四氢大麻酚 | 1972-08-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: 四氢大麻酚
• 中文别名: 屈大麻酚；9-四氢大麻酚；卓纳宾醇；卓那比醇；Δ9-四氢大麻酚；△-9-四羟基大麻醇；δ-9-四氢大麻酚
• 英文名称: dronabinol
• 英文别名: (-)-Δ⁹THC；THC；Δ⁹-tetrahydrocannabinol；tetrahydrocannabinol；delta-9-tetrahydrocannabinol；(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol；(-)-trans-Δ⁹-tetrahydrocannabinol；(-)-trans-Δ⁹-THC；Delta 9-THC；(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol；(−)-trans-Δ⁹-tetrahydrocannabinol；(2)-Δ⁹-tetrahydrocannabinol；(-)-trans-delta-9-tetrahydrocannabinol；δ9-THC；(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol
• CAS: 1972-08-3
• 化学式: C₂₁H₃₀O₂
• 分子量: 314.468
• InChiKey: CYQFCXCEBYINGO-IAGOWNOFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

大麻素（THC）主要在肝脏通过微粒体羟基化和氧化反应进行代谢，这些反应由细胞色素P450酶催化。11-羟基-Δ9-四氢大麻酚（11-OH-THC）是主要的活性代谢物，能够产生心理和行为效应，然后它被代谢成11-nor-9-羧基-Δ9-四氢大麻酚（THC-COOH），这是大麻素的主要非活性代谢物。屈大麻酚及其主要活性代谢物11-OH-Δ9-THC在血浆中的浓度大约相等。口服给药后，母药和代谢物的浓度在大约0.5到4小时达到峰值，并在几天内下降。

THC is primarily metabolized in the liver by microsomal hydroxylation and oxidation reactions catalyzed by Cytochrome P450 enzymes. 11-hydroxy-▵9-tetrahydrocannabinol (11-OH-THC) is the primary active metabolite, capable of producing psychological and behavioural effects, which is then metabolized into 11-nor-9-carboxy-▵ 9-tetrahydrocannabinol (THC-COOH), THC's primary inactive metabolite. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days.

来源:DrugBank

代谢

delta-8-和delta-9-THC的镇痛活性主要是由于11-羟基代谢物。

The analgesic activity of delta-8- and delta-9-THC is mainly due to the 11-hydroxy metabolite.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大麻素代谢物的研究现状与展望 大麻素是存在于大麻植物中的一类化合物，具有广泛的药理作用，包括镇痛、抗炎、抗肿瘤等。近年来，随着大麻素的合法化和医疗用途的增加，对大麻素代谢物的研究越来越受到关注。 大麻素的主要成分是Δ9-四氢大麻酚（THC），其代谢过程相对复杂，已经鉴定出超过80种代谢物。然而，对于大麻素结合物的形成和命运的了解要少得多。胆汁排泄是消除第二相代谢物的重要途径。本研究适应、验证并应用了一种液相色谱-串联质谱（LC-MS/MS）方法来测量口腔液体中的大麻素，并将其应用于10个胆汁样本。 在固相萃取和LC-MS/MS之后，测定了THC、11-羟基-Δ9-四氢大麻酚（11-OH-THC）、11-诺-9-羧基-Δ9-四氢大麻酚（THCCOOH）、大麻酚（CBN）、大麻二酚（CBD）、Δ9-四氢大麻酚酸A（THC-A）、11-诺-9-羧基-Δ9-四氢大麻酚葡萄糖苷酸（THCCOOH-gluc）和Δ9-四氢大麻酚葡萄糖苷酸（THC-gluc）。在胆汁样本中发现了高浓度的THCCOOH-gluc（范围：139-21275 ng/mL）。THCCOOH（7.7-1548 ng/mL）和THC-gluc（38-1366 ng/mL）的相对高水平也被测量到。THC-A，THC的植物前体，是唯一未被检测到的大麻素。这些结果表明，胆汁排泄是大麻素结合物消除的重要途径，其肠肝循环在分析大麻素血液消除曲线时是一个重要的考虑因素。此外，我们建议胆汁是筛选第二相大麻素代谢物的首选基质。

