恩他卡朋 | 130929-57-6

• 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 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 中文名称: 恩他卡朋
• 中文别名: (2E)-2-氰基-3-(3,4-二羟基-5-硝基苯基)-N,N-二乙基-2-丙烯酰胺；安托卡朋F·S；(E)-2-氰基-3-(3,4-二羟基-5-硝基苯基)-N,N-二乙基-2-丙烯酰胺；安托卡朋；(E)-2-氰基-3-(3,4二羟基-5-硝基苯)-N,N二乙基丙烯酰胺
• 英文名称: entacapone
• 英文别名: (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide；(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide；(2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide；(E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide；(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide
• CAS: 130929-57-6
• 化学式: C₁₄H₁₅N₃O₅
• 分子量: 305.29
• InChiKey: JRURYQJSLYLRLN-BJMVGYQFSA-N

物化性质

• 熔点：
  162-1630C
• 沸点：
  526.6±50.0 °C(Predicted)
• 密度：
  1.392±0.06 g/cm3(Predicted)
• 溶解度：
  在DMSO中的溶解度为20mg/mL，澄清
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from acetic acid + hydrochloric acid
• 蒸汽压力：
  3.25 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 解离常数：
  pKa1 = 5.95 (primary phenol); pKa2 = 10.41 (secondary phenol) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

通过异构化转化为顺式异构体，然后是母体和顺式异构体的直接葡萄糖醛酸化。

Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.

来源:DrugBank

代谢

在大鼠和狗中，恩他卡朋的代谢物主要随粪便排出（三分之二为葡萄糖苷酸或硫酸盐结合物），三分之一随尿液排出，未改变的恩他卡朋剂量少于1.5%。在第一小时内，约30-45%的剂量在胆汁中回收，其中大约10%的放射性物质通过肠肝循环。

In rats and dogs, entacapone metabolites are predominantly excreted in the feces (two thirds as glucuronide or sulfate conjugates) and one third in the urine with less than 1.5% of the dose as unchanged entacapone. After the first hour 30-45% of the dose was recovered in the bile, with an enterohepatic circulation accounting for about 10% of the given radioactivity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Entacapone在所有物种的肝脏中广泛代谢，包括人类，主要的代谢途径是葡萄糖醛酸化、硫酸化和由（E）-异构体到（Z）-异构体（活性代谢物）的异构化。跨物种的类似途径包括侧链C-C双键的还原（在大鼠和人体中不太重要）和对3,4-二羟基-5-硝基苯甲醛的水解。差异在于酰胺N-脱烷基化、硝基还原和O-甲基化（仅在大鼠中），酰胺水解和腈水解（仅在狗中）以及二乙酰胺组中一个乙基基团的氧化水解（仅在人中）。

Entacapone is extensively metabolised in the liver in all species including humans, the main metabolic pathway being glucuronidation, sulfation and isomerisation from (E)- to (Z)-isomer (active metabolite). Similar pathways across species are the reduction of the C-C double bond of the side chain (less important in rat and in man) and the hydrolysis to 3,4-dihydroxy-5-nitrobenzaldehyde. The dissimilarities consists of amide N-dealkylation, nitro reduction and O-methylation (only in rats), amide hydrolysis and nitrile hydrolysis (only in dogs) and oxidative hydrolysis of one of the ethyl groups of the diethylamide group (only in man).

来源:Hazardous Substances Data Bank (HSDB)

代谢

Entacapone在排泄前几乎完全代谢，只有极少量（剂量的0.2%）以原形出现在尿液中。主要的代谢途径是异构化为顺式异构体，然后是母体和顺式异构体的直接葡萄糖醛酸化；葡萄糖醛酸苷结合物是无效的。

Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Entacapone 经历广泛的代谢，主要在肝脏进行。Entacapone 在人体内的主要代谢途径是异构化为顺式异构体，随后是母体和顺式异构体的直接葡萄糖醛酸化；葡萄糖醛酸苷结合物是无效的。

