卡芬太尼 | 59708-52-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 卡芬太尼
• 英文名称: carfentanil
• 英文别名: methyl 4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate；methyl 1-phenethyl-4-(N-phenylpropionamido)piperidine-4-carboxylate；3-demethyllofentanil；carfentanyl；4-((1-oxopropyl)-phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid methyl ester；methyl 1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxylate
• CAS: 59708-52-0
• 化学式: C₂₄H₃₀N₂O₃
• 分子量: 394.514
• InChiKey: YDSDEBIZUNNPOB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

芬太尼是一种超强力合成阿片类药物。目前还没有关于人类芬太尼代谢的数据。据报道，2002年俄罗斯警方在莫斯科的一次人质事件中使用了芬太尼和瑞芬太尼。这种所谓的使用激起了人们对芬太尼在人身上的药理学和毒理学的兴趣。我们的研究旨在确定人类芬太尼的代谢物，并评估芬太尼的代谢清除率，这可能是其在人类中急性毒性的一个因素。我们使用Simulations Plus的ADMET Predictor和Molecular Discovery的MetaSite来预测可能的代谢物形成。两个程序给出了类似的结果，通常都是好的，但没有捕捉到在体外看到的所有代谢物。我们将芬太尼与人类肝细胞一起孵化长达1小时，并使用Sciex 3200 QTRAP质谱仪分析样本，以测量母体化合物的消耗，并据此推断出内在清除率。然后将混合的人类原代肝细胞与芬太尼一起孵化长达6小时，并在Sciex 5600+ TripleTOF（QTOF）高分辨率质谱仪上进行代谢物鉴定分析。MS和MS/MS分析阐明了最丰富代谢物的结构。总共鉴定出12种代谢物。哌啶环的N-脱烷基化和单羟基化是主要的代谢途径。观察到了两种N-氧化物代谢物和一种葡萄糖苷酸代谢物。令人惊讶的是，酯水解并不是芬太尼的主要代谢途径。虽然人类肝脏微体系统通过CYP酶显示了快速的清除，但肝细胞孵化显示了更慢的清除，这可能为芬太尼效果持续时间长提供了一些洞见。

Carfentanil is an ultra-potent synthetic opioid. No human carfentanil metabolism data are available. Reportedly, Russian police forces used carfentanil and remifentanil to resolve a hostage situation in Moscow in 2002. This alleged use prompted interest in the pharmacology and toxicology of carfentanil in humans. Our study was conducted to identify human carfentanil metabolites and to assess carfentanil's metabolic clearance, which could contribute to its acute toxicity in humans. We used Simulations Plus's ADMET Predictor and Molecular Discovery's MetaSite to predict possible metabolite formation. Both programs gave similar results that were generally good but did not capture all metabolites seen in vitro. We incubated carfentanil with human hepatocytes for up to 1 hr and analyzed samples on a Sciex 3200 QTRAP mass spectrometer to measure parent compound depletion and extrapolated that to represent intrinsic clearance. Pooled primary human hepatocytes were then incubated with carfentanil up to 6 h and analyzed for metabolite identification on a Sciex 5600+ TripleTOF (QTOF) high-resolution mass spectrometer. MS and MS/MS analyses elucidated the structures of the most abundant metabolites. Twelve metabolites were identified in total. N-Dealkylation and monohydroxylation of the piperidine ring were the dominant metabolic pathways. Two N-oxide metabolites and one glucuronide metabolite were observed. Surprisingly, ester hydrolysis was not a major metabolic pathway for carfentanil. While the human liver microsomal system demonstrated rapid clearance by CYP enzymes, the hepatocyte incubations showed much slower clearance, possibly providing some insight into the long duration of carfentanil's effects.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：卡芬太尼是一种二级管制物质。它是一种用于鹿科动物（鹿、麋鹿、驼鹿）的大型动物麻醉剂，也用作动物园动物的兽医麻醉剂。卡芬太尼是一种超高效合成阿片类药物。这些物质可以存在多种形式，包括粉末、吸墨纸、片剂和喷雾 - 它们可以通过皮肤吸收或意外吸入空气中的粉末。人体研究：在美国，卡芬太尼在尸检和生前案例中在海洛因供应中被发现，单独存在或与海洛因和/或其他芬太尼类似物混合。卡芬太尼的效力大约是吗啡的10,000倍，是芬太尼的100倍。在某些案例中，卡芬太尼被识别并确认为死亡原因，单独存在或与其他药物混合。2002年10月，俄罗斯军队使用了一种神秘的“气体”来使莫斯科剧院内的车臣叛军失去行动能力。现有证据强烈表明，在这种情况下使用了类似于卡芬太尼的高效气溶胶芬太尼衍生物和吸入性麻醉剂（如氟烷）的组合。另一项研究建议，气溶胶是由两种麻醉剂 - 卡芬太尼和瑞芬太尼的混合物组成。动物研究：在给予卡芬太尼柠檬酸盐后，3匹马出现严重的心悸和高血压，导致1匹马因肺水肿而死亡。肌内注射的依托芬和卡芬太尼在山羊中引起高血压、心动过缓和呼吸抑制。在木野牛中使用的卡芬太尼平均剂量为7.0微克/千克。使用的阿片类药物拮抗剂是纳曲酮、纳洛酮和M5050。