The metabolism of delta(9)-tetrahydrocannabinol (THC) is relatively complex, and over 80 metabolites have been identified. However, much less is known about the formation and fate of cannabinoid conjugates. Bile excretion is known to be an important route for the elimination of phase II metabolites. A liquid chromatography-tandem mass spectrometry LC-MS/MS procedure for measuring cannabinoids in oral fluid was adapted, validated and applied to 10 bile samples. THC, 11-hydroxy-delta(9)-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol (THCCOOH), cannabinol (CBN), cannabidiol (CBD), delta(9)-tetrahydrocannabinolic acid A (THC-A), 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol glucuronide (THCCOOH-gluc) and delta(9)-tetrahydrocannabinol glucuronide (THC-gluc) were determined following solid-phase extraction and LC-MS/MS. High concentrations of THCCOOH-gluc were found in bile samples (range: 139-21,275 ng/mL). Relatively high levels of THCCOOH (7.7-1548 ng/mL) and THC-gluc (38-1366 ng/mL) were also measured. THC-A, the plant precursor of THC, was the only cannabinoid that was not detected. These results show that biliary excretion is an important route of elimination for cannabinoids conjugates and that their enterohepatic recirculation is a significant factor to consider when analyzing blood elimination profiles of cannabinoids. Furthermore, we suggest that the bile is the matrix of choice for the screening of phase II cannabinoid metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

大麻代谢物11-诺-9-羧基-Δ-9-四氢大麻酚（C-THC）在头发中的存在通常被认为是摄入Δ-9-四氢大麻酚（THC）的决定性证据。在头发分析过程中，通过洗涤程序去除可能导致大麻烟雾或密切个人接触的任何潜在C-THC外部污染至关重要。在这里，我们进行了一系列实验来证明，当与正确的洗涤程序结合以去除潜在的外部污染时，C-THC是摄入大麻的可靠指标。

The presence of the metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (C-THC) in hair is generally accepted as the definitive proof of delta-9-tetrahydrocannabinol (THC) ingestion. During hair analysis, the removal of any potential C-THC external contamination that could result from marijuana smoke or close personal contact via a wash procedure is critical. Here, we performed a series of experiments to demonstrate that C-THC is the reliable indicator of marijuana ingestion when paired with the correct washing procedure to remove potential external contamination.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Dronabinol 经历广泛的首过肝脏代谢，主要通过微粒体羟基化，产生活性和非活性代谢物。Dronabinol 及其主要活性代谢物 11-OH-Δ-9-THC 在血浆中的浓度大约相等。

Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：delta 9-四氢大麻酚（THC，合成大麻酚）是一种浅黄色的树脂状油。在美国，这是一种被列为一级管制的物质。大麻的唯一合法医疗用途是减少癌症患者化疗的副作用，一些患者使用THC来降低青光眼的眼睛压力。 人体研究：口服20毫克的delta-9-THC或吸烟含有2% delta-9-THC的香烟，会对情绪、记忆、运动协调、认知能力、感觉、时间感和自我感知产生影响。最常见的反应是幸福感或欣快感增加，伴有放松和嗜睡的感觉，尤其是在独处时；在可以互动的情况下，嗜睡感不那么明显，并且常常会有自发性的大笑。短期记忆受损，执行需要多个心理步骤才能达到特定目标任务的能力下降。高剂量的delta 9-THC可以引起明显的幻觉、妄想和偏执感。思维变得混乱和无组织；人格解体和时间感改变更加突出。焦虑达到恐慌程度可能会取代欣快感，通常是因为感觉药物引起的状态将永远持续。足够高的剂量下，临床表现为伴有幻觉、人格解体和洞察力丧失的毒性精神病；这种情况可能会急性发生，也可能在使用数月后发生。由于吸食大麻，临床表现在青少年中长期记忆力受损，精神分裂症的发病率增加了六倍，19至30岁的口、颚、舌和肺癌，胎儿毒性，以及吸食大麻的母亲生的儿童的非淋巴细胞性白血病。研究飞机驾驶员在吸食一枝含有20毫克THC的香烟后的表现，表明性能受损可能持续吸烟后长达24小时。使用者可能没有意识到药物的影响。孕期吸食大麻的母亲所生的婴儿平均体重比不吸食大麻的控制组母亲所生的婴儿轻3.4盎司；在胎龄或先天性异常的发生率上没有统计学意义上的差异。 动物研究：没有证据表明1-顺式-delta 9-四氢大麻酚对给予12.5、25或50 mg/kg的雄性和雌性大鼠具有致癌活性。基于125 mg/kg组甲状腺滤泡细胞腺瘤发生率增加，THC在雄性和雌性小鼠中的致癌活性证据不明确。雄性和雌性小鼠的甲状腺滤泡细胞增生发生率增加，雄性小鼠的前胃增生和溃疡发生率增加。雌性大鼠的乳腺纤维腺瘤和子宫间质息肉的发生率降低，以及雄性大鼠的胰腺腺瘤、垂体腺瘤和睾丸间质细胞腺瘤的发生率降低，以及小鼠肝脏肿瘤的发生率降低。在一项长达77天的大鼠长期研究中，口服给药合成大麻酚的剂量为30至150 mg/平方米，降低了腹侧前列腺、精囊和附睾的重量，并导致精液量减少。睾丸中的精子生成、发育中的生殖细胞数量和莱迪格细胞数量也观察到减少。然而，精子计数、交配成功和睾酮水平并未受到影响。合成大麻酚在Ames试验、中国仓鼠卵巢细胞的体外染色体畸变试验和小鼠体内微核试验中不具有基因毒性。然而，在中国仓鼠卵巢细胞的姐妹染色单体交换试验中产生了微弱的阳性反应。大麻素通过激活大脑和周围组织中的G蛋白偶联大麻素受体产生许多效果。此外，还有证据表明存在非受体依赖性机制。

