西布曲明 | 106650-56-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 西布曲明
• 中文别名: 1-(4-氯苯基)-N,N-二甲基-Α-(2-甲基丙基)环丁甲胺；斯丁垂明；诺美亭；N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N-二甲胺；N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N,N’-二甲胺一水合盐酸盐；西部曲明
• 英文名称: sibutramine
• 英文别名: N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine；1-[1-(4-chlorophenyl)cyclobutyl]-N,N,3-trimethylbutan-1-amine
• CAS: 106650-56-0
• 化学式: C₁₇H₂₆ClN
• mdl: MFCD00865450
• 分子量: 279.853
• InChiKey: UNAANXDKBXWMLN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

为了研究在单次口服西布曲明后，西布曲明的两个药理活性代谢物（代谢物1和2）在健康青年和老年志愿者体内的药代动力学。这是一项开放、平行组研究，由12名青年（六男六女；平均年龄24.0岁）和12名老年（六男六女；平均年龄70.3岁）健康志愿者完成。在给药后长达48小时内，间隔采集血样。使用HPLC-MS测定血浆中代谢物的浓度。比较了两个年龄组两种代谢物的模型独立药代动力学参数。两种去甲基代谢物的血浆浓度曲线相似，表明尽管由于年龄可能导致肝脏功能降低，但这两个代谢物的形成速率和程度在青年和老年志愿者中是相同的，即西布曲明在老年受试者中的代谢没有受损。两组之间代谢物2的消除也没有显著差异，尽管老年组显示出轻微的k(el)降低趋势。在这项研究中，西布曲明的两个药理活性代谢物（代谢物1和2）的药代动力学在青年和老年组之间没有显著差异。基于这些信息，对于青年和老年人群，可以采用类似的给药方案。

To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine. This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 hr post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups. The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in k(el). The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly.

来源:Hazardous Substances Data Bank (HSDB)

代谢

西布曲明主要在肝脏通过细胞色素P450（3A4）同工酶代谢，形成去甲基代谢物M1和M2。这些活性代谢物通过羟基化和结合进一步代谢为药理学上不活跃的代谢物M5和M6。在口服放射性标记的西布曲明后，血浆中几乎所有的峰值放射性物质都是由未改变的西布曲明（3%）、M1（6%）、M2（12%）、M5（52%）和M6（27%）组成。M1和M2的血浆浓度在给药四天内达到稳态，并且比单次给药后大约高两倍。M1和M2的消除半衰期分别为14小时和16小时，在重复给药后保持不变。

Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M1 (6%), M2 (12%), M5 (52%), and M6 (27%). M1 and M2 plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M1 and M2, 14 and 16 hours, respectively, were unchanged following repeated dosing.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏 消除途径：西布曲明主要在肝脏通过细胞色素P450（3A4）同工酶代谢，生成去甲基代谢物M1和M2。这些活性代谢物通过羟基化和结合进一步代谢为药理学上不活跃的代谢物M5和M6。大约85%（范围68-95%）的单次口服给药的放射性剂量在15天的收集期内通过尿液和粪便排出，其中大部分剂量（77%）通过尿液排出。M1和M2的主要排泄途径是肝脏代谢，而M5和M6的主要排泄途径是肾脏排泄。 半衰期：1.1小时

Hepatic Route of Elimination: Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion. Half Life: 1.1 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

西布曲明通过抑制神经突触中的去甲肾上腺素（NE）、血清素（5-羟色胺，5-HT）以及较少程度上多巴胺的再摄取，产生其治疗作用。通过抑制这些神经递质的再摄取，西布曲明促进饱腹感和食欲减少，从而减少食物摄入。动物研究的数据还表明，西布曲明可能通过在基础状态和进食状态下增加热生成效应来增加能量消耗，但这在人类中尚未得到证实。西布曲明及其主要药理活性代谢物（M1和M2）并非通过释放单胺发挥作用。

