氟西汀 | 54910-89-3

• 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 - 苯和取代衍生物
• 中文名称: 氟西汀
• 中文别名: 氟西丁；N-甲基-3-苯基-3-(对三氟甲基苯氧基)丙胺；氟烷苯胺丙醚；氟西汀盐酸盐
• 英文名称: FLUOXETINE
• 英文别名: N-methyl-3-phenyl-3-(4-(trifluoromethyl)phenoxy)propan-1-amine；prozac；Flx；(±)-fluoxetine；N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine
• CAS: 54910-89-3
• 化学式: C₁₇H₁₈F₃NO
• mdl: MFCD00072041
• 分子量: 309.331
• InChiKey: RTHCYVBBDHJXIQ-UHFFFAOYSA-N

物化性质

• 熔点：
  158 °C
• 沸点：
  395.1±42.0 °C(Predicted)
• 密度：
  1.159±0.06 g/cm3(Predicted)
• 溶解度：
  12.5mg/mL DMSO 溶液、16mg/mL DMF 溶液、12.5mg/mL 乙醇溶液
• 物理描述：
  Solid
• 碰撞截面：
  176.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  1887.9;1870.4;1856.1;1868.3;1869.8
• 稳定性/保质期：
  盐酸氟西汀(Fluoxetine Hydrochloride)：化学式为C17H18F3NO.HCl，[59333-67-4]。它是一种白色至类白色的结晶性固体，熔点在158.4～158.9℃之间。易溶于甲醇或乙醇，在乙腈、丙酮或氯仿中可溶解，微溶于乙酸乙酯、二氯甲烷或水（需振荡pH分别为1.2、4.5和7.0），几乎不溶于环己烷、己烷或甲苯。其在不同溶剂中的最大溶解度如下：甲醇和乙醇＞100 mg/mL，丙酮、乙腈和氯仿为33～100 mg/mL，二氯甲烷5～10 mg/mL，水1～2 mg/mL，乙酸乙酯2～2.5 mg/mL，环己烷、己烷和甲苯则为0.5～0.67 mg/mL。在水中最大溶解度可达14 mg/mL。其紫外吸收光谱的最大吸收波长分别为227 nm、264 nm、268 nm、275 nm（E1cm1%值分别为372.0、29.2、29.3、21.5）。口服急性毒性实验中，小鼠和大鼠的LD50分别为248 mg/kg和452 mg/kg。 草酸氟西汀(Fluxetine Oxalate)：化学式为C17H18F3NO·C2H2O4。它通过乙酸乙酯-甲醇结晶得到，熔点在179～182℃（分解）。

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.294
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

氟西汀在摄入后会被CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP3A4和CYP3A5代谢成诺氟西汀。尽管所有提到的酶都参与了氟西汀的N-脱甲基化，但CYP2D6、CYP2C9和CYP3A4似乎是I期代谢的主要贡献酶。此外，有证据表明CYP2C19和CYP3A4介导了氟西汀和诺氟西汀的O-脱烷基化，产生对三氟甲基苯酚，随后被代谢成马尿酸。氟西汀和诺氟西汀都经历葡萄糖苷酸化以促进排泄。值得注意的是，母药和活性代谢物都抑制CYP2D6同种型，因此接受氟西汀治疗的患者容易发生药物相互作用。

Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions.

来源:DrugBank

代谢

氟西汀已知的人体代谢物包括去甲氟西汀、对三氟甲基苯酚以及(2S,3S,4S,5R)-3,4,5-三羟基-6-[甲基-[3-苯基-3-[4-(三氟甲基)苯氧基]丙基]氨基]氧杂环己烷-2-羧酸。

Fluoxetine has known human metabolites that include Norfluoxetine, p-Trifluoromethyl phenol, and (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[methyl-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]amino]oxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

