伊博格碱 | 83-74-9

• 物质功能分类: 天然产物 - 生物碱
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 依波格型生物碱
• 中文名称: 伊博格碱
• 英文名称: ibogaine
• 英文别名: Ibogain；12-methoxyibogamine；(1R,15R,17S,18S)-17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraene
• CAS: 83-74-9
• 化学式: C₂₀H₂₆N₂O
• 分子量: 310.439
• InChiKey: HSIBGVUMFOSJPD-CFDPKNGZSA-N

物化性质

• 熔点：
  152-153°
• 比旋光度：
  D20 -53° (in 95% ethanol)
• 沸点：
  450.59°C (rough estimate)
• 密度：
  1.0633 (rough estimate)
• 溶解度：
  In water, 257 mg/L at 25 °C (est)
• 蒸汽压力：
  3.03X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions. /Ibogaine hydrochloride/

• 旋光度：
  Specific optical rotation: -53 deg at 20 °C/D in ethanol
• 解离常数：
  pKa1 = -5.03; pKa2 = 8.97 (tertiary amine); pKa3 = 17.08 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  28.3
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

伊博加因是一种具有潜在治疗鸦片和可卡因成瘾作用的活性生物碱。其主要代谢物通过在12位上进行O-脱甲基反应产生12-羟基伊博加胺。在本报告中，提出了证据表明伊博加因在人肝微粒体中观察到的O-脱甲基反应主要由多态性表达的细胞色素P-4502D6（CYP2D6）催化。对汇集人肝微粒体中伊博加因O-脱甲基酶活性的酶动力学检查表明，有两个（或更多）酶参与这一反应：一个具有低KMapp（1.1 uM），另一个具有高KMapp（>200 uM）。低KMapp活性占总内在清除率的>95%。来自三个个体捐赠者的肝微粒体显示出相似的酶动力学参数（低和高KM活性的平均KMapp分别为0.55 +/- 0.09 uM和310 +/- 10 microM）。然而，第四个肝微粒体样本似乎是一个表型CYP2D6差代谢者，仅具有高KMapp活性。在一组人捐赠者的肝微粒体中，低KMapp伊博加因O-脱甲基酶活性与CYP2D6催化的布夫拉醇1'-羟基化酶活性相关，而与其他P450同种型特异性活性无关。奎尼丁，一种CYP2D6特异性抑制剂，抑制了伊博加因O-脱甲基酶（IC50 = 0.2 uM），而其他P450同种型特异性抑制剂没有抑制这种活性。此外，在一组重组异源表达的人P450同种型中，只有rCYP2D6具有显著的伊博加因O-脱甲基酶活性。因此，可以得出结论，伊博加因O-脱甲基酶是由CYP2D6催化的，并且这个同种型是人类伊博加因O-脱甲基的主要酶。报告还讨论了这些发现的潜在药理影响。

Ibogaine is a psychoactive alkaloid that possesses potential as an agent to treat opiate and cocaine addiction. The primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine. In this report, evidence is presented that the O-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaine O-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low KMapp (1.1 uM) and the other with a high KMapp (>200 uM). The low KMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean KMapp = 0.55 +/- 0.09 uM and 310 +/- 10 microM for low and high KM activities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high KMapp activity. In hepatic microsomes from a panel of human donors, the low KMapp ibogaine O-demethylase activity correlated with CYP2D6-catalyzed bufuralol 1'-hydroxylase activity but not with other P450 isoform-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibited ibogaine O-demethylase (IC50 = 0.2 uM), whereas other P450 isoform-specific inhibitors did not inhibit this activity. Also, of a battery of recombinant heterologously expressed human P450 isoforms, only rCYP2D6 possessed significant ibogaine O-demethylase activity. Thus, it is concluded that ibogaine O-demethylase is catalyzed by CYP2D6 and that this isoform is the predominant enzyme of ibogaine O-demethylation in humans. The potential pharmacological implications of these findings are discussed.

