左啡诺 | 77-07-6

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 中文名称: 左啡诺
• 中文别名: 左啡烷
• 英文名称: Levorphanol
• 英文别名: dextrorphan；(1R,9R,10R)-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-4-ol
• CAS: 77-07-6；297-90-5
• 化学式: C₁₇H₂₃NO
• 分子量: 257.376
• InChiKey: JAQUASYNZVUNQP-USXIJHARSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  19
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

左啡诺在肝脏中广泛代谢，并以葡萄糖苷酸代谢物的形式被消除。

Levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite.

来源:DrugBank

代谢

硫酸左啡诺主要在肝脏代谢，它与葡萄糖醛酸结合，并主要以葡萄糖醛酸结合物的形式通过尿液排出。

Levorphanol tartrate is metabolized primarily in the liver where it undergoes conjugation with glucuronic acid and is excreted primarily in urine as the glucuronide conjugate.

来源:Hazardous Substances Data Bank (HSDB)

代谢

左啡诺在肝脏中广泛代谢，并以葡萄糖苷酸代谢物的形式被消除。 半衰期：11-16小时

Levorphanol is extensively metabolized in the liver and is eliminated as the glucuronide metabolite. Half Life: 11-16 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

与其他mu-激动剂阿片类药物一样，人们认为它在大脑和脊髓的室周和导水管周围灰质上的受体发挥作用，以改变疼痛的传递和感知。

Like other mu-agonist opioids it is believed to act at receptors in the periventricular and periaqueductal gray matter in both the brain and spinal cord to alter the transmission and perception of pain.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

像大多数阿片类止痛药一样，左啡诺在治疗期间并未与血清酶水平升高或特异质、临床上明显的肝损伤病例有关联。 关于左啡诺的安全性和潜在肝毒性的参考资料在《阿片类药物》概述部分给出，最后更新于2019年4月。 药物类别：阿片类药物

Like most opioid analgesics, levorphanol has not been linked to serum enzyme elevations during therapy or to instances of idiosyncratic, clinically apparent liver injury. References on the safety and potential hepatotoxicity of levorphanol are given in the 0verview section of the Opioids, last updated April 2019. Drug Class: Opioids

来源:LiverTox

毒理性

• 药物性肝损伤

左啡诺

Compound:levorphanol

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：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

左啡诺在口服给药后吸收良好，给药后大约1小时血药浓度达到峰值。

Levorphanol is well absorbed after PO administration with peak plasma concentrations occurring approximately 1 hour after dosing.

来源:DrugBank

吸收、分配和排泄

• 分布容积

10到13升/千克

10 to 13 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

0.78到1.1升/公斤/小时

0.78 to 1.1 L/kg/hr

来源:DrugBank

吸收、分配和排泄

麻醉性镇痛药左啡诺的血浆浓度已在对患者进行静脉注射、肌肉注射和口服治疗剂量药物后确定。在两名接受单次静脉注射左啡诺的患者中，每个受试者的血浆浓度-时间曲线最好由三指数下降描述，其终末半衰期（t1/2）约为11小时。肌肉注射和口服给药后，完整药物的血药峰浓度通常分别在约0.5和1小时后达到。所有给药途径后，结合型（对β-葡萄糖醛酸酶敏感）左啡诺迅速出现在血浆中，并迅速达到比完整药物高5到10倍的浓度。在接受广泛范围的慢性口服和肌肉注射剂量的药物的患者中，有效的镇痛稳态浓度范围从大约10到100纳克/毫升，这些浓度与剂量或达到的主观镇痛效果无明显相关性。后者可能是药物在体内广泛且可变的“首过”代谢以及受体水平上不同程度的药理学耐受性的反映。然而，在非耐受患者中，似乎血浆浓度约为10纳克/毫升与积极的镇痛效果相关。此外，似乎对于每个受试者，镇痛作用通常在一个较窄的血浆浓度范围内维持，因为在一些患者中血浆浓度的相对较小降低可能与轻度或严重疼痛相关。在10名患者中的稳态血浆蛋白结合率平均为40 +/- 2.6%。在研究的2名患者的脑脊液中，药物的浓度是相应血浆水平的60到70%。

