Conformational and configurational behaviour of κ-agonistic 3,7-diazabicyclo[3.3.1]nonan-9-ones—synthesis, nuclear magnetic resonance studies and semiempirical PM3 calculations

Abstract

2,4-Diaryl substituted 3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diesters were found to have a high affinity for κ-opioid receptors. To develop highly potent analgesics, the purpose of this study was the synthesis and the structural characterisation of the novel 2,4-bis(4-nitrophenyl), 2,4-bis(3-nitrophenyl), 2,4-bis(4-quinolyl), 2,4-bis(2-quinolyl), 2,4-bis(1-naphthyl) and 2,4-bis(2-naphthyl) substituted 3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diesters by means of NMR spectroscopy and molecular modelling. It could be proved that several derivatives undergo trans–cis-isomerisation of the aromatic rings linked to the rigid skeleton whereas others show rotational isomerisation. Semiempirical quantum-chemical PM3 calculations were performed to analyse the thermodynamic stability of the isomers as well as the mechanism of the trans–cis- or cis–trans-conversion.

References

1. B. Kögel, T. Christoph, E. Friderichs, H.-H. Hennies, T. Mathiesen, J. Schneider and U. Holzgrabe, CNS Drug Rev., 1998, 4, 54.
2. R. Jeyaraman and S. Avila, Chem. Rev., 1981, 81, 149.
3. N. S. Zefirov and V. A. Palyulin, Top. Stereochem., 1991, 20, 171.
4. U. Holzgrabe-Ashauer and T. Busch, Z. Naturforsch., Teil B, 1988, 43, 873.
5. W. Brandt, S. Drosihn, M. Haurand, U. Holzgrabe and C. Nachtsheim, Arch. Pharm. Pharm. Med. Chem., 1996, 329, 311.
6. R. Haller and H. Unholzer, Arch. Pharm. (Weinheim), 1971, 304, 654.
7. H. Küppers, Hesse, U. Holzgrabe and R. Haller, Z. Naturforsch., Teil B, 1987, 42, 221.
8. U. Holzgrabe and E. Erciyas, Arch. Pharm. (Weinheim), 1992, 325, 657.
9. A. Samhammer, U. Holzgrabe and R. Haller, Arch. Pharm. (Weinheim), 1989, 322, 551.
10. H. Günther, NMR-Spektroskopie, VCH, Weinheim, 1983, p. 228.
11. A. E. Derome, Modern NMR Techniques for Chemistry Research, Pergamon Press, Oxford, 1987, p. 109.
12. H. Günther, NMR Spektroskopie, Thieme, Stuttgart, 1983, p. 75.
13. E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994, p. 1150.
14. Tripos Associates Inc., 1699 S. Hanley Road, Suite 3.
15. M. Clark, R. D. Cramer III and N. Van Opdenbosch, J. Comput. Chem., 1989, 10, 982.
16. J. Gasteiger and M. Marsili, Tetrahedron, 1980, 36, 3219.
17. J. Gasteiger and H. Saller, Angew. Chem., 1985, 97, 699.
18. J. J. P. Stewart, J. Comput. Chem., 1989, 10, 209.