IDENTIFICATION AND USE: Carfentanil is a Schedule II controlled substance. It is a large animal immobilizing agent use in Cervidae (deer, elk, moose), and veterinary anesthetic used for zoo animals. Carfentanil is an ultra-potent synthetic opioid. These substances can come in several forms, including powder, blotter paper, tablets, and spray - they can be absorbed through the skin or accidental inhalation of airborne powder. HUMAN STUDIES: Carfentanil has been discovered in postmortem and antemortem cases throughout the United States in the heroin supply either alone or mixed with heroin and/or other fentanyl analogs. The potency of carfentanil is approximately 10,000 times greater than morphine and 100 times greater than fentanyl. In some cases, carfentanil was identified and ruled to be the cause of death, either alone or in combination with other drugs. In October 2002, the Russian military used a mysterious "gas" to incapacitate Chechen rebels at a Moscow theater. The available evidence strongly suggests that a combination of a potent aerosolized fentanyl derivative, such as carfentanil, and an inhalational anesthetic, such as halothane, was used in this case. Other study suggested that aerosol comprised a mixture of two anaesthetics -carfentanil and remifentanil. ANIMAL STUDIES: After carfentanil citrate administration, 3 horses developed severe tachycardia and hypertension, which resulted in the death of 1 horse from pulmonary edema. Intramuscularly administered etorphine and carfentanil induce hypertension, bradycardia, and bradypnea in goats. The mean dose of carfentanil used in wood bison was 7.0 ug/kg. Narcotic antagonists used were naltrexone, naloxone and M5050.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

采用交叉研究设计，研究了家养山羊（Capra hircus）通过静脉、肌肉和皮下给药途径给予卡芬太尼和纳洛酮的药代动力学。在给予卡芬太尼后，连续采集血液样本直至120小时，并使用液相色谱和质谱法测定血浆中药物浓度。所有山羊通过肌肉注射40微克/千克卡芬太尼进行麻醉，尽管产生的神经学效果差异较大。血浆浓度资料显示卡芬太尼吸收迅速，并在12-48小时内呈现简单的双相下降。在给予卡芬太尼后30分钟，按100毫克纳洛酮/毫克卡芬太尼的剂量给予纳洛酮，可以迅速逆转所有给药途径的麻醉状态。在给药后的前2.5-3.5小时内观察到纳洛酮血浆浓度的波动变化，随后是更加一致的双相下降。与皮下纳洛酮相比，静脉纳洛酮给药后站立时间显著缩短，尽管时间差异（1分钟）在临床上意义不大。三种纳洛酮给药途径的纳洛酮药代动力学参数之间没有统计学上的显著差异，尽管主观上认为肌肉注射给药的恢复最为平稳。给予不同途径纳洛酮的山羊，卡芬太尼的半衰期没有显著差异。尽管目前建议将纳洛酮剂量分为皮下和静脉两部分，但这种做法似乎并没有带来任何益处。

