Magriotis Plato A
Department of Pharmacy , Laboratory of Medicinal Chemistry , University of Patras , Rio26504 , Greece . Email:
RSC Med Chem. 2020 May 22;11(7):745-759. doi: 10.1039/d0md00053a. eCollection 2020 Jul 1.
The important requirement for approval of a new drug, in case it happens to be chiral, is that both enantiomers of the drug should be studied in detail, which has led synthetic organic and medicinal chemists to focus their attention on the development of new methods for asymmetric synthesis especially of relevant saturated N-heterocycles. On the other hand, the piperazine ring, besides defining a major class of saturated N-heterocycles, has been classified as a privileged structure in medicinal chemistry, since it is more than frequently found in biologically active compounds including several marketed blockbuster drugs such as Glivec (imatinib) and Viagra (sildenafil). Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contained a piperazine ring. Nevertheless, analysis of the piperazine substitution pattern reveals a lack of structural diversity, with almost every single drug in this category (83%) containing a substituent at both the N1- and N4-positions compared to a few drugs having a substituent at any other position (C2, C3, C5, and C6). Significant chemical space that is closely related to that known to be biologically relevant, therefore, remains unexplored. In order to explore this chemical space, efficient and asymmetric syntheses of carbon-substituted piperazines and related heterocycles must be designed and developed. Initial, recent efforts toward the implementation of this particular target are in fact the subject of this review.
对于一种新药（如果它恰好是手性的），获批的重要要求是该药物的两种对映体都应进行详细研究，这使得有机合成化学家和药物化学家将注意力集中在开发不对称合成新方法上，尤其是相关饱和氮杂环的不对称合成。另一方面，哌嗪环除了定义了一大类饱和氮杂环外，在药物化学中还被归类为特权结构，因为它在包括几种已上市的重磅药物（如格列卫（伊马替尼）和伟哥（西地那非））在内的生物活性化合物中经常出现。事实上，2012年最畅销的200种小分子药物中有13种含有哌嗪环。然而，对哌嗪取代模式的分析表明缺乏结构多样性，这类药物中几乎每一种（83%）在N1和N4位置都有取代基，相比之下，只有少数药物在其他位置（C2、C3、C5和C6）有取代基。因此，与已知具有生物学相关性的化学空间密切相关的重要化学空间仍未被探索。为了探索这个化学空间，必须设计和开发碳取代哌嗪及相关杂环的高效不对称合成方法。事实上，本文综述的主题就是为实现这一特定目标而进行的初步的、近期的努力。
