9-胺-1,2,3,4-四氢盐酸氯酯 | 321-64-2

• 物质功能分类: 原料药 - 专科用药 - 解毒药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 9-胺-1,2,3,4-四氢盐酸氯酯
• 中文别名: 他克林；呆克宁；5-氨基四氢吖啶；单满吖啶氨；9-氨基-1,2,3,4-四氢吖啶
• 英文名称: tacrin
• 英文别名: 1,2,3,4-Tetrahydro-9-acridinamine；tacrine；1,2,3,4-tetrahydroacridin-9-amine；TAC
• CAS: 321-64-2
• 化学式: C₁₃H₁₄N₂
• mdl: MFCD00046923
• 分子量: 198.268
• InChiKey: YLJREFDVOIBQDA-UHFFFAOYSA-N

物化性质

• 熔点：
  183.5℃
• 沸点：
  325.59°C (rough estimate)
• 密度：
  0.9827 (rough estimate)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 保留指数：
  2160;2140;2165

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.307
• 拓扑面积：
  38.9
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

肝脏。细胞色素P450 1A2是参与他克林代谢的主要同种酶。主要代谢物1-羟基他克林（velnacrine）具有中枢胆碱能活性。

Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine (velnacrine), has central cholinergic activity.

来源:DrugBank

代谢

他克林已知的人类代谢物包括4-羟基他克林、2-羟基他克林、7-羟基他克林和N4-羟基胺。

Tacrine has known human metabolites that include 4- Hydroxytacrine, 2-Hydroxytacrine, 7-Hydroxytacrine, and N4-hydroxylamine.

来源:NORMAN Suspect List Exchange

代谢

肝脏。细胞色素P450 1A2是参与他克林代谢的主要同种酶。主要代谢物1-羟基他克林（velnacrine）具有中枢胆碱能活性。 半衰期：2到4小时

Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine (velnacrine), has central cholinergic activity. Half Life: 2 to 4 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

他克林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。

Tacrine 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

显著地，使用他克林治疗与近一半患者血清转氨酶升高有关。这些升高通常在开始治疗后的6到8周内出现，并在停止治疗时迅速解决。高于正常上限3倍的升高发生在25%的患者中，高于10倍的ULN在6%的患者中，高于20倍的ULN在2%的患者中。碱性磷酸酶和胆红素的伴随升高很少见，ALT异常通常无症状，并在停止治疗或减量时迅速解决。建议在他克林治疗期间监测血清转氨酶水平，对于高于3倍ULN的ALT升高进行剂量调整，如果水平升至5倍ULN以上则停止治疗。在上市前研究中，没有报告出现黄疸的明显急性肝损伤的实例。然而，随后有几例因使用他克林而引起的急性肝细胞损伤伴黄疸的报道，通常在开始治疗后的2到8周内出现，并在停止治疗时通常迅速解决。他克林引起的肝损伤常伴有嗜酸性粒细胞增多，但皮疹和发热不常见，自身抗体也不常见。重新挑战往往导致肝损伤的复发，潜伏期稍短，但病程相似或较轻。在许多患者中，即使没有停止药物或调整剂量，血清转氨酶升高也会解决。然而，有几例因他克林导致的致命性肝损伤的病例报告给了赞助商。建议在治疗的前六个月定期监测血清转氨酶水平。然而，由于其他口服抗胆碱酯酶抑制剂的使用，这些药物只需每天一次或两次，不需要ALT监测，并且很少引起肝酶升高，这导致了他克林在美国临床使用中的撤回。

