Synthesis and Regioselective Functionalization of Piperazin‐2‐ones Based on Phe‐Gly Pseudodipeptides

Abstract

The synthesis of 1,4‐unsubstituted piperazin‐2‐ones by one‐pot reductive cyclization of PheΨ[CH(CN)NH]Gly pseudodipeptides is described. Studies on the reactivity of the piperazin‐2‐one ring showed a higher reactivity at the N4 position than at the N1 position. The stepwise regioselective functionalization of piperazin‐2‐one derivatives showed great potential for molecular diversity generation.

Exploring the Phe-Gly Dipeptide-Derived Piperazinone Scaffold in the Search for Antagonists of the Thrombin Receptor PAR1

“…Two alternative retrosynthetic routes were considered for the building of the desired piperazinones derivatives B from the starting 1-(benzyloxycarbonyl)methyl-piperazinones 1 [23]. These routes differ in the order of incorporation of the basic amino acid and the urea moieties.…”

“…In view of the good results in the synthesis of the 4-unsubstituted-piperazinone derivatives 11a , b and 12a , b , a parallel synthetic scheme was applied to the synthesis of the 4-benzyl-piperazinone derivatives 19a – c and 20a , b from the (3:1) epimeric mixture of 4-benzyl-piperazinones 13 [23] (Scheme 3). Based on the biological results of the previous library A , besides ornithine ( a ) and lysine ( b ), arginine ( c ) was also included in this series.…”

From Multiple PAR1 Receptor/Protein Interactions to their Multiple Therapeutic Implications

“…The capacity of these derivatives to suppress SFLLRN-NH 2 induced platelet aggregation-and thrombinmediated calcium signaling was moderated. Additionally, the synthesis of diverse small directed libraries of different scaffolds able to assemble, at least, one or two aromatic groups and one or two basic groups at variable distances and orientation have recently been described, as well as their evaluation as human PAR1 antagonists in a platelet aggregation assay and as cytotoxic agents in human cancer cell lines [405][406][407][408]. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at µM concentration.…”

Highly functionalized 2-oxopiperazine-based peptidomimetics: An approach to PAR1 antagonists

“…Initially, this benzylation was attempted by applying previously described conditions developed for 2-oxopiperazine analogues [49], that is MW-activated reaction with BnBr in CH 3 CN at 150 ºC, using Cs 2 CO 3 as base ( Table 2, entry 1). This attempt revealed the simultaneous alkylation at the guanidino group of arginine, in spite of being protected with the Pbf group.…”

“…We now describe the synthesis and biological evaluation of a library of pseudodipeptidebased 2-oxopiperazine derivatives of general formula B, which could be considered as conformational restricted analogues of the urea derivatives A. The 2-oxopiperazine skeleton was selected as central core taking into account our synthetic experience in this heterocycle [48,49] and that the piperazine ring is included among privileged scaffolds in medicinal chemistry. Actually, there are 165 drug entries for this heterocycle in the DrugBank database [50].…”