海米那 | 72-44-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 海米那
• 中文别名: 2-甲基-3-(2-甲基苯基)-4(3H)喹唑啉酮；甲喹酮；2-甲基-3-邻甲苯基喹唑酮-[4]；安眠酮
• 英文名称: methaqualone
• 英文别名: 2-methyl-3-(o-tolyl)quinazolin-4(3H)-one；2-methyl-3-o-tolyl-4(3H)-quinazolinone；Aqual；2-methyl-3-(2-methylphenyl)quinazolin-4-one
• CAS: 72-44-6
• 化学式: C₁₆H₁₄N₂O
• 分子量: 250.3
• InChiKey: JEYCTXHKTXCGPB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.125
• 拓扑面积：
  32.7
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

超过99%的药物通过肝微粒体系统代谢，4-羟基甲喹酮和N'-氧化物是主要的初级代谢物。至少还形成了另外八种羟基代谢物。

MORE THAN 99% OF THE DRUG IS METABOLIZED BY THE HEPATIC MICROSOMAL SYSTEM, AND 4-HYDROXYMETHAQUALONE AND THE N'-OXIDE ARE THE MAJOR PRIMARY METABOLITES. AT LEAST EIGHT OTHER HYDROXYL METABOLITES ARE FORMED.

来源:Hazardous Substances Data Bank (HSDB)

代谢

产量 3-(3-羟基-2-甲基苯基)-2-甲基-4(3H)-喹唑啉酮，3-(4-羟基-2-甲基苯基)-2-甲基-4(3H)-喹唑啉酮，和 6-羟基-2-甲基-3-(邻甲苯基)-4(3H)-喹唑啉酮 在人体中。/来自表格/

YIELDS 3-(3-HYDROXY-2-METHYLPHENYL)-2-METHYL-4(3H)-QUINAZOLINONE, 3-(4-HYDROXY-2-METHYLPHENYL)-2-METHYL-4(3H)-QUINAZOLINONE, & 6-HYDROXY-2-METHYL-3-(O-TOLYL)-4(3H)-QUINAZOLINONE IN MAN. /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 甲喹酮 ... 产生了2-硝基苯甲酸-邻-甲苯酯 ... 作为人体尿液的代谢物。

... METHAQUALONE ... GAVE 2-NITROBENZO-ORTHO-TOLUIDIDE ... AS HUMAN URINARY METABOLITE.

来源:Hazardous Substances Data Bank (HSDB)

代谢

生物转化...预计会通过羟基化进行，这在实践中很大程度上是发生的，当葡萄糖苷酸在...2-甲基-3-(3-羟基-2-甲基苯基)-4(3H)-喹唑啉酮，2-甲基-3-邻甲苯基-6-羟基-4(3H)-喹唑啉酮和2-甲基-3-邻甲苯基-8-羟基-4(3H)-喹唑啉酮...在大鼠尿液中排出。

BIOTRANSFORMATION ... WOULD BE EXPECTED TO PROCEED BY HYDROXYLATION, & THIS LARGELY OCCURS IN PRACTICE, WHEN GLUCURONIDES OF ... 2-METHYL-3-(3-HYDROXY-2-METHYLPHENYL)-4(3H)-QUINAZOLINONE, 2-METHYL-3-O-TOLYL-6-HYDROXY-4(3H)-QUINAZOLINONE & 2-METHYL-3-O-TOLYL-8-HYDROXY-4(3H)-QUINAZOLINONE ... EXCRETED IN URINE OF ... RATS.

来源:Hazardous Substances Data Bank (HSDB)

代谢

美沙酮在人体内已知的代谢物包括羟基美沙酮。

Methaqualone has known human metabolites that include hydroxy-methaqualone.