Using a crossover study design, the pharmacokinetics of carfentanil and naltrexone after i.v., i.m., and s.c. administration were determined in eight domestic goats (Capra hircus). Serial blood samples were taken up to 120 hr after carfentanil administration, and the plasma drug concentrations were determined using liquid chromatography and mass spectroscopy. All goats were immobilized with 40 ug/kg carfentanil i.m., although the resulting neurologic effects varied considerably. Plasma profiles showed rapid carfentanil absorption and a simple biphasic decline for 12-48 hr. Naltrexone given at 100 mg naltrexone/mg carfentanil 30 min after carfentanil administration produced rapid reversal of immobilization after all routes of administration. Variable fluctuations in the naltrexone plasma concentrations during the first 2.5-3.5 hr were observed, followed by a more consistent biphasic decline. The time to standing was significantly shorter after i.v. compared with s.c. naltrexone, although the time difference (1 min) had little clinical relevance. No statistically significant differences between the naltrexone pharmacokinetic parameters measured for the three routes of naltrexone administration were identified, although the recoveries after i.m. administration were, subjectively, the smoothest. The carfentanil half-life did not differ significantly in the goats given naltrexone by different routes. Although it is currently recommended that the naltrexone dose be divided into s.c. and i.v. portions, this practice does not appear to offer any benefit.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

使用交叉研究设计，我们研究了纳洛酮给药对八只健康的落基山马鹿（Cervus elaphus nelsoni）的呼吸和心血管效应，这些马鹿用卡芬太尼（10 ug/kg i.m.）和赛拉嗪（0.1 mg/kg）麻醉。在纳洛酮给药前，麻醉动物表现出显著的低氧血症和轻微的高碳酸血症、心动过速、高血压和酸中毒。在放置监测设备后，动物被给予纳洛酮（2 ug/ug卡芬太尼 i.v.）或等量的生理盐水。纳洛酮组和盐水组之间的PaO2、PaCO2、心率和呼吸率的平均值有显著差异，但平均血压、血细胞比容和血清电解质浓度没有差异。在纳洛酮或盐水给药前，平均PaO2为23.0 +/- 4.1 mm Hg，在纳洛酮给药后增加到50.2 +/- 7.3 mm Hg。盐水处理的动物的平均PaO2没有显著变化。三只盐水处理的动物的心电图提示心肌缺氧。低氧血症似乎是由呼吸抑制、血流动力学改变和侧卧位引起的。除了一只动物外，所有动物在纳洛酮给药后仍然保持麻醉状态。所有动物的麻醉在4分钟内通过纳曲酮（100 mg/mg卡芬太尼 i.v. s.c.）和育亨宾（0.1 mg/kg i.v.）被逆转。一次纳洛酮剂量就改善了卡芬太尼-赛拉嗪麻醉的马鹿的氧合。

With the use of a crossover study design, we investigated the respiratory and cardiovascular effects of naloxone administration in eight healthy Rocky Mountain wapiti (Cervus elaphus nelsoni) anesthetized with carfentanil (10 ug/kg i.m.) and xylazine (0.1 mg/kg). Anesthetized animals showed profound hypoxemia with mild hypercapnia, tachycardia, hypertension, and acidosis prior to naloxone administration. After monitoring equipment was placed, animals were administered either naloxone (2 ug/ug carfentanil i.v.) or an equivalent volume of normal saline. Mean values for PaO2, PaCO2, heart rate, and respiratory rate were significantly different between naloxone- and saline-treated groups, but mean blood pressure, hematocrit, and serum electrolyte concentrations were not. Mean PaO2 was 23.0 +/- 4.1 mm Hg prior to administration of naloxone or saline and increased to 50.2 +/- 7.3 mm Hg after naloxone administration. Mean PaO2 of saline-treated animals did not change significantly. Electrocardiograms of three saline-treated animals suggested myocardial hypoxia. Hypoxemia appeared to be caused by respiratory depression, hemodynamic alterations, and lateral recumbency. All but one animal remained anesthetized after naloxone administration. Anesthesia in all animals was reversed in < or = 4 min with naltrexone (100 mg/mg carfentanil i.v. s.c.) and yohimbine (0.1 mg/kg i.v.). One bolus of naloxone improved oxygenation in carfentanil-xylazine-anesthetized wapiti.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

