氨苯恶唑啉 | 2207-50-3

• 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: 氨苯恶唑啉
• 中文别名: 阿米雷司
• 英文名称: 2-amino-5-phenyl-2-oxazoline
• 英文别名: 5-phenyl-4,5-dihydro-2-oxazolamine；Aminoxaphen；aminorex；5-phenyl-4,5-dihydro-oxazol-2-ylamine；4,5-dihydro-5-phenyl-2-oxazolamine；2-Amino-5-phenyl-2-oxazolin；5-phenyl-4,5-dihydro-1,3-oxazol-2-amine
• CAS: 2207-50-3
• 化学式: C₉H₁₀N₂O
• 分子量: 162.191
• InChiKey: SYAKTDIEAPMBAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

毒理性

• 人类毒性摘录

病例报告/ 对9名女性患者的肺动脉肌肉病变进行了检查，这些患者在服用了一种厌食性药物，富马酸氨茴香后9至17年间死于肺动脉高压。病变通过多种方法进行了检查（光学显微镜，病变计数，形态测量）。病变计数显示纤维化和扩张病变占主导地位，但也存在活动性病变（内膜增生，网状病变）。形态测量显示，与对照动脉或之前系列的动脉相比，中膜的 平均厚度增加，平均血管体积减少。存在硬化性病变和血管体积的减少可能解释了肺动脉高压的持续性，新鲜病变有助于加重病情。似乎功能和解剖学改变由于药物的作用已经变得自我延续，并可能在服用减肥药多年后最终导致这些患者的致命结果。/富马酸氨茴香/

/CASE REPORTS/ The lesions of pulmonary muscular arteries of 9 female patients who died of pulmonary hypertensive disease between 9 and 17 years after intake of an anorexigenic drug, aminorex fumarate, have been examined by various methods (light microscopy, numeration of lesions, morphometry). The numeration of lesions showed the predominance of fibrotic and dilatation lesions, but also the presence of active lesions (intimal hyperplasia, plexiform lesions). Morphometry revealed an increase in mean thickness of the media, compared to that of the arteries of controls or those of a previous series, and a reduction in mean vascular volume. The existence of sclerotic lesions and reduction of vascular volume may explain the persistence of pulmonary hypertension, which fresh lesions helped to aggravate. It seems likely that functional and morphologic modifications due to the action of the drug had become self-perpetuating and may finally have induced the fatal outcome in these patients many years after intake of the slimming pill. /Aminorex fumarate/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

案例报告/选定的严重特发性肺动脉高压和相关的肺血管疾病的病例与口服摄入氨雷司酮有关，氨雷司酮是一种食欲抑制剂，显然是1967年至1970年间西欧特发性肺动脉高压流行的原因。这份报告描述了一名女性患者与氨雷司酮相关的肺动脉高压的十五年随访，以及疾病晚期形成过大的梭形肺动脉瘤的不常见发现。通过系列的胸部X光片和重复的右心导管检查来跟踪进展的临床过程。通过二维超声心动图非侵入性地确立了主肺动脉瘤的诊断，并通过对比增强计算机断层扫描和放射性核素血池成像得到证实。患者目前仍然存活，因此目前没有这种实体的组织学相关性。/氨雷司酮/

/CASE REPORTS/ Selected cases of severe primary pulmonary arterial hypertension and associated pulmonary vascular disease have been related to the oral ingestion of aminorex fumarate, an anorexigen obviously responsible for an epidemic of primary pulmonary hypertension in Western Europe between 1967 and 1970. This report describes a fifteen year follow-up of a female patient with aminorex fumarate related pulmonary hypertension and the uncommon finding of the formation of an excessive fusiform pulmonary trunk aneurysm in the late stage of the disease process. The progressive clinical course was followed by serial chest x-ray films and repeat right heart catheterization. The diagnosis of a main stem pulmonary artery aneurysm was noninvasively established by two-dimensional echocardiography and confirmed by contrast-enhanced computed tomography and radionuclide blood pool imaging. The patient is alive, thus no histologic correlate of this entity is available at present. /Aminorex fumarate/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/流行病学研究/ 在20世纪60年代末，一种原发性肺动脉高压（PPH）的流行病在欧洲出现，这就在引入了一种强效食欲抑制剂——盐酸阿米雷司之后不久。最近发表的一项来自欧洲的病例对照研究报告称，使用其他食欲抑制剂（其中最常见的是右芬氟拉明）也与PPH风险增加有关。这导致了对于重复流行病的警告，特别是在右芬氟拉明在北美市场推出之后。目标：比较PPH与阿米雷司和右芬氟拉明之间的流行病学关联，无论是关联强度（相对风险的估计）还是公共卫生影响（病因分数），从而评估PPH新流行的可能性。/研究者/根据来自瑞士伯尔尼和巴塞尔的报告病例系列以及来自德国汉诺威的随机人口样本，构建了一个针对阿米雷司的“综合”病例对照研究，并将结果与最近报告的右芬氟拉明进行了比较。使用对照组的暴露率来估计人群暴露流行率，进而得出病因分数。PPH与任何阿米雷司暴露的关联的估计比值比（及其95%置信区间）为97.8（78.9-121.3），相应的病因分数为77%。右芬氟拉明的相应数字分别为3.7（1.9-7.2）和17%。阿米雷司与PPH之间的强烈关联可能导致PPH发病率增加5倍，从而形成了一个非常明显的流行病。与右芬氟拉明的关联将导致发病率仅增加20%。根据现有证据，PPH的重复流行病似乎不太可能发生。