Entacapone undergoes extensive metabolism, mainly in the liver. The main metabolic pathway of entacapone in humans is the isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：恩他卡朋是一种选择性和可逆性的儿茶酚-O-甲基转移酶（COMT）抑制剂，用于辅助左旋多巴和卡比多巴治疗帕金森病患者出现的剂量末期“失效”现象。人类暴露和毒性：上市后数据显示，有几例过量服用的情况。报告的最高恩他卡朋剂量至少为40,000毫克。在这些病例中常见的急性症状和体征包括嗜睡和活动减少，与意识水平降低相关的状态（昏迷、混乱和定向障碍）以及皮肤、舌头和尿液的变色，以及不安、激越和攻击性。恩他卡朋治疗对儿茶酚-O-甲基转移酶（COMT）的抑制是剂量依赖性的。理论上，大量过量的恩他卡朋可能在人类中产生100%的COMT酶抑制，从而阻止内源性和外源性儿茶酚的代谢。上市后报告还表明，患者在恩他卡朋治疗期间或开始治疗或增加剂量后，可能会经历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。因此，患有主要精神病的患者通常不应使用恩他卡朋，因为可能会加剧精神病。恩他卡朋在存在代谢激活的情况下，对培养的人淋巴细胞具有断裂作用。动物研究：大鼠通过口服灌胃，每天以20、90或400 mg/kg的剂量接受恩他卡朋治疗两年。在最高剂量治疗的雄性大鼠中发现了肾小管腺瘤和癌的增加。在大鼠和兔中以高达1000 mg/kg/天和300 mg/kg/天的剂量进行了繁殖研究。在最高剂量治疗的大鼠后代中明显出现了胎儿变异的增加，而在母体毒性不明显的情况下。在母体毒性剂量为100 mg/kg/天或以上的兔后代中观察到了流产和晚期/总吸收率的增加以及胎儿体重的减少。在这些研究中没有发现致畸性。当恩他卡朋在交配前和早期妊娠期间给予雌性大鼠时，在母体毒性不明显的情况下，以160 mg/kg/天或更高剂量治疗的母鼠后代中，胎儿眼部异常（巨眼症、小眼症和无眼症）的发生率增加。在妊娠后期和整个哺乳期间给予雌性大鼠高达700 mg/kg/天的剂量，没有发现后代发育受损的证据。恩他卡朋在以高达700 mg/kg/天的剂量治疗的大鼠中，没有损害生育力或一般生殖性能。在以700 mg/kg/天的剂量治疗的雌性大鼠中，出现了延迟交配，但没有生育力损害。恩他卡朋在小鼠淋巴瘤tk体外试验中，在存在和不存在代谢激活的情况下，都具有突变和断裂作用。恩他卡朋单独使用或与左旋多巴和卡比多巴联合使用，在小鼠体内微核试验中没有断裂作用，在细菌反向突变试验（Ames试验）中也没有突变作用。

IDENTIFICATION AND USE: Entacopone, a selective and reversible inhibitor of catechol-O-methyl-transfersase (COMT) is used as an adjunct to levodopa and carbidopa to treat end-of-dose "wearing-off" in patients with Parkinson's disease. HUMAN EXPOSURE AND TOXICITY: The postmarketing data include several cases of overdose. The highest reported dose of entacapone was at least 40,000 mg. The acute symptoms and signs commonly seen in these cases included somnolence and decreased activity, states related to depressed level of consciousness (coma, confusion and disorientation) and discolorations of skin, tongue, and urine, as well as restlessness, agitation, and aggression. Catechol-O-methyltransferase (COMT) inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in humans, thereby preventing the metabolism of endogenous and exogenous catechols. Postmarketing reports also indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during entacapone treatment or after starting or increasing the dose of entacapone. Therefore, patients with a major psychotic disorder should ordinarily not be treated with entacapone because of the risk of exacerbating psychosis. Entacapone was clastogenic in cultured human lymphocytes in the presence of metabolic activation. ANIMAL STUDIES: Rats were treated for two years with entacapone at daily doses of 20, 90, or 400 mg/kg by oral gavage. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose. Reproduction studies have been performed in rats and rabbits at doses up to 1000 mg/kg/day and 300 mg/kg/day, respectively, of entacapone. Increased incidence of fetal variations was evident in litters from rats treated at the highest dose in the absence of overt maternal toxicity. Increased frequencies of abortion and late/total resorptions and decreased fetal weights were observed in litters of rabbits treated with maternotoxic doses of 100 mg/kg/day or greater. There was no evidence of teratogenicity in these studies. When entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, and anophthalmia) was observed in litters of dams treated with doses of 160 mg/kg/day or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day to female rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairments in the offspring. Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg/kg/day. Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg/kg/day of entacapone. Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation. Entacapone, either alone or in combination with levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

entacapone的作用机制被认为是通过其抑制外周组织中COMT的能力，改变左旋多巴的血浆药代动力学。当entacapone与左旋多巴和一种芳香族氨基酸脱羧酶抑制剂（如卡比多巴）联合使用时，血浆中左旋多巴的水平比单独使用左旋多巴和芳香族氨基酸脱羧酶抑制剂后更高且更持久。据信，在给定的左旋多巴给药频率下，这些更持久的左旋多巴血浆水平导致大脑中多巴胺能刺激更加恒定，从而在减少帕金森病症状方面带来更大的效果。

The mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to a greater reduction in the manifestations of parkinsonian syndrome.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

