纳曲酮 | 16590-41-3

• 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 - 苯类化合物 - 菲及其衍生物
• 中文名称: 纳曲酮
• 中文别名: 纳屈酮；17-(环丙甲基)-4,5-环氧-3,14-二羟基吗啡烷-6-酮
• 英文名称: Naltrexone
• 英文别名: NTX；(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
• CAS: 16590-41-3
• 化学式: C₂₀H₂₃NO₄
• 分子量: 341.407
• InChiKey: DQCKKXVULJGBQN-XFWGSAIBSA-N

物化性质

• 熔点：
  168-170°
• 沸点：
  477.03°C (rough estimate)
• 密度：
  1.2064 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from acetone
• 蒸汽压力：
  3.11X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Naltrexone hydrochloride/
• 分解：
  Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas. /Naltrexone hydrochloride/
• 解离常数：
  pKa1 (for the proton on the nitrogen) = 8.38; pKa2 (for the phenolic hydrogen) = 9.93, at 20 °C /Naltrexone hydrochloride/
• 碰撞截面：
  176.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  70
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

肝脏。当口服给药时，纳曲酮经历广泛的生物转化，并代谢为6-β-纳曲醇（这可能有助于治疗效果）和其他次要代谢物。

Hepatic. When administered orally, naltrexone undergoes extensive biotransformation and is metabolized to 6 beta-naltrexol (which may contribute to the therapeutic effect) and other minor metabolites.

来源:DrugBank

代谢

纳曲酮主要在肝脏中通过将纳曲酮的6-酮基团还原为6-β-纳曲醇（6-β-羟基纳曲酮）来代谢。纳曲酮还通过儿茶酚-O-甲基转移酶（COMT）代谢，形成2-羟基-3-甲氧基-6-β-纳曲醇（HMN）和2-羟基-3-甲氧基纳曲酮。还鉴定出了几种次要代谢物，包括去甲氧吗啡和3-甲氧基-6-β-纳曲醇。由于纳曲酮口服给药而非肌内注射给药会导致药物在首次通过肝脏时大量代谢，因此肌内注射给药后6-β-纳曲醇的浓度远低于口服给药后获得的代谢物浓度。经过慢性给药后，纳曲酮似乎不会抑制或诱导其自身的代谢。细胞色素P-450（CYP）同工酶不参与纳曲酮的代谢。纳曲酮及其代谢物与葡萄糖醛酸发生结合反应。在血浆和尿液中的总药物和代谢物的主要部分是由结合的代谢物组成。药物及其代谢物可能发生肠肝循环。

Naltrexone is metabolized in the liver principally by reduction of the 6-keto group of naltrexone to 6-beta-naltrexol (6-beta-hydroxynaltrexone). Naltrexone also undergoes metabolism by catechol-O-methyl transferase (COMT) to form 2-hydroxy-3-methoxy-6-beta-naltrexol (HMN) and 2-hydroxy-3-methoxynaltrexone. Several minor metabolites have also been identified, including noroxymorphone and 3-methoxy-6-beta-naltrexol. Because oral but not im administration of naltrexone results in substantial first-pass hepatic metabolism of the drug, 6-beta-naltrexol concentrations following im administration are substantially lower than concentrations of the metabolite obtained following oral administration. Naltrexone does not appear to inhibit or induce its own metabolism following chronic administration. Cytochrome P-450 (CYP) isoenzymes are not involved in the metabolism of naltrexone. Naltrexone and its metabolites undergo conjugation with glucuronic acid. The major fraction of total drug and metabolites in both plasma and urine consists of conjugated metabolites. The drug and its metabolites may undergo enterohepatic circulation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

纳曲酮的代谢物可能有助于该药物的阿片拮抗剂活性。与纳曲酮一样，6-β-纳曲醇是一种基本上纯粹的阿片拮抗剂，其在大鼠中引发对吗啡生理依赖的撤退症状的效力为纳曲酮的6-8%，在小鼠中为纳曲酮的1.25-2%。由于2-羟基-3-甲氧基-6-β-纳曲醇（HMN）对阿片受体的亲和力较弱，它可能不会显著贡献纳曲酮的阿片拮抗剂活性；然而，HMN或2-羟基-3-甲氧基纳曲酮的体内阿片拮抗剂活性尚未研究。纳洛西摩芬，纳曲酮的一个次要代谢物，是一种强效的阿片激动剂，可能是接受纳曲酮治疗的人偶尔出现的激动剂活性（例如，瞳孔缩小）的原因。

