去甲肾上腺素 | 51-41-2

• 物质功能分类: 原料药 - 循环系统用药 - 抗休克血管活性药
• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 中文名称: 去甲肾上腺素
• 中文别名: (R)-4-(2-氨基-1-羟基乙基)-1,2-苯二酚；L-去甲肾上腺素
• 英文名称: norepinephrine
• 英文别名: (R)-4-(2-amino-1-hydroxyethyl)-1,2-benzenediol；noradrenaline；L-norepinephrine；(R)-(-)-Norepinephrine；4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol
• CAS: 51-41-2
• 化学式: C₈H₁₁NO₃
• 分子量: 169.18
• InChiKey: SFLSHLFXELFNJZ-QMMMGPOBSA-N

物化性质

• 熔点：
  220-230°C
• 比旋光度：
  D25 -37.3° (c = 5 in water with 1 equiv HCl)
• 沸点：
  298.46°C (rough estimate)
• 密度：
  1.2435 (rough estimate)
• 溶解度：
  可溶于酸性水溶液（少许）、DMSO（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Colorless microcrystals
• 蒸汽压力：
  7.5X10-8 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: -37.3 deg at 25 °C/D (c = 5 in water with 1 equiv hydrochloric acid)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa = 8.58 (conjugate acid)
• 碰撞截面：
  137.3 Ų [M+H-H2O]+ [CCS Type: DT, Method: single field calibrated with Agilent tune mix (Agilent)]
• 稳定性/保质期：

  稳定但可能对光敏感，避免与酸、碱及氧化剂接触。应储存在-20°C的环境中。

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  86.7
• 氢给体数：
  4
• 氢受体数：
  4

ADMET

代谢

去甲肾上腺素的药理作用主要通过在交感神经末梢的摄取和代谢而终止。该药物在肝脏和其他组织中通过涉及酶儿茶酚-O-甲基转移酶（COMT）和单胺氧化酶（MAO）的一系列反应被代谢。主要代谢物是去甲肾上腺素和3-甲氧基-4-羟基扁桃酸（香草扁桃酸，VMA），这两种物质都是无活性的。其他无活性的代谢物包括3-甲氧基-4-羟基苯乙醇酸、3,4-二羟基扁桃酸和3,4-二羟基苯乙醇酸。去甲肾上腺素的代谢物主要以硫酸盐结合物形式在尿液中排泄，其次是以葡萄糖醛酸结合物形式排泄。只有少量去甲肾上腺素以原形排泄。

The pharmacologic actions of norepinephrine are terminated primarily by uptake and metabolism in sympathetic nerve endings. The drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglycol. Norepinephrine metabolites are excreted in urine primarily as the sulfate conjugates and, to a lesser extent, as the glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged.

来源:Hazardous Substances Data Bank (HSDB)

代谢

尿素毒素倾向于通过饮食过量或肾脏过滤不良在血液中积聚。大多数尿素毒素是代谢废物，通常通过尿液或粪便排出。

Uremic toxins tend to accumulate in the blood either through dietary excess or through poor filtration by the kidneys. Most uremic toxins are metabolic waste products and are normally excreted in the urine or feces.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

尿毒症毒素如去甲肾上腺素通过有机离子转运体（特别是OAT3）积极运输到肾脏中。尿毒症毒素水平的升高可以刺激活性氧种类的产生。这看起来是通过尿毒症毒素直接结合或抑制酶NADPH氧化酶（特别是肾脏和心脏中丰富的NOX4）（A7868）来介导的。活性氧种类可以诱导几种不同的DNA甲基转移酶（DNMTs），这些酶参与沉默一种名为KLOTHO的蛋白质。KLOTHO已被确定在抗衰老、矿物质代谢和维生素D代谢中具有重要作用。许多研究表明，在急性或慢性肾脏疾病中，由于局部活性氧种类水平升高，KLOTHO mRNA和蛋白水平会降低（A7869）。去甲肾上腺素通过作用于α-肾上腺素能受体而作为周围血管收缩剂。它也是心脏的正性肌力刺激剂，由于它在β-肾上腺素能受体上的活动，它还能扩张冠状动脉。