代谢

动物研究中有限的数据表明，氟西汀可能会经历首过代谢，可能通过肝脏和/或肺部发生。氟西汀似乎被广泛代谢，很可能在肝脏中，转化为去甲氟西汀和其他代谢物。去甲氟西汀是主要的活性代谢物，通过氟西汀的N-脱甲基作用形成。去甲氟西汀的药理效力似乎与氟西汀相当。氟西汀和去甲氟西汀都在肝脏中进行第II阶段葡萄糖苷酸化反应。还认为氟西汀和去甲氟西汀经历O-脱烷基化反应，形成对-三氟甲基苯酚，然后进一步代谢为马尿酸。 消除途径：主要的消除途径似乎是肝脏代谢为无活性代谢物，由肾脏排出。S-对映体消除得更慢，是在稳态下存在的主要对映体。 半衰期：1-3天（急性给药）；4-6天（慢性给药）；4-16天（去甲氟西汀，急性给药和慢性给药）。

Limited data from animal studies suggest that fluoxetine may undergo first-pass metabolism may occur via the liver and/or lungs. Fluoxetine appears to be extensively metabolized, likely in the liver, to norfluoxetine and other metabolites. Norfluoxetine, the principal active metabolite, is formed via <i>N</i>-demethylation of fluoxetine. Norfluoxetine appears to be comparable pharmacologic potency as fluoxetine. Fluoxetine and norfluoxetine both undergo phase II glucuronidation reactions in the liver. It is also thought that fluoxetine and norfluoxetine undergo <i>O</i>-dealkylation to form <i>p</i>-trifluoromethylphenol, which is then subsequently metabolized to hippuric acid. Route of Elimination: The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. The S-enantiomer is eliminated more slowly and is the predominant enantiomer present at steady state. Half Life: 1-3 days [acute administration]; 4-6 days [chronic administration]; 4-16 days [norfluoxetine, acute and chronic administration].

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

氟西汀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（或称'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效的神经毒素，在低剂量下会导致过度流涎和流泪，随后是肌肉痉挛，最终导致死亡。神经毒气和许多用于杀虫剂的物质已被证明通过绑定乙酰胆碱酯酶活性位点上的丝氨酸，完全抑制该酶。乙酰胆碱酯酶分解神经递质乙酰胆碱，后者在神经和肌肉接点处释放，以使肌肉或器官放松。乙酰胆碱酯酶抑制的结果是乙酰胆碱积累并持续作用，使得任何神经冲动不断传输，肌肉收缩不会停止。最常见的乙酰胆碱酯酶抑制剂之一是磷基化合物，这些化合物被设计用于绑定到酶的活性位点。结构要求是一个带有两个亲脂性基团、一个离去基团（如卤素或硫氰酸酯）以及一个端氧原子的磷原子。

Fluoxetine 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

肝脏测试异常在服用氟西汀的患者中很少见（少于1%），而且升高的程度通常较轻，通常不需要调整剂量或停药。在服用氟西汀的患者中，有报道称罕见出现急性、临床上明显的肝脏损伤，伴有显著肝酶升高，可伴有或不伴有黄疸。损伤的发生通常在2到12周内，血清酶升高的模式通常是肝细胞型的，但也有描述了混合型和胆汁淤积型损伤的令人信服的病例。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。

Liver test abnormalities have been reported to occur rarely in patients on fluoxetine (less than 1%), 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 fluoxetine. The onset of injury is usually within 2 to 12 weeks and the pattern of serum enzyme elevations is usually hepatocellular, but convincing cases of mixed and cholestatic injury have also been described. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

来源:LiverTox

毒理性

• 药物性肝损伤

复合物：氟西汀

Compound:fluoxetine

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

氟西汀的口服生物利用度小于90%，这是由于肝脏首过代谢的结果。在一项生物等效性研究中，已确立的参考制剂中氟西汀20毫克的Cmax（最高血药浓度）为11.754纳克/毫升，而拟议的通用制剂的Cmax为11.786纳克/毫升。氟西汀非常亲脂并且与血浆蛋白高度结合，这使得药物及其活性代谢物去甲氟西汀能够分布到大脑中。

The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain.

