6-氨基-1,3-二乙基-2,4(1H,3H)-嘧啶二酮 | 41740-15-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 6-氨基-1,3-二乙基-2,4(1H,3H)-嘧啶二酮
• 中文别名: 1,3-二乙基-6-氨基尿嘧啶
• 英文名称: 6-amino-1,3-diethyluracil
• 英文别名: 1,3-diethyl-6-aminouracil；6-amino-1,3-diethylpyrimidine-2,4(1H,3H)-dione；6-amino-1,3-diethylpyrimidine-2,4-dione
• CAS: 41740-15-2
• 化学式: C₈H₁₃N₃O₂
• mdl: MFCD00086294
• 分子量: 183.21
• InChiKey: WPEWOBMDJKQYJK-UHFFFAOYSA-N

物化性质

• 熔点：
  178-179°C
• 沸点：
  276.2±43.0 °C(Predicted)
• 密度：
  1.177±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿、DMF、DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 危险等级：
  IRRITANT
• 海关编码：
  2933599090

反应信息

• 作为反应物：
  描述：

  6-氨基-1,3-二乙基-2,4(1H,3H)-嘧啶二酮 在 sodium nitrite 作用下， 以 水 、 溶剂黄146 为溶剂， 反应 3.0h， 生成 6-amino-1,3-diethyl-5-nitro-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  一种1,3-二乙基-3,7-二氢嘌呤-2,6-二酮的合成方法

  摘要：

  本发明涉及1,3‑二乙基‑3,7‑二氢嘌呤‑2,6‑二酮的合成方法，主要解决现有合成方法存在的使用保险粉还原导致收率不稳定、环境污染大，使用昂贵金属催化剂导致原材料成本高，以及贵金属回收不易控制的技术问题。本发明合成方法包括以下步骤：以1,3‑二乙基脲和氰基乙酸的参与下环合反应，得到6‑胺基‑1,3‑二乙基‑1H‑嘧啶‑2,4‑二酮；然后与亚硝酸钠在有机酸条件下进行亲电加成反应，得到6‑胺基‑1,3‑二乙基‑5‑亚硝基‑1H‑嘧啶‑2,4‑二酮；之后在锌粉和甲酸的作用下，还原和酰化反应得到N‑(6‑氨基‑1,2,4‑二乙基‑1,2,3,4‑四氢嘧啶‑5‑基)‑甲酰胺；最后在强碱性条件下闭环，再酸化得到1,3‑二乙基‑3,7‑二氢嘌呤‑2,6‑二酮。该类化合物在很多新药研究领域是重要的药物化合物前期原料和中间体。

  公开号：

  CN107141290A
• 作为产物：
  描述：

  N'-(1,3-diethyl-2,6-dioxopyrimidin-4-yl)-N,N-dimethylmethanimidamide 生成 6-氨基-1,3-二乙基-2,4(1H,3H)-嘧啶二酮
  参考文献：
  名称：

  FURUKAWA Y.; MIYASHITA O.; SHIMA S., CHEM. AND PHARM. BULL. , 1976, 24, NO 5, 970-978

  摘要：

  DOI：

文献信息

• Synthesis of 8-substituted xanthines via 5,6-diaminouracils: an efficient route to A2A adenosine receptor antagonists
  作者：Ma Dong、Mikhail Sitkovsky、Amy E. Kallmerten、Graham B. Jones

  DOI：10.1016/j.tetlet.2008.05.071

  日期：2008.7

  A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. The process, promoted by (bromodimethyl)sulfonium bromide, is mild and efficient and eliminates the need for external oxidants. Yields are good and the process is applicable to a range of substrates including a family of A2A adenosine receptor antagonists. Preparation of a new analog of the antagonist

  由5，6-二氨基尿嘧啶和羧醛开发了一种一锅法制备8-取代的黄嘌呤的方法。由（溴二甲基）溴化promote促进的该方法温和有效，并且不需要外部氧化剂。收率良好，并且该方法适用于多种底物，包括A 2A腺苷受体拮抗剂家族。介绍了拮抗剂KW-6002的新类似物的制备，并证明了芳基取代产物的原位溴化。
• 8-Triazolylxanthine derivatives, processes for their production and their use as adenosine receptor antagonists
  申请人：Life & Brain GmbH