Uremic toxins such as noradrenalin are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (A7868). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (A7869). Norepinephrine functions as a peripheral vasoconstrictor by acting on alpha-adrenergic receptors. It is also an inotropic stimulator of the heart and dilator of coronary arteries as a result of it's activity at the beta-adrenergic receptors.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

去甲肾上腺素

Compound:norepinephrine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

去甲肾上腺素主要存在于交感神经组织中。该药物可以穿过胎盘，但不能穿过血脑屏障。

Norepinephrine localizes mainly in sympathetic nervous tissue. The drug crosses the placenta but not the blood-brain barrier.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服norepinephrine（去甲肾上腺素）在胃肠道被破坏，药物在皮下注射后吸收不良。静脉注射后，迅速出现升压反应。该药物作用时间短，停止输注后1-2分钟内升压作用停止。

Orally ingested norepinephrine is destroyed in the GI tract, and the drug is poorly absorbed after subcutaneous injection. After IV administration, a pressor response occurs rapidly. The drug has a short duration of action, and the pressor action stops within 1-2 minutes after the infusion is discontinued.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

去甲肾上腺素，像肾上腺素一样，口服给药无效，并且从皮下注射部位吸收不良。它在体内被同样的酶迅速灭活，这些酶可以使肾上腺素甲基化和氧化脱氨。正常情况下，尿液中会有少量存在。在患有嗜铬细胞瘤的患者中，排泄率可能会大幅增加。

Norepinephrine, like epinephrine, is ineffective when given orally and is absorbed poorly from sites of subcutaneous injection. It is rapidly inactivated in the body by the same enzymes that methylate and oxidatively deaminate epinephrine. Small amounts normally are found in the urine. The excretion rate may be greatly increased in patients with pheochromocytoma.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  T+
• 安全说明：
  S28,S36/37,S45
• 危险类别码：
  R26/27/28
• WGK Germany：
  3
• 海关编码：
  2922509090
• 危险品运输编号：
  UN 2811 6.1/PG 2
• 危险类别：
  6.1
• RTECS号：
  DN5950000
• 包装等级：
  II
• 储存条件：
  充氩气密封，并在4℃避光条件下保存。

SDS

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Section 1. Chemical Product and Company Identification
L-Norepinephrine
Common Name/
Trade Name
L-Norepinephrine

---

Section 3. Hazards Identification
Potential Acute Health Effects Very hazardous in case of ingestion. Slightly hazardous in case of skin contact (irritant), of eye contact (irritant),
of inhalation. Severe over-exposure can result in death.
Potential Chronic Health Effects CARCINOGENIC EFFECTS: Not available.
MUTAGENIC EFFECTS: Mutagenic for bacteria and/or yeast.
TERATOGENIC EFFECTS: Not available.
DEVELOPMENTAL TOXICITY: Not available.
The substance is toxic to cardiovascular system.
The substance may be toxic to muscle tissue.
Repeated or prolonged exposure to the substance can produce target organs damage. Repeated exposure to a
highly toxic material may produce general deterioration of health by an accumulation in one or many human
organs.

---

Section 4. First Aid Measures
Eye Contact Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at
least 15 minutes. Get medical attention if irritation occurs.
Skin Contact Wash with soap and water. Cover the irritated skin with an emollient. Get medical attention if irritation develops.
Not available.
Serious Skin Contact
If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen.
Inhalation
Get medical attention.
Serious Inhalation Evacuate the victim to a safe area as soon as possible. Loosen tight clothing such as a collar, tie, belt or
waistband. If breathing is difficult, administer oxygen. If the victim is not breathing, perform mouth-to-mouth
resuscitation. Seek medical attention.
Ingestion If swallowed, do not induce vomiting unless directed to do so by medical personnel. Never give anything by
mouth to an unconscious person. Loosen tight clothing such as a collar, tie, belt or waistband. Get medical
attention immediately.
Serious Ingestion Not available.

