Aldrich ChemFiles 2006, 6.6, 7.

Aldrich ChemFiles 2006, 6.6, 7.

The piperazine scaffold is frequently found in biologically active compounds across a number of different therapeutic areas. As a result, medicinal chemists have been interested in piperazine building blocks in the construction of screening libraries. One recent report uses a series of different piperazines to create a series of aza-5[H]-phenanthridin-6-ones that exhibit significant protective effects in rat models of stroke and heart ischemia (Scheme 11).1

Scheme 11

Recent work by Bernotas utilized 1-Boc-3-oxopiperazine to obtain isoxazolidines from a common nitrone intermediate (Scheme 12).2 Boc-protected piperazinone has also been used to synthesize macrocyclic piperazinones that demonstrate dual farnesyltransferase (FPTase) and geranylgeranyltransferase-I (GGPTase-I) inhibitory activity (Scheme 13).3

Scheme 12

Scheme 13

Substituted benzylpiperazines are also of increasing interest to medicinal chemists. Zhao and co-workers have reported the synthesis of a series of mixed D2/D4 receptor antagonists using benzylpiperazines as key building blocks (Scheme 14).4 In another report, a (4-fluorobenzyl)piperazine-modified analogue of KN-62 was prepared that showed greater antagonistic activity than the parent molecule, completely inhibiting the release of cytokine IL-1b (Scheme 15).5

Scheme 14

Scheme 15

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  1. Ferraris, D. et al. J. Med. Chem. 2003, 46, 3138.
  2. Bernotas, R. C. et al. Synthesis, 2005, 465.
  3. Dinsmore, C. J. et al. Bioorg. Med. Chem. Lett. 2004, 14, 639.
  4. Zhao, H. et al. Bioorg. Med. Chem. Lett. 2002, 12, 3105.
  5. Baraldi, P. G. et al. J. Med. Chem. 2003, 46, 1318.

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