来源:Hazardous Substances Data Bank (HSDB)

代谢

作者们报告了在一例48岁的白人男性体内，主要代谢物为诺伊波加因的伊波加因的组织分布情况。该男性有药物滥用史，因摄入伊波加因树皮后在家中死亡。使用完全验证的液相色谱-电喷雾质谱法对组织和液体中的伊波加因和诺伊波加因进行了量化。除了心脏组织外，所有调查的组织中均发现了伊波加因和诺伊波加因。在脾、肝、脑和肺中发现了最高的浓度。伊波加因的组织/锁骨下血液浓度比分别为1.78、3.75、1.16和4.64，诺伊波加因的比分别为0.83、2.43、0.90和2.69，分别对应脾、肝、脑和肺。在前列腺组织中发现了这两种药物非常低的浓度。伊波加因和诺伊波加因都会分泌到胆汁中并穿越血脑屏障。在大多数研究组织中还检测到了另外四种化合物。其中一种被确认为伊波加胺。不幸的是，由于缺乏参考物质，作者们无法确定另外三种化合物的身份。其中两种可能归因于以下氧化产物：伊波替宁和去甲氧基伊波替宁。第三种化合物可能是伊波加啉。

/The authors/ report ... the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated. The highest concentrations were found in spleen, liver, brain, and lung. The tissue/subclavian blood concentration ratios averaged 1.78, 3.75, 1.16, and 4.64 for ibogaine and 0.83, 2.43, 0.90, and 2.69 for noribogaine for spleen, liver, brain, and lung, respectively. Very low concentrations of the two drugs were found in the prostatic tissue. Both ibogaine and noribogaine are secreted in the bile and cross the blood-brain barrier. Four other compounds were detected in most of the studied matrices. One of them was identified as ibogamine. Unfortunately, /the authors/ were not able to positively identify the other three compounds because of the unavailability of reference substances. Two of them could possibly be attributed to the following oxidation products: iboluteine and desmethoxyiboluteine. The third compound could be ibogaline.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/CASE REPORTS/ /The authors/报告了一名男子在摄入粉状伊博加根后十二小时死亡的案例，通常人们因其刺激性和致幻性质而服用它。通过液-液提取后的GC-MS/MS方法，在摄入的粉末和受害者的体液中定量了伊博加因和伊博加胺。在现场采取的血样和尸检过程中采取的外周血、尿液和胃液样本中测得的伊博加因浓度分别为0.65、1.27、1.7和53.5微克/毫升，而粉末中的伊博加含量为7.2%。此外，对生物样本的系统毒理分析显示，存在治疗浓度的地西泮和美沙酮。死亡归因于同时摄入大量伊博加、美沙酮和地西泮。

/CASE REPORTS/ /The authors/ report the case of a man who died twelve hours after ingesting powdered iboga root, commonly taken for its stimulant and hallucinogenic properties. Ibogaine and ibogamine were quantified in the powder ingested and the victim's body fluids by GC-MS/MS after liquid-liquid extraction. The concentrations of ibogaine measured in the blood samples taken at the scene and in the peripheral blood, urine, and gastric fluid samples taken during the autopsy were 0.65, 1.27, 1.7, and 53.5 ug/mL, while the iboga content in the powder was 7.2%. Moreover, systematic toxicological analyses of biological samples showed the presence of diazepam and methadone in therapeutic concentrations. Death was attributed to the ingestion of a substantial quantity of iboga in the context of simultaneous methadone and diazepam consumption.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/病例报告/ 伊博格碱是一种天然生物碱，来源于雨林灌木Tabernanthe iboga的根部。已经发生了与使用伊博格碱有关的暂时性死亡事件。然而，尽管伊博格碱没有被批准作为治疗药物，且有证据表明伊博格碱可能会干扰心脏的节律，这种生物碱目前在替代医学中作为抗成瘾药物用于戒毒目的。我们报告了一个男性使用伊博格碱进行酒精戒毒治疗12-24小时后突然死亡的案例。尸检发现了肝硬化和重度脂肪浸润。伊博格碱的浓度为2 mg/L。讨论了伊博格碱使用的潜在风险，特别是对于有病理医学背景的人。

/CASE REPORTS/ Ibogaine is a naturally occurring alkaloid derived from the roots of the rain forest shrub Tabernanthe iboga. Deaths have occurred temporarily related to the use of ibogaine. However, although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, this alkaloid is currently used as an anti-addiction drug in alternative medicine for detoxification purposes. We report the case of a man who died suddenly 12-24 hr after ibogaine use for alcohol detoxification treatment. In the autopsy liver cirrhosis and heavy fatty infiltration was found. The concentration of ibogaine was 2 mg/L. The potential risks of ibogaine use, especially for persons with pathological medical background, are discussed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了研究伊博格因这种潜在的抗成瘾生物碱的药代动力学特性，在大鼠静脉输注后长达3小时的时间内，定量测定了血浆和组织中这种药物的浓度。在31-35分钟输注后（20 mg/kg），平均血浆伊博格因水平为373 ng/mL；此后这些值迅速以双指数方式下降。7只动物中有5只的血浆时间过程与双室药代动力学模型非常吻合，α和β半衰期分别为7.3分钟和3.3小时。药物清除率估计为5.9 L/hr（n = 7）。药物输注结束3小时后，大脑、肝脏和肾脏中的伊博格因水平为143-170 ng/g，接近于模拟的外周药代动力学室值。然而，3小时后脂肪组织中的药物水平要高得多（3,328 ng/g），这意味着需要更复杂的药代动力学模型。血浆中伊博格因最初迅速消失的机制可能包括代谢去甲基化以及重新分布到体内储存。脂肪组织对伊博格因的隔离可能是药物在体内持续存在的原因之一。这种持续性可能被本研究报告的β半衰期所低估。

