文拉法辛 | 93413-69-5

• 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 - 苯类化合物 - 苯酚醚
• 中文名称: 文拉法辛
• 中文别名: 顽发克星；维拉法司；文拉法新；(R/S)-1-[2-(二甲胺)-1-(4-甲氧苯基)乙基]环己醇
• 英文名称: 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol
• 英文别名: VENLAFAXINE；1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol
• CAS: 93413-69-5
• 化学式: C₁₇H₂₇NO₂
• 分子量: 277.407
• InChiKey: PNVNVHUZROJLTJ-UHFFFAOYSA-N

物化性质

• 熔点：
  72-74°C
• 沸点：
  397.6±27.0 °C(Predicted)
• 密度：
  1.060±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二氯甲烷、乙酸乙酯
• LogP：
  0.4-600
• 解离常数：
  9.4 at 23℃
• 物理描述：
  Solid
• 蒸汽压力：
  2.46X10-7 mm Hg at 25 °C (est)
• 碰撞截面：
  171.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2080.3;2056.9;2133.1

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

在吸收之后，文拉法辛在肝脏经历广泛的预处理系统代谢。它主要经历CYP2D6介导的脱甲基作用，形成其活性代谢物O-去甲基文拉法辛（ODV）。文拉法辛还可以通过CYP2C9、CYP2C19和CYP3A4介导的N-脱甲基作用形成N-去甲基文拉法辛（NDV），但这是一条次要的代谢途径。ODV和NDV进一步通过CYP2C19、CYP2D6和/或CYP3A4代谢，形成N,O-双去甲基文拉法辛（NODV），NODV可以进一步代谢形成N, N, O-三去甲基文拉法辛，随后可能发生葡萄糖醛酸化。

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation.

来源:DrugBank

代谢

在吸收之后，文拉法辛在肝脏中经历广泛的预处理系统代谢，主要转化为O-去甲文拉法辛，但也转化为N-去甲文拉法辛、N,O-二去甲文拉法辛以及其他少量代谢物。体外研究表明，O-去甲文拉法辛的形成由CYP2D6催化；这一发现在一项临床研究中得到了证实，该研究发现CYP2D6水平较低的患者（"弱代谢者"）与CYP2D6水平正常的患者（"广泛代谢者"）相比，文拉法辛的水平增加，而O-去甲文拉法辛的水平降低。然而，CYP2D6弱代谢者和广泛代谢者之间的差异预计在临床上不会重要，因为文拉法辛和O-去甲文拉法辛的总和在两组中相似，且文拉法辛和O-去甲文拉法辛在药理作用上大约是等效和等效的。

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to O-desmethylvenlafaxine, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of O-desmethylvenlafaxine is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels ("poor metabolizers") had increased levels of venlafaxine and reduced levels of O-desmethylvenlafaxine compared to people with normal CYP2D6 ("extensive metabolizers"). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and O-desmethylvenlafaxine is similar in the two groups and venlafaxine and O-desmethylvenlafaxine are pharmacologically approximately equiactive and equipotent.

来源:Hazardous Substances Data Bank (HSDB)