Metabolites of naltrexone may contribute to the opiate antagonist activity of the drug. Like naltrexone, 6-beta-naltrexol is an essentially pure opiate antagonist, with a potency of 6-8% that of naltrexone in precipitating withdrawal symptoms in dogs physically dependent on morphine and 1.25-2% that of naltrexone in mice. Because of its weak affinity for opiate receptors, 2-hydroxy-3-methoxy-6-beta-naltrexol (HMN) may not contribute appreciably to the opiate antagonist activity of naltrexone; however, the in vivo opiate antagonist activity of HMN or 2-hydroxy-3-methoxynaltrexone has not been studied. Noroxymorphone, a minor metabolite of naltrexone, is a potent opiate agonist and may be responsible for the agonist activity (eg, miosis) that occurs infrequently in individuals receiving naltrexone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

纳曲酮及其代谢物（未结合和结合的）主要通过肾小球滤过在尿液中排泄；6-β-纳曲醇、结合的6-β-纳曲醇和结合的纳曲酮也通过肾小管分泌排泄。纳曲酮还可能通过肾小管部分重吸收。在单次或多次口服纳曲酮氢氯酸盐后，分别大约有38-60%或70%的剂量在尿液中回收，主要作为6-β-纳曲醇（结合和未结合的）。口服给药后，大部分纳曲酮的尿液排泄发生在前4小时内。在24小时内，口服给药剂量中不到2%以未改变的形式在尿液中排泄。在24小时内，大约5-10%、19-35%、7-16%、3.5-4.6%和0.45%的口服剂量分别以结合的纳曲酮、6-β-纳曲醇、结合的6-β-纳曲醇、2-羟基-3-甲氧基-6-β-纳曲醇（HMN）和2-羟基-3-甲氧基纳曲酮的形式在尿液中排泄。在单次或多次口服给药后的24小时内，少于5%的剂量在粪便中排泄，主要是6-β-纳曲醇。在一例患者口服50毫克放射性标记的纳曲酮后，大约93%的放射性标记剂量在133小时内排泄；大约79%和14%分别通过尿液和粪便排泄。

Naltrexone and its metabolites (unconjugated and conjugated) are excreted principally in urine via glomerular filtration; 6-beta-naltrexol, conjugated 6-beta-naltrexol, and conjugated naltrexone are also excreted via tubular secretion. Naltrexone may also undergo partial reabsorption by the renal tubules. Following single- or multiple-dose oral administration of naltrexone hydrochloride, respectively, approximately 38-60 or 70% of a dose has been recovered in urine, principally as 6-beta-naltrexol (conjugated and unconjugated). Most urinary excretion of naltrexone occurs within the first 4 hours after oral administration. Less than 2% of an orally administered dose is excreted unchanged in urine within 24 hours. Approximately 5-10, 19-35, 7-16, 3.5-4.6, and 0.45% of an oral dose are excreted in urine as conjugated naltrexone, 6-beta-naltrexol, conjugated 6-beta-naltrexol, 2-hydroxy-3-methoxy-6-beta-naltrexol (HMN), and 2-hydroxy-3-methoxynaltrexone, respectively, within 24 hours. Less than 5% of a dose is excreted in feces, principally as 6-beta-naltrexol, within 24 hours following single- or multiple-dose oral administration of the drug. Following oral administration of 50 mg of radiolabeled naltrexone in one patient, approximately 93% of the radiolabeled dose was excreted within 133 hours; about 79 and 14% were excreted in urine and feces, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在给予纳曲酮缓释注射剂后，纳曲酮和6-β-纳曲醇的半衰期是5-10天。