IDENTIFICATION AND USE: delta 9-tetrahydrocannabinol (THC, dronabinol) is light yellow resinous oil. This is a Schedule I controlled substance in the USA. The only legal medical application for marijuana is to reduce the adverse effects of chemotherapy for cancer patients, some patients have been given THC to reduce the pressure in the eye from glaucoma. HUMAN STUDIES: An oral dose of 20 mg of delta-9-THC or the smoking of a cigarette containing 2% delta-9-THC produces effects on mood, memory, motor coordination, cognitive ability, sensorium, time sense, and self-perception. Most commonly there is an increased sense of well-being or euphoria, accompanied by feelings of relaxation and sleepiness when subjects are alone; where users can interact, sleepiness is less pronounced and there is often spontaneous laughter. Short-term memory is impaired, and there is a deterioration in capacity to carry out tasks requiring multiple mental steps to reach a specific goal. High doses of delta 9-THC can induce frank hallucinations, delusions, and paranoid feelings. Thinking becomes confused and disorganized; depersonalization and altered time sense are accentuated. Anxiety reaching panic proportions may replace euphoria, often as a result of the feeling that the drug-induced state will never end. With high enough doses, the clinical picture is that of a toxic psychosis with hallucinations, depersonalization, and loss of insight; this can occur acutely or only after months of use. Clinical manifestations due to marijuana smoking have included long-term impairment of memory in adolescents, a sixfold increase in the incidence of schizophrenia, cancer of the mouth, jaw, tongue, and lungs in 19- to 30-year olds, fetotoxicity, and nonlymphoblastic leukemia in children of marijuana-smoking mothers. Studies of aircraft pilot performance following the smoking of one cigarette containing 20 mg of THC suggest that impairment of performance can last as long as 24 hours after smoking. The user may be unaware of the drug's influence. Babies born to mothers who smoked marijuana during pregnancy weighed an average of 3.4 ounces less than babies born to a control group of mothers who did not smoke marijuana; there was no statistically significant difference in either gestational age or frequency of congenital abnormalities. ANIMAL STUDIES: There was no evidence of carcinogenic activity of 1-trans-delta 9-tetrahydrocannabinol in male or female rats administered 12.5, 25, or 50 mg/kg. There was equivocal evidence of carcinogenic activity of THC in male and female mice based on the increased incidences of thyroid gland follicular cell adenomas in 125 mg/kg groups. Increased incidences of thyroid gland follicular cell hyperplasia occurred in male and female mice, and increased incidences of hyperplasia and ulcers of the forestomach were observed in male mice. The incidences of mammary gland fibroadenomas and uterine stromal polyps were decreased in dosed groups of female rats, as were the incidences of pancreatic adenomas, pituitary gland adenomas, and interstitial cell adenomas of the testis in dosed male rats and liver neoplasms in dosed mice. In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/sq m reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在服用 dronabinol 治疗期间，血清转氨酶升高的情况在接受治疗的病人中报告发生率为6%，而接受癌症化疗的对照组中发生率为4.3%。转氨酶升高是短暂的，严重程度为轻至中度，并且没有伴随症状或黄疸。在文献中尚未有令人信服的因 dronabinol 导致临床上明显的肝损伤的案例发表，因此，如果 dronabinol 真的导致严重肝损伤，这种情况也极为罕见。

Serum aminotransferase elevations during dronabinol therapy were reported to occur in 6% of treated patients compared to 4.3% in controls who receiving cancer chemotherapy. The aminotransferase elevations were transient, mild-to-moderate in severity, and not associated with symptoms or jaundice. There have been no convincing cases of clinically apparent liver injury attributable to dronabinol published in the literature and, thus, significant liver injury from dronabinol must be exceeding rare, if it occurs at all.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：马林醇

Compound:marinol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous 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：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

