Advanced Synthesis & Catalysis ( IF 4.4 ) Pub Date : 2024-07-03 , DOI: 10.1002/adsc.202400781 Elena Graziano 1 , Philipp Natho 1 , Michael Andresini 2 , Fabrizio Mastrolorito 1 , Iktedar Mahdi 1 , Ernesto Mesto 1 , Marco Colella 2 , Leonardo Degennaro 2 , Orazio Nicolotti 1 , Renzo Luisi 1
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Introduction
Despite improvements in technology, developments in synthetic methodology, advancements in computer-aided design and high-throughput screening, the number of new drugs approved per billion US dollars spent on research and development has halved approximately every nine years.1-3 This counterintuitive trend has, at least in part, been attributed to compound libraries tending to be very limited in skeletal and stereochemical diversity due to favoring achiral, aromatic compounds. In fact, a representative screening library contains only 103 chemotypes, although up to 1062 chemotypes would comply with Lipinski's Rule of Five.1, 4, 5 A shift towards higher molecular complexity, and hence a higher fraction of sp3-hybridized carbons, has been shown to correlate with reduced promiscuity, lowered toxicity and reduced candidate failure.6-9 It is thus unsurprising that fully saturated N-heterocycles containing exclusively sp3-hybridised carbons (e. g., piperidine, pyrrolidine, or piperazine) are one of the most popular building blocks in modern pharmaceuticals, being prevalent in 88% of FDA-approved pharmaceuticals between 2015–2020.10 Recently, the discovery of bioisosteres for these classical non-strained heterocycles has gained significant traction for the occurrence of new binding events in first-in-class small-molecule drug development. For this purpose, strained spiro heterocycles (SSHs) have received particular attention, given their improved metabolic stability, decreased lipophilicity and increased solubility, imparted by their high 3D-character and molecular rigidity.11 Their limited conformational freedom offers predictable vectorization and hence a more selective target interaction.12, 13 Seminal contributions by Carreira,14-21 followed more recently by Mikhailiuk,22-24 Grygorenko,25, 26 Morandi27 and others28-31 showcased the importance of SSHs such as 2,6-diazaspiro[3.3]heptane (DASE), 1-oxa-6-azaspiro[3.3]heptane (1-OASE), 2-oxa-6-azaspiro[3.3]heptane (2-OASE), 2-azaspiro[3.3]heptane (2-ASE) and 1-azaspiro[3.3]heptane (1-ASE), as potential bioisosteres of piperazines, morpholines and piperidines. The imminent positive impact of the available synthetic strategies for accessing such strained spirocyclic heterocycles as bioisosteres is witnessed by the development of potential drugs such as AZD1979 bearing the 2-ASE motif by Astra Zeneca (Figure 1).32, 33 Notably, an advancement in pharmacokinetics was also demonstrated in the substitution of the piperazine motif in ciprofloxacin with DASE (Figure 1).15 Evidently, adding further such easily accessible potential bioisosteres to the medicinal chemists’ toolbox could positively impact drug development.34, 35 In line with this theme, we hypothesized that the hitherto underexplored strained spiro heterocycle 1-oxa-2,6-diazaspiro[3.3]heptane (ODASE) might serve as a bioisostere for saturated non-strained N-heterocycles. Our interest in this scaffold for potential integration into drug discovery programs was sparked by the presence of an additional heteroatom, which introduces possibilities for unforeseen biological properties, stemming from its hydrogen bond acceptor capability.
(A) Drug candidates containing strained spiro heterocycles as property-improving bioisosteres. (B) This work – ODASE as a novel bioisostere.
中文翻译：
1-Oxa-2,6-二氮杂螺[3.3]庚烷作为一种新的潜在哌嗪生物等排体——氮杂双环[1.1.0]丁烷的应变释放的流动辅助制备和衍生化
介绍
尽管技术不断进步，合成方法不断发展，计算机辅助设计和高通量筛选也取得了进步，但每十亿美元研发费用中批准的新药数量大约每九年减少一半。 1-3这种违反直觉的趋势至少部分归因于化合物库由于偏爱非手性芳香化合物而在骨架和立体化学多样性方面往往非常有限。事实上，代表性筛选文库仅包含 10 3 种化学型，尽管多达 10 62 种化学型符合Lipinski 的五法则。 1, 4, 5向更高分子复杂性的转变，以及因此更高比例的sp 3杂化碳，已被证明与减少混杂、降低毒性和减少候选失败相关。 6-9因此，完全饱和的N杂环仅含有sp 3杂化碳（例如哌啶、吡咯烷或哌嗪）是现代药物中最流行的结构单元之一，在 88% 的 FDA 中普遍存在，这一点也就不足为奇了。 2015年至2020年期间批准的药品。 10最近，这些经典非应变杂环化合物的生物等排体的发现对一流小分子药物开发中新结合事件的发生产生了重大影响。 为此，应变螺杂环 (SSH) 受到了特别关注，因为它们的高 3D 特征和分子刚性赋予了它们改善的代谢稳定性、降低的亲脂性和增加的溶解度。 11它们有限的构象自由度提供了可预测的矢量化，从而提供了更具选择性的目标相互作用。 12, 13 Carreira, 14-21的开创性贡献，最近 Mikhailiuk, 22-24 Grygorenko, 25, 26 Morandi 27和其他人28-31展示了 SSH 的重要性，例如 2,6-diazaspiro[3.3]heptane (DASE )、1-氧杂-6-氮杂螺[3.3]庚烷 (1-OASE)、2-氧杂-6-氮杂螺[3.3]庚烷 (2-OASE)、2-氮杂螺[3.3]庚烷 (2-ASE) 和 1 -azaspiro[3.3]heptane (1-ASE)，作为哌嗪、吗啉和哌啶的潜在生物等排体。 Astra Zeneca 开发的潜在药物（例如带有 2-ASE 基序的 AZD1979）见证了现有合成策略即将产生的积极影响，这些合成策略可用于获得此类紧张螺环杂环作为生物电子等排体（图 1）。 32, 33值得注意的是，用 DASE 取代环丙沙星中的哌嗪基序也证明了药代动力学的进步（图 1）。 15显然，在药物化学家的工具箱中进一步添加这种易于获得的潜在生物等排体可能会对药物开发产生积极影响。34, 35根据这一主题，我们假设迄今为止尚未充分探索的应变螺杂环 1-oxa-2,6-二氮杂螺[3.3]庚烷 (ODASE) 可能充当饱和非应变N杂环的生物等排体。我们对这种可能整合到药物发现计划中的支架的兴趣是由额外杂原子的存在引起的，该杂原子由于其氢键受体能力而引入了不可预见的生物特性的可能性。
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(A) 含有应变螺杂环作为性能改善生物电子等排体的候选药物。 (B) 这项工作——ODASE 作为一种新型生物电子等排体。
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