多萘哌齐碱 | 120014-06-4

• 物质功能分类: 原料药 - 神经系统用药 - 脑代谢调节药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 多萘哌齐碱
• 中文别名: 多奈哌齐；多奈哌齐碱；1-苄基-4-[(5,6-二甲氧基茚满酮-2-基)甲基]哌啶
• 英文名称: donepezil
• 英文别名: 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one；DNP；aricept；DPZ；donezepil；2-((1-benzylpiperidin-4-yl)-methyl)-5,6-dimethoxy-2,3-dihydroinden-1-one；donepezil hydrochloride；dopenezil；donepzil；DNPZ；(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one；(2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one)；1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine；2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-1-indanone；DNZ；DON；2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one
• CAS: 120014-06-4
• 化学式: C₂₄H₂₉NO₃
• mdl: MFCD00912833
• 分子量: 379.499
• InChiKey: ADEBPBSSDYVVLD-UHFFFAOYSA-N

物化性质

• 熔点：
  207°C
• 沸点：
  527.9±50.0 °C(Predicted)
• 密度：
  1.141±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于丙酮（少许）、氯仿（少许）
• 物理描述：
  Solid
• 蒸汽压力：
  6.77X10-10 mm Hg at 25 °C (est)
• 碰撞截面：
  198.1 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：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.458
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

多奈哌齐首次通过肝脏代谢，主要由CYP3A4以及CYP2D6进行。此后，发生O-脱烷基化、羟基化、N-氧化、水解和O-葡萄糖苷酸化，产生各种代谢物，这些代谢物的半衰期与未改变的母药相似。一项对放射性标记的多奈哌齐的药代动力学研究表明，约53%的血浆放射性以未改变形式的多奈哌齐出现，11%被识别为代谢物6-O-去甲基多奈哌齐，该代谢物对乙酰胆碱酯酶酶的抑制效力相似。这种药物被大量代谢为四种主要代谢物，其中两种被认为具有药理活性，同时还产生多种非活性和未识别的代谢物。

Donepezil is metabolized by first pass metabolism in the liver, primarily by CYP3A4, in addition to CYP2D6. After this, O-dealkylation, hydroxylation, N-oxidation, hydrolysis, and O-glucuronidation occur, producing various metabolites with similar half-lives to the unchanged parent drug. A study of the pharmacokinetics of radiolabeled donepezil demonstrated that about 53% of plasma radioactivity appeared as donepezil in the unchanged form, and 11% was identified as the metabolite 6-O-desmethyl donepezil, which exerts similar potency inhibition of the acetylcholinesterase enzyme. This drug is heavily metabolized to four primary metabolites, two of which are considered pharmacologically active, as well as to multiple inactive and unidentified metabolites.

来源:DrugBank

代谢

多奈哌齐既以完整形式从尿液中排出，也广泛代谢成四种主要代谢物，其中两种已知具有活性，还有许多次要代谢物，并未全部被识别。多奈哌齐通过CYP 450同工酶2D6和3A4代谢并经历葡萄糖苷酸化。在给予14C标记的多奈哌齐后，血浆中的放射性，以给药剂量的百分比表示，主要是完整的多奈哌齐（53%）和6-O-去甲基多奈哌齐（11%），据报道，后者在体外抑制AChE的程度与多奈哌齐相同，在血浆中的浓度约为多奈哌齐的20%。

