普拉克索 | 104632-26-0

• 物质功能分类: 原料药 - 神经系统用药 - 帕金森综合症药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 普拉克索
• 中文别名: 盐酸普拉克索；S(-)-2-氨基-6-正丙氨基-4,5,6,7-四氢苯并噻唑；普拉克索碱；(S)-N6-丙基-4,5,6,7-四氢苯并噻唑-2,6-二胺；普拉克索杂质D；帕尔米斯；2-氨基-4,5,6,7-四氢-6-丙基氨苯噻唑；盐酸普拉米索尔；(S)-2-氨基-4,5,6,7-四氢-6-丙基氨苯噻唑
• 英文名称: pramipexole
• 英文别名: (S)-(-)-pramipexole；(S)-N⁶-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine；(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole；Mirapex；(6S)-6-N-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
• CAS: 104632-26-0
• 化学式: C₁₀H₁₇N₃S
• mdl: MFCD00869076
• 分子量: 211.331
• InChiKey: FASDKYOPVNHBLU-ZETCQYMHSA-N

物化性质

• 熔点：
  288-290°C
• 沸点：
  378.0±42.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 蒸汽压力：
  1.55X10-5 mm Hg at 25 °C (est)
• 水溶性：
  -3.2
• 稳定性/保质期：
  二盐酸普拉克索（Pramipexole Dihydrochloride）的化学式为C10H17N3S·2HCl，其CAS号为[104632-25-9]。该物质从甲醇结晶后，熔点为296-298℃。其旋光度在甲醇中的测量值大于-67.2℃（D20）。
• 分解：
  Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx), Sulfur oxides, Hydrogen chloride gas. /Pramipexole dihydrochloride/
• 解离常数：
  pKa1 = 4.65 (imine); pKa2 = 10.31 (secondary amine); pKa3 = 17.66 (primary amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  79.2
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

这种药物在人体内几乎不发生代谢。

This drug undergoes little metabolism in humans.

来源:DrugBank

代谢

普拉克索仅被代谢到可忽略的程度（<10%）。在人体血浆或尿液中没有发现特定的活性代谢物。

Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

血浆或尿液中未鉴定出代谢物。 消除途径：尿液排泄是普拉克索消除的主要途径，90%的普拉克索剂量在尿液中回收，几乎全部为未改变的药物。非肾脏途径可能在很小程度上有助于普拉克索的消除，尽管在血浆或尿液中未鉴定出代谢物。 半衰期：8小时