逆转卡芬太尼引起的呼吸抑制涉及静脉注射纳洛酮或纳曲酮，但这种方法有缺点。因此，需要寻找更合适的治疗方法来对抗卡芬太尼的抑制作用。在目前的研究中，以纳洛酮为对照，我们调查了纳美芬对抗卡芬太尼抑制作用的疗效。大鼠连续接受卡芬太尼（10微克/千克，静脉注射）和纳美芬（9.4-150.0微克/千克，肌肉注射）治疗，并记录失去翻正反射（LORR）的持续时间。在自由活动的大鼠中使用整体测压计测量呼吸参数，在大鼠连续接受卡芬太尼（20微克/千克，静脉注射）和纳美芬（9.4-150.0微克/千克，肌肉注射）后。还检查了动脉血气的参数。纳美芬（9.4-150.0微克/千克，肌肉注射）治疗剂量依赖性地减少了卡芬太尼引起的LORR持续时间。纳美芬（150.0微克/千克，肌肉注射）治疗60分钟后的呼吸频率从34.3 ± 5.3次/分钟增加到117.8 ± 18.9次/分钟，增强暂停从1.1 ± 0.1减少到0.4 ± 0.1，接近正常大鼠的水平。此外，纳美芬（37.5-150.0微克/千克）治疗可以使PaO2、SaO2和PaCO2在注射后10分钟（卡芬太尼注射后15分钟）或30分钟（卡芬太尼注射后25分钟）接近正常水平。而单次注射纳洛酮（150.0微克/千克，肌肉注射）仅实现了呼吸抑制的部分缓解。这些数据表明，纳美芬更有效地对抗卡芬太尼引起的抑制作用，与纳洛酮相比，是更合适的治疗卡芬太尼毒性的方法。

Reversing the respiratory depression induced by carfentanil involves intravenous administration of naloxone or naltrexone, but this treatment has disadvantages. Hence, finding a more appropriate treatment to counter the depressive actions of carfentanil is needed. In the present study, with the naloxone as a control, we investigated the efficacy of nalmefene for countering the depressive actions of carfentanil. Rats were treated successively with carfentanil (10 ug/kg, i.v.) and nalmefene (9.4-150.0 ug/kg, i.m.), and the duration of loss of righting reflex (LORR) recorded. Respiratory parameters were measured in free-moving rats using a whole-body plethysmograph after rats were administered carfentanil (20 ug/kg, i.v.) and nalmefene (9.4-150.0 ug/kg, i.m.) sequentially. The parameters of arterial blood gases were also examined. Nalmefene (9.4-150.0 ug/kg, i.m.) treatment dose-dependently decreased the duration of carfentanil-induced LORR. The respiratory rate after 60 min of nalmefene (150.0 ug/kg, i.m.) treatment increased from 34.3 +/- 5.3 bursts/min to 117.8 +/- 18.9 bursts/min, and enhanced pause decreased from 1.1 +/- 0.1 to 0.4 +/- 0.1, and was close to those of normal rats. Furthermore, nalmefene (37.5-150.0 ug/kg) treatment could enable the PaO2, SaO2 and PaCO2 to approach normal levels 10 min (15 min after carfentanil injection) or 30 min (25 min after carfentanil injection) after injection. While, a single injection of naloxone (150.0 ug/kg, i.m.) only achieved partial remission of respiratory depression. These data suggest that nalmefene more effectively counters the depressive actions induced by carfentanil and is a more appropriate treatment to antagonize carfentanil toxicity compared with naloxone.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

我们评估了纳曲酮对12只圈养的落基山脉马鹿（Cervus elaphus nelsoni）拮抗卡芬太尼麻醉效果的疗效和安全性，使用了一个随机不完全区组实验。在三个重复试验中，马鹿被肌肉注射10微克/千克体重的卡芬太尼柠檬酸盐。在每只马鹿倒下15分钟后，我们给予了纳曲酮HCl（25%剂量静脉注射，75%皮下注射），剂量为0（对照组）、25、50或100毫克/毫克卡芬太尼；在额外的15分钟麻醉后，对照组接受了500毫克纳曲酮HCl/毫克卡芬太尼。在36次尝试中有34次成功麻醉了马鹿；平均（+/-SE）诱导时间为3.1 +/- 0.2分钟。无论剂量如何，所有马鹿在接受纳曲酮后< 9分钟内都能站立；对照组在接受拮抗剂之前一直处于麻醉状态。恢复时间随着纳曲酮剂量的增加没有差异（P = 0.31），个体间也没有差异（P = 0.16）。接受100或500毫克纳曲酮/毫克卡芬太尼的马鹿没有再次麻醉，但接受50和25毫克纳曲酮/毫克卡芬太尼的8只和9只马鹿中分别有3只和7只马鹿在8到24小时后表现出轻微的再次麻醉迹象（P = 0.0002）。我们没有观察到接受<或= 500毫克纳曲酮/毫克卡芬太尼的马鹿出现不良反应。根据这些数据，我们推荐100毫克/毫克卡芬太尼作为快速拮抗麻醉和防止再次麻醉的最小有效剂量。

