伐伦克林 | 249296-44-4

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 中文名称: 伐伦克林
• 中文别名: 7,8,9,10-四氢-6,10-亚甲基-6H-吡嗪并2,3-h3苯并氮杂卓；伐伦克林游离碱；瓦伦尼克林；伐尼克兰；7,8,9,10-四氢-6,10-亚甲基-6H-吡嗪并[2,3-h][3]苯并氮杂卓；伐尼游离碱
• 英文名称: varenicline
• 英文别名: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine；6,10-Methano-6H-pyrazino[2,3-h][3]benzazepine, 7,8,9,10-tetrahydro-；5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2,4,6,8,10-pentaene
• CAS: 249296-44-4
• 化学式: C₁₃H₁₃N₃
• 分子量: 211.266
• InChiKey: JQSHBVHOMNKWFT-UHFFFAOYSA-N

物化性质

• 熔点：
  138.5 °C
• 沸点：
  400.6±40.0 °C(Predicted)
• 密度：
  1.247±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜
• 蒸汽压力：
  4.65X10-6 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 分解：
  Hazardous decomposition products: Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx)
• 解离常数：
  pKa1 = 1.82 (amine); pKa2 = 9.73 (secondary amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  37.8
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

代谢有限（<10%）。大部分活性化合物通过肾脏排出（81%）。少量的伐尼克兰被葡萄糖醛酸化、氧化、N-甲酰化，以及与己糖结合。

Metabolism is limited (<10%). Most of the active compound is excreted by the kidneys (81%). A minor amount of varenicline is glucuronidated, oxidated, N-formylated, as well as conjugated to form a hexose.

来源:DrugBank

代谢

伐尼克兰经历最少的代谢，92%以原形从尿液中排出。

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

伐尼克兰在体内经历极少量代谢，92%以原形通过尿液排出，不到10%以代谢物形式排出。尿液中的次要代谢物包括伐尼克兰N-羧甲酰葡萄糖苷酸和羟基伐尼克兰。在循环系统中，伐尼克兰占药物相关物质的91%。循环系统中的次要代谢物包括伐尼克兰N-羧甲酰葡萄糖苷酸和N-葡萄糖基伐尼克兰。

Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug related material. Minor circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：伐尼克兰作为辅助手段用于戒烟。人类暴露和毒性：伐尼克兰作为戒烟辅助手段的安全性和有效性已在3659名患者（平均年龄43岁；79-96%白人；平均吸烟史约25年）中进行了6项安慰剂对照或活性比较剂研究得到证实，这些患者每天至少吸10支香烟（平均约21支）。伐尼克兰的安全性和有效性也在703名患有稳定记录的心血管疾病（除高血压外）的患者中进行了一项随机、双盲、安慰剂对照的研究，这些患者每天至少吸10支香烟；接受伐尼克兰和安慰剂的患者在基线特征上相似，包括年龄（平均年龄分别为57岁和55.9岁）、种族（分别为80.3%和80.8%白人）、性别（分别为75.2%和82.2%男性）和平均吸烟史（分别为40年和39年，以及每天22.1支和22.9支香烟）。伐尼克兰的安全性和有效性也在460名轻度至中度慢性阻塞性肺病（支气管扩张剂后FEV1/FVC低于70%，FEV1至少为预测正常值的50%）的患者中进行了一项随机、双盲、安慰剂对照的研究，这些患者每天至少吸10支香烟。在患者使用伐尼克兰的上市后经验中，报告了严重的神经精神症状，包括情绪变化（例如，抑郁、躁狂）、精神疾病、幻觉、偏执、妄想、杀人意念、敌意、激动、攻击性、焦虑、恐慌和自杀倾向（例如，自杀意念、自杀未遂和完成自杀）。在患者使用伐尼克兰的上市后经验中，还报告了过敏反应，包括血管性水肿。尚未在18岁以下的患者中建立伐尼克兰的安全性和有效性，不推荐在此年龄组使用该药物。伐尼克兰在体外人淋巴细胞中，无论有无代谢激活，均未表现出遗传毒性。动物研究：伐尼克兰在动物中分布到乳汁中。大鼠通过口服灌胃给予伐尼克兰（1、5和15 mg/kg/天）持续2年。在雄性大鼠（每个剂量组每性别65只）中，中等剂量（1个肿瘤，5 mg/kg/天，相当于最大推荐人类日暴露量的23倍，基于AUC）和最大剂量（2个肿瘤，15 mg/kg/天，相当于最大推荐人类日暴露量的67倍，基于AUC）的棕色脂肪肿瘤（hibernoma）发生率增加。在雌性大鼠中没有致癌性的证据。伐尼克兰琥珀酸盐在动物繁殖研究中显示出对胎儿的有害影响。给怀孕的兔子口服伐尼克兰琥珀酸盐导致在30 mg/kg/天的剂量下胎儿体重减轻（是人类AUC的50倍）；在10 mg/kg/天（最大推荐日人类暴露量的23倍，基于AUC）的治疗后，这种减少并不明显。此外，在怀孕大鼠使用伐尼克兰琥珀酸盐后，后代在15 mg/kg/天（最大推荐人类日暴露量的36倍，基于AUC）的口服剂量下出现了生育能力下降和听觉惊跳反应增加。伐尼克兰琥珀酸盐在大鼠和兔子中口服剂量分别高达15和30 mg/kg/天时，并未表现出致畸性（分别为最大推荐人类日暴露量的36和50倍，基于AUC）。伐尼克兰在以下试验中无论有无代谢激活均未表现出遗传毒性： Ames细菌突变试验；哺乳动物CHO/HGPRT试验；以及在大鼠骨髓中进行的体内细胞遗传学异常试验。

