阿芬太尼 | 71195-58-9

• 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: 阿芬太尼
• 中文别名: 阿芬他尼
• 英文名称: alfentanil
• 英文别名: N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide；N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)piperidin-4-yl]-N-phenylpropanamide；alfentanyl；N-{1-[2-(4-ethyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-ethyl]-4-methoxymethyl-piperidin-4-yl}-N-phenyl-propionamide；N-[1-(2-(4-ethyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)ethyl)-4-(methoxymethyl)piperidin-4-yl]-N-phenylpropionamide；N-[1-[2-(4-ethyl-5-oxotetrazol-1-yl)ethyl]-4-(methoxymethyl)piperidin-4-yl]-N-phenylpropanamide
• CAS: 71195-58-9
• 化学式: C₂₁H₃₂N₆O₃
• 分子量: 416.523
• InChiKey: IDBPHNDTYPBSNI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  81
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

肝脏是生物转化的主要场所。

The liver is the major site of biotransformation.

来源:DrugBank

代谢

阿芬太尼迅速代谢成大量代谢物，主要代谢途径是piperidine氮上的氧化O-脱甲基化和氧化N-脱烷基化。

Alfentanil was rapidly metabolized into a large number of metabolites with oxidative O-demethylation and oxidative N-dealkylation at the piperidine nitrogen as the major metabolic pathways.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏是生物转化的主要场所。

The liver is the major site of biotransformation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

alfentanil 已知的人体代谢物包括 Noralfentanil、2-(4-乙基-5-氧代-1,2,3,4-四唑-1-基)乙醛和 N-苯基丙酰胺。

Alfentanil has known human metabolites that include Noralfentanil, 2-(4-ethyl-5-oxo-1,2,3,4-tetrazol-1-yl)acetaldehyde, and N-phenylpropionamide.

来源:NORMAN Suspect List Exchange

代谢

肝脏是生物转化的主要场所。 消除途径：仅有1.0%的剂量以未改变药物的形态排出；尿液排泄是代谢物消除的主要途径。 半衰期：90-111分钟

The liver is the major site of biotransformation. Route of Elimination: Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Half Life: 90-111 minutes

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别和使用：阿芬太尼是二级管制物质。作为一种阿片类镇痛药，阿芬太尼可能对于麻醉、镇痛或类似于芬太尼的镇静有用途。人体研究：阿芬太尼注射液使患者和其他使用者面临阿片类药物成瘾、滥用和误用的风险，这可能导致过量服用和死亡。阿芬太尼注射液的急性过量可能表现为呼吸抑制、嗜睡进而发展为昏迷、骨骼肌松弛、皮肤湿冷、瞳孔缩小，在某些情况下还可能出现肺水肿、心动过缓、低血压、气道部分或完全阻塞、异常打鼾和死亡。在过量情况下，由于低氧血症，可能会出现显著的瞳孔散大而不是瞳孔缩小。由阿片类药物引起的呼吸抑制导致的二氧化碳潴留可能会加剧阿片类药物的镇静作用。当阿芬太尼以高剂量用于麻醉诱导时，胸壁僵直经常发生。已有报告称，在使用阿芬太尼注射液的同时使用血清素能药物时，出现了血清素综合征的病例，这是一种可能危及生命的情况。动物研究：阿芬太尼是一种强效且短效的μ阿片受体激动剂，可产生抗痛觉和肌肉僵直的作用。雄性和雌性比格犬每天静脉注射0、0.08、0.31或1.25 mg/kg的阿芬太尼，持续4周。在最初几天，有剂量相关的共济失调、僵直和呼吸暂停的发生。高剂量组的犬只偶尔出现呼吸暂停、抽搐和运动障碍。雄性和雌性大鼠每天静脉注射0、0.08、0.31或1.25 mg/kg的阿芬太尼，持续4周。阿芬太尼给药后2小时内死亡，归因于窒息。所有组别中观察到暂时的肌肉僵直、眼球突出和失去平衡反射。雌性大鼠从怀孕第16天开始至3周的哺乳期，静脉注射0、0.08、0.31或1.25 mg/kg的阿芬太尼。在19个高剂量窝中，有2个出现了食仔现象。0.31 mg/kg组的出生体重较低。0.31和1.25 mg/kg组的后代存活率较低，但没有观察到致畸作用。阿芬太尼的致突变潜力在Ames试验、微核试验和鼠优势致死试验中进行了评估。在任何试验中都没有发现致突变的证据。