We evaluated efficacy and safety of naltrexone for antagonizing carfentanil immobilization in 12 captive Rocky Mountain elk (Cervus elaphus nelsoni) using a randomized incomplete block experiment. In three replicate trials, elk were hand-injected with 10 micrograms carfentanil citrate/kg body weight intramuscularly. Fifteen min after each elk became recumbent, we administered naltrexone HCl (25% of dose intravenously, 75% subcutaneously) dosed at 0 (control), 25, 50, or 100 mg/mg carfentanil; after an additional 15 min of immobilization, controls received 500 mg naltrexone HCl/mg carfentanil. Elk were immobilized in 34 of 36 attempts; the mean (+/-SE) induction time was 3.1 +/- 0.2 min. Regardless of dose, all elk stood < 9 min after receiving naltrexone; controls remained immobilized until they received antagonist. Mean recovery times did not differ with increasing naltrexone dose (P = 0.31) or among individuals (P = 0.16). None of the elk receiving 100 or 500 mg naltrexone/mg carfentanil renarcotized, but three of eight and seven of nine elk receiving 50 and 25 mg naltrexone/mg carfentanil, respectively, showed signs of mild renarcotization 8 to 24 hr later (P = 0.0002). We observed no adverse clinical effects in elk receiving < or = 500 mg naltrexone/mg carfentanil. Based on these data, we recommend 100 mg/mg carfentanil as a minimum effective dose for rapidly antagonizing immobilization and preventing renarcotization.

来源:Hazardous Substances Data Bank (HSDB)

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  4-(苯基丙酰氨基)哌啶-4-羧酸甲酯	norcarfentanil	72996-78-2	C16H22N2O3	290.362
  ——	methyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate	61085-55-0	C21H26N2O2	338.45
  ——	N-(cyclohexen-1-yl)-1-(2-phenylethyl)-4-(N-propanoylanilino)piperidine-4-carboxamide	1233201-80-3	C29H37N3O2	459.632

反应信息

• 作为产物：
  描述：

  1-phenethylpiperidine-4-carboxylic acid 在 氯化亚砜 、 甲烷磺酸 、 potassium carbonate 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 7.0h， 生成 卡芬太尼
  参考文献：
  名称：

  一种麻醉镇痛药物的合成方法

  摘要：

  本发明公开了一种麻醉镇痛药物的合成方法，所述合成方法以4‑哌啶甲酸为原料，经烷基化、溴代、甲基化、酰化等步骤，制备为麻醉镇痛药。该方法避免使用剧毒氰化物，提高了操作的安全性和可控性；避免了在反应过程中的消除反应，加快了反应速度，将反应时间缩短，利用该方法，降低了反应温度，缩短了反应时间，更适宜工业化生产。

  公开号：

  CN110577489B

文献信息

• Sustained-release analgesic compounds
  申请人：——

  公开号：US20030022876A1

  公开（公告）日：2003-01-30

  A pharmaceutically active inventive compound comprises two independently active analgesic moieties covalently conjoined through a physiologically labile linker. A preferred embodiment comprises an opioid, such as morphine, covalently linked to at least one analgesic compound selected from the group consisting of an opioid or a non-opioid compound through a physiologically labile linker. Suitable covalent linkers are covalently bonded to the two independently active analgesic compounds through one or more lactone, lactam, or sulfonamido linkages. Suitable linkers include endogenous carboxylate, amido, and sulfonamido moieties, and exogenous moieties that form the aforementioned lactone, lactam or sulfonamido linkages.

  一种药理活性的创新化合物包括通过生理易降解的连接物共价连接的两个独立活性镇痛基团。一种首选实施例包括阿片类药物，如吗啡，通过生理易降解的连接物与来自阿片类或非阿片类化合物组成的群中选择的至少一种镇痛化合物共价连接。适当的共价连接物通过一个或多个内源的内酯、内酰胺或磺酰胺连接而与这两个独立活性的镇痛化合物共价结合。适当的连接物包括内源的羧酸酯、酰胺和磺酰胺基团，以及形成上述内酯、内酰胺或磺酰胺连接的外源基团。
• [EN] COMBINATION THERAPY FOR PREVENTING ADDICTION<br/>[FR] POLYTHÉRAPIE POUR LA PRÉVENTION D'UNE ADDICTION
  申请人：AMYGDALA NEUROSCIENCES INC

  公开号：WO2019079209A1

  公开（公告）日：2019-04-25

  Disclosed is a novel combination therapy to reduce or prevent the acquisition of a conditioned response in a mammal comprising administering to the mammal a therapeutically effective amount of an aldehyde dehydrogenase (ALDH-2) inhibitor compound, such as a compound of Formula (I), in combination with a substance that produces the conditioned response, such as a medication containing a dopamine-producing agent such as an opioid, whereby the combination acts to reduce or prevent the acquisition of a conditioned response, and the deleterious side-effect of misuse, dependence, abuse, and/or addiction.