Following im administration of naltrexone extended-release injection, the half-life of naltrexone and 6-beta-naltrexol is 5-10 days.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：纳曲酮是一种阿片类药物拮抗剂。它也用于治疗酒精依赖。纳曲酮盐酸盐被美国食品和药物管理局（FDA）指定为维持阿片类药物戒断的孤儿药。人体研究：纳曲酮与阿片类药物受体竞争，并从这些受体上取代阿片类药物，从而逆转它们的效果。它能够拮抗所有阿片类药物受体。纳曲酮在酒精依赖中的作用机制尚不清楚。在一项研究中，接受每日800毫克纳曲酮盐酸盐治疗长达一周的患者未表现出毒性迹象。然而，据报道，一些患者使用较低剂量时出现了肝毒性。在几个健康个体单次给予纳曲酮剂量高达784毫克（作为缓释注射剂）后，未观察到严重的不良反应。纳曲酮与美沙酮暴露的新生儿中观察到的高新生儿死亡率和先天性异常无关。体外暴露于纳曲酮的人类淋巴细胞发生了诱变变化和染色体损伤。动物研究：小鼠、大鼠和狗对纳曲酮的急性毒性导致因强直阵挛性癫痫和/或呼吸衰竭而死亡。在猴子皮下注射100毫克/千克剂量的纳曲酮后，出现了体重下降，而在皮下注射300毫克/千克剂量后，出现了卧倒、癫痫和死亡。在猴子口服1克/千克剂量的纳曲酮后，出现了活动减少、流涎和呕吐，而在口服3克/千克剂量后，出现了癫痫和死亡。在未麻醉的狗静脉注射纳曲酮盐酸盐5-80微克/千克剂量后，出现了心动过缓，然而，在整个剂量范围内，呼吸频率、血压、动脉血气和脑电图均保持不变。在猫静脉注射1毫克/千克剂量后20分钟内，全脑氧气消耗量减少了约48%，全脑和脑桥的血流量减少了约40%。在一项为期2年的纳曲酮致癌潜力研究中，雄性大鼠的间皮瘤发生率增加，雌雄大鼠的血管来源肿瘤也增加。在几项为期2年的小鼠或大鼠纳曲酮剂量为每日30或100毫克/千克的其他研究中，未观察到致癌性证据。在大鼠中，每日100毫克/千克的纳曲酮剂量导致假孕增加和交配大鼠的怀孕率降低。纳曲酮在体内小鼠微核试验中未表现出致裂变性。在包括细菌、酵母或第二种哺乳动物细胞系的基因突变试验和染色体畸变试验在内的其他体外测试范围内，未观察到基因毒性潜力。然而，在中国仓鼠卵巢细胞、果蝇隐性致死试验以及使用大肠杆菌和WI-38细胞的非特异性DNA修复试验中，体外暴露于纳曲酮时发生了诱变变化和染色体损伤。生态毒性研究：为了评估季节（性腺成熟阶段）对内源性阿片肽在鱼类促黄体生成激素（LH）分泌调节作用的影响，将性成熟的雄性鲤鱼（Cyprinus carpio L.）在自然产卵期（6月）或性腺再生期（12月）静脉注射纳曲酮-阿片受体拮抗剂（5或50微克/千克）。在6月，纳曲酮显著降低了与注射生理盐水的雄性相比的LH水平。在12月，注射生理盐水与纳曲酮的鲤鱼之间没有差异。