来源:NORMAN Suspect List Exchange

毒理性

• 相互作用

严重的中枢神经系统抑制作用可能会在使用美沙酮与乙醇或其他中枢神经系统抑制剂联合使用时发生。美沙酮增强了单胺氧化酶抑制剂和三环类抗抑郁药的效果。与吩噻嗪类药物和三环类抗抑郁药联合使用时，可能会导致鼻出血和月经不调。

SEVERE CNS DEPRESSION MAY OCCUR WHEN METHAQUALONE IS TAKEN IN COMBINATION WITH ETHANOL OR OTHER CNS DEPRESSANTS. METHAQUALONE INCREASES THE EFFECTS OF MAO INHIBITORS AND TRICYCLIC ANTIDEPRESSANTS. IN COMBINATION WITH PHENOTHIAZINES AND TRICYCLIC ANTIDEPRESSANTS, IT MAY CAUSE EPISTAXIS AND MENSTRUAL IRREGULARITIES.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

十二名健康受试者接受了三次单独口服剂量（250毫克）的甲喹酮，或与盐酸去氢羟麻黄碱（25毫克）联合使用。每次给药后收集了48小时内的血液样本，并分析了甲喹酮及其主要代谢物，2-甲基-3-(2'-羟甲基苯基)-4(3H)-喹唑啉酮。峰值血药浓度在1.0至2.7微克/毫升之间，口服剂量后大约1-2小时出现。在治疗组合产品中使用的盐酸去氢羟麻黄碱剂量水平并未改变甲喹酮或其代谢物的血药水平。

TWELVE HEALTHY SUBJECTS RECEIVED THREE SINGLE ORAL DOSES (250 MG) OF METHAQUALONE ALONE OR IN COMBINATION WITH DIPHENHYDRAMINE (25 MG). BLOOD SAMPLES WERE COLLECTED FOR A 48-HOUR PERIOD AFTER EACH DOSE AND ANALYZED FOR METHAQUALONE AND ITS MAJOR METABOLITE, 2-METHYL-3-(2'-HYDROXYMETHYLPHENYL)-4(3H)-QUINAZOLINONE. PEAK BLOOD CONCENTRATIONS RANGING FROM 1.0 TO 2.7 UG/ML OCCURRED APPROXIMATELY 1-2 HOURS AFTER THE ORAL DOSE. DIPHENHYDRAMINE ADMINISTERED AT THE DOSAGE LEVEL USED IN THERAPEUTIC COMBINATION PRODUCTS DID NOT ALTER THE BLOOD LEVELS OF METHAQUALONE OR ITS METABOLITE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

甲喹酮与苯海拉明联合使用，被强烈怀疑是导致1名患者出现固定药疹的原因。

Methaqualone in conjunction with diphenhydramine was strongly suspected of being responsible for a fixed drug eruption in 1 patient.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在正常剂量下使用3周后，人体中安替比林或非那宗的半衰期没有显著变化，6β-羟基皮质醇的排泄也没有变化。但在催眠药依赖者中，安替比林的半衰期适度缩短，效果不如巴比妥类药物依赖者明显...。

IN MAN, AFTER 3 WK OF USE IN NORMAL DOSAGE, THERE IS NO SIGNIFICANT CHANGE IN HALF-LIFE OF ANTIPYRINE OR PHENYLBUTAZONE OR IN EXCRETION OF 6BETA-HYDROXYCORTISOL BUT IN HYPNOTIC-DEPENDENT SUBJECTS ANTIPYRINE HALF-LIFE IS MODERATELY SHORTENED, EFFECT BEING LESS THAN IN BARBITURATE DEPENDENCE ... .