IDENTIFICATION AND USE: Alfentanil is a Schedule II Controlled Substance. An opioid analgesic, alfentanil may be useful for anesthesia, analgesia, or sedation similar to fentanyl. HUMAN STUDIES: Alfentanil injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Acute overdose with Alfentanil injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. When alfentanil was given in high doses for anesthesia induction, chest wall rigidity occurred frequently. Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Alfentanil injection with serotonergic drugs. ANIMAL STUDIES: Alfentanil is a potent and short-acting mu opioid agonist that produces both antinociceptive effects and muscle rigidity. Male and female Beagle dogs were administered 0, 0.08, 0.31 or 1.25 mg/kg IV alfentanil daily for 4 weeks. There was a dose-related incidence of ataxia, catatonia, and apnea during the first few days. Dogs in the high-dose group experienced sporadic apnea, convulsions and dyskinesia. Alfentanil was administered daily to male and female rats in doses of 0, 0.08, 0.31 and 1.25 mg/kg IV for 4 weeks. Death occurred within 2 hours of alfentanil administration and were attributed to suffocation. Transient muscle rigidity, exophthalmos and loss of righting reflex were observed in all groups. Female rats were administered IV alfentanil 0, 0.08, 0.31 or 1.25 mg/kg from day 16 of pregnancy through a 3-week lactation period. Cannibalism occurred in 2 of 19 high-dose litters. Birth weight was lower in the 0.31 mg/kg group. Survival rates were lower in the offspring of the 0.31 and 1.25 mg/kg groups, but no teratogenic effects were observed. The mutagenicity potential of alfentanil was assessed in the Ames test, micronucleus test and the mouse dominant lethal test. There was no evidence of mutagenicity in any test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

阿片类药物的受体与G蛋白偶联，并通过激活效应蛋白的G蛋白，作为突触传递的正负调节因子。阿片类药物的结合刺激G蛋白复合物上的GTP与GDP的交换。由于效应系统是位于质膜内表面的腺苷酸环化酶和cAMP，阿片类药物通过抑制腺苷酸环化酶来降低细胞内cAMP。随后，抑制了如P物质、GABA、多巴胺、乙酰胆碱和去甲肾上腺素等伤害性神经递质的释放。阿片类药物还抑制vasopressin（血管加压素）、somatostatin（生长抑素）、胰岛素和胰高血糖素的释放。Alfentanil（阿芬太尼）的镇痛活性很可能是由于其转化为吗啡。阿片类药物关闭N型电压门控钙通道（OP2受体激动剂）并打开钙依赖性内向整流钾通道（OP3和OP1受体激动剂）。这导致超极化并减少神经元的兴奋性。

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Alfentanil's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

药物：阿芬太尼

Compound:alfentanil

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

仅供静脉注射或静脉输注使用。

For intravenous injection or infusion only.

来源:DrugBank

吸收、分配和排泄

• 消除途径

只有1.0%的剂量以未改变的药物形式被排出；尿液排泄是代谢物消除的主要途径。

Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.4到1升/千克

0.4 to 1 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

5毫升/千克/分钟

5 mL/kg/min

来源:DrugBank

吸收、分配和排泄

研究了阿芬太尼这种新的短效镇痛药在五位手术患者体内的分布和消除动力学。在给予120微克/毫升的剂量后，其行为符合三室开放模型分布。药物从血浆中消失的速度很快（t 1/2 pi = 3.5 +/- 1.3分钟，t 1/2 alpha = 16.8 +/- 6.4分钟），1小时内从血浆中清除了96.4%的药物，表明药物广泛转移到远端外周室。随后是较慢的消除阶段，t 1/2 beta为94 +/- 38分钟。总体分布容积为1.03 +/- 0.50 L/kg。总血浆清除率为456 +/- 155 ml/min。这种药物的短效镇痛作用可能归因于药物从中央和中间室迅速转移到远端外周室。大约25%的注射剂量在阿芬太尼给药后30至60分钟出现在远端外周室。由于药物从外周室返回到中央室的速度慢于药物的消除速率，这可能是阿芬太尼从体内消除的限速步骤。