IDENTIFICATION AND USE: Varenicline is used as an adjunct in the cessation of cigarette smoking. HUMAN EXPOSURE AND TOXICITY: Safety and efficacy of varenicline as an adjunct for smoking cessation have been established in 6 placebo-controlled or active-comparator studies in 3659 patients (mean age: 43 years; 79-96% white; mean smoking history: about 25 years) who smoked at least 10 cigarettes daily (mean: about 21 cigarettes daily). Safety and efficacy of varenicline also have been evaluated in a randomized, double-blind, placebo-controlled study in 703 patients with stable, documented cardiovascular disease (other than hypertension) who smoked at least 10 cigarettes daily; patients receiving varenicline and placebo were comparable in baseline characteristics, including age (mean age 57 and 55.9 years, respectively), race (80.3 and 80.8% white, respectively), gender (75.2 and 82.2% male, respectively), and mean smoking history (40 and 39 years, and 22.1 and 22.9 cigarettes daily, respectively). Safety and efficacy of varenicline also have been evaluated in a randomized, double-blind, placebo-controlled study in 460 patients (mean age 57 years, 82-84% white, approximately 62% male, mean smoking history of approximately 40 years) with mild to moderate chronic obstructive pulmonary disease (postbronchodilator FEV1/FVC below 70% and FEV1 at least 50% of predicted normal value) who smoked at least 10 cigarettes daily. Serious neuropsychiatric symptoms, including changes in mood (e.g., depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, and suicidality (e.g., suicidal ideation, attempted and completed suicides), have been reported during postmarketing experience in patients receiving varenicline. Hypersensitivity reactions, including angioedema, have been reported during postmarketing experience in patients receiving varenicline. Safety and efficacy of varenicline have not been established in patients younger than 18 years of age and use of the drug in this age group is not recommended. Varenicline was not genotoxic, with or without metabolic activation in vitro in human lymphocytes. ANIMAL STUDIES: Varenicline is distributed into milk in animals. Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n = 65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). There was no evidence of carcinogenicity in female rats. Varenicline succinate has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline succinate to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline succinate there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC). Varenicline succinate was not teratogenic in rats and rabbits at oral doses up to 15 and 30 mg/kg/day, respectively (36 and 50 times the maximum recommended human daily exposure based on AUC, respectively). Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

伐尼克兰在治疗期间并未与血清酶水平升高率大于安慰剂治疗的情况相关联，但关于这些异常的信息有限，偶尔会有无症状的ALT升高导致停药的报告。在数千名患者的上市前关键注册试验中，伐尼克兰并未与黄疸或肝炎的病例相关。自获得许可以来，有罕见的病例报告在开始使用伐尼克兰后的4周内出现无黄疸的血清酶升高，但主要发生在有其他肝脏损伤原因的患者中（酒精性肝病、丙型肝炎）。这种损伤在过程中是自限性的，并未与免疫过敏或自身免疫特征相关。在冰岛，已经报告了一例伐尼克兰肝毒性的病例（案例1），自该药物引入以来，估计有20,000人接受了该药物治疗。