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

立即注意保护气道、呼吸和心血管状况。昏迷患者的气管插管后应进行大口径管胃灌洗、活性炭和泻药。在消除美沙酮的过程中，没有强利尿的作用……。在美沙酮严重过量且对保守治疗无反应，血浆水平超过4mg/dl的情况下，血液透析或更理想的是吸附血液灌注，已被证明在逆转昏迷、降低血浆水平和实现完全康复方面是有效的。

Immediately attention is directed to preservation of the airway, the respiration, and the cardiovascular status. Tracheal intubation in a comatose patient should be followed by gastric lavage with a large bore tube, activated charcoal, and a cathartic. There is no role for forced diuresis in the elimination of methaqualone, ... . In very severe methaqualone overdose unresponsive to conservative therapy, with plasma levels exceeding 4 mg/dl, hemodialysis, or more preferably sorbent hemoperfusion, has been shown to be effective in reversing coma, reducing plasma levels, and effecting a complete recovery.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在人體中，99%的甲喹酮在2小時內被吸收。在血浆中，70到90%與白蛋白結合。...代謝物...主要是結合形式並通過尿液排出，但4-羟基代謝物則排入膽汁中。藥代動力學呈現為兩室系統模型，其分布半衰期小於1小時，消除半衰期為10到40小時。

IN MAN, 99% OF METHAQUALONE IS ABSORBED IN 2 HOURS. IN THE PLASMA, 70 TO 90% IS BOUND TO ALBUMIN. ... METABOLITES ... ARE MAINLY CONJUGATED AND EXCRETED IN THE URINE, BUT THE 4-HYDROXY METABOLITE IS EXCRETED INTO BILE. THE PHARMACOKINETICS IS THAT OF A TWO-COMPARTMENT SYSTEM, WITH A DISTRIBUTION HALF-LIFE OF LESS THAN 1 HOUR AND AN ELIMINATION HALF-LIFE OF 10 TO 40 HOURS.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吸收后，美沙酮被脂肪组织摄取并在几天内逐渐释放。释放时，它迅速经历葡萄糖醛酸苷结合...并在尿液和粪便中排出，持续6-7天。在有毒剂量下，未代谢的美沙酮也存在于尿液中。

AFTER ABSORPTION METHAQUALONE IS TAKEN UP BY ADIPOSE TISSUE & GRADUALLY RELEASED OVER PERIOD OF SEVERAL DAYS. AS IT IS RELEASED IT RAPIDLY UNDERGOES GLUCURONIDE CONJUGATION ... & IS EXCRETED EQUALLY IN URINE & FECES FOR UP TO 6-7 DAYS. IN TOXIC DOSES UNMETABOLIZED METHAQUALONE IS ALSO FOUND IN URINE.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

急性中毒患者血液和尿液样本研究。在尿液中发现了4种主要的单羟基化代谢物，以结合形式存在。在尿液和血液中发现了未结合的2-甲基-3-[2-(羟基甲基)苯基]-4(3H)-喹唑啉酮。

BLOOD & URINE SAMPLES FROM ACUTELY INTOXICATED PATIENT STUDIED. 4 MAJOR MONOHYDROXYLATED METABOLITES FOUND CONJUGATED IN URINE. 2-METHYL-3-[2-(HYDROXYMETHYL)PHENYL]-4(3H)-QUINAZOLINONE FOUND UNCONJUGATED IN URINE & BLOOD.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尿液排泄5-C-羟基代谢物和美沙酮-N-氧化物，在老年患者口服250毫克后的测量结果。24小时内6种代谢物的总排泄量大约是年轻健康成人组的一半。

URINARY EXCRETION OF 5 C-MONOHYDROXY METABOLITES & METHAQUALONE N-OXIDE MEASURED FOLLOWING ORAL ADMIN OF 250 MG TO GERIATRIC PT. TOTAL EXCRETION OF 6 METABOLITES IN 24 HR WAS APPROX ONE-HALF THAT IN GROUP OF YOUNG, HEALTHY ADULTS.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

制备方法

由邻乙酰氨基苯甲酸（见00150）与邻氨基甲苯环合而成。将邻乙酰氨基苯甲酸溶解在甲苯中，加热至80℃并搅拌，然后加入邻氨基甲苯，再滴加三氯化磷的甲苯溶液，回流反应即可生成甲喹酮。