来源:DrugBank

吸收、分配和排泄

• 消除途径

氟西汀主要通过尿液排出。

Fluoxetine is primarily eliminated in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

氟西汀及其代谢物的分布体积在20到42 L/kg之间变化。

The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

氟西汀在健康患者体内的清除率为9.6毫升/分钟/千克。

The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg.

来源:DrugBank

安全信息

• 安全说明：
  S23,S26,S27,S3,S36/37/39,S37/39,S45
• 危险品运输编号：
  UN 3265 8/PG 2
• WGK Germany：
  2
• 海关编码：
  29036990
• 危险类别：
  8
• 危险品标志：
  Xi,C
• 危险类别码：
  R34,R36/37/38,R36/37
• 包装等级：
  III
• 储存条件：
  室温

制备方法与用途

抗抑郁药——氟西汀

氟西汀是一种选择性血清再吸收抑制剂（SSRI）型的抗抑郁药，其化学名称为盐酸氟西汀（Fluoxetine hydrochloride），商品名包括“百优解”或“百忧解”（Prozac）。由美国礼来公司研发，并于20世纪90年代上市。该药物主要用于治疗成人抑郁症、强迫症、神经性贪食症以及具有或不具广场恐惧症的惊恐症，因其良好的抗抑郁效应而被广泛应用于临床。

氟西汀的主要药理作用是选择性地抑制中枢神经系统突触前释放的5-羟色胺（5-HT）的再摄取。它几乎不对α-肾上腺素能、β-肾上腺素能、5-羟色胺能、多巴胺能等其他受体产生结合力。

氟西汀口服后能够良好地从胃肠道吸收，大约6～8小时达到血浆浓度峰值，进食不会显著影响其生物利用度。它在肝脏中被代谢成多种产物，并通过尿液排出体外。服用期间可能会出现恶心、失眠、口干等副作用，但大多数情况下这些症状会随着时间的推移而逐渐减轻。

氟西汀的合成方法

方法一

1. 通过Mannich反应生成β-甲氨基苯丙酮的盐酸盐。
2. 将仲胺在碳酸钾水溶液中溶解，加入乙醇并逐步加入硼氢化钾。
3. 减压蒸除乙醇后，用乙醚和氯仿萃取剩余液。调整pH值至8.0后干燥。
4. 通过重结晶纯化N-甲基-3-苯基-3-羟基丙胺（收率89.7%）。
5. 该仲胺溶于DMAC，加入氢化钠并升温至70℃保温。再加入碘化钾和对氯三氟甲苯，在90℃反应后加水稀释，并用乙醚萃取。
6. 将提取液调整pH值至1.0放置析晶，过滤并干燥。最后通过乙酸乙酯重结晶得到盐酸氟西汀（收率80%，熔点152～153℃）。

方法二

1. β-甲氨基苯丙酮经硼烷还原成醇后氯化生成3-甲氨基-1-苯基-1-丙醇。
2. 该醇与对三氟苯酚钠反应，最终得到氟西汀。

方法三

1. 在温和条件下使用溴化氰处理N,N-二甲基-3-(4-三氟甲基苯氧基)-3-苯基丙胺，并在室温下继续进行。
2. 将产物溶于氢氧化钾、乙二醇和水的混合物中，在130℃回流反应20小时。
3. 冷却后加入乙醚提取，调整pH值至8.0后进一步处理，最后通过重结晶得到氟西汀（收率64%）。

以上就是关于氟西汀的一些基本信息和合成方法。请注意，使用任何药物都应在医生指导下进行，并且严格按照医嘱服用。

反应信息

• 作为反应物：
  描述：

  氟西汀 在 5%-palladium/activated carbon 作用下， 以 甲醇 为溶剂， 反应 6.0h， 以82%的产率得到盐酸氟西汀B
  参考文献：
  名称：