IDENTIFICATION AND USE: Naltrexone is a narcotic antagonist. It is also used in the treatment of alcoholism. Naltrexone hydrochloride is designated an orphan drug by the US Food and Drug Administration (FDA) in the maintenance of opiate cessation. HUMAN STUDIES: Naltrexone competes for opiate receptors and displaces opioid drugs from these receptors, thus reversing their effects. It is capable of antagonizing all opiate receptors. The mechanism of action of naltrexone in alcohol dependence is not known. Patients receiving 800 mg of naltrexone hydrochloride daily for up to 1 week in one study showed no evidence of toxicity. However, lower dosages reportedly have been hepatotoxic in some patients. No serious adverse effects were observed following administration of single naltrexone doses of up to 784 mg (as the extended-release im injection) in several healthy individuals. Naltrexone was not associated with the high rates of neonatal mortality or congenital anomalies seen in methadone-exposed neonates. Mutagenic changes and chromosomal damage have occurred in vitro in human lymphocytes exposed to naltrexone. ANIMAL STUDIES: Acute toxicity from naltrexone in mice, rats, and dogs resulted in death secondary to tonic-clonic seizures and/or respiratory failure. Weight loss occurred in monkeys following subcutaneous administration of 100 mg/kg doses, and prostration, seizures, and death occurred following subcutaneous administration of 300 mg/kg doses. Hypoactivity, salivation, and emesis occurred in monkeys following oral administration of 1 g/kg doses, and seizures and death occurred following oral administration of 3 g/kg doses. Bradycardia has occurred following iv naltrexone hydrochloride doses of 5-80 ug/kg in unanesthetized dogs, however, respiratory rate, blood pressure, arterial blood gases, and EEG remained unchanged throughout the dose range. Within 20 minutes of 1 mg/kg iv doses in cats, total brain oxygen consumption decreased by about 48% and blood flow to the entire brain and the pons decreased by about 40%. In a 2-year study of the carcinogenic potential of naltrexone, there was an increase in the frequency of mesotheliomas in male rats and tumors of vascular origin in both male and female rats. No evidence of carcinogenicity was observed in several other 2-year studies in mice or rats receiving naltrexone dosages of 30 or 100 mg/kg daily. Naltrexone dosages of 100 mg/kg daily in rats produced an increase in pseudopregnancy and a decrease in the pregnancy rate in mated rats. Naltrexone did not exhibit clastogenicity in an in-vivo mouse micronucleus assay. No evidence of genotoxic potential was observed in a range of other in-vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay. However, mutagenic changes and chromosomal damage have occurred in vitro in Chinese hamster ovarian cells, in the Drosophila recessive lethal assay, and in nonspecific DNA repair tests with Escherichia coli and WI-38 cells. ECOTOXICITY STUDIES: In order to evaluate the influence of the season (the stage of gonad maturity) on the modulatory role of endogenous opioid peptides in LH secretion in fish, sexually mature male carp (Cyprinus carpio L.) were intravenously injected with naltrexone-opioid receptor antagonist (5 or 50 ug/kg) in the period of natural spawning (June) or gonad recrudescence (December). In June, naltrexone significantly lowered LH levels in comparison to saline injected males. In December, there were no differences between saline and naltrexone-injected carps.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

纳曲酮是一种纯阿片类药物拮抗剂，几乎没有或没有激动剂活性。纳曲酮在治疗酒精依赖中的作用机制尚不清楚；然而，临床前数据表明内源性阿片系统可能参与其中。认为纳曲酮在大脑中的μ、κ和δ受体上充当竞争性拮抗剂，对μ受体的亲和力最高。纳曲酮与这些受体竞争性结合，可能阻止内源性阿片类药物的作用。这导致拮抗了大多数阿片类药物的主观和客观效应，包括呼吸抑制、瞳孔缩小、欣快和药物渴求。纳曲酮的主要代谢物6-β-纳曲醇也是一种阿片类药物拮抗剂，可能有助于药物的拮抗活性。

Naltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, kappa, and delta receptors in the CNS, with the highest affintiy for the mu receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-beta-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

Naltrexone疗法通常用于患有高基础肝病发生率的病人（注射吸毒者或酗酒者），并且与血清酶水平升高的不同发生率有关（0%至50%），高于正常上限3倍的情况在大约1%的患者中出现，偶尔会导致停药。然而，几项研究表明，在纳曲酮治疗期间ALT升高的发生率与安慰剂相似。在纳曲酮治疗期间，大多数血清转氨酶升高是轻微且自限性的，即使在继续治疗的情况下也会解决。尽管有几例报告称使用纳曲酮的患者出现了急性、临床上明显的肝病，但药物在肝损伤中的作用并不总是明确的，而且肝损伤的临床特征也没有明确的描述。因此，尽管纳曲酮通常被认为具有肝毒性，但它并没有被明确地与临床上明显肝损伤的病例联系起来。

Naltrexone therapy is typically given to patients with a high background rate of liver disease (injection drug use or alcoholism) and has been associated with variable rates of serum enzyme elevations (0% to 50%), values above 3 times the upper limit of normal occurring in approximately 1% of patients and occasionally leading to drug discontinuation. However, several studies have shown that the rate of ALT elevations during naltrexone therapy is similar to that with placebo. Most serum aminotransferase elevations during naltrexone therapy are mild and self-limiting, resolving even with continuation of therapy. While several rare instances of acute, clinically apparent liver disease have been reported in patients taking naltrexone, the role of the medication in the liver injury has not always been clear and there has been no clear description of the clinical features of the injury. Thus, while often considered hepatotoxic, naltrexone has not been definitively linked to cases of clinically apparent liver injury.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：纳曲酮