代谢

抑郁症药物文拉法辛（VF）在体外研究中被转化为其主要两种代谢物：O-去甲基文拉法辛（ODV）和N-去甲基文拉法辛（NDV），使用人肝微粒体和含有单个人类细胞色素P450（CYP）的微粒体进行。文拉法辛与选择性CYP抑制剂和几种选择性5-羟色胺再摄取抑制剂（SSRIs）共同培养，以评估它们对文拉法辛代谢的抑制效果。与人微粒体共同培养的ODV形成速率符合单一酶介导反应的米氏动力学，并受到底物抑制。通过非线性回归确定的平均参数为：Vmax = 0.36 nmol/min/mg蛋白质，Km = 41微M，Ks = 22901微M（Ks代表一个常数，反映了底物抑制的程度）。奎尼丁（QUI）是ODV形成的强效抑制剂，其Ki为0.04微M，帕罗西汀（PX）是最有效的SSRI抑制剂，其平均Ki值为0.17微M。使用表达的细胞色素的研究表明，ODV由CYP2C9、-2C19和-2D6形成。CYP2D6占主导地位，具有最低的Km，23.2微M，以及最高的内在清除率（Vmax/Km比率）。对于所有四个测试的肝脏，没有独特的模型适用于NDV的形成。应用单一酶模型确定的参数为Vmax = 2.14 nmol/min/mg蛋白质，Km = 2504微M。酮康唑是NDV生成的强效抑制剂，尽管其抑制活性不如纯3A底物观察到的强。NDV形成也受到针对大鼠肝CYP3A1的多克隆兔抗体的42%抑制。使用表达的细胞色素的研究表明，NDV由CYP2C9、-2C19和-3A4形成。最高的内在清除率归因于CYP2C19，最低的归因于CYP3A4。然而，3A亚型的高体内丰度将放大这一细胞色素的重要性。氟伏沙明（FX）在20微M的浓度下，将NDV的产生降低了46%，这与FX抑制CYP3A、2C9和2C19的能力一致。这些结果与先前的研究一致，表明CYP2D6和-3A4在ODV和NDV的形成中发挥着重要作用。此外，我们还展示了其他几种CYP在文拉法辛的生物转化中发挥着重要作用。

The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitro with human liver microsomes and with microsomes containing individual human cytochromes from cDNA-transfected human lymphoblastoid cells. VF was coincubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effect on VF metabolism. Formation rates for ODV incubated with human microsomes were consistent with Michaelis-Menten kinetics for a single-enzyme mediated reaction with substrate inhibition. Mean parameters determined by non-linear regression were: Vmax = 0.36 nmol/min/mg protein, K(m) = 41 microM, and Ks 22901 microM (Ks represents a constant which reflects the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV formation with a Ki of 0.04 microM, and paroxetine (PX) was the most potent SSRI at inhibiting ODV formation with a mean Ki value of 0.17 microM. Studies using expressed cytochromes showed that ODV was formed by CYP2C9, -2C19, and -2D6. CYP2D6 was dominant with the lowest K(m), 23.2 microM, and highest intrinsic clearance (Vmax/K(m) ratio). No unique model was applicable to the formation of NDV for all four livers tested. Parameters determined by applying a single-enzyme model were Vmax = 2.14 nmol/min/mg protein, and K(m) = 2504 microM. Ketoconazole was a potent inhibitor of NDV production, although its inhibitory activity was not as great as observed with pure 3A substrates. NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, -2C19, and -3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 microM, decreased NDV production by 46% consistent with the capacity of FX to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies that show CYP2D6 and -3A4 play important roles in the formation of ODV and NDV, respectively. In addition we have shown that several other CYPs have important roles in the biotransformation of VF.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在此案例报告中，一名被表型和基因型识别为广泛代谢型CYP2D6的患者在服用450毫克/天的文拉法辛和多种合并用药的情况下，三次测量到了异常高的文拉法辛血浆浓度。在第一次血样中，文拉法辛和O-去甲基文拉法辛的值分别确定为1.54和0.60毫克/升，这给出了一个异常高的文拉法辛到O-去甲基文拉法辛的比例。这表明文拉法辛到O-去甲基文拉法辛的代谢受损，最可能是由于米安色林（240毫克/天）和普萘洛尔（40毫克/天）的代谢相互作用。在此血样中测量的(S)-文拉法辛浓度几乎是(R)-文拉法辛的两倍((S)/(R)比例：1.94)。在第二次采血时，加入了强有力的CYP2D6抑制剂硫利达嗪（260毫克/天），文拉法辛的浓度进一步增加（2.76毫克/升），而O-去甲基文拉法辛的浓度降低（0.22毫克/升）。(S)/(R)-文拉法辛比例的降低（-20%）表明在这些高文拉法辛浓度下，参与文拉法辛O-去甲基化的酶可能对(R)-对映体具有立体选择性。在第三次采血时，中断了硫利达嗪治疗后，文拉法辛和O-去甲基文拉法辛的浓度与第一次血样中测量的相似。这个病例报告显示了进行关于遗传决定或获得的代谢缺陷对文拉法辛动力学影响的研究的重要性。