  An assembly of structurally diverse small and simple 5-aminomethylene derivatives of 2,4-thiazolidinedione and studies of their biological activity

  摘要：

  The synthesis of a novel series of substituted 5-(aminomethylene)thiazolidine-2,4-diones was achieved using a wide range of heterocyclic models derived from eight drug-like molecules. The primary aim of this study was to combine medicinally known, biologically active molecules bearing a 2A degrees amine functionality, such as terbinafine, fluoxetine, atomoxetine, cetirizine, risperidone, aripiprazole, ziprasidone, and clopidogrel, with a thiazolidinedione ring via an amino-methylene linker. By targeting this synergistic approach to compounds with skeletal, functional, and stereochemical diversity, we have developed a simple synthetic concept to enrich the thiazolidinedione collection with various biological activities. The biological activities of the newly synthesized 5-(aminomethylene)thiazolidine-2,4-dione derivatives were explored. All compounds were found to have antibacterial activity, with compounds bearing pyridine or piperazine moieties showing good to excellent antibacterial activity. Compounds with piperazine moieties were also found to show good antifungal activity, whereas none of the synthesized compounds showed high cytotoxic activity.

  DOI：

  10.1007/s00044-015-1447-0
• 作为产物：
  描述：

  phenyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropyl-amine-N-carboxylate 在 甲基氯化镁 、 水 、 氯化铵 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 生成 氟西汀
  参考文献：
  名称：

  [EN] METHOD FOR THE PREPARATION OF N-METHYL-ARYLOXY-PROPANAMINE DERIVATIVES
  [FR] PROCÉDÉ DE PRÉPARATION DE DÉRIVÉS DE N-MÉTHYL-ARYLOXY-PROPANAMINE

  摘要：

  公开号：

  WO2010010412A8
• 作为试剂：
  描述：

  1,2-二油酰基-sn-甘油-3-磷酸胆碱 在 氟西汀 作用下， 以 aq. buffer 为溶剂， 反应 24.0h， 生成 (2R)-2-羟基-3-[(9Z)-9-十八碳烯酰基氧基]丙基 2-(三甲基铵基)乙基磷酸酯 、 2-油酰基-sn-甘油-3-磷酰胆碱
  参考文献：
  名称：

  药物与脂膜的溶解反应†

  摘要：

  普萘洛尔被证明在三种类型的脂膜中发生脂化反应：（1）合成单组分甘油磷脂脂质体；(2)由从大肠杆菌或肝细胞中提取的复杂脂质混合物形成的脂质体；(3) Hep G2 细胞中的纤维素。在补充普萘洛尔的培养基中培养的 Hep G2 细胞的提取物中鉴定出 14 种不同的脂化普萘洛尔同系物。从肝细胞中分离脂质化药物分子证明了生命系统中的新药物反应性。酰基从脂质转移到普萘洛尔的醇基团比转移到仲胺更有利。酰基从醇到胺的迁移减少。所检查的其他药物没有形成可检测水平的脂化产物，但其中许多药物确实影响模型膜中的溶血脂水平。人们发现，化合物在模型系统中诱导溶血脂形成的倾向是纤维素中磷脂沉积活性的预测因子。

  DOI：

  10.1039/c8sc04831b

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、-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。
• [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] 2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY<br/>[FR] 2,4-DIAMINOQUINAZOLINES UTILES POUR LE TRAITEMENT D'UNE ATROPHIE MUSCULAIRE SPINALE
  申请人：DECODE CHEMISTRY INC

  公开号：WO2005123724A1

  公开（公告）日：2005-12-29

  2,4-Diaminoquinazolines of formulae I-IV and VI (I, II, III, IV and VI) are useful for treating spinal muscular atrophy (SMA).

  2,4-二氨基喹唑啉的化学式I-IV和VI（I，II，III，IV和VI）可用于治疗脊髓性肌萎缩症（SMA）。
• [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。