Strikingly, therapy with tacrine was associated with serum aminotransferase elevations in almost half of patients. These elevations usually arose within 6 to 8 weeks of starting therapy and rapidly resolved when therapy was stopped. Elevations above 3 times the upper limit of the normal range (ULN) occurred in 25%, above 10 times ULN in 6% and above 20 times ULN in 2% of patients. Accompanying elevations in alkaline phosphatase and bilirubin were rare, and the ALT abnormalities were usually asymptomatic and resolved rapidly when therapy was stopped or with dose reduction. Monitoring of serum aminotransferase levels during tacrine therapy was recommended, with dose modification for ALT elevations above 3 times the ULN and discontinuation if levels rose above 5 times the ULN. In prelicensure studies, no instances of clinically apparent acute liver injury with jaundice were reported. Subsequently, however, several cases of acute hepatocellular injury with jaundice attributed to tacrine were reported, generally arising within 2 to 8 weeks of starting therapy and usually resolving rapidly with discontinuation. Eosinophilia often accompanied the hepatic injury due to tacrine, but rash and fever were uncommon as were autoantibodies. Rechallenge often led to recurrence of the hepatic injury with a somewhat shorter latency but similar or milder course. In many patients, the serum aminotransferase elevations resolved even without drug discontinuation or dose modification. Nevertheless, fatal cases of liver injury attributed to tacrine were reported to the sponsor. Routine monitoring of serum aminotransferase levels for the first six months of therapy was recommended. However, the availability of other oral anticholinesterase inhibitors that are given only once or twice daily, do not require ALT monitoring and only rarely cause liver enzyme elevations has led to the withdrawal of tacrine from clinical use in the United States.

来源:LiverTox

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

急性接触胆碱酯酶抑制剂可能会导致胆碱能危象，表现为严重的恶心/呕吐、流涎、出汗、心动过缓、低血压、崩溃和抽搐。肌肉无力可能性增加，如果呼吸肌受到影响，可能会导致死亡。在运动神经积累的乙酰胆碱会导致神经肌肉接头处尼古丁受体的过度刺激。当这种情况发生时，可以看到肌肉无力、疲劳、肌肉痉挛、肌束震颤和麻痹的症状。当自主神经节积累乙酰胆碱时，这会导致交感系统中尼古丁受体的过度刺激。与此相关的症状包括高血压和低血糖。由于乙酰胆碱积累，中枢神经系统中尼古丁乙酰胆碱受体的过度刺激会导致焦虑、头痛、抽搐、共济失调、呼吸和循环抑制、震颤、全身无力，甚至可能昏迷。当由于乙酰胆碱过量在毒蕈碱乙酰胆碱受体上出现毒蕈碱过度刺激时，可能会出现视力障碍、胸部紧绷、由于支气管收缩引起的喘息、支气管分泌物增加、唾液分泌增加、流泪、出汗、肠蠕动和排尿的症状。对于男性和女性的生育、生长和发育，某些生殖效应与有机磷农药暴露有特定联系。关于生殖效应的大多数研究都是在农村地区使用农药和杀虫剂的农民中进行的。在女性中，月经周期紊乱、怀孕时间延长、自然流产、死产以及后代的一些发育效应与有机磷农药暴露有关。产前暴露与胎儿生长和发育受损有关。神经毒性效应也与有机磷农药中毒有关，在人类中引起四种神经毒性效应：胆碱能综合症、中间综合症、有机磷诱导的迟发性多发性神经病（OPIDP）和慢性有机磷诱导的神经精神障碍（COPIND）。这些综合症在急性 and 慢性暴露于有机磷农药后出现。

Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口腔。 他克林吸收迅速。他克林的绝对生物利用度大约为17%。

Oral. Tacrine is rapidly absorbed. Absolute bioavailability of tacrine is approximately 17%.

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

毒扁豆碱吸收迅速。毒扁豆碱的绝对生物利用度大约为17%。

Tacrine is rapidly absorbed. Absolute bioavailability of tacrine is approximately 17%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

349 ± 193 L

349 ± 193 L

来源:DrugBank

安全信息

• 危险类别码：
  R25
• 海关编码：
  2933990090
• 危险品标志：
  T
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P201,P202,P261,P264,P270,P271,P280,P302+P352,P304+P340,P305+P351+P338,P308+P313,P310,P330,P332+P313,P337+P313,P361,P403+P233,P405,P501
• 危险品运输编号：
  2811
• 危险性描述：
  H301,H311,H315,H319,H331,H335,H351
• 安全说明：
  S28A,S45
• 储存条件：
  应存放在室温、干燥、避光的环境中。