Compound:naltrexone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：模糊的药物性肝损伤关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

尽管纳曲酮口服吸收良好，但它会受到显著的首过代谢影响，口服生物利用度估计在5%到40%之间。

Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

原药和代谢物主要通过肾脏排泄（占剂量的53%至79%），然而，未改变的纳曲酮经尿液排泄的量不到口服剂量的2%，粪便排泄是一条次要的消除途径。纳曲酮的肾清除率范围为30至127毫升/分钟，这表明肾脏消除主要是通过肾小球滤过。

Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration.

来源:DrugBank

吸收、分配和排泄

• 分布容积

1350毫升 [静脉给药]

1350 L [intravenous administration]

来源:DrugBank

吸收、分配和排泄

• 清除

静脉给药后约3.5升/分钟

~ 3.5 L/min [after IV administration]

来源:DrugBank

吸收、分配和排泄

盐酸纳曲酮口服给药后能从胃肠道迅速且几乎完全（约96%）吸收，但药物在肝脏经历广泛的首过代谢。只有5-40%的口服给药剂量以未改变的形式到达系统循环。据报道，在单次给药后头24小时内，个体间对药物吸收的差异相当大。盐酸纳曲酮片的生物利用度据报道与药物的口服溶液（在美国未商业上市）相似。

Naltrexone hydrochloride is rapidly and almost completely (about 96%) absorbed from the GI tract following oral administration, but the drug undergoes extensive first-pass metabolism in the liver. Only 5-40% of an orally administered dose reaches systemic circulation unchanged. Considerable interindividual variation in absorption of the drug during the first 24 hours after a single dose has been reported. The bioavailability of naltrexone hydrochloride tablets is reportedly similar to that of an oral solution of the drug (not commercially available in the US).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  F,T
• 安全说明：
  S16,S36/37,S45
• 危险类别码：
  R11,R23/24/25,R39/23/24/25
• WGK Germany：
  1,2
• 海关编码：
  2939190000

制备方法与用途

药理作用

纳屈酮（Naltrexone）的化学结构为17-环丙甲基-4，5a-环氧-3，14-双羟基吗啡烷-6-酮。它本身无耐受性和成瘾性，是一种纯阿片类拮抗剂。通过在阿片受体部位的竞争性结合，纳屈酮能完全阻断静脉注射阿片类物质（如海洛因等）的药理效能。此外，纳屈酮还能使患者体内阿片受体系统超敏感化或发生上调，从而缓解和消除慢性戒断反应，并降低复吸率。因此，纳屈酮是目前国内外阿片类成瘾者脱毒后巩固疗效、抗复吸的唯一药物。

不良反应

可能引起恶心、腹痛及皮疹等症状。肝功能不良患者应慎用。

类别与性质

类别: 有毒物品
毒性分级: 高毒
急性毒性: 皮下-小鼠 LD50: 551 毫克/公斤
可燃性危险特性: 可燃；火场分解产生有毒氮氧化物烟雾
储运特性: 库房应保持通风、低温和干燥，且需与氧化剂及食品分开储存运输。
灭火剂: 适宜使用水、砂土或泡沫进行扑灭。

反应信息

• 作为反应物：
  描述：

  纳曲酮 在 肼 、 甲烷磺酸 作用下， 以 N,N-二甲基甲酰胺 、 二甲基亚砜 为溶剂， 生成 去甲-BINALTORPHIMINE二盐酸盐
  参考文献：
  名称：

  Major Effect of Pyrrolic N-Benzylation in Norbinaltorphimine, the Selective κ-Opioid Receptor Antagonist

  摘要：

  Indolic N-benzylation of naltrindole reportedly extends the duration of delta-opioid receptor (DOR) antagonism. Similar modification of the kappa-opioid receptor (KOR) antagonist norBNI (1a) and its 17,17'-diNMe analogue (1d), a low potency mu-opioid receptor (MOR) partial agonist, was found to affect predominantly their MOR activity. When administered systemically in mouse antinociceptive assays, N-benzyl-norBNI (1b) had only MOR agonist activity of relatively short duration whereas on central administration it had only a KOR-antagonist action of extremely long duration.