SYNDROS在健康男性和女性受试者中的相对生物利用度数据显示，在空腹条件下，服用4.2毫克SYNDROS的剂量可以提供与5毫克 dronabinol胶囊相当的系统暴露（Cmax和AUC），Cmax和AUCinf分别为1.9 ± 1.3 ng/mL和3.8 ± 1.8 ng·h/mL。在口服SYNDROS后约0.5至4小时，dronabinol及其主要活性代谢物（11-羟基-Δ-9-THC）的浓度达到峰值，并在几天内下降。在健康受试者中服用SYNDROS后，dronabinol药代动力学（Cmax和AUCinf）的受试者间和受试者内变异性大约为66%和47%，以及67%和14%。

Dronabinol is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first-pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions, with the Cmax and AUCinf of 1.9 ± 1.3 ng/mL and 3.8 ± 1.8 ng.h/mL respectively. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (Cmax and AUCinf) was approximately 66% and 47% and 67% and 14%, respectively, following the administration of SYNDROS to healthy subjects.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Dronabinol 及其生物转化产物通过粪便和尿液排出。胆汁排泄是主要的排泄途径，大约有一半的口服放射性剂量在 72 小时内通过粪便排出，相比之下，通过尿液排出的只有 10% 到 15%。口服剂量的不到 5% 以原形通过粪便排出。由于再分布，Dronabinol 及其代谢物可能会在长时间内被排出。在单次给药后，Dronabinol 的代谢物在尿液和粪便中可以检测到超过 5 周。在一项涉及艾滋病患者的 Dronabinol 胶囊研究中，对尿液中大麻素/肌酐浓度比值进行了为期六周的每周两次的研究。尿液中大麻素/肌酐比值与剂量密切相关。在治疗的前两周内没有观察到大麻素/肌酐比值的增加，这表明已经达到了大麻素的稳态水平。这一结论与基于观察到的 Dronabinol 终末半衰期所作的预测一致。

Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Due to its re-distribution, dronabinol and its metabolites may be excreted for prolonged periods of time. Following single-dose administration, dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six-week period. The urinary cannabinoid/creatinine ratio was closely correlated with the dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.

来源:DrugBank

吸收、分配和排泄

• 分布容积

Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility.

Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility.

来源:DrugBank

吸收、分配和排泄

• 清除

清除率的平均值约为0.2 L/kg-hr，但由于大麻素分布的复杂性，这个值具有很高的变异性。

The value for clearance average is about 0.2 L/kg-hr but is highly variable due to the complexity of cannabinoid distribution.

来源:DrugBank

吸收、分配和排泄

为了建立一种快速、灵敏、可重复的液相色谱-串联质谱(LC-MS/MS)方法来研究四氢大麻酚(THC)的药代动力学特性，并比较THC及其固体分散体在小鼠中的相对生物利用度。将200只小鼠随机分为两组，在禁食后口服给予THC和THC固体分散体（按THC计算：400 mg/kg），使用HPLC-MS/MS方法测定给药后以下时间点的THC浓度：基线（给药前）、15、30、45分钟、1、1.5、2、3、4、6、24小时。根据C-t曲线计算药代动力学参数，然后使用Phoenix WinNonlin软件进行数据分析。THC的校准曲线在9.06-972 ug/L范围内线性良好（R2 = 0.999）。检测限(LOD)为0.7 ug/L。THC的平均提取回收率超过75%，方法回收率在79%至108%之间。日内和日间RSD均小于13%，稳定性测试表明血浆样本在不同条件下是稳定的（RSD < 15%）。精密度、准确度、回收率和适用性均适用于药代动力学研究。THC及其固体分散体口服给药到小鼠的药代动力学参数如下：T(max)分别为60和15分钟，AUC(0-t)分别为4400.43和57497.81 mg·L^-1·min^-1，AUC(0-infinity)分别为51226.00和68031.48 mg·L^-1·min^-1，MRT(0-infinity)分别为596.9156和661.7477分钟，CL(z)/F分别为0.007809和0.00588 L·min^-1·kg^-1。与THC相比，THC固体分散体的MRT和t1/2都有所延长，t(max)显著缩短，AUC(0-24小时)、AUC(0-infinity)和C(max)都显著更高，THC固体分散体的相对生物利用度是THC的1.34倍。实验结果表明，精密度、准确度、回收率和适用性都适用于药代动力学研究。口服给药到小鼠后，THC固体分散体的相对生物利用度与THC相比有显著提高。

To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 hr after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 ug/L for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 ug/L, respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 00.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51226.00 and 68031.48 mg/L x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L/min x kg. Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 hr), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  四氢大麻酚 在 Amberlyst-15 作用下， 以 正庚烷 为溶剂， 反应 2.0h， 以89%的产率得到(-)-Δ8-四氢大麻酚
  参考文献：
  名称：