No metabolites have been identified in plasma or urine. Route of Elimination: Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. Nonrenal routes may contribute to a small extent to pramipexole elimination, although no metabolites have been identified in plasma or urine. Half Life: 8 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别和使用：普拉克索，一种合成苯噻唑胺衍生物，是一种非麦角衍生物多巴胺受体激动剂。它用于对症治疗特发性帕金森综合症。它也用于对症治疗中到重度原发性不宁腿综合症。人类暴露和毒性：没有关于重大过量的临床经验。在一项用于研究性用途的临床试验中，一名患者连续两天每天服用11毫克普拉克索。尽管脉搏率增加到每分钟100到120次，但血压保持稳定。没有报告与增加剂量有关的其他不良反应。在使用治疗帕金森病药物（包括普拉克索）的上市后报告中，表明患者可能会在治疗期间或开始服用或增加普拉克索剂量后出现新的或加重的精神状态和行为变化，这些变化可能是严重的，包括类似精神病的行为。其他用于改善帕金森病症状的处方药也可能对思维和行为产生类似的影响。这种异常思维和行为可能包括一种或多种表现，如偏执观念、妄想、幻觉、混乱、类似精神病的行为、定向障碍、攻击性行为、激动和谵妄。病例报告和横断面研究的结果表明，患者在服用一种或多种增加中枢多巴胺能张力的药物（包括普拉克索）期间，可能会经历强烈的赌博欲望、性欲增加、无法控制的强烈消费欲望、暴饮暴食和/或其他强烈欲望以及无法控制这些欲望，这些药物通常用于治疗帕金森病。在某些情况下，尽管不是全部，这些欲望在剂量减少或停药后被报告停止。动物研究：对普拉克索在口服给药后的单次剂量毒性进行了大鼠、狗和猴子的研究。在大鼠中，高剂量的中枢相关症状包括共济失调、呼吸困难和不颤/惊厥。在狗中，0.0007毫克/千克及以上剂量时发生呕吐。猴子在3.5毫克/千克时表现出极度兴奋。将普拉克索以0.3、2或10毫克/千克/天的药物-饮食剂量给小鼠服用两年。除了在10毫克/千克雄性中肾上腺皮质腺瘤的发病率显著降低和在2和10毫克/千克雌性中恶性淋巴瘤的发病率显著降低外，治疗动物和对照动物的新生物变化发生率相似。将普拉克索以0.3、2或8毫克/千克/天的药物-饮食剂量给大鼠服用两年。在2和8毫克/千克雄性中，睾丸细胞腺瘤的发病率显著增加。在大鼠中，以下新生物在2和8毫克/千克的剂量下显著减少：雌性乳腺新生物、两性的垂体腺瘤、雌性原发性新生物的总数。此外，在0.3、2和8毫克/千克/天雌性大鼠中观察到良性肾上腺髓质新生物的发病率降低。尽管在2或8毫克/千克/天给白化大鼠服用时观察到视网膜变性，但在0.3毫克/千克/天的低剂量下没有观察到视网膜变性。在两年的小鼠致癌性研究中，一年期的大鼠药物-饮食研究中，或任何其他物种的研究中都没有看到视网膜变性。白化大鼠服用普拉克索明显降低了光感受器细胞的盘脱落率。这种变化与白化大鼠视网膜对光损伤作用的敏感性增加有关。相比之下，色素大鼠视网膜的任何部分都没有变性。当怀孕大鼠在整个怀孕期间服用普拉克索时，2.5毫克/千克的剂量抑制了着床。在器官发生期给怀孕大鼠服用1.5毫克/千克/天的普拉克索，导致胚胎完全吸收的高发生率。这些发现被认为是由普拉克索降低催乳素的作用引起的，因为催乳素对大鼠（但不包括兔或人类）的着床和早期怀孕的维持是必要的。在器官发生期给怀孕兔服用高达10毫克/千克/天的普拉克索后，没有发现对胚胎-胎儿发育产生不利影响的证据。在怀孕后期和整个哺乳期间给大鼠服用0.5毫克/千克/天或更高剂量的普拉克索，抑制了后代的后天生长。在大鼠生育研究中，普拉克索以2.5毫克/千克/天的剂量延长了发情周期并抑制了着床。在体外（细菌反向突变、V79/HGPRT基因突变、CHO细胞染色体畸变）和体内（小鼠微核）的一系列实验中，普拉克索没有表现出致突变或致裂变的作用。

IDENTIFICATION AND USE: Pramipexole, a synthetic benzothiazolamine derivative, is a nonergot-derivative dopamine receptor agonist. It is used for the symptomatic management of idiopathic parkinsonian syndrome. It is also used for the symptomatic management of moderate-to-severe primary restless legs syndrome. HUMAN EXPOSURE AND TOXICITY: There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose. Postmarketing reports with medication used to treat Parkinson's disease, including pramipexole, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole or after starting or increasing the dose of pramipexole. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including pramipexole, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. ANIMAL STUDIES: Single dose toxicity of pramipexole after oral administration was studied in rodents, dogs and monkeys. In rodents, CNS-related signs at high doses included ataxia, dyspnea and tremor/convulsions. In dogs, vomiting occurred at 0.0007 mg/kg and above. Monkeys displayed major excitation at 3.5 mg/kg. Pramipexole was administered to mice for two years at drug in-diet-doses of 0.3, 2, or 10 mg/kg/day. With the exception of statistically significant decreases in adrenal cortical adenomas in males at 10 mg/kg and malignant lymphomas in females at 2 and 10 mg/kg, the incidence of neoplastic changes was similar in treated and control animals. Pramipexole was administered to rats for two years by drug-in-diet, at doses of 0.3, 2, or 8 mg/kg/day. A statistically significant increase in the incidence of Leydig cell adenomas was noted in males at 2 and 8 mg/kg. The following neoplasms were significantly decreased in rats at 2 and 8 mg/kg: mammary gland neoplasia in females, pituitary adenomas in both sexes, total number of primary neoplasms in females. Additionally, a decrease in the incidence of benign adrenal medullary neoplasms was observed in female rats at 0.3, 2, and 8 mg/kg/day. Although retinal degeneration was observed in albino rats given 2 or 8 mg/kg/day, no retinal degeneration was noted at the low dose of 0.3 mg/kg/day. No retinal degeneration was seen in the two year carcinogenicity study in mice, in the one year drug-in-diet rat study, or in any other study in any species. The treatment of albino rats with pramipexole clearly reduced the rate of disk shedding from photoreceptor cells. This change was associated with increased sensitivity of the retina of albino rats to the damaging effects of light. In contrast, pigmented rats had absolutely no degeneration of any portion of the retina. When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis. Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day or greater during the latter part of pregnancy and throughout lactation. In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day, prolonged estrus cycles and inhibited implantation. Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