Plasma concentrations of the narcotic analgesic, levorphanol, have been determined following i.v., i.m. and oral administration of therapeutic doses of the drug to patients with pain. In two patients who received single i.v. doses of levorphanol the plasma concentration-time profile in each subject was best described by a triexponential decline of the concentrations with terminal half-lives (t 1/2) of about 11 hr. Following i.m. and oral administrations, peak plasma concentrations of intact drug were generally reached after about 0.5 and 1 hr, respectively. Conjugated (beta-glucuronidase labile) levorphanol appeared rapidly in plasma following all routes of administration and quickly reached concentrations which were 5 to 10 fold higher than the intact drug. Effective analgesic steady-state concentrations of levorphanol in patients receiving a wide range of chronic oral and i.m. dosages of the drug ranged from about 10 to 100 ng/ml and these concentrations showed no apparent correlation with either the dose or the subjective analgesic response achieved. The latter observations are probably a reflection of extensive and variable inter-subject "first-pass" metabolism of the drug combined with different degrees of pharmacologic tolerance at the receptor level. However, in the non-tolerant patient it appears that a plasma concentration of about 10 ng/ml is associated with a positive analgesic effect. Furthermore it seems that analgesia is often maintained within a narrow plasma concentration range for each subject in that relatively small decreases in plasma concentration in some patients may be associated with either mild or severe pain. Plasma protein binding at steady-state in 10 patients averaged 40 +/- 2.6%. Concentrations of the drug in the cerebrospinal fluid of 2 patients studied were 60 to 70% of the corresponding plasma levels of the drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

酒石酸左啡诺口服给药后吸收良好。口服给药后，大约1小时达到血浆峰浓度。多次口服给药后，通常在3天内达到稳态血浆浓度。酒石酸左啡诺的镇痛作用持续时间（6-8小时）比吗啡或美沙酮产生的时间长。

Levorphanol tartrate is well absorbed following oral administration. Following oral administration, peak plasma concentrations are achieved in about 1 hour. With multiple oral dosing, steady-state plasma concentrations usually are achieved in 3 days. Levorphanol's duration of analgesic effect (6-8 hours) is longer than that produced by morphine or meperidine.

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
  左美沙芬	levomethorphan	125-70-2	C18H25NO	271.403
  羟啡烷	rac-morphinan-3-ol	1531-12-0	C16H21NO	243.349
  (9alpha,13alpha,14alpha)-3-甲氧基-吗喃-17-甲醛	17-formyl-3-methoxymorphinan	28973-48-0	C18H23NO2	285.386

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  右羟吗喃	(+)-dextrorphan	125-73-5	C17H23NO	257.376
  ——	MCL-108	——	C20H29NO	299.456
  ——	butorphan	4163-26-2	C21H29NO	311.467
  非诺啡烷	MCL-112	468-07-5	C24H29NO	347.5
  17-(环丙基甲基)吗喃-3-醇	cyclorphan	4163-15-9	C20H27NO	297.44
  ——	MCL-126	——	C20H26N2O	310.439
  ——	MCL-107	——	C19H26FNO	303.42
  ——	NIH 9354	——	C19H24N2O	296.412
  ——	MCL-117	736-76-5	C19H23NO	281.398
  左洛啡烷	levallorphan	152-02-3	C19H25NO	283.414

反应信息

• 作为反应物：
  描述：

  左啡诺 在 水 作用下， 以 丙酮 为溶剂， 生成 3-hydroxy-N-methylmorphinan monohydrate
  参考文献：
  名称：

  Crystalline Forms of Levorphanol

  摘要：

  本发明涉及左旋吗啡的新型结晶多型形式，包括水合、溶剂化和非水合（非溶剂化）形式。该发明还描述了制备各种多型形式的方法。本发明还涉及含有左旋吗啡结晶多型的药物组合物，以及通过给药该药物组合物来缓解疼痛的方法。