  [EN] NOVEL METHODS AND RELATED TOOLS FOR CBD CONVERSION TO THC
  [FR] NOUVELLES MÉTHODES ET OUTILS ASSOCIÉS POUR CONVERSION DE CBD EN THC

  摘要：

  本发明涉及利用非侵害性方法从CBD生产THC的方法，从而实现大幅增加产量，并基于这些新颖方法构建的设备。这些方法和设备具有材料高效性，在某些实施方式中是无溶剂的。特别是，在某些实施方式中，这些方法和相关设备适用于商业生产从CBD中提取THC。此外，在某些实施方式中，本发明提供了一种从CBD中生产THC的方法，以便可调整THC-8和THC-9比例的选择。

  公开号：

  WO2020146907A1
• 作为产物：
  描述：

  (6aR,9S,10aR)-9-Chloro-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol 在 盐酸 、 potassium 2-methylbutan-2-olate 、 zinc(II) chloride 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 1.0h， 生成 四氢大麻酚
  参考文献：
  名称：

  Addition and elimination of HCl to tetrahydrocannabinol isomers. A method for the preparation of stereospecifically 2H-labeled cannabinoids

  摘要：

  Addition of HCl gas to (-)Delta(8)-, (-)Delta(9)-, or (-)Delta(9,11)-THC solutions at -60 degrees C results in the formation of 9 alpha- and 9 beta-chlorohexahydrocannabinol (Cl-HHC). The addition appears to involve initial protonation of the double bond in the form of a bridged hydrogen cation followed by attack of the chloride anion at the most substituted 9-position. For both steps in the addition reaction the stereochemistry is dependent on the double bond position in the THC isomer. Elimination of HCl from each of the two addition products using potassium-tert-amylate leads exclusively to Delta(9)-THC in the case of 9 beta-Cl-HHC and to Delta(9,11)-THC in the case of 9 alpha-Cl-HHC. The individual addition products can be separated and used to obtain regio-and stereochemically H-2-isotopically labeled tetrahydrocannabinols which can be used in biophysical and biochemical studies.

  DOI：

  10.1002/(sici)1099-1344(199802)41:2<121::aid-jlcr55>3.0.co;2-s
• 作为试剂：
  描述：

  四氢呋喃 、 大麻酚 、 、 硼氢化钠 在 四氢大麻酚 、 水 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 114.5h， 生成 四氢大麻酚
  参考文献：
  名称：

  Immunoassay for tetrahydrocannabinol metabolites

  摘要：

  提供了新型的大麻酚衍生物，可用于改进的免疫测定中，用于检测血液或尿液样品中的大麻酚代谢物。

  公开号：

  US05219747A1

文献信息

• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• Synthesis of (-)-Δ⁹-<i>trans</i>-Tetrahydrocannabinol:  Stereocontrol via Mo-Catalyzed Asymmetric Allylic Alkylation Reaction
  作者：Barry M. Trost、Kalindi Dogra

  DOI：10.1021/ol063022k

  日期：2007.3.1

  [reaction: see text] Delta9-THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum-catalyzed asymmetric alkylation reaction of the extremely sterically congested bis-ortho-substituted cinnamyl carbonate in high regio- and enantioselectivity.

  [反应：见正文] Delta9-THC以对映体纯形式合成，其中所有立体化学均来自极空间拥挤的双邻位取代肉桂酸碳酸酯在高区域和对映体选择性下的钼催化的不对称烷基化反应。
• Enantioselective Total Synthesis of Cannabinoids—A Route for Analogue Development
  作者：Zachary P. Shultz、Grant A. Lawrence、Jeffrey M. Jacobson、Emmanuel J. Cruz、James W. Leahy

  DOI：10.1021/acs.orglett.7b03668

  日期：2018.1.19

  A practical synthetic approach to Δ9-tetrahydrocannabinol (1) and cannabidiol (2) that provides scalable access to these natural products and should enable the generation of novel synthetic analogues is reported.

  一种实用的合成方法，以Δ 9 -四氢大麻酚（1）和大麻二酚（2），其提供到这些天然产品可伸缩的访问和应使新合成的类似物的生成报告。
• SYNTHESIS OF CANNABINOIDS
  申请人：Leahy James William

  公开号：US20190023680A1

  公开（公告）日：2019-01-24

  Provided are synthesis processes and intermediates for preparing cannabinoids and analogs.

  提供了制备大麻素和类似物的合成过程和中间体。

表征谱图