尽管帕金森病的确切作用机制尚不清楚，但人们认为这与普拉克索能够刺激纹状体中的多巴胺受体有关。

The precise mechanism of action of Pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

普拉克索据报道会在一小部分患者中引起血清转氨酶升高，但这些异常通常是轻微的、无症状的，并且即使不调整剂量也是自我限制的。普拉克索尚未在临床上明显的急性肝损伤案例中被涉及，如果这种情况确实发生，也一定是罕见的。

Pramipexole has been reported to cause serum aminotransferase elevations in a small proportion of patients, but these abnormalities are usually mild, asymptomatic and self-limiting even without dose adjustment. Pramipexole has not been implicated in cases of clinically apparent acute liver injury which must be rare, if it occurs at all.

来源:LiverTox

毒理性

• 药物性肝损伤

多巴胺受体激动剂：普拉克索

Compound:pramipexole

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

普拉克索的 生物利用度超过90%，表明其吸收水平很高。

The bioavailability of pramipexole is higher than 90%, indicating a high level of absorption.

来源:DrugBank

吸收、分配和排泄

• 消除途径

多奈哌齐的主要消除途径是肾脏，90%的多奈哌齐剂量在尿液中找到，几乎全部为未改变的药物。

The main route of pramipexole elimination, with 90% of a pramipexole dose found in the urine, almost entirely as unchanged drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

这种药物在体内的分布非常广泛，分布容积大约为500升。

This drug is extensively distributed in the body with a volume of distribution of approximately 500 L.

来源:DrugBank

吸收、分配和排泄

• 清除

肾清除率约为400毫升/分钟，这表明肾小管有大量分泌。

Renal clearance is about 400 mL/min, indicating heavy secretion by the renal tubules.

来源:DrugBank

吸收、分配和排泄

普拉克索在体内广泛分布，分布容积约为500升。在血浆中，蛋白结合率低于20%；其中，白蛋白占血清中大部分的蛋白结合。普拉克索能分布进入红细胞，红细胞与血浆的比例大约为2.0，血液与血浆的比例大约为1.5。与人体的较大分布容积一致，大鼠的整体放射性自显影和脑组织水平表明普拉克索在体内广泛分布，包括大脑。

Pramipexole is extensively distributed, having a volume of distribution of about 500 L. Protein binding is less than 20% in plasma; with albumin accounting for most of the protein binding in human serum. Pramipexole distributes into red blood cells as indicated by an erythrocyte to plasma ratio of approximately 2.0 and a blood to plasma ratio of approximately 1.5. Consistent with the large volume of distribution in humans, whole body autoradiography and brain tissue levels in rats indicated that pramipexole was widely distributed throughout the body, including the brain.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S26,S36
• WGK Germany：
  3
• 海关编码：
  2934999090
• 危险品标志：
  Xi
• 危险品运输编号：
  OTH
• 危险类别码：
  R36/37/38
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20°C freezer

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Pramipexole
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Pramipexole
CAS number: 104632-26-0

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels, refrigerated.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C10H17N3S
Molecular weight: 211.3

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, sulfur oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

生物活性

Pramipexole (SND 919) 是部分/全部D2S、D2L、D3、D4受体激动剂，作用于这些受体的Ki值分别为3.9 nM、2.2 nM、0.5 nM和5.1 nM。

靶点

Target	Value
D3 receptor	0.5 nM (Ki)
D2L Receptor	2.2 nM (Ki)
D2S Receptor	3.9 nM (Ki)
D4 receptor	5.1 nM (Ki)

化学性质

二盐酸普拉克索（Pramipexole Dihydrochloride）：C₁₀H₁₇N₃S·2HCl。熔点为296-298℃，[α]₂₀⁺ = -67.2°(C=1, 甲醇)。