  公开号：

  US20070281957A1
• 作为产物：
  描述：

  dextromethorphan hydrobromide 在 氢溴酸 作用下， 以100%的产率得到左啡诺
  参考文献：
  名称：

  3-取代的17-甲基吗啡喃类似物作为潜在的抗惊厥药的合成和评价。

  摘要：

  右美沙芬（1，（+）-3-甲氧基-17-甲基吗啡喃）在多种惊厥作用的体外和体内模型中均表现出抗惊厥活性。众所周知，1被代谢为其酚类衍生物右旋芬（2），该代谢产物也是有效的抗惊厥药。制备了一系列（+）-3-取代的17-甲基吗啡喃，它们在结构上与1相似，但预期不会代谢为2，或者与1相比可能以较低的速率代谢。三个类似物5（（（+）-3-氨基-17-甲基吗啡喃），14（（+）-3-乙氧基-17-甲基吗啡喃）和15（（+）-3-（2-丙氧基）-17-在大鼠超最大电击（MES）测试中，发现吗啡（甲基吗啡喃）具有强效的抗惊厥活性，且具有完全效力（分别为ED50 25、5.6和3.9 mg / kg，sc）。确定了这些化合物与大鼠脑和豚鼠脑亚细胞级分与[3H]右美沙芬（[3H] 1）标记的受体位点以及大鼠脑中[3H]噻吩基环己基哌啶（TCP）和[3H]甘氨酸的结合力。大多数类似物从其结合位点置换[3H] 1，化合物14（IC50

  DOI：

  10.1021/jm00100a019

文献信息

• Chromenone derivatives useful for the treatment of neurodegenerative diseases
  申请人：AxoGlia Therapeutics S.A.

  公开号：EP2112145A1

  公开（公告）日：2009-10-28

  Compounds of general formula (I) and (II) in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meanings given in the specification, are useful in the treatment of neurodegenerative disease.

  通式（I）和（II）的化合物 其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14和R15具有规范中给定的含义，在神经退行性疾病的治疗中是有用的。
• [EN] HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES POUR LE TRAITEMENT D'ÉTATS LIÉS AU STRESS
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2010137738A1

  公开（公告）日：2010-12-02

  The present invention provides a novel heterocyclic compound. A heterocyclic compound represented by general formula (1) wherein, R1 and R2, each independently represent hydrogen; a phenyl lower alkyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and the like on a benzene ring and/or a lower alkyl group; or a cyclo C3-C8 alkyl lower alkyl group; or the like; R3 represents a lower alkynyl group or the like; R4 represents a phenyl group that may have a substituent(s) selected from the group consisting of a 1,3,4-oxadiazolyl group that may have e.g., halogen or a heterocyclic group selected from pyridyl group and the like; the heterocyclic group may have at least one substituent(s) selected from a lower alkoxy group and the like or a salt thereof.

  本发明提供了一种新颖的杂环化合物。一种由通式（1）表示的杂环化合物，其中，R1和R2分别独立表示氢；苯基较低烷基基团，可能在苯环和/或较低烷基基团上具有从较低烷基基团等组成的取代基；或环C3-C8烷基较低烷基基团；或类似物；R3表示较低炔基基团或类似物；R4表示可能具有从1,3,4-噁二唑基团（例如，卤素）或从吡啶基团等组成的取代基的苯基团；所述杂环基可能具有至少一个从较低烷氧基等选择的取代基或其盐。
• [EN] ROR-GAMMA INHIBITORS<br/>[FR] INHIBITEURS DE ROR-GAMMA
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019063748A1

  公开（公告）日：2019-04-04

  The present invention relates to compounds of formula I and pharmaceutical compositions comprising compounds of formula I. Compounds of Formula I are useful in treatment of inflammatory, metabolic or autoimmune diseases which are mediated by RORy.

  本发明涉及公式I的化合物和包含公式I化合物的药物组合物。公式I的化合物在治疗由RORγ介导的炎症性、代谢性或自身免疫性疾病方面是有用的。
• [EN] NOVEL COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2015180612A1

  公开（公告）日：2015-12-03

  Disclosed are novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.

  揭示了新型视黄醇相关孤儿受体γ（RORγ）调节剂及其在通过RORγ介导的疾病治疗中的应用。
• Anti-angiogenic compounds
  申请人：Bradshaw W. Curt

  公开号：US20060205670A1

  公开（公告）日：2006-09-14

  The present invention provides AA targeting compounds which comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to treat disorders connected to abnormal angiogenesis.

  本发明提供了包括与抗体的结合位点连接的AA靶向剂-连接剂共轭物的AA靶向化合物。提供了化合物的各种用途，包括治疗与异常血管生成相关的疾病的方法。

表征谱图