/EPIDEMIOLOGY STUDIES/ In the late 1960s, an epidemic of primary pulmonary hypertension (PPH) occurred in Europe shortly after the introduction of aminorex fumarate, a potent anorexigen. A recently published case-control study from Europe reported that use of other anorexigens (the most prevalent of which was dexfenfluramine) was also associated with an increased risk of PPH. This led to warnings of a repeat epidemic, especially after the introduction of dexfenfluramine on the North American market. OBJECTIVE: To compare the epidemiologic associations of PPH with aminorex and dexfenfluramine, both with respect to strength of association (estimate of relative risk) and public health impact (etiologic fraction) and thus to assess the potential for a new epidemic of PPH. /The investigators/ constructed a "synthetic" case-control study for aminorex based on reported case series from Berne and Basel, Switzerland, and a random population sample from Hanover, Germany, and compared the results with those recently reported for dexfenfluramine. Control rates of exposure were used to estimate population exposure prevalences and, hence, etiologic fractions. The estimated odds ratio (and 95% confidence interval) for the association between PPH and any exposure to aminorex was 97.8 (78.9-121.3), with a corresponding etiologic fraction of 77%. The corresponding figures for dexfenfluramine were 3.7 (1.9-7.2) and 17%, respectively. The strong association between aminorex and PPH probably led to a 5-fold increase in PPH incidence, and thus a very noticeable epidemic. The association with dexfenfluramine would result in an increase in incidence of only 20%. Based on the available evidence, a repeat PPH epidemic seems unlikely.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

替代和体外测试/厌食剂如aminorex fumarate和dexfenfluramine与严重肺动脉高压（PH）的发展有关，这在临床和病理学上被认为与特发性或原发性肺动脉高压（PPH）无法区分。在当前研究中，我们询问了厌食剂相关的PH是否以单克隆肺内皮细胞增殖为特征（如PPH中那样），或者，另一种可能是与继发性PH中发现的克隆性内皮细胞增殖有关。通过人和雄激素受体检测对克隆性的分析，在两名厌食剂相关PH的患者的微解剖的plexiform病变的内皮细胞中进行了。患者1的四个plexiform病变和患者2的六个与厌食剂相关的PH表现出单克隆扩张的肺内皮细胞，平均克隆性比率为0.03±0.01 SE。我们的结果表明，食欲抑制剂相关的PH在临床和病理学特征上不仅与PPH相同，而且在分子水平上，在内皮细胞增殖的单克隆性质方面也与PPH相同。厌食剂可能会加速患有发展PPH倾向的患者的肺内皮细胞生长。/aminorex fumarate/

/ALTERNATIVE and IN VITRO TESTS/ Anorexigens such as aminorex fumarate and dexfenfluramine are associated with the development of severe pulmonary hypertension (PH), which clinically and histopathologically is considered indistinguishable from idiopathic or primary pulmonary hypertension (PPH). For the current study, we asked whether anorexigen-associated PH is characterized by monoclonal pulmonary endothelial cell proliferation (such as in PPH) or, alternatively, is associated with a polyclonal endothelial cell proliferation as found in secondary PH. Analysis of clonality by the human androgen receptor assay was performed in microdissected endothelial cells of plexiform lesions of two patients with anorexigen-associated PH. The four plexiform lesions of Patient 1 and the six of Patient 2 with anorexigen-associated PH exhibited a monoclonal expansion of pulmonary endothelial cells, with a mean clonality ratio of 0.03 +/- 0.01 SE. Our results indicate that appetite suppressant-associated PH is identical to PPH not only in clinical and histopathologic features but also, at a molecular level, in terms of the monoclonal nature of the endothelial cell proliferation. The anorexigens may accelerate the growth of pulmonary endothelial cells in patients with predisposition to develop PPH. /Aminorex fumarate/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/其他毒性信息/ 自1967年起，在奥地利、联邦德国和瑞士爆发了一场慢性肺动脉高压的流行病，高峰期在1968/69年，1972年后消失。导致肺动脉高压的机制是慢性小动脉前血管阻塞，由于丛状肺动脉病。这场流行病与食欲抑制剂盐酸氨氟拉明的市场营销和摄入有着密切的地理和时间关系（美诺西尔）。流行病爆发10年后，一半的患者已经死亡，通常死于右心衰竭。在幸存的病人中，有一半显示出肺血管阻塞的明显退化。在最初诊断后，死亡患者的平均生存期为3.5年。与幸存者相比，这些患者的肺动脉压（+22%）和肺小动脉阻力（+40%）在观察期开始时更高；右心衰竭的发生率也显著更高（84比58%）。在幸存的病人中，唯一的不同是，那些在开始减肥治疗时年龄较大的患者病情有所进展。在服用氨氟拉明后，血管源性慢性肺动脉高压（CPHVO）的10年生存概率显著高于“经典”原发性肺动脉高压（未知原因的CPHVO）和由于反复沉默性肺栓塞引起的CPHVO。这种预后差异支持了在服用抑制食欲的药物氨氟拉明后发展的慢性肺动脉高压的同一性。 /盐酸氨氟拉明/