Varenicline has not been associated with rates of serum enzyme elevations during therapy greater than occurs with placebo therapy, but information on these abnormalities is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation have been reported. In prelicensure pivotal registration trials in several thousand patients, varenicline was not associated with cases of jaundice or hepatitis. Since licensure, rare case reports of serum enzyme elevations without jaundice arising within 4 weeks of starting varenicline have been published, but largely in patients with other causes of liver injury (alcoholic liver disease, hepatitis C). The injury was self-limited in course and not associated with immunoallergic or autoimmune features. In Iceland, a single case of varenicline hepatotoxicity has been reported (Case 1), there having been an estimated 20,000 persons treated with the drug in the country since its introduction.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：伐尼克兰

Compound:varenicline

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

毒理性

• 药物性肝损伤

严重程度等级：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

伐尼克兰经历最少的代谢，92%以原形通过尿液排出。伐尼克兰的肾脏消除主要是通过肾小球滤过以及可能的有机阳离子转运蛋白OCT2介导的活跃的肾小管分泌。

Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.

来源:DrugBank

吸收、分配和排泄

瓦伦尼克林的最大血浆浓度通常在口服给药后3-4小时内出现。在多次口服瓦伦尼克林剂量后，稳态条件在4天内达到。在推荐的剂量范围内，瓦伦尼克林在单次或重复剂量后表现出线性药代动力学。在一项质量平衡研究中，口服给药后瓦伦尼克林的吸收几乎完全，系统可用性约为90%。瓦伦尼克林的口服生物利用度不受食物或每日定时给药的影响。瓦伦尼克林的血浆蛋白结合率较低（<=20%）且与年龄和肾功能无关。

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low (</=20%) and independent of both age and renal function.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Varenicline主要通过尿液以原药形式排出。药物的肾脏消除主要是通过肾小球滤过以及积极的肾小管分泌。

Varenicline is eliminated principally in urine as unchanged drug. Renal elimination of the drug occurs primarily through glomerular filtration along with active tubular secretion.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Varenicline 在动物中会分布到乳汁中。尚不清楚 Varenicline 是否会分布到人乳中。

Varenicline is distributed into milk in animals. Not known whether varenicline is distributed into human milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 包装等级：
  III
• 危险类别：
  9
• 危险性防范说明：
  P273,P301+P312+P330,P305+P351+P338,P314
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H372,H410
• 储存条件：
  2-8℃

制备方法与用途

简介

伐伦克林即伐尼克兰，是一种烟碱乙酰胆碱受体部分激动剂，主要用于帮助戒烟。自广泛批准使用以来，伐伦克林导致血清酶升高发生率较低，且极少引起明显的急性肝损伤。

作用机制

伐伦克林作为α4β2-烟碱乙酰胆碱受体的部分激动剂，通过阻止尼古丁（烟碱）与α4β2-尼古丁乙酰胆碱受体的结合，并提供部分激动作用，从而减轻对尼古丁的依赖。在戒烟过程中使用伐伦克林可提高戒烟成功率并减少复发情况。

反应信息

• 作为反应物：
  描述：

  伐伦克林 在 氢溴酸 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以84%的产率得到varenicline hydrobromide
  参考文献：
  名称：

  [EN] VARENICLINE SALTS AND CRYSTAL FORMS THEREOF
  [FR] SELS DE LA VARÉNICLINE ET LEURS FORMES CRISTALLINES

  摘要：

  本发明提供了瓦伦尼克林的盐和固态形式，制备瓦伦尼克林盐和固态形式的方法，以及其制剂。

  公开号：

  WO2011140431A1
• 作为产物：
  描述：

  N-benzylvarenicline 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以90%的产率得到伐伦克林
  参考文献：
  名称：

  伐尼克兰的合成方法

  摘要：

  本发明涉及一种制备伐尼克兰或其药学上可接受的盐的工艺。本发明还涉及在此过程中有用的中间化合物和这种中间化合物的制备。

  公开号：

  CN113185513B

文献信息

• [EN] COMBINATION THERAPY FOR NICOTINE ADDICTION<br/>[FR] POLYTHÉRAPIE POUR LA DÉPENDANCE À LA NICOTINE
  申请人：AMYGDALA NEUROSCIENCES INC

  公开号：WO2020023792A1

  公开（公告）日：2020-01-30

  Disclosed is a combination therapy for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of an ALDH-2 inhibitor, such as a compound of Formula (I), in combination with an amount of the nicotinic acetylcholine receptor agonist, varenicline. The disclosure further relates to methods and pharmaceutical compositions useful with the combination therapy.