On three occasions, unusually high trough plasma concentrations of venlafaxine were measured in a patient phenotyped and genotyped as being an extensive CYP2D6 metabolizer and receiving 450 mg/day of venlafaxine and multiple comedications. Values of 1.54 and of 0.60 mg/l of venlafaxine and O-desmethylvenlafaxine, respectively, were determined in the first blood sample, giving an unusually high venlafaxine to O-desmethylvenlafaxine ratio. This suggests an impaired metabolism of venlafaxine to O-desmethylvenlafaxine, and is most likely due to metabolic interactions with mianserin (240 mg/day) and propranolol (40 mg/day). Concentration of (S)-venlafaxine measured in this blood sample was almost twice as high as (R)-venlafaxine ((S)/(R) ratio: 1.94). At the second blood sampling, after addition of thioridazine (260 mg/day), which is a strong CYP2D6 inhibitor, concentrations of venlafaxine were further increased (2.76 mg/l), and concentrations of O-desmethylvenlafaxine decreased (0.22 mg/l). A decrease of the (S)/(R)-venlafaxine ratio (-20%) suggests a possible stereoselectivity towards the (R)-enantiomer of the enzyme(s) involved in venlafaxine O-demethylation at these high venlafaxine concentrations. At the third blood sampling, after interruption of thioridazine, concentrations of venlafaxine and O-desmethylvenlafaxine were similar to those measured in the first blood sample. This case report shows the importance of performing studies on the effects of either genetically determined or acquired deficiency of metabolism on the kinetics of venlafaxine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大约87%的文拉法辛剂量在48小时内以未改变的文拉法辛（5%）、未结合的O-去甲基文拉法辛（29%）、结合的O-去甲基文拉法辛（26%）或其他少量无效代谢物（27%）的形式在尿液中回收。因此，肾脏消除文拉法辛及其代谢物是主要的排泄途径。

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated O-desmethylvenlafaxine (29%), conjugated O-desmethylvenlafaxine (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

盐酸文拉法辛的准确作用机制尚不清楚，但似乎与其在中枢神经系统中增强神经递质活性的作用有关。盐酸文拉法辛及其活性代谢物O-去甲文拉法辛（ODV）可抑制5-HT和NE的再摄取，对5-HT再摄取过程的抑制效力大于NE再摄取过程。文拉法辛和ODV代谢物对多巴胺的再摄取有轻微的抑制作用，但与三环类抗抑郁药不同，且与SSRIs相似，它们在组胺能、毒蕈碱能或α1-肾上腺素能受体上无活性。

The exact mechanism of action of venlafaxine is unknown, but appears to be associated with the its potentiation of neurotrasmitter activity in the CNS. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), inhibit the reuptake of both serotonin and norepinephrine with a potency greater for the 5-HT than for the NE reuptake process. Both venlafaxine and the ODV metabolite have weak inhibitory effects on the reuptake of dopamine but, unlike the tricyclics and similar to SSRIs, they are not active at histaminergic, muscarinic, or alpha(1)-adrenergic receptors.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

肝脏测试异常在接受文拉法辛或去甲文拉法辛治疗的患者中报告的发生率不到1%，而且升高的程度通常较轻，通常不需要调整剂量或停药。在接受文拉法辛治疗的患者中，但未在去甲文拉法辛治疗的患者中报告了急性、临床上明显的肝脏损伤的罕见病例，表现为肝酶显著升高，伴或不伴黄疸，这可能是由于对较新批准的药物使用较少。损伤的发生通常在1到3个月内。血清酶升高的模式从胆汁淤积到肝细胞不等。所有病例都是自限性的，并在几个月内解决。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）不常见或轻微。估计的发生频率为每5000名患者暴露一年中有1例。 可能性评分（文拉法辛）：B（很可能是临床上明显肝脏损伤的罕见原因）。 可能性评分（去甲文拉法辛）：E*（怀疑但未证实的临床上明显肝脏损伤的原因）。