/OTHER TOXICITY INFORMATION/ There was an epidemic of chronic pulmonary hypertension in Austria, the Federal Republic of Germany and Switzerland, starting in 1967, peaking in 1968/69, and disappearing after 1972. The mechanism leading to pulmonary hypertension was chronic precapillary vascular obstruction due to plexogenic pulmonary arteriopathy. There was a close geographic as well as temporal relation of the epidemic to the marketing and intake of the appetite depressing drug aminorex fumarate (Menocil). 10 years after the epidemic, half of the patients have died, usually of right heart failure. Of those surviving, half present a definite regression of the pulmonary vascular obstruction. Average survival after the initial diagnosis was 3.5 years in those patients who died. Their PA pressure (+22%) and pulmonary arteriolar resistance (+40%) was higher at the onset of the observation period if compared with the corresponding values of the survivors; also the incidence of right heart failure was significantly higher (84 vs. 58%). Among the surviving patients, the only difference between those with an improved and those with a worsened hemodynamic situation was the age at the beginning of the weight-reducing treatment, those with a progression being 10 years older. The probability of survival after 10 years is considerably higher in chronic pulmonary hypertension of vascular origin (CPHVO) after aminorex than in "classical" primary pulmonary hypertension (CPHVO of unknown cause) and in CPHVO due to recurrent silent pulmonary thromboembolism. This difference in prognosis is an argument in favor of the identity of chronic pulmonary hypertension developing after the intake of the appetite depressing drug aminorex. /Aminorex fumarate/

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  氨苯恶唑啉 在 盐酸 作用下， 生成 (2-hydroxy-2-phenylethyl)urea
  参考文献：
  名称：

  2-氨基5-芳基-2-恶唑酮。强大的新型阳极代理商。

  摘要：

  DOI：

  10.1021/jm00339a011
• 作为产物：
  描述：

  扁桃腈 在 lithium aluminium tetrahydride 、 sodium acetate 作用下， 以 甲醇 、 乙醚 为溶剂， 生成 氨苯恶唑啉
  参考文献：
  名称：

  2-氨基5-芳基-2-恶唑酮。强大的新型阳极代理商。

  摘要：

  DOI：

  10.1021/jm00339a011

文献信息

• [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。
• 1,5-Substituted indol-2-yl amide derivatives
  申请人：Nettekoven Matthias

  公开号：US20070123515A1

  公开（公告）日：2007-05-31

  The present invention relates to compounds of formula I wherein R 1 to R 4 and G are as defined in the description and claims and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

  本发明涉及式I的化合物，其中R1至R4和G如描述和索赔中定义的，并且其药学上可接受的盐。这些化合物可用于治疗和/或预防与H3受体调节相关的疾病。
• INDOL-2-YL-PIPERAZIN-1-YL-METHANONE DERIVATIVES
  申请人：Nettekoven Matthias

  公开号：US20080188484A1

  公开（公告）日：2008-08-07

  The present invention relates to compounds of formula I wherein A and R 1 to R 4 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

  本发明涉及公式I的化合物，其中A和R1至R4如描述和声明中所定义，并且其药学上可接受的盐。这些化合物可用于治疗和/或预防与H3受体调节相关的疾病。
• BENZOFURAN AND BENZOTHIOPHENE-2-CARBOXYLIC ACID AMIDE DERIVATIVES
  申请人：Mohr Peter

  公开号：US20090029976A1

  公开（公告）日：2009-01-29

  The present invention relates to compounds of formula I wherein X, A and R 1 to R 4 are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

  本发明涉及公式I的化合物，其中X，A和R1至R4如描述和索赔中所定义，并且其药学上可接受的盐。这些化合物可用于治疗和/或预防与H3受体调节相关的疾病。
• [EN] NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS<br/>[FR] NOUVEAUX AGENTS ANTIDIABÉTIQUES UTILES AVEC DES DÉRIVÉS DE BENZIMIDAZOLE CYCLIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010051176A1

  公开（公告）日：2010-05-06

  Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

  结构式（I）的新化合物是AMP-蛋白激酶的激活剂，可用于治疗、预防和抑制由AMPK激活的蛋白激酶介导的疾病。本发明的化合物对于治疗2型糖尿病、高血糖、代谢综合征、肥胖、高胆固醇血症和高血压是有用的。