  DOI：

  10.1021/jm049172n
• 作为产物：
  描述：

  吗啡 生成 纳曲酮
  参考文献：
  名称：

  Preparation of 14-hydroxynormorphinones from normorphinone dienol

  摘要：

  这项发明提供了将诺莫啡酮及其衍生物（可从吗啡合成）转化为相应的14-羟基诺莫啡酮及其衍生物，包括盐酸羟考酮、羟吗啡、诺羟吗啡和纳曲酮的过程。诺羟吗啡是生产重要的麻醉镇痛剂和拮抗剂的关键中间体。该发明还提供了某些新颖的中间体。

  公开号：

  US05869669A1

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] HYBRID MU OPIOID RECEPTOR AND NEUROPEPTIDE FF RECEPTOR BINDING MOLECULES, THEIR METHODS OF PREPARATION AND APPLICATIONS IN THERAPEUTIC TREATMENT<br/>[FR] RÉCEPTEUR D'OPIOÏDE MU HYBRIDE ET MOLÉCULES DE LIAISON DE RÉCEPTEUR DE NEUROPEPTIDE FF, LEURS PROCÉDÉS DE PRÉPARATION ET D'APPLICATIONS DANS UN TRAITEMENT THÉRAPEUTIQUE
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2019170919A1

  公开（公告）日：2019-09-12

  The present invention relates to molecules binding the mu opioid receptor (MOR) and the neuropeptide FF receptor (NPFFR) and in particular molecules having a MOR agonist and NPFFR modulatory activity. The present invention relates to pharmaceutical compositions, and in particular useful in the treatment of pain and/or hyperalgesia.

  本发明涉及结合μ阿片受体（MOR）和神经肽FF受体（NPFFR）的分子，特别是具有MOR激动剂和NPFFR调节活性的分子。本发明涉及药物组合物，特别是在治疗疼痛和/或过敏症方面有用。
• [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] 2-(1H-INDOLE-3-CARBONYL)-THIAZOLE-4-CARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS ARYL HYDROCARBON RECEPTOR (AHR) AGONISTS FOR THE TREATMENT OF E.G. ANGIOGENESIS IMPLICATED OR INFLAMMATORY DISORDERS<br/>[FR] DÉRIVÉS DE 2-(1H-INDOLE-3-CARBONYL)-THIAZOLE-4-CARBOXAMIDE ET COMPOSÉS CORRESPONDANTS UTILISÉS EN TANQUE QUE AGONISTES DU RÉCEPTEUR D'HYDROCARBURE ARYLE (AHR) UTILISÉS POUR LE TRAITEMENT DE, P.EX., DE L'ANGIOGENÈSE IMPLIQUÉE OU DE TROUBLES INFLAMMATOIRES
  申请人：IKENA ONCOLOGY INC

  公开号：WO2021127302A1

  公开（公告）日：2021-06-24

  2-(1H-lndole-3-carbonyl)-thiazole-4-carboxamide derivatives and the corresponding imidazole, oxazole and thiophene derivatives and related compounds as aryl hydrocarbon receptor (AHR) agonists for the treatment of angiogenesis implicated disorders, such as e.g. retinopathy, psoriasis, rheumatoid arthritis, obesity and cancer, or inflammatory disorders. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 27 to 32 and 59 to 219; examples 1 to 8; compounds 1-1 to 1-97; tables 1-a, 2 and 3).

  2-(1H-吲哚-3-甲酰基)-噻唑-4-羧酰胺衍生物及相应的咪唑、噁唑和噻吩衍生物以及相关化合物作为芳香烃受体（AHR）激动剂，用于治疗涉及血管生成的疾病，例如视网膜病变、银屑病、类风湿性关节炎、肥胖和癌症，或炎症性疾病。本说明书揭示了示例化合物的合成和表征以及其药理数据（例如第27至32页和59至219页；示例1至8；化合物1-1至1-97；表1-a、2和3）。