  公开号：EP2465859A1

  公开（公告）日：2012-06-20

  The invention relates to derivatives of the general formulae I and II to processes for the production thereof, to pharmaceutical preparations containing said compounds and/or physiologically compatible salts, or solvates which can be produced therefrom as well as to the pharmaceutical use of said compounds, the salts, or solvates thereof as adenosine receptor antagonists, in particular for the treatment of neurodegenerative disorders, e.g. stroke, amylotrophic lateral sclerosis, dementia, Alzheimer's disease, Parkinson's disease, ischemia/reperfusion injury, inflammation, and/or neurological disorder. The blockade of adenosine receptors could also be useful for other indications regarding the metabolism, e.g. diabetic retinopathy, diabetes mellitus, hyperbaric oxygen-induced retinopathy and/or obesity. Applications could also be the treatment of allergic diseases and autoimmune diseases, including mast cell degranulation, asthma, bronchoconstriction, pulmonary fibrosis, inflammatory or obstructive airways disease and/or chronic obstructive pulmonary disease (COPD). In addition, they could be used to treat cancer, e.g. proliferating tumor, cell proliferation disorders, angiogenesis, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, skin cancer, vascular endothelial cancer, cancer of the central nervous system, esophageal cancer, cancer of the larynx, gastrointestinal cancer, colon cancer, colorectal cancer, rectal cancer, liver cancer, renal cancer, prostate cancer, bladder cancer, cervical cancer, ovarian cancer, endometrial cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, non-small cell lung cancer selected from squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquam- ous carcinoma and/or undifferentiated carcinoma. The diseases associated with adenosine receptors are also diabetes, diarrhea, inflammatory bowel disease and/or gastrointestinal tract disorders. Adenosine receptor antagonists could be effective for treating a hepatic disease or condition for reducing fat deposition in the liver or fibrosis of the liver. The use of compounds of general formulae I and II can be associated with many applications e.g., scleroderm arthritis, atherosclerosis, urticaria, myocardial infarction, myocardial reperfusion after ischemia, vasodilation, hypertension, hypersensitivity, myocardial ischemia, heart attack and/or retinopathy of prematurity.

  本发明涉及具有通用公式I和II的衍生物，以及它们的制备方法，包含所述化合物的药物制剂以及/或可以从它们产生的生理上相容的盐或溶剂化物，以及所述化合物、盐或溶剂化物作为腺苷受体拮抗剂的药物用途，特别是用于治疗神经退行性疾病，例如中风、肌萎缩侧索硬化、痴呆、阿尔茨海默病、帕金森病、缺血/再灌注损伤、炎症和/或神经系统疾病。腺苷受体的阻断还可能对其他与代谢有关的适应症有益，例如糖尿病视网膜病变、糖尿病、高氧引起的视网膜病变和/或肥胖。应用还可能是治疗过敏性疾病和自身免疫性疾病，包括肥大细胞脱粒、哮喘、支气管收缩、肺纤维化、炎症性或阻塞性气道疾病和/或慢性阻塞性肺病（COPD）。此外，它们还可用于治疗癌症，例如增殖性肿瘤、细胞增殖障碍、血管生成、肺癌、乳腺癌、胰腺癌、甲状腺癌、皮肤癌、血管内皮癌、中枢神经系统癌症、食管癌、喉癌、胃肠癌、结肠癌、结直肠癌、直肠癌、肝癌、肾癌、前列腺癌、膀胱癌、宫颈癌、卵巢癌、子宫内膜癌、黑色素瘤、鳞状细胞癌、基底细胞癌、非小细胞肺癌（包括鳞状细胞癌、腺癌、大细胞癌、腺鳞癌和/或未分化癌）。与腺苷受体相关的疾病还包括糖尿病、腹泻、炎症性肠病和/或胃肠道的疾病。腺苷受体拮抗剂可能对治疗肝脏疾病或状况有效，用于减少肝脏脂肪沉积或肝脏纤维化。通用公式I和II的化合物的使用可以与许多应用相关，例如，硬皮病关节炎、动脉粥样硬化、荨麻疹、心肌梗死、缺血后心肌再灌注、血管扩张、高血压、过敏反应、心肌缺血、心脏病发作和/或早产儿视网膜病变。
• An efficient route to xanthine based A2A adenosine receptor antagonists and functional derivatives
  作者：Paul LaBeaume、Ma Dong、Michail Sitkovsky、Elizabeth V. Jones、Rhiannon Thomas、Sara Sadler、Amy E. Kallmerten、Graham B. Jones

  DOI：10.1039/c003382k

  日期：——

  A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A2A adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

  已开发出一条从5,6-二氨基尿嘧啶和羰基化合物出发，制备8-取代黄嘌呤的一锅法路线。该方法产率高，适用于多种底物，包括一组A2A腺苷受体拮抗剂。本文介绍了一条制备KW-6002拮抗剂家族的新路线，包括一种前药变体，并应用于开发相关造影剂。
• [EN] 8-TRIAZOLYLXANTHINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE AS ADENOSINE RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS DE 8-TRIAZOLYLXANTHINE, LEURS PROCÉDÉS DE FABRICATION ET LEUR UTILISATION EN TANT QU'AGONISTES DE RÉCEPTEURS DE L'ADÉNOSINE
  申请人：LIFE & BRAIN GMBH

