Piperazines

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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Materials

     

References

  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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