SDS

Name:	9-Amino-1 2 3 4-tetrahydroacridine hydrochloride hydrate 99+% (tlc) Material Safety Data Sheet
Synonym:	THA; Tacrine hydrochlorid
CAS:	321-64-2

Section 1 - Chemical Product MSDS Name:9-Amino-1 2 3 4-tetrahydroacridine hydrochloride hydrate 99+% (tlc) Material Safety Data Sheet
Synonym:THA; Tacrine hydrochlorid

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
321-64-2	9-Amino-1,2,3,4-tetrahydroacridine hyd	99+%	206-291-2

Hazard Symbols: T
Risk Phrases: 25

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Toxic if swallowed.The toxicological properties of this material have not been fully investigated.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation.
Ingestion:
Harmful if swallowed.
Inhalation:
May cause respiratory tract irritation.
Chronic:
No information found.

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Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes.
Ingestion:
If victim is conscious and alert, give 2-4 cupfuls of milk or water.
Get medical aid immediately. Wash mouth out with water.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

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Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear.
Extinguishing Media:
Use water spray, dry chemical, carbon dioxide, or chemical foam.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container.

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Section 7 - HANDLING and STORAGE
Handling:
Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use with adequate ventilation. Avoid contact with skin and eyes. Avoid ingestion and inhalation.
Storage:
Store in a cool, dry place. Store in a tightly closed container.

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 321-64-2: Personal Protective Equipment Eyes: Wear appropriate protective eyeglasses or chemical safety goggles as described by OSHA's eye and face protection regulations in 29 CFR 1910.133 or European Standard EN166.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to prevent skin exposure.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Solid
Color: white
Odor: Not available.
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 283 - 284 deg C
Autoignition Temperature: Not available.
Flash Point: Not available.
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature:
Solubility in water: soluble in water
Specific Gravity/Density:
Molecular Formula: C13H14N2.HCl.xH2O
Molecular Weight: 234.72

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Stable under normal temperatures and pressures.
Conditions to Avoid:
Incompatible materials.
Incompatibilities with Other Materials:
Strong oxidizing agents, acid chlorides, acid anhydrides.
Hazardous Decomposition Products:
Hydrogen chloride, nitrogen oxides, carbon monoxide, carbon dioxide.
Hazardous Polymerization: Has not been reported.

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 321-64-2: AR9532100 LD50/LC50:
CAS# 321-64-2: Oral, mouse: LD50 = 39800 ug/kg; Oral, rat: LD50 = 70 mg/kg.
Carcinogenicity:
9-Amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

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Section 12 - ECOLOGICAL INFORMATION

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Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

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Section 14 - TRANSPORT INFORMATION

IATA
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.*
Hazard Class: 6.1
UN Number: 2811
Packing Group: III
IMO
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing Group: III
RID/ADR
Shipping Name: TOXIC SOLID, ORGANIC, N.O.S.
Hazard Class: 6.1
UN Number: 2811
Packing group: III

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: T
Risk Phrases:
R 25 Toxic if swallowed.
Safety Phrases:
S 28A After contact with skin, wash immediately with
plenty of water.
S 45 In case of accident or if you feel unwell, seek
medical advice immediately (show the label where
possible).
WGK (Water Danger/Protection)
CAS# 321-64-2: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 321-64-2 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 321-64-2 is not listed on the TSCA inventory.
It is for research and development use only.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

化学性质
从烯醇得到八面体结晶体，熔点为183～184℃。盐酸他克林（Tacrine Hydrochloride）：C₁₃H₁₄N₂·HCI，[1684-40-8]。从浓盐酸中获得黄色针状结晶，熔点283～284℃，味苦且易溶于水。其1.5%的水溶液pH值为4.5～6。