The distribution and elimination kinetics of alfentanil, a new short-acting analgesic, were studied in five surgical patients. Its behavior, following a bolus injection of 120 micrograms/ml, was compatible with a three-compartment open-model distribution. The disappearance of the drug from plasma was rapid (t 1/2 pi = 3.5 +/- 1.3 minutes, t 1/2 alpha = 16.8 +/- 6.4 minutes) with 96.4% of the drug eliminated from plasma in 1 hour, indicating extensive transfer to the remote peripheral compartment. This was followed by a slower elimination phase with a t 1/2 beta of 94 +/- 38 minutes. Total volume of distribution was 1.03 +/- 0.50 L/kg. Total plasma clearance was 456 +/- 155 ml/min. The short analgesic effect of this drug might be attributed to the rapid displacement of the drug from the central and intermediate compartments to the remote peripheral compartment. Approximately 25% of the injected dose was present in the remote peripheral compartment 30 to 60 minutes after alfentanil administration. As the return of drug from this peripheral to the central compartment is slower than the elimination rate of the drug, it could be the rate-limiting step in the elimination of alfentanil from the body.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  阿芬太尼 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 生成 盐酸阿芬他尼
  参考文献：
  名称：

  一种利用连续流微通道反应器制备苯胺基哌啶类药物的合成方法

  摘要：

  本发明公开了一种利用连续流微通道反应器制备苯胺基哌啶类药物的合成方法。该方法通过控制物料流速和连续流微通道反应器各模块的温度，能有效提高苯胺基哌啶类药物最后一步合成的反应选择性和转化率。在此基础上，反应液经过简单的提取、浓缩操作后，有机溶剂溶解浓缩剩余物，加入相应的酸成盐，析晶，过滤，得到该药物的酸式盐粗品，再经过脱色和重结晶得到相应的酸式盐。此方法提供了一种利用连续流微通道反应器进行苯胺基哌啶类药物合成的途径，提高了反应的转化率和选择性，降低了杂质含量，简化了成盐精制步骤，提高产物收率，同时使产物纯度均达到99.8%以上。

  公开号：

  CN114262320A
• 作为产物：
  描述：

  盐酸阿芬他尼 在 盐酸阿芬他尼 、 盐酸 、 final product 、 甲烷 作用下， 以 水 为溶剂， 反应 2.0h， 生成 阿芬太尼
  参考文献：
  名称：

  New methods for the synthesis of alfentanil, sufentanil, and remifentanil

  摘要：

  本文披露了合成芬太尼衍生物或类似物的合成途径。具体而言，揭示了合成阿芬太尼、舒芬太尼和瑞芬太尼的途径。所披露的方法所需步骤较少，产量比先前报告的方法更高。

  公开号：

  US20060149071A1

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• 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。
• Controlled-release compositions containing opioid agonist and antagonist
  申请人：——

  公开号：US20020010127A1

  公开（公告）日：2002-01-24

  Controlled-release dosage forms containing an opioid agonist; an opioid antagonist; and a controlled release material release during a dosing interval an analgesic or sub-analgesic amount of the opioid agonist along with an amount of said opioid antagonist effective to attenuate a side effect of said opioid agonist. The dosage form provides analgesia for at least about 8 hours when administered to human patients. In other embodiments, the dose of antagonist released during the dosing interval enhances the analgesic potency of the opioid agonist.

  含有阿片激动剂、阿片拮抗剂和受控释放材料的控释剂型，其在给药间隔期间释放阿片激动剂的镇痛或亚镇痛量以及足以减轻所述阿片激动剂的副作用的阿片拮抗剂的量。当给予人类患者时，该剂型提供至少约8小时的镇痛作用。在其他实施例中，给药间隔期释放的拮抗剂剂量增强了阿片激动剂的镇痛效力。
• [EN] ANALGESIC COMPOUNDS<br/>[FR] COMPOSÉS ANALGÉSIQUES
  申请人：ZENO ROYALTIES & MILESTONES LLC

  公开号：WO2018213140A1

  公开（公告）日：2018-11-22

  Disclosed herein are compounds of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), methods of synthesizing compounds of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It), and methods of using compounds of Formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is) and (It) as an analgesic.

  本文披露了化合物的化学式（Ia）、（Ib）、（Ic）、（Id）、（Ie）、（If）、（Ig）、（Ih）、（Ik）、（Im）、（In）、（Io）、（Ip）、（Iq）、（Ir）、（Is）和（It），合成化合物的方法的化学式（Ia）、（Ib）、（Ic）、（Id）、（Ie）、（If）、（Ig）、（Ih）、（Ik）、（Im）、（In）、（Io）、（Ip）、（Iq）、（Ir）、（Is）和（It），以及使用化合物的方法的化学式（Ia）、（Ib）、（Ic）、（Id）、（Ie）、（If）、（Ig）、（Ih）、（Ik）、（Im）、（In）、（Io）、（Ip）、（Iq）、（Ir）、（Is）和（It）作为镇痛剂。
• [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。