  揭示了一种用于减少哺乳动物尼古丁成瘾或帮助戒烟或减少烟草使用的联合疗法，包括向该哺乳动物施用一定量的ALDH-2抑制剂，如式（I）化合物，与一定量的尼古丁乙酰胆碱受体激动剂维拉尼克林相结合。该公开还涉及与该联合疗法有用的方法和药物组合。
• AZOLOPYRIDIN-3-ONE DERIVATIVES AS INHIBITORS OF LIPASES AND PHOSPHOLIPASES
  申请人：Petry Stefan

  公开号：US20130157941A1

  公开（公告）日：2013-06-20

  The present invention relates to azolopyridin-3-one derivatives of the general formula (I) with the meanings specified in the description, to their pharmaceutically usable salts and to their use as drug substances.

  本发明涉及通式（I）所示的咪唑吡啶-3-酮衍生物，其含义如描述中所指定的，以及它们的药用盐和作为药物物质的用途。
• [EN] HIGHLY PURE VARENICLINE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF SUBSTANTIALLY FREE OF METHYLVARENICLINE IMPURITY<br/>[FR] VARÉNICLINE DE HAUTE PURETÉ OU SON SEL PHARMACEUTIQUEMENT ACCEPTABLE SENSIBLEMENT EXEMPT D'IMPURETÉ MÉTHYLVARÉNICLINE
  申请人：ACTAVIS GROUP PTC EHF

  公开号：WO2011110954A1

  公开（公告）日：2011-09-15

  Provided herein is an impurity of varenicline, 6-methyl-5,8,14-triazatetracyclo[l 0.3.1.02'n,04'9]hexadeca-2(l l),3,5,7,9-pentaene (methylvarenicline) impurity, and a process for the preparation and isolation thereof. Provided further herein is a highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity, a process for the preparation thereof, and pharmaceutical compositions comprising highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity.

  本文提供了瓦伦尼克林的杂质，即6-甲基-5,8,14-三氮杂四环[10.3.1.02'n,04'9]十六烯-2(11),3,5,7,9-五烯（甲基瓦伦尼克林）杂质的制备和分离方法。此外，本文还提供了一种高纯度的瓦伦尼克林或其在实质上不含甲基瓦伦尼克林杂质的药用盐，以及其制备方法和包含高纯度瓦伦尼克林或其在实质上不含甲基瓦伦尼克林杂质的药用盐的药物组合物。
• Catalytic Enantioselective Pyridine <i>N</i>-Oxidation
  作者：Sheng-Ying Hsieh、Yu Tang、Simone Crotti、Elizabeth A. Stone、Scott J. Miller

  DOI：10.1021/jacs.9b10414

  日期：2019.11.20

  The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center

  描述了取代吡啶的催化、对映选择性 N-氧化反应。该方法基于生物分子启发的催化循环，其中当天冬氨酰侧链在游离酸和过酸形式之间穿梭时，含天冬氨酸的肽提供高水平的不对称诱导。证明了带有被能够与催化剂形成氢键的基团取代的远程前立体中心的双(吡啶)底物的去对称化。我们的方法为富含杂环的分子环境中的手性吡啶框架提供了新的途径。对映体富集的吡啶 N-氧化物的代表性官能化进一步证明了该方法的实用性。两种古老的类药物支架（氯雷他定和伐尼克兰）中的不对称 N-氧化证明表明该方法在高度可变和独特的手性环境中可能具有普遍性，同时也揭示了该方法适用于吡啶和 1, 4-吡嗪类。
• Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine <i>N</i> ‐Acetyltransferase NAT2
  作者：Louis P. Conway、Veronica Rendo、Mário S. P. Correia、Ingvar A. Bergdahl、Tobias Sjöblom、Daniel Globisch

  DOI：10.1002/anie.202005915

  日期：2020.8.17

  play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N‐acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamine N‐acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased

  N-乙酰基转移酶在异生物质（包括临床药物）的失活和清除中发挥着关键作用。NAT2被归类为芳胺N-乙酰转移酶，主要转化芳香胺、羟胺和肼。在此，我们证明人芳胺N-乙酰转移酶 NAT2 也乙酰化脂肪族内源胺。代谢组学分析和化学合成表明，与慢速乙酰化NAT2表型相比，表达快速乙酰化剂NAT2表型的人类细胞系中单乙酰化亚精胺和二乙酰化亚精胺的细胞内浓度增加。NAT2 对单乙酰化亚精胺的区域选择性N 8乙酰化回答了二乙酰亚精胺来源这一长期存在的问题。我们还发现了 NAT2 对结构多样的含烷基胺药物的选择性乙酰化，这可能会导致患者反应的变化。结果表明 NAT2 具有以前未知的功能和潜在的调节作用，我们建议应考虑对该酶进行重新分类。