rohypnol, to determine how long after drug administration 7-aminoflunitrazepam can be detected. A highly sensitive NCI-GC-MS method for the simultaneous quantitation of flunitrazepam (LOQ 100 pg/mL) and 7-aminoflunitrazepam (LOQ 10 pg/mL) in urine was developed. All samples were screened for benzodiazepines using optimized micro-plate enzyme immunoassay. The highest concns of 7-aminoflunitrazepam (70-518 ng/mL) and flunitrazepam (0.7-2.8 ng/mL) in urine were observed 6 hr after drug administration in 9 subjects and after 24 hr in one subject. In 6 subjects 7-aminoflunitrazepam was detected up to 14 days after flunitrazepam admin, in one subject up to 21 days and in 3 subjects up to 28 days. In urine samples collected from 6 volunteers, flunitrazepam was detected 3 days after Rohypnol intake, in 3 subjects 24 hr, and in one subject 5 days later. Benzodiazepine micro-plate enzyme immunoassay kit allowed the detection of flunitrazepam and metabolities 5 to 21 days after drug administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了研究氟硝西泮（用于新生儿和婴儿的镇静）的药代动力学，确定胎龄和出生后年龄对药代动力学参数的影响，并分析血流动力学参数与氟硝西泮血药浓度的关系。氟硝西泮以单次剂量（0.2 mg x kg(-1)）和多次剂量（0.1 mg x kg(-1)）的方式输注20分钟。每位患者采集6到8个1毫升的血样。通过气相色谱-质谱法测量氟硝西泮的血药浓度。共有31名患者（25名新生儿和6名婴儿）被纳入研究，其中只有3人接受了多次剂量。单次剂量后（n = 28），半衰期为22.6 +/- 7.3小时，清除率为0.15 +/- 0.14 L x kg x h(-1)，分布体积为4.6 +/- 4.1 L x kg(-1)（平均值 +/- 标准差）。血浆清除率和分布体积随着出生后年龄的增加而显著增加（P < .05），但没有任何药代动力学参数随着胎龄的变化而显著变化。随着氟硝西泮血药浓度的增加，舒张压显著降低（P < .05）。出生后年龄而不是胎龄影响新生儿和婴儿的氟硝西泮药代动力学参数。舒张压与氟硝西泮血药浓度呈负相关。

To study the pharmacokinetics of flunitrazepam (used for sedation in neonates and infants), to determine the influence of both gestational and postnatal age on the pharmacokinetic parameters, and to analyze the relationship between the hemodynamic parameters and flunitrazepam plasma concentration. Flunitrazepam was infused for 20 minutes as a single dose (0.2 mg x kg(-1)) and as multiple doses (0.1 mg x kg(-1)). Six to eight 1-mL blood samples were collected per patient. Flunitrazepam plasma concentration was measured by gas chromatography-mass spectrometry. Thirty-one patients (25 neonates and six infants) were included in the study. Only three of them received multiple doses. After the single dose (n = 28), half-life was 22.6 +/- 7.3 hours, clearance was 0.15 +/- 0.14 L x kg x h(-1), and volume of distribution was 4.6 +/- 4.1 L x kg(-1) (mean +/- SD). Plasma clearance and volume of distribution significantly increased with postnatal age (P < .05), but no pharmacokinetic parameter varied significantly with gestational age. Diastolic blood pressure significantly decreased with increasing flunitrazepam plasma concentrations (P < .05). Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants. Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  氟硝西泮 在 human hepatocytes 、 Williams' Medium E cell culture medium 作用下， 以 乙腈 为溶剂， 反应 1.0h， 生成 3-羟基氟硝西泮
  参考文献：
  名称：

  Prediction of metabolic clearance using fresh human hepatocytes: Comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines

  摘要：

  1. Predictions of in vivo intrinsic clearance from cryopreserved human hepatocytes may be systematically low. In the current study, the metabolite kinetics of a series of CYP3A4 substrates (benzodiazepines) in fresh human hepatocytes from five donors, via a major UK supplier, were investigated and compared with those previously reported (by the authors' laboratory) for cryopreserved human hepatocytes and hepatic microsomes.2. A high incidence of autoactivation (up to tenfold) and heteroactivation (by testosterone, up to 14-fold) among the major pathways was observed. CYP capacity (V-max) was marginally lower and 'affinity' constants (K-M, S-50) were marginally greater compared with cryopreserved hepatocytes.3. Average intrinsic clearance (based on maximal clearance, CLmax) was sevenfold lower than in cryopreserved hepatocytes (reflecting sensitivity of intrinsic clearance estimation in vitro to mechanistic parameter values, particularly those involving atypical kinetics), but scaled intrinsic clearances for fresh (and cryopreserved) hepatocytes were within the range previously determined in hepatic microsomes.4. There was no evidence from this series of studies that fresh hepatocytes provide quantitatively improved estimates of intrinsic clearance over cryopreserved hepatocytes.

  DOI：

  10.1080/00498250701834665
• 作为产物：
  描述：

  2-chloro-N-[2-(2-fluorobenzoyl)-4-nitrophenyl]-N-methylacetamide 在 乌洛托品 、 1,3,5,7-四氮杂三环[3.3.1.L3,7]癸烷盐酸盐六亚甲基四胺盐酸盐 作用下， 以 乙醇 为溶剂， 以92%的产率得到氟硝西泮
  参考文献：
  名称：

  Clarke, George M.; Lee, J. Barry; Swinbourne, Frederick J., Journal of Chemical Research, Miniprint, 1980, # 12, p. 4777 - 4793

  摘要：

  DOI：

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。
• Substituted 1,3-thiazole compounds, their production and use
  申请人：——

  公开号：US20040053973A1

  公开（公告）日：2004-03-18

  (1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

  (1) 一种1,3-噻唑化合物，其5位被取代为含有一个取代基的4-吡啶基团，该取代基不包括芳香基，或者(2) 一种1,3-噻唑化合物，其5位被取代为一个吡啶基团，该吡啶基团的氮原子邻近位置有一个取代基，该取代基不包括芳香基，具有出色的p38 MAP激酶抑制活性。

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