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究旨在调查在给予单次5毫克（液体）口服剂量（含未标记和14C标记的多奈哌齐混合物）后，多奈哌齐HCl在人体内的代谢和消除情况。... 在每个基质中，未改变的多奈哌齐占据了回收剂量中最大的一部分。确定了三种代谢途径：（i）O-脱烷基化和羟基化形成代谢物M1和M2，随后与葡萄糖醛酸结合形成代谢物M11和M12；（ii）水解形成代谢物M4；（iii）N-氧化形成代谢物M6。在血浆中，母化合物在每个采样期间回收的剂量中约占25%，以及在累积回收剂量中也是如此。回收的残留物中，羟基化代谢物M1和M2的水平高于它们的葡萄糖醛酸结合物M11和M12。在尿液中，母化合物平均占每个合并样本回收剂量的17%，以及总回收剂量也是如此。主要的代谢物是水解产物M4，其次是葡萄糖醛酸结合物M11和M12。在粪便中，尽管母化合物仅占回收剂量的1%，但仍然占主导地位。粪便中大部分放射性物质是由在薄层色谱原点保留的未识别的极性代谢物组成。在提取的代谢物中，羟基化产物M1和M2最丰富，其次是水解产物M4和N-氧化产物M6。多奈哌齐在肝脏中代谢，母药物及其代谢物的主要消除途径是肾脏，因为79%的回收剂量在尿液中，剩余的21%在粪便中。此外，母化合物多奈哌齐是尿液中主要的消除产物。多奈哌齐的主要代谢物包括M1和M2（通过O-脱烷基化和羟基化）、M11和M12（分别通过M1和M2的葡萄糖醛酸化）、M4（通过水解）和M6（通过N-氧化）。

The aim of this study was to investigate the metabolism and elimination of donepezil HCl in humans, following the administration of a single 5 mg (liquid) oral dose containing a mixture of unlabelled and 14C-labelled donepezil. ... Unchanged donepezil accounted for the largest component of the recovered dose in each matrix. Three metabolic pathways were identified: (i) O-dealkylation and hydroxylation to metabolites M1 and M2, with subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N-oxidation to metabolite M6. In plasma, the parent compound accounted for about 25% of the dose recovered during each sampling period, as well as of the cumulative dose recovered. The recovered residue showed higher levels of the hydroxylated metabolites M1 and M2 than of their glucuronide conjugates M11 and M12, respectively. In urine, the parent compound accounted for 17%, on average, of the dose recovered from each pooled sample, as well as of the total recovered dose. The major metabolite was the hydrolysis product M4, followed by the glucuronidated conjugates M11 and M12. In feces, the parent compound also predominated, although it accounted for only 1%, of the recovered dose. A large percentage of the radioactivity in feces consisted of unidentified very polar metabolites, which were retained at the TLC origin. Of the extracted metabolites, the hydroxylation products M1 and M2 were the most abundant, followed by the hydrolysis product M4 and the N-oxidation product M6. Donepezil is hepatically metabolized and the predominant route for the elimination of both parent drug and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% found in the feces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O-dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2, respectively), M4 (via hydrolysis) and M6 (via N-oxidation).

来源:Hazardous Substances Data Bank (HSDB)

代谢

多奈哌齐已知的人类代谢物包括6-O-去甲基多奈哌齐、5,6-二甲氧基-2-(哌啶-4-基甲基)-2,3-二氢吲哚-1-酮和5-O-去甲基多奈哌齐。

Donepezil has known human metabolites that include 6-O-Desmethyl Donepezil, 5,6-dimethoxy-2-(piperidin-4-ylmethyl)-2,3-dihydroinden-1-one, and 5-O-Desmethyl Donepezil.

来源:NORMAN Suspect List Exchange

代谢

多奈哌齐通过肝脏的CYP 450同工酶2D6和3A4代谢，并经历葡萄糖苷酸化。主要代谢物6-O-去甲基多奈哌齐在体外实验中被报告具有与多奈哌齐相同的抑制乙酰胆碱酯酶的能力。 消除途径：多奈哌齐既以原型从尿液中排出，也广泛代谢成四个主要代谢物，其中两个已知具有活性，以及一些次要代谢物，并非所有次要代谢物都已被识别。 半衰期：70小时

Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and also undergoes glucuronidation. The main metabolite, 6-O-desmethyl donepezil, has been reported to inhibit AChE to the same extent as donepezil in vitro. Route of Elimination: Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Half Life: 70 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Donepezil是一种胆碱酯酶或乙酰胆碱酯酶（AChE）抑制剂。胆碱酯酶抑制剂（或“抗胆碱酯酶”）抑制乙酰胆碱酯酶的作用。由于其基本功能，干扰乙酰胆碱酯酶作用的化学物质是强大的神经毒素，在低剂量时会导致过度流涎和眼泪，随后是肌肉痉挛，最终导致死亡。神经气体和许多用于杀虫剂的物质已被证明通过结合乙酰胆碱酯酶活性位点的丝氨酸，完全抑制该酶。乙酰胆碱酯酶分解神经递质乙酰胆碱，该递质在神经和肌肉接头处释放，以允许肌肉或器官放松。乙酰胆碱酯酶抑制的结果是乙酰胆碱积聚并继续发挥作用，使得任何神经冲动不断传递，肌肉收缩不会停止。最常见的乙酰胆碱酯酶抑制剂之一是基于磷的化合物，它们被设计用来结合到酶的活性位点上。结构要求是一个带有两个亲脂性基团的磷原子，一个离去基团（如卤素或硫氰酸盐），以及一个末端的氧。

Donepezil is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在几项大型临床试验中，与安慰剂治疗相比，多奈哌齐治疗并未与血清酶升高率增加有关。此外，将剂量从每天10毫克增加到23毫克，与维持在较低剂量的患者相比，并未随后出现ALT升高的增加。然而，自从多奈哌齐进入临床使用以来，有几份孤立的病例报告指出其与明显的肝毒性有关。发病时间短（1到6周），血清酶升高的模式为胆汁淤积性或混合性。病情过程可能严重，伴有持久的黄疸和瘙痒（案例1），但尚未有致命案例的报道。免疫过敏和自身免疫特征并不常见。

In several large clinical trials, donepezil therapy was not associated with an increased rate of serum enzyme elevations compared to placebo treatment. Furthermore, escalation of the dose from 10 to 23 mg daily was not followed by an increased rate of ALT elevations compared to patients maintained on the lower dose. Nevertheless, since its introduction into clinical use, donepezil has been implicated in several isolated case reports of clinically apparent hepatotoxicity. The time to onset was short (1 to 6 weeks) and the pattern of serum enzyme elevations was cholestatic or mixed. The course of illness can be severe with prolonged jaundice and itching (Case 1), but fatal instances have not been published. Immunoallergic and autoimmune features are not common.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：多奈哌齐

Compound:donepezil

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

多奈哌齐通过口服给药后，缓慢通过胃肠道吸收。达峰时间（Tmax）为3到4小时，生物利用度为100%，稳态血药浓度在给药后15到21天内达到。在一项药代动力学研究中确定的达峰时间（Tmax）为4.1 ± 1.5小时。根据加拿大专论，5毫克多奈哌齐片剂的Cmax估计为8.34 ng/mL。5毫克多奈哌齐片剂的药时曲线下面积（AUC）已被确定为221.90-225.36 ng·hr/mL。

Donepezil is slowly absorbed via the gastrointestinal tract after oral administration. Tmax is 3 to 4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15 to 21 days of administration. The Tmax in one pharmacokinetic study determined a Tmax of 4.1 ± 1.5 hours. The Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph. The AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在一项对健康成年人进行的放射性标记阿托伐他汀的研究中，测定的放射性活性的57%在尿液中，5%在大便中。

In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

多奈哌齐的分布体积为11.8 ± 1.7 L/kg（5毫克剂量）和11.6 ± 1.91 L/kg（10毫克剂量）。它主要分布在血管外隙。多奈哌齐能穿过血脑屏障，上述剂量下的脑脊液浓度已测量为15.7%。根据美国食品药品监督管理局（FDA）的标签，多奈哌齐的稳态分布体积范围为12 - 16 L/kg。