用途
这是一种具有中枢神经系统活性的毒扁豆碱酯酶药物，用于治疗阿尔茨海默病。

生产方法
首先将苯胺与羟胺及水合三氯乙醛反应，然后在硫酸催化下环合成靛红，收率为63.4%。接着，靛红、过量的盐酸羟胺、乙酸钠三水合物和水，在60℃条件下剧烈搅拌后室温放置过夜。过滤并用乙醇-水重结晶得靛红-3-肟，收率92%。随后加热靛红-3-肟至熔融状态，强烈分解生成邻氨基苯甲腈，用乙醚溶解并收集之。去除乙醚后，进行减压蒸馏得产品，收率为86.8%，沸点112～114℃/0.8kPa，熔点48～50℃。再将邻氨基苯甲腈溶于环己酮中，并加入等摩尔的无水二氯化锌搅拌回流。冷却后过滤，固体用乙醚洗数次后再悬于水中。加入30%氢氧化钠至强碱性后进行二氯甲烷提取。提取液用水洗涤、干燥并浓缩后，再用甲苯重结晶得微黄色片状的他克林结晶，收率为92.6%，熔点为182～184℃。

反应信息

• 作为反应物：
  描述：

  9-胺-1,2,3,4-四氢盐酸氯酯 在 氢氧化钾 作用下， 以 乙腈 为溶剂， 反应 16.0h， 生成 N-[7-(1,2,3,4-tetrahydroacridin-9-ylsulfanyl)heptyl]-1,2,3,4-tetrahydroacridin-9-amine
  参考文献：
  名称：

  Specific Targeting of Acetylcholinesterase and Butyrylcholinesterase Recognition Sites. Rational Design of Novel, Selective, and Highly Potent Cholinesterase Inhibitors

  摘要：

  Tacrine-based AChE and BuChE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BuChE active site gorges.

  DOI：

  10.1021/jm0255668
• 作为产物：
  描述：

  四氢氨基吖啶 在 碳酸氢钠 作用下， 反应 1.0h， 生成 9-胺-1,2,3,4-四氢盐酸氯酯
  参考文献：
  名称：

  塔克林，Trolox和色氨酸作为主要化合物，用于设计和合成阿尔茨海默氏病治疗的多靶标药物。

  摘要：

  他克林，trolox和β-咔啉衍生物的多种生物活性使其成为开发多功能阿尔茨海默氏病（AD）药物的有前途的先导结构。基于胆碱酯酶和其他与AD发病机理有关的目标蛋白的活性位点的拓扑结构，我们设计和合成了具有不同接头链长度的他克林-trolox和他克林-隐氨酸杂种。含有trolox部分（8a-8d）的杂种表现出中等至高的TcAChE抑制作用（IC50：17.37-2200 nM），eqBuChE抑制作用（IC50：3.16-128.82 nM）和自由基清除活性（IC50：11.48-49.23 µM）。通常，具有较长连接子链长度的杂种表现出更好的ChE抑制活性。不出所料 自由基清除活性不受接头链长度变化的显着影响。杂色化合物含有通过7个碳间隔基连接至他克林（14）的色氨酸部分，显示出最佳的AChE和BuChE抑制活性（IC50 = 17.37和3.16 nM）。对接实验表明，化合物8d和14能够

  DOI：

  10.2174/1874104501711010024
• 作为试剂：
  描述：

  碘代硫代乙酰胆碱 在 9-胺-1,2,3,4-四氢盐酸氯酯 、 acetylcholinesterase 作用下， 生成 2-巯基-N,N,N-三甲基-乙铵碘化物(1:1)
  参考文献：
  名称：

  The Kinetic Inhibition of Acetylcholinesterase from Human Herytrocyte by Tacrine and Some Tacrine Derivatives

  摘要：

  The kinetics of the reaction catalyzed by human erythrocyte Acetylcholinesterase (AChE) is studied in the presence of its inhibitor Tacrine (1,2,3,4-tetrahydro-9-acridinamine), and of two newly synthesized compounds, 6-metoxy-Tacrine and N-eptyl-Tacrine. The proposed kinetic model describes the rate of the enzymatic reaction in terms of competitive and uncompetitive mixed inhibition of the three different inhibitors. The kinetic parameters describing the rate of the reaction are obtained. The competitive and uncompetitive inhibition constants of the different inhibitors are reported and the mixed competitive-uncompetitive inhibition is discussed. (C) 1999 Academic Press.

  DOI：

  10.1006/bioo.1998.1121

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] 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。
• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• 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。

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