To investigate the pharmacokinetic properties of ibogaine, a putatively anti-addictive alkaloid, levels of this drug were quantified in plasma and tissues for up to 3 hr following i.v. infusion in rats. Immediately following a 31-35 min infusion (20 mg/kg), mean plasma ibogaine levels were 373 ng/mL; these values declined rapidly thereafter in a biexponential manner. The plasma time course in 5 of 7 animals demonstrated an excellent fit to a two-compartment pharmacokinetic model, with alpha and beta half-lives of 7.3 min and 3.3 hr, respectively. Drug clearance was estimated to be 5.9 L/hr (n = 7). Ibogaine levels in brain, liver and kidney 3 hr after the end of drug infusion were 143-170 ng/g, close to simulated values for the peripheral pharmacokinetic compartment. However, 3-hr drug levels in adipose tissue were much higher (3,328 ng/g), implying the need for a more complex pharmacokinetic model. Mechanisms for the initial, rapid disappearance of plasma ibogaine are thought to include metabolic demethylation as well as redistribution to body stores. The sequestration of ibogaine by adipose tissue probably contributes to a protracted persistence of drug in the body. This persistence may be underestimated by the beta half-life reported in the present study.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

疑似具有抗成瘾作用的物质伊波加因在大鼠经腹腔（ip）和皮下（sc）给药后的血浆、大脑、肾脏、肝脏和脂肪中的分布进行了测量。腹腔给药一小时后（剂量为40 mg/kg），药物水平从106 ng/ml（血浆）到11,308 ng/g（脂肪）不等，皮下给药同一剂量后药物水平显著更高。给药12小时后，药物水平降低了10-20倍。这些结果提示：1）伊波加因在腹腔给药后受到了显著的“首过效应”，这通过皮下给药后更高的药物水平得到了证明，2）伊波加因在脂肪组织中大量积累，与其亲脂性性质一致，3）药物在脂肪中的持久性可能是其作用持续时间长的原因。

The distribution of the putative anti-addictive substance ibogaine was measured in plasma, brain, kidney, liver and fat after ip and sc administration in rats. One hr after ip dosing (40 mg/kg), drug levels ranged from 106 ng/ml (plasma) to 11,308 ng/g (fat), with significantly higher values after sc administration of the same dose. Drug levels were 10-20 fold lower 12 hr after the same dose. These results suggest that: 1) ibogaine is subject to a substantial "first pass" effect after ip dosing, demonstrated by higher drug levels following the sc route, 2) ibogaine shows a large accumulation in adipose tissue, consistent with its lipophilic nature, and 3) persistence of the drug in fat may contribute to a long duration of action.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

作者们报告了在一例48岁的白人男性体内，伊博加因（ibogaine）及其主要代谢物诺伊博加因（noribogaine）的分布情况，该男性有药物滥用史，因摄入Tabernanthe iboga树根皮导致中毒，在其家中被发现死亡。使用完全验证的液相色谱-电喷雾质谱法对组织和液体中的伊博加因和诺伊博加因进行了量化。除了心脏组织外，所有调查的组织中均检测到伊博加因和诺伊博加因。在脾、肝、脑和肺中发现了最高的浓度。伊博加因的组织/锁骨下血液浓度比分别为1.78、3.75、1.16和4.64，诺伊博加因的比分别为0.83、2.43、0.90和2.69，分别对应脾、肝、脑和肺。前列腺组织中发现了这两种药物非常低的浓度。伊博加因和诺伊博加因都会分泌到胆汁中并跨越血脑屏障。在大多数研究组织中还检测到了另外四种化合物。其中一种被确认为伊博胺（ibogamine）。遗憾的是，由于缺乏参考物质，作者们无法确认另外三种化合物。其中两种可能归因于以下氧化产物：伊博醇（iboluteine）和去甲氧基伊博醇（desmethoxyiboluteine）。第三种化合物可能是伊博拉因（ibogaline）。