---

Section 5. Fire and Explosion Data
Flammability of the Product May be combustible at high temperature.
Not available.
Auto-Ignition Temperature
Not available.
Flash Points
Not available.
Flammable Limits
These products are carbon oxides (CO, CO2), nitrogen oxides (NO, NO2...).
Products of Combustion
Slightly flammable to flammable in presence of heat.
Fire Hazards in Presence of
Various Substances
Explosion Hazards in Presence of Risks of explosion of the product in presence of mechanical impact: Not available.
Various Substances Risks of explosion of the product in presence of static discharge: Not available.
SMALL FIRE: Use DRY chemical powder.
Fire Fighting Media
LARGE FIRE: Use water spray, fog or foam. Do not use water jet.
and Instructions
As with most organic solids, fire is possible at elevated temperatures
Special Remarks on
Fire Hazards
Fine dust dispersed in air in sufficient concentrations, and in the presence of an ignition source is a potential dust
Special Remarks on Explosion
explosion hazard.
Hazards
L-Norepinephrine

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Section 6. Accidental Release Measures
Use appropriate tools to put the spilled solid in a convenient waste disposal container.
Small Spill
Poisonous solid.
Large Spill
Stop leak if without risk. Do not get water inside container. Do not touch spilled material. Use water spray to
reduce vapors. Prevent entry into sewers, basements or confined areas; dike if needed. Eliminate all ignition

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Section 7. Handling and Storage
Keep away from heat. Keep away from sources of ignition. Ground all equipment containing material. Do not
Precautions
ingest. Do not breathe dust. Wear suitable protective clothing. If ingested, seek medical advice immediately and
show the container or the label. Keep away from incompatibles such as oxidizing agents, acids, alkalis.
Keep container tightly closed. Keep container in a cool, well-ventilated area. Do not store above -20°C (-4°F).
Storage
Freeze.

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Section 8. Exposure Controls/Personal Protection
Engineering Controls Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below
recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to
airborne contaminants below the exposure limit.
Personal Protection Safety glasses. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent.
Gloves.
Personal Protection in Case of a Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used
Large Spill to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist
BEFORE handling this product.
Exposure Limits Not available.

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Section 9. Physical and Chemical Properties
Physical state and appearance Solid. (Crystalline solid. Crystalline powder.) Not available.
Odor
Taste Not available.
Molecular Weight 169.18 g/mole
Off-white.
Color
Not available.
pH (1% soln/water)
Not available.
Boiling Point
Melting Point 220°C (428°F)
Critical Temperature Not available.
Not available.
Specific Gravity
Not applicable.
Vapor Pressure
Vapor Density Not available.
Not available.
Volatility
Not available.
Odor Threshold
Water/Oil Dist. Coeff. Not available.
Ionicity (in Water) Not available.
Not available.
Dispersion Properties
Not available.
Solubility
L-Norepinephrine

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Section 10. Stability and Reactivity Data
The product is stable.
Stability
Instability Temperature Not available.
Conditions of Instability Excess heat, incompatible materials
Reactive with oxidizing agents, acids, alkalis.
Incompatibility with various
substances
Not available.
Corrosivity
Not available.
Special Remarks on
Reactivity
Not available.
Special Remarks on
Corrosivity
Polymerization Will not occur.

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Section 11. Toxicological Information
Routes of Entry Inhalation. Ingestion.
Toxicity to Animals Acute oral toxicity (LD50): 20 mg/kg [Mouse].
Chronic Effects on Humans MUTAGENIC EFFECTS: Mutagenic for bacteria and/or yeast.
Causes damage to the following organs: cardiovascular system.
May cause damage to the following organs: muscle tissue.
Other Toxic Effects on Humans Very hazardous in case of ingestion.
Slightly hazardous in case of skin contact (irritant), of inhalation.
Special Remarks on Not available.
Toxicity to Animals
Human: passes the placental barrier.
Special Remarks on
May cause adverse reproductive effects and birth defects (teratogenic).
Chronic Effects on Humans
May affect genetic material (mutagenic)
Acute Potential Health Effects:
Special Remarks on other Toxic
Skin: May cause skin irritation.
Effects on Humans
Eyes: May cause eye irritation.
Inhalation: Dust may cause respiratory tract irritation.
Ingestion: May be fatal if swallowed. May cause nausea, vomiting, and hypersalivation. Affects the
cardiovascular system/heat (hypertension, dradycardia, arrhythmias, anginal pain, palpitations, cardiac arrest,
sudden death. May affect metabolism (altered glucose metabolism). May affect the blood (aggregated pltelets
and occlusive platelet thrombi), behavior/central nervous system (fear, anxiety, restlessness, tremor, insomnia,
somnolence, muscle weakness, confusion, irritability, weakness, psychosis), kidneys (nephrotoxicity), respiration
(dyspnea).