恩他卡朋治疗仅与0.3%至0.5%的患者血清转氨酶升高（超过正常上限的3倍）有关，这与接受安慰剂的对象的比例相似或略高。这些升高通常是暂时的和无症状的，很少需要调整剂量。在初步的临床试验中，没有报告出现临床明显的严重肝损伤和黄疸。随后，赞助商收到了个别肝毒性的报告，损伤发生在开始恩他卡朋治疗后的2到6周，表现为轻度黄疸和胆汁淤积性肝酶升高模式，并在停药后迅速恢复。免疫过敏和自身免疫特征未出现。损伤的临床表型和相关特征尚未在任何细节中报告。因此，恩他卡朋可能会罕见地引起临床明显的肝损伤，但它并未与托卡朋诱导的肝损伤中特征的严重肝炎和急性肝衰竭病例相关联。

Entacapone therapy has been associated with serum aminotransferase elevations (above 3 times the upper limit of normal) in only 0.3% to 0.5% of patients, which is similar or minimally higher than the rate in subjects receiving placebo. The elevations were usually transient and asymptomatic and rarely required dose adjustment. In preliminary clinical trials, there were no reports of clinically apparent serious liver injury with jaundice. Subsequently, isolated instances of hepatotoxicity have been reported to the sponsor, injury arising 2 to 6 weeks after starting entacapone with mild jaundice and cholestatic pattern of liver enzyme elevations, and rapid recovery on stopping. Immunoallergic and autoimmune features were not present. The clinical phenotype of injury and associated features have not been reported in any detail. Thus, entacapone may rarely cause clinically apparent liver injury, but it has not been associated with the severe hepatitis and acute liver failure that characterized cases of tolcapone induced liver injury.

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：恩他卡朋

Compound:entacapone

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

吸收、分配和排泄

• 吸收

Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.

Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Entacapone在排泄前几乎完全被代谢，只有非常少量的原形药物（剂量的0.2%）在尿液中未发生变化。由于大约只有10%的Entacapone剂量以原化合物和结合的葡萄糖醛酸苷形式在尿液中排出，胆汁排泄似乎是这种药物的主要排泄途径。

Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

20升

20 L

来源:DrugBank

吸收、分配和排泄

• 清除

每分钟850毫升

850 mL/min

来源:DrugBank

吸收、分配和排泄

在大鼠和人体中，绝对生物利用度随剂量而变化，在大鼠单次给药10、65和400 mg/kg时，生物利用度范围从20%到55%，而在人体单次给药5、25、50、100、200、400和800 mg时，生物利用度范围从29%到49%。

In rats and in humans, the absolute bioavailability was dose-dependent and ranged from 20% to 55%, following single dose of 10, 65 and 400 mg/kg, in rats and from 29% to 49%, following single dose of 5, 25, 50, 100, 200, 400 and 800 mg, in humans.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  1
• 海关编码：
  2942000000
• 安全说明：
  S16,S26,S36,S36/37/39,S39,S45
• 危险品运输编号：
  UN 1986 3/PG 3
• 危险类别：
  3
• 危险品标志：
  Xn,F,T
• 危险类别码：
  R20/21/22,R38,R36/37/38,R10,R37/38,R62,R41
• RTECS号：
  KM5250000
• 包装等级：
  III
• 危险性防范说明：
  P261,P273,P305+P351+P338
• 危险性描述：
  H315,H319,H335,H413
• 储存条件：
  |-20°C冷冻库|

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Entacapone
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: Entacapone
CAS number: 130929-57-6

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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: C14H15N3O5
Molecular weight: 305.3

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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.

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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

抗帕金森病药

恩他卡朋是一种抗帕金森病药物，由瑞典Orion Pharma公司研发。它是一种高选择性强效儿茶酚氧位甲基转移酶（COMT）抑制剂，主要在肠道起作用，很少穿透血-脑脊液屏障。恩他卡朋通过剂量相关性地降低血清和脑的3-OMD水平，并提高脑中左旋多巴、多巴胺和DOPAC的水平，显著减少提高纹状体多巴胺浓度所需的剂量。与左旋多巴及卡比多巴合用时，能显著增加左旋多巴的生物利用度（约3～4倍）。在800mg剂量下，恩他卡朋可最大抑制红细胞中COMTI活性达82%，因此可用于原发性帕金森病的辅助治疗。

药动学

口服后，恩他卡朋迅速被吸收，生物利用度呈剂量依赖性（30%～45%）。在5～800mg范围内，药动学表现为线性关系，血浆峰浓度与AUC和剂量相关。食物不影响其吸收，98%的恩他卡朋与血浆中的白蛋白结合，在组织中分布较少。帕金森病患者同时服用左旋多巴/卡比多巴时，1～2小时内可观察到恩他卡朋的峰浓度。该药物透过血脑屏障率低，血浆消除半衰期为1.5～3.5小时。口服后，恩他卡朋（E-构型）在血液中代谢成Z-异构体，并存在于血浆和红细胞中。Z-异构体对临床疗效影响不大，其药-时曲线与恩他卡朋极为相似。在健康人及帕金森病患者中，恩他卡朋能增加左旋多巴的生物利用度，在短期服用的PD患者中AUC可增加25%，长期服用则可增加到50%。3-OMD的AUC相对减少60%。单剂量服用恩他卡朋在肝病患者中的AUC和Cmax是正常肝功能患者的两倍，因此需调整用药剂量；而在轻度或中度肾病患者中无需调整剂量，在接受透析的肾病患者中可延长给药间隔。