Sibutramine produces its therapeutic effects by inhibition of norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), and to a lesser extent, dopamine reuptake at the neuronal synapse. By inhibiting the reuptake of these neurotransmitters, sibutramine promotes a sense of satiety and decrease in appetite, thereby reducing food intake. Data from animal studies also suggest that sibutramine may also increase energy expenditure through thermogenic effects in both the basal and fed states, but this has not been confirmed in humans. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

尽管西布曲明长期可用，但仅有一份关于西布曲明引起急性肝损伤的病例报告已发表。发病时间为2周，肝酶升高的模式为胆汁淤积型。肝损伤是非黄疸性的，病程自我限制（案例1）。免疫过敏和自身免疫特征缺失。目前尚未有关于西布曲明导致急性肝衰竭或慢性肝损伤的报告。

Sibutramine has not been linked to an increased rate of serum enzyme elevations during therapy, but the results of serum ALT monitoring have been reported only rarely. Despite its long term availability, only a single case report of acute liver injury attributed to sibutramine has been published. The time to onset was 2 weeks and the pattern of liver enzyme elevation was cholestatic. The liver injury was anicteric and self-limited in course (Case 1). Immunoallergic and autoimmune features were absent. There have been no reports of acute liver failure or chronic liver injury attributed to sibutramine.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：西布曲明

Compound:sibutramine

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：低药物性肝损伤关注

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：4

Severity Grade:4

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后快速吸收。西布曲明的绝对生物利用度尚不清楚，但至少77%的单次口服剂量被吸收。

Rapid absorption following oral administration. Absolute bioavailability is not known, but at least 77% of a single oral dose of sibutramine is absorbed.

来源:DrugBank

吸收、分配和排泄

• 消除途径

西布曲明主要在肝脏通过细胞色素P450（3A4）同种酶代谢，形成去甲基代谢物M1和M2。这些活性代谢物通过羟基化和结合进一步代谢为药理学上不活跃的代谢物M5和M6。大约85%（范围68-95%）的单次口服给予的放射性剂量在15天的收集期内通过尿液和粪便排出，其中大部分剂量（77%）通过尿液排出。M1和M2的主要排泄途径是肝脏代谢，而M5和M6的主要排泄途径是肾脏排泄。

Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion.

来源:DrugBank

吸收、分配和排泄

• 清除

口服 cl=1750 L/h [口服给药]

Oral cl=1750 L/h [oral administration]

来源:DrugBank

吸收、分配和排泄

口服放射性示踪的西布曲明后，血浆中峰值放射性物质几乎全部由未改变的西布曲明（3%）、M1（6%）、M2（12%）、M5（52%）和M6（27%）组成。

Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M1 (6%), M2 (12%), M5 (52%), and M6 (27%).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

西布曲明口服给药后从胃肠道迅速吸收（达峰时间为1.2小时），并在肝脏经历广泛的首过代谢（口服清除率为1750 L/小时，半衰期为1.1小时），形成药理活性的单脱甲基和双脱甲基代谢物M1和M2。M1和M2的血浆峰值浓度在3到4小时内达到。根据质量平衡研究，平均至少77%的西布曲明单次口服剂量被吸收。西布曲明的绝对生物利用度尚未确定。

Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/hr and half-life of 1.1 hr) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

制备方法

对氯苯乙腈、KOH和乙腈混合，按25%的比例缓慢滴入1,3-二溴丙烷。滴加完毕后继续搅拌1小时，然后加入蒸馏水并用乙酸乙酯萃取。萃取液经水洗、饱和食盐水洗，干燥过滤，减压浓缩后蒸馏，收集160℃/2.13kPa的馏分，得到化合物(Ⅰ)，收率73%～74%。

镁片溶于无水THF中，滴加异丁基溴反应1小时，然后缓慢滴加入化合物(Ⅰ)的无水THF溶液。滴完后回流4小时，冷却至室温。再将其滴入KBH4的异丙醇溶液中，继续回流4小时。放冷后加入适量水，并用乙酸乙酯萃取。萃取液经水和饱和食盐水洗涤、干燥过滤，滤液减压浓缩后蒸馏，收集170℃/0.67kPa的馏分，得到化合物(Ⅱ)，收率76%～79%。