/The authors/ report ... the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated. The highest concentrations were found in spleen, liver, brain, and lung. The tissue/subclavian blood concentration ratios averaged 1.78, 3.75, 1.16, and 4.64 for ibogaine and 0.83, 2.43, 0.90, and 2.69 for noribogaine for spleen, liver, brain, and lung, respectively. Very low concentrations of the two drugs were found in the prostatic tissue. Both ibogaine and noribogaine are secreted in the bile and cross the blood-brain barrier. Four other compounds were detected in most of the studied matrices. One of them was identified as ibogamine. Unfortunately, /the authors/ were not able to positively identify the other three compounds because of the unavailability of reference substances. Two of them could possibly be attributed to the following oxidation products: iboluteine and desmethoxyiboluteine. The third compound could be ibogaline.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  F,T
• 安全说明：
  S16,S36/37,S45,S7
• 危险类别码：
  R11,R23/24/25,R39/23/24/25
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 1544

反应信息

• 作为反应物：
  描述：

  伊博格碱 在 盐酸 作用下， 以 乙醚 为溶剂， 生成 伊菠加因盐酸盐
  参考文献：
  名称：

  A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats

  摘要：

  Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 mu M of free drug), while the ibogaine's antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine similar to 0.5 mu M, noribogaine similar to 2.5 mu M). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.

  DOI：

  10.1021/acschemneuro.0c00152
• 作为产物：
  描述：

  12-methoxy-ibogamin-19-one 在 四氢呋喃 、 lithium aluminium tetrahydride 作用下， 生成 伊博格碱
  参考文献：
  名称：

  US2877229

  摘要：

  公开号：

文献信息

• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• [EN] A NEW CLASS OF MU-OPIOID RECEPTOR AGONISTS<br/>[FR] NOUVELLE CLASSE D'AGONISTES DU RÉCEPTEUR MU-OPIOÏDE
  申请人：UNIV COLUMBIA

  公开号：WO2015138791A1

  公开（公告）日：2015-09-17

  The present invention provides a compound having the structure (I) or a pharmaceutically acceptable salt or ester thereof.

  本发明提供了一种具有结构（I）的化合物或其药用可接受的盐或酯。
• Heteroaryl-Substituted Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
  申请人：Pfizer Inc.

  公开号：US20140228356A1

  公开（公告）日：2014-08-14

  The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, and the variables R 1 and R 2 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明涉及所披露的化合物、互变异构体和该化合物的药用可接受盐，其中该化合物具有如下式的结构， 变量R1和R2如规范中所定义。还披露了相应的药用组合物、治疗方法、合成方法和中间体。
• Heterocyclic Substituted Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds
  申请人：PFIZER INC.

  公开号：US20130296308A1

  公开（公告）日：2013-11-07

  Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  揭示了化合物、互变异构体和该化合物的药学上可接受的盐，其中该化合物具有如规范中定义的Formula I的结构。还披露了相应的药物组合物、治疗方法、合成方法和中间体。
• [EN] DEUTERATED MORPHINE DERIVATIVES<br/>[FR] DÉRIVÉS DE MORPHINE DEUTÉRÉS
  申请人：SZEGEDI TUDOMÁNYEGYETEM

  公开号：WO2014170704A1

  公开（公告）日：2014-10-23

  The invention relates to new morphine derivatives deuterated at the 7,8-position of the morphine ring, furthermore to a process for the preparation thereof, and to pharmaceutical compositions comprising them. The new deuterated morphine derivatives show high and selective μ-opioid receptor binding activity leading to the benefit of higher analgesic activity at lower dosages inducing thereby reduced adverse effects compared to the hydrogenated derivatives. The compounds of the invention are useful for example in the treatment of pain or can be used as antitussive agents with a reduced risk of the possibility of drug abuse.

  这项发明涉及新的吗啡衍生物，其在吗啡环的7,8-位置被氘代取，此外还涉及其制备方法以及包含它们的药物组合物。这些新的氘代吗啡衍生物显示出高度和选择性的μ-阿片受体结合活性，从而在较低剂量下产生更高的镇痛活性，因此与氢化衍生物相比，减少了不良反应。该发明的化合物可用于例如治疗疼痛，或可用作镇咳剂，具有较低的药物滥用可能性。