不良反应

恩他卡朋常见不良反应包括腹泻、帕金森症状加重及体位性低血压。有时尿液会变成红棕色，但这种现象无害。罕见有肝酶升高；大剂量使用时可能出现中枢神经系统反应，如幻觉、谵妄及精神病样反应。

生物活性

恩他卡朋（OR-611）抑制儿茶酚-O-甲基转移酶（COMT）活性，IC50为151 nM。它是FTO去甲基化的一种抑制剂，IC50值为3.5 μM，可用于代谢研究。

化学性质

恩他卡朋是一种结晶体，熔点为162～163℃。

用途

恩他卡朋作为一种COMT抑制剂，用于治疗帕金森病。

生产方法

以3,4-二羟基-5-硝基苯甲醛和N,N-二乙基氰基乙酰胺（催化剂为哌啶乙酸盐）溶于干燥乙醇中搅拌过夜制备粗品，熔点153～156℃。在90℃下加热溶解粗品，缓慢冷却后过滤收集结晶，用冷甲苯洗并在45℃真空下干燥，得纯恩他卡朋，熔点162～163℃。

反应信息

• 作为反应物：
  描述：

  恩他卡朋 在 盐酸 作用下， 以 丙酮 、 乙腈 为溶剂， 反应 22.0h， 生成 methyl (2S)-2-[[5-[(E)-2-cyano-3-(diethylamino)-3-oxoprop-1-enyl]-2-hydroxy-3-nitrophenoxy]carbonylamino]-3-(3,4-dihydroxyphenyl)propanoate
  参考文献：
  名称：

  Design and Synthesis of a Novel L-Dopa−Entacapone Codrug

  摘要：

  A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate codrug provides adequate stability [t(1/2) = 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t(1/2) = 7 min; pH 7.4) at 37 degreesC. The therapeutical potential of this novel codrug is discussed.

  DOI：

  10.1021/jm010980d
• 作为产物：
  描述：

  N,N-diethyl-2-cyano-3-(3-ethoxy-4-hydroxy-5-nitrophenyl)acrylamide 在 吡啶 、 aluminum (III) chloride 作用下， 以 二氯甲烷 为溶剂， 反应 50.0h， 以87.3%的产率得到恩他卡朋
  参考文献：
  名称：

  [EN] IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE
  [FR] PROCEDE AMELIORE DE PREPARATION DE L'ENTACAPONE

  摘要：

  这份申请中披露的发明涉及一种改进的恩他卡朋的制备过程，包括：(i)在温度范围为50-115°C的条件下，在温和酸性催化剂和溶剂的存在下，将3-烷氧基-4-羟基-5-硝基苯甲醛与N,N-二乙基氨基氰基乙酰胺反应，得到3-O-烷基化（甲基或乙基）恩他卡朋，并在有机碱和溶剂存在的条件下，在20-60°C的温度范围内用酸性催化剂处理，得到恩他卡朋。

  公开号：

  WO2005063693A1
• 作为试剂：
  描述：

  3,4-二羟基-5-硝基苯甲醛 、 、 2-氰基-N,N-二乙基乙酰胺 、 、 甲苯 、 乙酸乙酯 在 恩他卡朋 作用下， 以 哌啶乙酸盐 为溶剂， 以to obtain crude Entacapone i.e. N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide of formula (IV) with high yield的产率得到entacapone
  参考文献：
  名称：

  Process for the preparation of (E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide (entacapone)

  摘要：

  本发明涉及一种改进的制备(E)-N,N-二乙基-2-氰基-3-(3,4-二羟基-5-硝基苯基)丙烯酰胺式(I)的方法，包括以下步骤：(a) 在存在催化剂和可选的相转移催化剂的溶剂中，将式(II)的3,4-二羟基-5-硝基苯甲醛与式(III)的N,N-二乙基氰乙酰胺缩合，所选溶剂包括乙酸乙酯、乙腈、烃类如甲苯、二甲苯等或其混合物，从而得到(E)和(Z)异构体的混合物，式为(IV)。(b) 在催化剂量下，在溶剂中处理步骤(a)中得到的(E)和(Z)异构体的混合物的卤素，从而得到(E)-N,N-二乙基-2-氰基-3-(3,4-二羟基-5-硝基苯基)丙烯酰胺式(I)。

  公开号：

  US20060258877A1

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。
• 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。
• [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。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。