  揭示了一种新颖的联合疗法，用于减少或预防哺乳动物获得条件反射，包括向哺乳动物施用治疗有效量的醛脱氢酶（ALDH-2）抑制剂化合物，例如公式（I）中的化合物，与产生条件反射的物质结合，例如含有多巴胺生成剂的药物，如阿片类药物，从而使该组合作用于减少或预防条件反射的获得，以及滥用、依赖、滥用和/或成瘾的有害副作用。
• 2-Bromo-6-isocyanopyridine as a Universal Convertible Isocyanide for Multicomponent Chemistry
  作者：Gydo van der Heijden、J. A. W. (Sjaak) Jong、Eelco Ruijter、Romano V. A. Orru

  DOI：10.1021/acs.orglett.6b00091

  日期：2016.3.4

  optimal reagent in terms of stability and synthetic efficiency. It combines sufficient nucleophilicity with good leaving group capacity of the resulting amide moiety under both basic and acidic conditions. To demonstrate the practical utility of this reagent, an efficient two-step synthesis of the potent opioid carfentanil is presented.

  据报道2-异氰基吡啶是用于多组分化学的新型可转化异氰酸酯。对该类别的12位代表进行的比较显示，就稳定性和合成效率而言，2-溴-6-异氰基吡啶是最佳试剂。它在碱性和酸性条件下都具有足够的亲核性和所得酰胺部分的良好离去基团能力。为了证明该试剂的实用性，提出了有效的两步有效合成有效的阿片样物质芬太尼。
• PYRAZOLYL PYRIMIDINONE COMPOUNDS AND THE USES THEREOF
  申请人：Purdue Research Foundation

  公开号：US20210100797A1

  公开（公告）日：2021-04-08

  The present invention relates to a method of treatment for chronic pain, opioid dependence, alcohol use disorder or autism using a class of pyrimidinone compounds, an adenylyl cyclase 1 (AC1) inhibitor. The invention described herein also pertains to pharmaceutical compositions and methods for treating diseases in mammals using those compounds disclosed herein.

  本发明涉及一种使用嘧啶酮化合物类治疗慢性疼痛、阿片类药物依赖、酒精使用障碍或自闭症的方法，该化合物为腺苷酸环化酶1（AC1）抑制剂。本发明还涉及使用本文所述化合物的药物组合物和用于治疗哺乳动物疾病的方法。
• [EN] 5-HT2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USE<br/>[FR] AGONISTES DE RÉCEPTEUR 5-HT2C ET COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：ARENA PHARM INC

  公开号：WO2017023679A1

  公开（公告）日：2017-02-09

  Provided in some embodiments are compounds of Formula A, as defined herein, that modulate the activity of 5-HT2C receptor. Also provided in some embodiments are methods, such as, for weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea.

  在某些实施例中提供了一些符合本文所定义的A式化合物，其调节5-HT2C受体的活性。在某些实施例中还提供了一些方法，例如用于体重管理、诱导饱腹感、减少食物摄入，以及预防和治疗肥胖、抗精神病药物引起的体重增加、2型糖尿病、普拉德-威利综合征、烟草/尼古丁依赖、药物成瘾、酒精成瘾、病理性赌博、奖赏缺乏综合征和性成瘾，强迫症谱系障碍和冲动控制障碍（包括咬指甲和咬甲症），睡眠障碍（包括失眠、睡眠结构碎裂和慢波睡眠紊乱），尿失禁，精神障碍（包括精神分裂症、厌食症和暴食症），阿尔茨海默病，性功能障碍，勃起功能障碍，癫痫，运动障碍（包括帕金森病和抗精神病药物引起的运动障碍），高血压，血脂异常，非酒精性脂肪肝病，肥胖相关肾脏疾病和睡眠呼吸暂停症。