---

Section 12. Ecological Information
Ecotoxicity Not available.
BOD5 and COD Not available.
Possibly hazardous short term degradation products are not likely. However, long term degradation products may
Products of Biodegradation
arise.
The products of degradation are less toxic than the product itself.
Toxicity of the Products
of Biodegradation
Not available.
Special Remarks on the
Products of Biodegradation
L-Norepinephrine

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Section 13. Disposal Considerations
Waste Disposal Waste must be disposed of in accordance with federal, state and local environmental
control regulations.

---

Section 14. Transport Information
DOT Classification CLASS 6.1: Poisonous material.
UNNA: 2811 : Toxic solid, organic, n.o.s(L-Norepinephrine) PG: II
Identification
Not available.
Special Provisions for
Transport
DOT (Pictograms)

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Section 15. Other Regulatory Information and Pictograms
Federal and State No products were found.
Regulations
California California prop. 65: This product contains the following ingredients for which the State of California has found to
cause cancer which would require a warning under the statute: No products were found.
Proposition 65
Warnings
California prop. 65: This product contains the following ingredients for which the State of California has found to
cause birth defects which would require a warning under the statute: No products were found.
OSHA: Hazardous by definition of Hazard Communication Standard (29 CFR 1910.1200).
Other Regulations
EINECS: This product is on the European Inventory of Existing Commercial Chemical Substances.
CLASS D-1A: Material causing immediate and serious toxic effects (VERY TOXIC).
Other Classifications WHMIS (Canada)
DSCL (EEC) R28- Very toxic if swallowed. S28- After contact with skin, wash immediately
with plenty of water
S36/37- Wear suitable protective clothing and
gloves.
S45- In case of accident or if you feel unwell,
seek medical advice immediately (show the
label where possible).
Health Hazard
HMIS (U.S.A.) 3 National Fire Protection
1 Flammability
1 Association (U.S.A.)
Fire Hazard
3 0 Reactivity
Health
Reactivity
0
Specific hazard
Personal Protection
E
WHMIS (Canada)
(Pictograms)
DSCL (Europe)
(Pictograms)
L-Norepinephrine
TDG (Canada)
(Pictograms)
ADR (Europe)
(Pictograms)
Protective Equipment
Gloves.
Lab coat.
Dust respirator. Be sure to use an
approved/certified respirator or equivalent.
Wear appropriate respirator when
ventilation is inadequate.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

根据您提供的信息,肾上腺素(去甲肾上腺素)的生产方法如下:

1. 首先由邻苯二酚与氯乙酰氯反应生成3,4-二羟基-2-氯代苯乙酮。

2. 然后该中间体再与氨或乌洛托品作用,从而制得肾上腺素。

这个合成路线简洁明了,原料较为常见且易得。主要步骤包括:

1. 邻苯二酚的氯代反应生成目标中间体。
2. 中间体与氨基化合物(如氨或乌洛托品)的偶联反应完成最终产品制备。

这种方法具有较好的工业化生产可行性,能够满足大规模制药需求。

需要注意的是,实际生产中还需要考虑催化剂的选择、反应条件优化等问题。此外,由于肾上腺素属于管制药品,其生产和销售需要严格遵守相关法律法规和标准要求。

这种合成方法体现了化学制药工业中的经典反应类型,也是有机合成学习中的重要案例之一。

反应信息

• 作为反应物：
  描述：

  去甲肾上腺素 在 (R)-epinephrine dehydrogenase 、 还原型辅酶Ⅰ 作用下， 以 aq. phosphate buffer 为溶剂， 生成 2-氨基-1-(3,4-二羟基苯基)乙烷-1-酮
  参考文献：
  名称：

  Purification and characterization of a novel carbonyl reductase involved in oxidoreduction of aromatic β-amino ketones/alcohols

