新型稠环吡唑类化合物的合成及其方法学研究
摘要
含有吡唑环的杂环化合物一直都是合成化学和药物化学研究的重点,吡唑类化合物在药学以及农药工业中都具有极为重要的作用,毗唑基团是许多具有生物活性化合物的重要组成部分,它们具有广泛的生物活性,如抗高血糖,镇痛,抗炎症,高热,抗菌,降血糖以及镇定作用等。近些年,研究发现稠环毗唑类化合物在药物化学领域有着很高的潜在药用价值。大量的稠环吡唑类化合物被合成出来,并广泛用于药物化学的各个领域。因而,合成稠环吡唑类化合物的方法学研究和合成设计具有极为重要的现实意义和价值。本文对一类新型稠环毗唑类化合物进行了合成和方法学研究。通过1,3-偶极环加成反应和1,3-二羰基化合物与肼的缩合反应的方法对目标稠环吡唑类化合物进行了合成,发展了两种绿色,温和,方便,迅速的合成方法,并进行了一系列底物扩展。
Fused pyrazoles are structural motifs increasingly found in a wide array of medicinal chemistry programs. For example, A class of 3-arylbenzofuropyrazolesn has been developed as inhibitors of certain tyrosine kinases for the treatment of diseases and disorders associated with abnormal cell proliferation. Fused pyrazoles, including benzothieno-and benzofuropyrazoles, have been identified as selective histamine H3 antagonists, which are potentially useful in the treatment of a host of CNS disorders such as ADHD, Parkinson's disease, memory, Alzheimer's, narcolepsy, sleep apnea, insomnia, etc. The synthesis of fused pyrazoles remains of great interest due to the wide applications of such heterocycles in the pharmaceutical and agrochemical industry. The most important methods for preparing this class of heterocycles are the reaction between hydrazines with a-difunctional compounds and 1,3-dipolar cycloadditions of diazo compounds onto triple bonds. A novel intramolecular 1,3-dipolar cycloaddition strategy and the reaction between hydrazines with a-difunctional compounds for a rapid entry into a new fused pyrazoles are described. By careful choice of solvent, base, and reaction conditions, the two entire sequences can be carried out with moderate yields. New synthetic methods that allow efficient access to this class of fused heterocycles is therefore of great value especially in the early stages of drug discovery and structure-activity studies. These compounds can then be further elaborated by substitution using palladium catalyzed coupling strategies. To demonstrate this utility, we investigated crosscoupling reactions to expand our compounds.
Fused pyrazoles are structural motifs increasingly found in a wide array of medicinal chemistry programs. For example, A class of 3-arylbenzofuropyrazolesn has been developed as inhibitors of certain tyrosine kinases for the treatment of diseases and disorders associated with abnormal cell proliferation. Fused pyrazoles, including benzothieno-and benzofuropyrazoles, have been identified as selective histamine H3 antagonists, which are potentially useful in the treatment of a host of CNS disorders such as ADHD, Parkinson's disease, memory, Alzheimer's, narcolepsy, sleep apnea, insomnia, etc. The synthesis of fused pyrazoles remains of great interest due to the wide applications of such heterocycles in the pharmaceutical and agrochemical industry. The most important methods for preparing this class of heterocycles are the reaction between hydrazines with a-difunctional compounds and 1,3-dipolar cycloadditions of diazo compounds onto triple bonds. A novel intramolecular 1,3-dipolar cycloaddition strategy and the reaction between hydrazines with a-difunctional compounds for a rapid entry into a new fused pyrazoles are described. By careful choice of solvent, base, and reaction conditions, the two entire sequences can be carried out with moderate yields. New synthetic methods that allow efficient access to this class of fused heterocycles is therefore of great value especially in the early stages of drug discovery and structure-activity studies. These compounds can then be further elaborated by substitution using palladium catalyzed coupling strategies. To demonstrate this utility, we investigated crosscoupling reactions to expand our compounds.
引文
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