Liver test abnormalities have been reported to occur in less than 1% of patients on venlafaxine or desvenlafaxine, and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on both venlafaxine but not desvenlafaxine, perhaps because of less overall use of the more recently approved agent. The onset of injury is usually within 1 to 3 months. The patterns of serum enzyme elevation have varied from cholestatic to hepatocellular. All cases have been self-limiting and resolved within a few months. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon or mild. The estimated frequency is 1 per 5000 patients years of exposure. Likelihood score (venlafaxine): B (highly likely rare causes of clinically apparent liver injury). Likelihood score (desvenlafaxine): E* (suspected but unproven cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

药物：文拉法辛

Compound:venlafaxine

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：低药物性肝损伤关注

DILI Annotation:Less-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：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，文拉法辛被很好地吸收，绝对生物利用度大约为45%。在质量平衡研究中，至少有92%的单次口服剂量的文拉法辛被吸收。在每日两次口服150毫克文拉法辛即释制剂后，Cmax（最高血药浓度）为150 ng/mL，Tmax（达到最高血药浓度的时间）为5.5小时。ODV（活性代谢物O-去甲基文拉法辛）的Cmax和Tmax分别为260 ng/mL和9小时。文拉法辛的缓释制剂吸收速率较慢，但吸收程度与即释制剂相同。在每日一次口服75毫克文拉法辛缓释制剂后，Cmax为225 ng/mL，Tmax为2小时。ODV的Cmax和Tmax分别为290 ng/mL和3小时。食物不影响文拉法辛或其活性代谢物ODV的生物利用度。

Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, Cmax was 150 ng/mL and Tmax was 5.5 hours. Cmax and Tmax of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, Cmax was 225 ng/mL and Tmax was two hours. Cmax and Tmax of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV).

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约87%的文拉法辛剂量在48小时内以未改变的文拉法辛（5%）、未结合的ODV（29%）、结合的ODV（26%）或其他次要的无效代谢物（27%）的形式在尿液中回收。

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%).

来源:DrugBank

吸收、分配和排泄

• 分布容积

稳态下，文拉法辛的表观分布容积为7.5 ± 3.7 L/kg，ODV为5.7 ± 1.8 L/kg。

The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV.

来源:DrugBank

吸收、分配和排泄

• 清除

稳态下，文拉法辛的平均±标准差血浆表观清除率为1.3 ± 0.6 L/h/kg，ODV（去甲文拉法辛）为0.4 ± 0.2 L/h/kg。

Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV.

来源:DrugBank

吸收、分配和排泄

盐酸文拉法辛（Venlafaxine）吸收良好……根据质量平衡研究，单次口服剂量的文拉法辛至少有92%被吸收。盐酸文拉法辛的绝对生物利用度约为45%。

Venlafaxine is well absorbed ... .On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 海关编码：
  2922509090
• 安全说明：
  S26,S37/39
• 危险类别码：
  R20/22,.R20/22,R36/37/38
• 储存条件：
  Refrigerator, Under Inert Atmosphere

制备方法与用途

根据提供的信息,可以总结出盐酸文拉法辛的制备过程:

1. 从消旋体出发:首先合成消旋的文拉法辛。

2. 分离光学异构体:

   • 使用二(对甲苯基)-L-酒石酸单水合物分离(+)-文拉法辛。
   • 使用二(对甲苯基)-D-酒石酸单水合物分离(-)-文拉法辛。

3. 重结晶纯化:

   • (+)-盐酸文拉法辛:用甲醇-乙酸乙酯混合液重结晶。
   • (-)-盐酸文拉法辛:同样用此方法重结晶。

4. 收率与熔点:

   • (+)-盐酸文拉法辛收率为68%,熔点240~240.5℃
   • (-)-盐酸文拉法辛收率为71%,熔点240~240.5℃

整个过程采用结晶、重结晶等方法纯化产物,并使用旋光仪测定光学活性。最终得到两种对映体形式的盐酸文拉法辛。

反应信息

• 作为反应物：
  描述：

  文拉法辛 在 盐酸 作用下， 以 水 、 异丙醇 、 甲苯 为溶剂， 反应 2.0h， 以47.4 kg的产率得到盐酸文拉法辛
  参考文献：
  名称：

  一种改进的无杂质的盐酸文拉法辛的大规模合成方法

  摘要：

  使用廉价的试剂，开发了一种用于大规模合成盐酸文拉法辛的无杂质的改进合成方法。通过该新开发的方法获得的总产率在高纯状态下为55％，通过HPLC纯度> 99.9％。

  DOI：

  10.1021/op200221y
• 作为产物：
  描述：

  盐酸文拉法辛 在 sodium hydroxide 作用下， 以 水 为溶剂， 以98.9%的产率得到文拉法辛
  参考文献：
  名称：

  文拉法辛的有效拆分和通过X射线晶体学的机理研究。

  摘要：

  研究了许多解决因素，以提高文拉法辛1的分离度。使用类似的“荷兰拆分”方法从酒石酸衍生物中筛选出一种有效的拆分剂，O，O'-二对甲苯甲酰（R，R）-酒石酸2。当rac- 1和2的比例在THF中，水很少时（10：1 v / v）时，分离效率高达88.4％。对映体纯的文拉法辛制备成具有99.1％ee的产率和82.2％的收率。首先通过X射线晶体学研究解释了手性拆分机理。一种具有良好溶解性的非对映异构盐形成酸性的盐（R）-1 · 2的圆柱状超分子结构而另一种溶解度较低的非对映异构盐则通过对映体自组装形成中性盐2（S）-1 · 2形成多层夹心超分子结构。如非对映异构体盐的特殊结构所示，水分子在光学拆分中起关键作用。

  DOI：

  10.1002/chir.22790

文献信息

• [EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2010104818A1

  公开（公告）日：2010-09-16

  MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.

  MCHR1拮抗剂具有以下化学式（I）：A1和A2独立地为C或N；E为C或N；Q1、Q2和Q3独立地为C或N，但至少其中一个为N，但不超过一个为N；D1为键，-CR8R9 X-，-XCR8R9-，-CHR8CHR9-，-CR10=CR10'-，-C≡C-，或1,2-环丙基；X为O、S或NR11；R1、R2和R3独立地从氢、卤素、低烷基、低环烷基、-CF3、-O 、-OR12和-SR12组成的群体中选择；G为O、S或-NR15；D2为低烷基、低环烷基、低烷基环烷基、低环烷基烷基、低环烷氧基烷基或低烷基环烷氧基，或当G为NR15时，G和D2一起可以选择形成氮杂环丙烷、吡咯烷或哌啶环；Z1和Z2独立地为氢、低烷基、低环烷基、低烷氧基、低环烷氧基、卤素、- 、-OCONR14R14'、-CN、-CONR14R14'、-SOR12、-SO2R12、-NR14COR14'、-NR14CO2R14'、-CO2R12、NR14SO2R12或COR12；R5、R6和R7独立地从氢、低烷基、低环烷基、- 、-SR12、低烷氧基、低环烷氧基、-CN、-CONR14R14'、SOR12、SO2R12、NR14COR14'、NR14CO2R12、CO2R12、NR14SO2R12和-COR12组成的群体中选择；R8、R9、R10、R10'、R11独立地为氢或低烷基；R12为低烷基或低环烷基；R14和R14'独立地为H、低烷基、低环烷基或R14和R14'与其连接的N一起形成具有4至7个原子的环；R15独立地从氢和低烷基组成的群体中选择。这些化合物对于治疗MCHR1介导的疾病，如肥胖症、糖尿病、炎症性肠病、抑郁症和焦虑症非常有用。
• [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。
• New Drug Delivery System for Crossing the Blood Brain Barrier
  申请人：Lipshutz H. Bruce

  公开号：US20070203080A1

  公开（公告）日：2007-08-30

  New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.

  新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。
• [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。