The volume of distribution of donepezil is 11.8 ± 1.7 L/kg for a 5-mg dose and 11.6 ± 1.91 L/kg for a 10-mg dose. It is largely distributed in the extravascular compartments. Donepezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%. The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12 - 16 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

根据FDA的标签，这种药物的平均表观血浆清除率是0.13-0.19 L/小时/公斤。在健康患者中，5毫克多奈哌齐的血浆清除率为0.110±0.02 L/小时/公斤。在10例确诊为酒精性肝硬化的患者中，与10例健康受试者相比，清除率平均下降了20%。在4例严重肾损害患者与4例健康受试者相比，清除率没有显著变化。

According to the FDA label, the average apparent plasma clearance of this drug is 0.13 – 0.19 L/hr/kg. A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.110±0.02 L/h/kg. In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects. In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted.

来源:DrugBank

吸收、分配和排泄

多奈哌齐吸收良好，相对口服生物利用度为100%，在3到4小时内达到血浆峰浓度。药代动力学在1到10毫克每日一次的剂量范围内呈线性。食物或给药时间（早晨与晚上）不影响多奈哌齐氢氯化物片的吸收速率或程度。

Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1 to 10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of donepezil hydrochloride tablets.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S36
• 危险类别码：
  R36/37/38
• 海关编码：
  29333990
• 危险品运输编号：
  UN 2811
• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H315,H319,H335
• 储存条件：
  室温

制备方法与用途

药理作用

多奈哌齐为第二代乙酰胆碱酶抑制剂（ChE），具有高度选择性的中枢神经系统乙酰胆碱酶（AChE）作用，周围副作用较低。它于1996年经美国FDA批准，并在同年获英国MCA批准进口注册。

副作用

服用多奈哌齐最常见的副作用包括腹泻、肌肉痉挛、疲乏、恶心呕吐、失眠和头晕。少数患者可能出现血肌酸激酶轻微增高，但未见明显实验室异常报道。

生物活性

Donepezil（Aricept, Donepezilo）是一种有效的可逆性、特异性和非竞争性的乙酰胆碱酯酶（AChE）抑制剂，用于治疗轻度至中度痴呆症。

靶点

Target	Value
AChE	6.7 nM

体外研究

Donepezil对AChE具有可逆性和非竞争性的抑制作用。它选择性地比对BuChE高500-1000倍。在人源SH-SY5Y神经母细胞瘤细胞中，短期和长期药物暴露可诱导浓度依赖性的细胞增殖抑制，并与毒蕈碱或烟碱受体的阻滞及凋亡无关。它还减少S-G2/M期细胞数量、增加G0/G1期数量、减少cyclin E和cyclin B在G1/S和G2/M转变中的表达，并增加细胞周期抑制子p21的表达。此外，Donepezil还可增加动作电位依赖的多巴胺释放，调节黑质多巴胺能神经元上的烟碱受体。

体内研究

Donepezil在体内的胃肠道吸收速度较慢，在年轻志愿者中的终末半衰期为50-70小时，在老年人中则大于100小时。该化合物在肝脏广泛代谢，血浆蛋白结合率为93%。通过细胞色素P450系统（CYP1A2-, CYP2D6-, CYP3A4-related enzymes) 代谢后，母体化合物在脑内不变，在神经组织中未发现代谢物。大部分Donepezil代谢物为O-葡萄糖醛酸苷，在血浆、尿液和胆汁中可被检测到。口服摄入后，在3-5小时内达到峰值浓度，且吸收不受食物影响。在1-10 mg/day的剂量范围内，Donepezil具有线性药代动力学特征。96%循环中的Donepezil是蛋白质结合的。

用途

多奈哌齐盐酸盐一水是一种中枢作用可逆的乙酰胆碱酯酶抑制剂。

反应信息

• 作为反应物：
  描述：

  多萘哌齐碱 在 palladium 10% on activated carbon ammonium formate 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以97%的产率得到5,6-二甲氧基-2-(4-哌啶基)亚甲基-1-茚酮
  参考文献：
  名称：

  Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors

  摘要：

  本发明提供了新颖的茚酮衍生物，可以优势地用于治疗和/或预防需要抑制胆碱酯酶的医疗状况。

  公开号：

  US20080153878A1
• 作为产物：
  描述：

  5,6-二甲氧基茚酮 在 氢气 、 sodium carbonate 、 对甲苯磺酸 作用下， 以 异丙醇 、 甲苯 为溶剂， 50.0 ℃ 、101.33 kPa 条件下， 反应 180.0h， 生成 多萘哌齐碱
  参考文献：
  名称：

  聚硅烷固定的 Rh-Pt 双金属纳米粒子作为强大的芳烃加氢催化剂：合成、间歇和流动条件下的反应以及反应机理

  摘要：

  芳烃的氢化不仅是储氢和运输氢的重要反应，也是合成药物和生物活性化合物等功能性分子的重要反应。在这里，我们描述了非均相 Rh-Pt 双金属纳米颗粒催化剂的开发，用于以廉价的聚硅烷作为载体氢化芳烃。该催化剂可用于间歇和连续流动系统，在温和条件下具有高性能，并显示出广泛的底物通用性。在连续流动系统中，只需将底物和 1 个大气压的 H2 通过装有催化剂的柱子即可获得产物。值得注意的是，在流动系统中观察到比在间歇系统中高得多的催化性能，并且在连续流动条件下表现出极强的耐久性（> 连续运行50天；营业额 >3.4 × 105）。此外，研究了反应机理的细节以及批次和流动中不同动力学的起源，并将获得的知识应用于开发含有两个芳环的化合物的完全选择性芳烃氢化以合成活性药物成分。

  DOI：

  10.1021/jacs.8b06015
• 作为试剂：
  描述：

  chloroamine-T 在 高氯酸 、 多萘哌齐碱 作用下， 以 水 为溶剂， 反应 24.0h， 生成 对甲苯磺酰胺
  参考文献：
  名称：

  多奈哌齐氧化：产品、机理和动力学的互补化学和光谱探索

  摘要：

  氧化是药物代谢的重要步骤，因此是药学相关的过程。本研究探讨了多奈哌齐（一种广泛用于治疗轻度至中度严重阿尔茨海默病的药物）在酸性介质中使用温和、多功能氧化剂氯胺-T 进行氧化的潜力。动力学研究揭示了速率对多奈哌齐和氧化剂的一级依赖性、对酸性介质的分数级依赖性、速率对离子浓度的独立性以及速率随着介电常数的增加而升高。概述了化学计量、热力学性质、速率方程、机械细节，反应产物的鉴定得到一致的氧化降解相关 UV、IR、1的支持H NMR和质谱数据。光谱结果与理论预测吻合较好，为对多奈哌齐氧化代谢途径的认识提供了启示和深化。

  DOI：

  10.1007/s11696-021-01934-y

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [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、-OCF3、-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、-CF3、-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、-CF3、-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。
• Chromenone derivatives useful for the treatment of neurodegenerative diseases
  申请人：AxoGlia Therapeutics S.A.

  公开号：EP2112145A1

  公开（公告）日：2009-10-28

  Compounds of general formula (I) and (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meanings given in the specification, are useful in the treatment of neurodegenerative disease.

  通式（I）和（II）的化合物 其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14和R15具有规范中给定的含义，在神经退行性疾病的治疗中是有用的。
• [EN] COMPOUNDS AND METHODS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：TAVARES FRANCIS XAVIER

  公开号：WO2016168118A1

  公开（公告）日：2016-10-20

  Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

  公开了化学式（II）的新化合物。化学式（II）的化合物包括鸟氨酸衍生物或可能代谢成鸟氨酸的化合物。还公开了使用化学式（II）的化合物治疗神经退行性疾病，如阿尔茨海默病的方法。
• [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。