  公开号：WO2012076974A1

  公开（公告）日：2012-06-14

  The invention relates to derivatives of the general formulae (I) and (II) to processes for the production thereof, to pharmaceutical preparations containing said compounds and/or physiologically compatible salts or solvates or prodrugs which can be produced therefrom as well as to the pharmaceutical use of said compounds, the salts or solvates thereof as adenosine receptor antagonists, in particular for the treatment of neurodegenerative disorders, e.g. stroke, amylotrophic lateral sclerosis, dementia, Alzheimer's disease, Parkinson's disease, ischemia/reperfusion injury, inflammation, and/or neurological disorder. The blockade of adenosine receptors could also be useful for other indications regarding the metabolism, e.g. diabetic retinopathy, diabetes mellitus, hyperbaric oxygen - induced retinopathy and/or obesity. Applications could also be the treatment of allergic diseases and autoimmune diseases, including mast cell degranulation, asthma, bronchoconstriction, pulmonary fibrosis, inflammatory or obstructive airways disease and/or chronic obstructive pulmonary disease (COPD). In addition, they could be used to treat cancer. The diseases associated with adenosine receptors are also diabetes, diarrhea, inflammatory bowel disease and/or gastrointestinal tract disorders. Adenosine receptor antagonists could be effective for treating a hepatic disease or condition for reducing fat deposition in the liver or fibrosis of the liver. The use of compounds of general formulae I or II can be associated with many applications e.g., scleroderm arthritis, atherosclerosis, urticaria, myocardial infarction, myocardial reperfusion after ischemia, vasodilation, hypertension, hypersensitivity, myocardial ischemia, heart attack and/or retinopathy of prematurity.

  本发明涉及具有通用公式(I)和(II)的衍生物，以及它们的制备方法，含有所述化合物的药物制剂以及/或可以从它们产生的生理上相容的盐或溶剂化物或前药，以及所述化合物、其盐或溶剂化物作为腺苷受体拮抗剂的药物用途，特别是用于治疗神经退行性疾病，例如中风、肌萎缩性侧索硬化症、痴呆、阿尔茨海默病、帕金森病、缺血/再灌注损伤、炎症和/或神经系统疾病。阻断腺苷受体对于涉及代谢的其他适应症也可能有用，例如糖尿病视网膜病变、糖尿病、高氧诱导视网膜病变和/或肥胖。应用还可以包括治疗过敏性疾病和自身免疫性疾病，包括肥大细胞脱粒、哮喘、支气管收缩、肺纤维化、炎症性或阻塞性气道疾病和/或慢性阻塞性肺病（COPD）。此外，它们还可以用于治疗癌症。与腺苷受体相关的疾病还包括糖尿病、腹泻、炎症性肠病和/或胃肠道疾病。腺苷受体拮抗剂可能对治疗肝病或减少肝脏脂肪沉积或肝脏纤维化有效。通用公式I或II的化合物的使用可以与许多应用相关联，例如，硬皮病关节炎、动脉硬化、荨麻疹、心肌梗死、缺血后心肌再灌注、血管舒张、高血压、过敏反应、心肌缺血、心脏病发作和/或早产儿视网膜病变。
• Novel 1,3-Disubstituted 8-(1-benzyl-1<i>H</i>-pyrazol-4-yl) Xanthines:  High Affinity and Selective A_2B Adenosine Receptor Antagonists
  作者：Rao V. Kalla、Elfatih Elzein、Thao Perry、Xiaofen Li、Venkata Palle、Vaibhav Varkhedkar、Arthur Gimbel、Tennig Maa、Dewan Zeng、Jeff Zablocki

  DOI：10.1021/jm051268+

  日期：2006.6.1

  analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A(2B) AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A(2B) AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1

  腺苷已被建议在哮喘患者中诱导支气管高反应性，据信这是A（2B）腺苷受体（AdoR）介导的途径。我们假设选择性的高亲和力A（2B）AdoR拮抗剂可能在哮喘的治疗中提供治疗益处。为了确定一种高亲和力，选择性的A（2B）AdoR拮抗剂，我们合成了8-（C-4-吡唑基）黄嘌呤。化合物22 8-（1H-吡唑-4-基）-1,3-二丙基黄嘌呤是N-1未取代的吡唑衍生物，对A（2B）具有良好的结合亲和力（K（i）= 9 nM） AdoR，但与A（1）AdoR相比只有2倍的选择性。在N-1-吡唑的22位引入苄基导致19，其具有中等选择性。SAR研究的最初重点是制备19的取代苄基衍生物，因为相对于19，相应的苯基，苯乙基和苯丙基衍生物显示出A（2B）AdoR亲和力和选择性降低。苯环上的首选取代如在33和36中分别在19中，C 1包含一个吸电子基团，特别是F或CF（3），在保持对A（2B）AdoR的亲和力的同时