稠环乙脲 | 18016-80-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 稠环乙脲
• 英文名称: lisuride
• 英文别名: Dopergin；3-[(6aR,9S)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinolin-9-yl]-1,1-diethylurea
• CAS: 18016-80-3
• 化学式: C₂₀H₂₆N₄O
• 分子量: 338.453
• InChiKey: BKRGVLQUQGGVSM-KBXCAEBGSA-N

物化性质

• 熔点：
  186°
• 比旋光度：
  D20 +313° (c = 0.60 in pyridine)
• 沸点：
  603.4±55.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 物理描述：
  Solid
• 溶解度：
  1.40e-01 g/L

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  51.4
• 氢给体数：
  2
• 氢受体数：
  2

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：美国食品药品监督管理局尚未批准在美国销售lisuride，但在其他国家有售。它能够降低血清催乳素水平，并被一些国家批准用于抑制泌乳。一些专家推荐lisuride作为抑制泌乳的更安全选择，以替代溴隐亭，但其他专家建议避免使用所有抑制泌乳的药物。目前的数据不足以推荐一种抑制泌乳的治疗方法优于另一种。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：Lisuride以剂量相关的方式抑制血清催乳素的增加。比较研究发现，lisuride在疗效上与溴隐亭相当，尽管在每日使用0.4毫克的lisuride治疗的患者中，反跳性泌乳的发生率高于每日使用5毫克溴隐亭治疗的患者。在使用更高剂量0.6毫克每日和15天的治疗而非10天的治疗中，反跳性泌乳似乎较少。

◉ Summary of Use during Lactation:Lisuride is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. It lowers serum prolactin and is approved in some countries for lactation suppression. Some experts recommend lisuride as a safer alternative to bromocriptine for lactation suppression, but others recommend avoiding all lactation suppressants. Data are insufficient recommend one treatment for lactation suppression over another. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Lisuride suppresses serum prolactin increases in a dose-related fashion. Comparative studies have found lisuride comparable in efficacy to bromocriptine, although rebound lactation occurred in more patients treated with lisuride 0.4 mg daily than in those treated with bromocriptine 5 mg daily. Rebound lactation appears to be less with a higher dose of 0.6 mg daily and with 15 days of therapy rather than 10 days.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

大约15%。

about 15%

来源:DrugBank

制备方法与用途

药理作用

稠环乙脲是一种部分合成的麦角碱制剂，主要作为多巴胺受体激动药，特别是对D2受体有较强的激动作用，并对Di受体有一定的轻度激动效果。此外，它还具有5-羟色胺抑制作用。

临床应用和适应症

稠环乙脲单独使用或与左旋巴合用，适用于治疗未经治疗的震颤麻痹患者及长期接受左旋多巴治疗后出现“开－关”现象（运动障碍）的患者。此外，它还能抑制乳汁分泌，用于断奶、月经不调、肢端肥大症、不育症以及垂体功能减退肿瘤等疾病的治疗。

用法用量

初始剂量为夜间口服0.1mg，每周逐渐增加至每日0.4～1mg，分三次服用。对于反应有明显波动的患者，可增至每次0.2～0.6mg，分六次服用。

不良反应

使用稠环乙脲可能引起恶心、头痛、疲劳、眩晕、反应迟钝、出汗和呕吐等症状，尤其是在治疗开始时，剂量增加过快还可能导致噩梦、幻觉、类偏执狂反应、模糊状态。此外，还会出现睡眠紊乱、皮肤反应和水肿，帕金森病患者还可能出现气短和肾功能异常。

药物相互作用

神经安定药和其他多巴胺拮抗剂可以减轻稠环乙脲的副作用。产后、分娩或产褥期间不宜与其他麦角碱类药物合用，慎与降压药物联合使用。

反应信息

• 作为反应物：
  描述：

  稠环乙脲 在 lithium amide 、 氨 、 lithium 、 苯胺 作用下， 以 四氢呋喃 为溶剂， 以95%的产率得到R-(+)-特麦角脲
  参考文献：
  名称：

  Reduction of 8α-Substituted 9,10-Didehydroergolines

  摘要：

  DOI：

  10.1055/s-1986-31850
• 作为产物：
  描述：

  R-(+)-马来酸麦角脲 在 水 作用下， 以 1,4-二氧六环 为溶剂， 生成 稠环乙脲
  参考文献：
  名称：

  Cerny, Antonin; Benes, Jan; Vachek, Jaroslav, Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 5, p. 1331 - 1339

  摘要：

  DOI：

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。
• [EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
  申请人：BAYER PHARMA AG

  公开号：WO2016174183A1

  公开（公告）日：2016-11-03

  The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

  本申请涉及至少两种组分的新型组合，组分A和组分B：·组分A是根据本文所定义的式(I)的IRAK4抑制化合物，或其对映体、对映异构体、代谢物、盐、溶剂合物或其盐的溶剂合物；·组分B是BTK抑制化合物，或其药学上可接受的盐；以及，可选地，·一种或多种组分C，它们是药用产品；其中上述定义的化合物A和B中的一种或两种可选择地存在于用于治疗和/或预防疾病的制剂中，准备用于同时、分开或顺序给药，用于治疗和/或预防疾病，以及用于生产用于治疗和/或预防疾病的药物的用途，特别是用于治疗和/或预防子宫内膜异位症、淋巴瘤、黄斑变性、慢性阻塞性肺病、肿瘤性疾病和牛皮癣。