用途简介

本品是一种非苯二氮䓬类催眠药。通常在服药后20-30分钟开始起效，并持续6-8小时。药物主要通过消化道吸收，在肝脏内代谢并通过肾脏排出。除了具有镇静和催眠作用外，还具备抗惊厥、解痉、局部麻醉以及较弱的抗组胺作用。大鼠口服的半数致死量为255毫克/千克。

反应信息

• 作为反应物：
  描述：

  海米那 在 正丁基锂 、 二异丙胺 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 、 氢化铝 为溶剂， 生成 2-acetonyl-3-o-tolyl-4(3H)-quinazolinone
  参考文献：
  名称：

  2-Ketoalkyl-4(3H)-quinazolinones

  摘要：

  2-酮烷基-4(3H)-喹唑啉酮的化学式为##STR1##其中R.sub.1是1-10个碳原子的脂肪烷基、环脂肪烷基或碳氢芳基；A是1至10个碳原子的二价烷基；R.sub.2是通过缩合具有化学式R.sub.2 COOR'的酰基酯形成的1-10个碳原子的脂肪烷基、环脂肪烷基、碳氢芳基或杂环基，该酰基酯可以解离形成--COR.sub.2和R'OH，其中R'是所述酯的醇部分；而R.sub.3和R.sub.4分别是氢、羟基、氨基、卤素、三氟甲基、烷基、烷氧基、烷硫基或烷基磺酰基，每种取代基均为1-4个碳原子，存在时通常位于喹唑啉酮核的6-和/或7-位置，提供具有作为中枢神经系统抑制剂和抗惊厥活性的化合物。提供了一种通过酯缩合制备这类化合物的方法，该方法通过在强离子溶剂的存在下，如回流1,2-二甲氧基乙烷中，使用相应的2-烷基-3-取代-4(3H)喹唑啉酮与可缩合酯和过量的氢化钠进行酯缩合来实现。

  公开号：

  US04183931A1
• 作为产物：
  描述：

  2-甲基-3-(2-甲基苯基)-1,2-二氢喹唑啉-4-酮 在 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以89%的产率得到海米那
  参考文献：
  名称：

  Deep eutectic solvent mediated synthesis of quinazolinones and dihydroquinazolinones: synthesis of natural products and drugs

  摘要：

  开发了一种温和且更环保的方法来合成取代的喹唑啉酮和二氢喹唑啉酮，通过深共融溶剂介导的环化反应，使用脂肪族、芳香族和杂环芳香族醛，产率良好至优异。

  DOI：

  10.1039/c6ra00855k

文献信息

• [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。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。
• Palladium-catalyzed four-component carbonylative synthesis of 2,3-disubstituted quinazolin-4(3H)-ones: Convenient methaqualone preparation
  作者：Jin-Bao Peng、Hui-Qing Geng、Wei Wang、Xinxin Qi、Jun Ying、Xiao-Feng Wu

  DOI：10.1016/j.jcat.2018.06.007

  日期：2018.9

  A palladium-catalyzed four-component carbonylative cyclization reaction for the synthesis of 2,3-disubstituted quinazolin-4(3H)-ones has been developed. A range of different 2,3-disubstituted quinazolin-4(3H)-one derivatives were prepared in moderate to good yields employing simple and readily accessible 2-iodoanilines, nitro compounds and acid anhydrides as the synthetic precursors. Mo(CO)6 acted

  已经开发了钯催化的四组分羰基环化反应，用于合成2,3-二取代的喹唑啉-4（3H）-one。使用简单且易于获得的2-碘苯胺，硝基化合物和酸酐作为合成前体，以中等至良好的产率制备了一系列不同的2,3-二取代的喹唑啉-4（3H）-one衍生物。Mo（CO）6既充当固体CO源又充当还原剂。值得注意的是，在我们的条件下，甲喹酮作为镇静剂和催眠药也可以很容易地制备，收率为68％（4b）。

表征谱图