将化合物(Ⅱ)、甲酸及1/2甲醛溶液在90～92℃下搅拌1小时。再加入剩余的1/2甲醛溶液，继续反应1小时。冷却至室温后，在搅拌下缓慢滴入氢氧化钠的碎冰液中，然后用乙醚萃取。萃取液经水和饱和食盐水洗涤、干燥过滤，滤液浓缩得到土黄色的西布曲明，收率94%。

分析样品可用乙醚重结晶，熔点为52～53℃。将西布曲明溶于甲醇中，加入浓盐酸并在50～60℃下反应10分钟。减压回收甲醇后，加入水并搅拌，冰浴冷却至室温过滤、洗涤，得到粗品盐酸西布曲明。用甲醇-水重结晶，可得白色结晶的盐酸西布曲明，熔点为194℃，收率83%。

合成制备方法

用于治疗肥胖症。

反应信息

• 作为反应物：
  描述：

  西布曲明 在 D-二苯甲酰酒石酸 作用下， 以 乙酸乙酯 为溶剂， 反应 0.5h， 生成 (R)-(+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine
  参考文献：
  名称：

  对映体纯西布曲明及其主要代谢物的首次制备，并通过单晶X射线分析确定其绝对构型

  摘要：

  用二苯甲酰基-d-酒石酸拆分外消旋的西布曲明，并通过其酒石酸二苯甲酰基酯的单晶X射线晶体学测定西布曲明的绝对立体化学。主要的活性代谢物（去甲基西布曲明）是通过将西布曲明用DEAD脱甲基而获得的。西布曲明的对映体纯度通过Ultron ES-OVM柱上的HPLC测定。

  DOI：

  10.1016/s0957-4166(99)00511-x
• 作为产物：
  描述：

  盐酸西布曲明 在 sodium hydroxide 作用下， 以 水 、 甲苯 为溶剂， 反应 0.25h， 以93%的产率得到西布曲明
  参考文献：
  名称：

  [EN] SIBUTRAMINE FREE BASE IN CRYSTALLINE FORM AND ITS PHARMACEUTICAL USE
  [FR] BASE LIBRE DE SIBUTRAMINE SOUS FORME CRISTALLINE ET UTILISATION PHARMACEUTIQUE DE CELLE-CI

  摘要：

  西布曲明，N- {1- [1- (4-氯苯基) 环丁基] -3-甲基丁基} -N，N-二甲基胺，以晶体形式存在的自由基，含有其的组合物和其用途。

  公开号：

  WO2004099119A1

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] IMIDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS IMIDAZOLE UTILES COMME INHIBITEURS DE LA FAAH
  申请人：MERCK & CO INC

  公开号：WO2009152025A1

  公开（公告）日：2009-12-17

  The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson's Disease.

  本发明涉及某些咪唑衍生物，其可用作脂肪酰胺水解酶（FAAH）的抑制剂。该发明还涉及包含这些化合物作为活性成分的药物配方，以及这些化合物及其配方在治疗某些疾病中的使用，包括骨关节炎、类风湿性关节炎、糖尿病性神经病、带状疱疹后神经痛、骨骼肌肉疼痛和纤维肌痛，以及急性疼痛、偏头痛、睡眠障碍、阿尔茨海默病和帕金森病。
• [EN] OXAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS D'OXAZOLE UTILES COMME INHIBITEURS DE FAAH
  申请人：MERCK & CO INC

  公开号：WO2010017079A1

  公开（公告）日：2010-02-11

  The present invention is directed to certain oxazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson's Disease.

  本发明涉及某些噁唑衍生物，其可用作脂肪酸酰胺水解酶（FAAH）的抑制剂。该发明还涉及包含这些化合物作为活性成分的药物配方，以及这些化合物及其配方在治疗某些疾病中的使用，包括骨关节炎、类风湿性关节炎、糖尿病神经病变、带状疱疹后神经痛、骨骼肌肉疼痛和纤维肌痛，以及急性疼痛、偏头痛、睡眠障碍、阿尔茨海默病和帕金森病。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。