用途

多巴胺D₂受体激动剂，用于治疗帕金森病。

生产方法

0.02 mol的2,6-二氨基-4,5,6,7-四氢苯并噻唑溶于34 ml DMF中，加入0.022 mol正丙醛，在50℃加热1小时。冷却后，再加入0.02 mol硼氢化钠，在50℃下继续加热30分钟。减压蒸出大部分溶剂后，剩余物溶解在20 ml水中，并用2 mol/L盐酸调至pH值1。水层用乙酸乙酯萃取，有机相和萃取液丢弃。向水层中加入碳酸钾以调节碱性，然后再次使用乙酸乙酯进行萃取，干燥后浓缩，加入含HCl的乙醚溶液得到二盐酸普拉克索，收率为42%，熔点为286-288℃。

另一种合成路线：将4-丙氨基环己酮(I)在乙酸中用氢溴酸进行溴化，生成物(Ⅱ)与硫脲缩合后酸化即得二盐酸普拉克索。

反应信息

• 作为反应物：
  描述：

  普拉克索 在 盐酸 作用下， 生成 pramipexole dihydrochloride
  参考文献：
  名称：

  Convenient N-Alkylation of amines using an effective magnetically separable supported ionic liquid containing an anionic polyoxometalate

  摘要：

  介绍了利用磁性可分离纳米粒子有效合成阴离子交换支撑离子液体及其对 N- 烷基化反应的催化作用。在催化剂设计的阴离子交换步骤中使用了阴离子聚氧化金属酸盐衍生物。在外部磁场的作用下，催化体系可以很容易地从反应混合物中分离出来，并在后续反应中循环使用。为了评估催化剂的可重复性，本文成功研究了在可回收催化剂存在下对苯胺、4-氨基苯磺酰胺、4-甲氧基苯胺、2-氨基嘧啶和 4,5,6,7-四氢苯并[d]噻唑-2,6-二胺等更多胺的 N- 烷基化反应。此外，该催化系统还成功合成了盐酸普拉克索（一种活性药物成分）。通过红外光谱、X 射线粉末衍射和扫描电子显微镜技术测定了催化剂的结构。有机产物的结构由 1H NMR、13C NMR、红外光谱和质谱测定。

  DOI：

  10.1007/s11164-016-2741-2
• 作为产物：
  描述：

  pramipexole dihydrochloride 在 氢氧化钾 作用下， 以 水 为溶剂， 反应 2.0h， 以86%的产率得到普拉克索
  参考文献：
  名称：

  Process for the reduction of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzo-thiazole

  摘要：

  本公开了一种还原(S)-2-氨基-6-丙酰胺基-4,5,6,7-四氢苯并噻唑醇的方法，包括在适当的有机溶剂存在下，将(S)-2-氨基-6-丙酰胺基-4,5,6,7-四氢苯并噻唑醇与硼烷试剂反应，得到(S)-2-氨基-6-丙基氨基-4,5,6,7-四氢苯并噻唑醇碱，可转化为其酸盐。本文提供的方法可以轻松、方便、廉价地进行扩大规模。

  公开号：

  US20060069263A1
• 作为试剂：
  描述：

  (S)-2,6-二氨基-4,5,6,7-四氢苯并噻唑 、 普拉克索 、 (±)-普拉克索 在 普拉克索杂质E 、 普拉克索 作用下， 反应 0.35h， 以are provided in Table 3的产率得到普拉克索杂质E
  参考文献：
  名称：

  Synthesis of Chirally Purified Substituted Benzothiazole Diamines

  摘要：

  本文提供了制备手性纯净的取代的4,5,6,7-四氢苯并噻唑二胺的方法，例如(6R)2-氨基-4,5,6,7-四氢-6-(丙基氨基)苯并噻唑，以及从手性富集的取代的4,5,6,7-四氢苯并噻唑二胺混合物中纯化优势对映体的方法。

  公开号：

  US20130079526A1

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。
• [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。
• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2018137593A1

  公开（公告）日：2018-08-02

  Provided are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases associated with or characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

  提供了抑制LRRK2激酶活性的新化合物，以及它们的制备方法、含有它们的组合物以及它们在治疗或预防与LRRK2激酶活性相关或以其为特征的疾病中的用途，例如帕金森病、阿尔茨海默病和肌萎缩侧索硬化症（ALS）。