  摘要：

  Aromatic beta-amino ketones/alcohols such as adrenalone play an important role in some stereoselective synthesis of pharmaceuticals. Unfortunately, the transformation of aromatic beta-amino ketones to their chiral alcohols has been carried out chemically as no corresponding biocatalyst has been available. Here, a novel carbonyl reductase responsible for the reduction of adrenalone to (R)-(-)-epinephrine was identified and characterized from Kocuria rhizophila. This enzyme was purified to homogeneity by ammonium sulfate precipitation followed by ion-exchange column chromatography, hydrophobic chromatography and gel chromatography. The purified enzyme yielded pure (R)-enantiomer product with high activity and utilized NADH as the cofactor. The enzyme had special significance by showing selectivity for many aromatic beta-amino ketones/alcohols such as 2-amino-acetophenone, 2-amino-4'-hydroxyacetophenone, isoproterenol and ephedrine. The maximum reaction rate (V-max) and apparent Michaelis-Menten constant (K-m) for adrenalone and NADH were 14.62 mu mol/(min mg) protein and 0.189 mM, 11.66 mu mol/(min mg) protein and 0.204 mM respectively. These properties ensure the enzyme a promising future for industrial application as a replacement of chemical synthesis of aromatic beta-amino chiral alcohols. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.procbio.2014.03.023
• 作为产物：
  描述：

  左旋多巴 在 phenylalanine decarboxylase 、 dopamine β-hydroxylase 、 氧气 、 维生素 C 作用下， 生成 去甲肾上腺素
  参考文献：
  名称：

  플라즈마 중합을 이용한 폴리도파민 합성방법

  摘要：

  本发明涉及利用等离子体聚合法制备儿茶酚胺类化合物的方法，具体而言，利用干法等离子体聚合法从苯酚（phenol）或苯胺（aniline）等儿茶酚前体物质制备各种儿茶酚，即具有苯环的邻位（ortho）-羟基（-OH）和对位（para）-羟基的各种烷基胺的单分子化合物的方法。

  公开号：

  KR20150094532A
• 作为试剂：
  描述：

  tris[triphenylphosphinegold(I)]oxonium tetrafluoroborate 在 去甲肾上腺素 作用下， 以 乙腈 为溶剂， 反应 0.05h， 生成 gold
  参考文献：
  名称：

  In situ derivatization of Au nanoclusters via aurophilic interactions of a triphenylphosphine gold(i) salt with neurotransmitters and their rapid MALDI-TOF-MS detection in mice brain tissue extracts

  摘要：

  使用三苯基膦金（i）盐作为高效基质，在小鼠脑组织提取物中快速检测神经递质的MALDI-TOF-MS。

  DOI：

  10.1039/c9tb01800j

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、-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] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• Dual Pharmacophores - PDE4-Muscarinic Antagonistics
  申请人：Callahan James Francis

  公开号：US20090203657A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use as dual chromaphores having inhibitory activity against PDE4 and muscarinic acetylcholine receptors (mAChRs), and thus being useful for treating respiratory diseases.

  本发明涉及具有式（I）的新化合物及其药用盐，药物组合物及其用作对PDE4和肌胆碱受体（mAChRs）具有抑制活性的双色素，因此可用于治疗呼吸道疾病。
• [EN] DUAL PHARMACOPHORES - PDE4-MUSCARINIC ANTAGONISTICS<br/>[FR] PHARMACOPHORES DUALS, ANTAGONISTES DES RÉCEPTEURS MUSCARINIQUES ET INHIBITEURS DE L'ACTIVITÉ PDE4
  申请人：GLAXO GROUP LTD

  公开号：WO2009100169A1

  公开（公告）日：2009-08-13

  The present invention is directed to novel compounds of Formula's (I) - (VI), and pharmaceutically acceptable salts thereof, pharmaceutical compositions and their use in therapy, for example as inhibitors of phosphodiesterase type IV (PDE4) and as antagonists of muscarinic acetylcholine receptors (mAChRs), in the treatment of and/or prophylaxis of respiratory diseases, including inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis (e.g. allergic rhinitis), atopic dermatitis or psoriasis.

  本发明涉及式(I) - (VI)的新化合物，以及其药学上可接受的盐、药物组合物及其在治疗中的应用，例如作为磷酸二酯酶IV (PDE4)的抑制剂和肌碱乙酰胆碱受体 (mAChRs)的拮抗剂，用于治疗和/或预防呼吸道疾病，包括炎症性和/或过敏性疾病，如慢性阻塞性肺病（COPD）、哮喘、鼻炎（例如过敏性鼻炎）、特应性皮炎或银屑病。