A. Hall et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1592–1597
1597
2. (a) Camu, F.; Shi, L.; Vanlersberghe, C. Drugs 2003, 63, 1;
(b) Bianchi, M.; Broggini, M. Drugs 2003, 63, 37; (c) Jeger,
R. V.; Greenberg, J. D.; Ramanathan, K.; Farkouh, M. E.
Exp. Rev. Clin. Immunol. 2005, 1, 37; (d) Lee, Y.;
Rodriguez, C.; Dionne, R. A. Curr. Pharm. Des. 2005,
11, 1737.
3. (a) Hawkey, C. J.; Jackson, L.; Harper, S. E.; Simon, T. J.;
Mortensen, E.; Lines, C. R. Aliment. Pharmacol. Ther. 2001,
15, 1; (b) Silverstein, F. E.; Faich, G.; Goldstein, J. L.;
Simon, L. S.; Pincus, T.; Whelton, A.; Makuch, R.; Eisen,
G.; Agrawal, N. M.; Stenson, W. F.; Burr, A. M.; Zhao, W.
W.; Kent, J. D.; Lefkowith, J. B.; Verburg, K. M.; Geis, G.
S. J. Am. Med. Assoc. (JAMA) 2000, 284, 1247.
reaction with serine methyl ester to give 21. Oxida-
tion furnished oxazole 6e upon ester hydrolysis
(Scheme 3)
Previously described boronic acid 225a was reacted with
thiazole derivative 25 under Suzuki conditions, to give
6g upon ester hydrolysis (Scheme 4). Thiazole 25 was
prepared by condensation of 1,3-dibromoacetone and
ethyl thiooxamate as shown (Scheme 4). Phenyl deriv-
ative 6o was prepared by reaction of 22 with 26
(Scheme 4).
4. Hall, A.; Billinton, A.; Giblin, G. M. P. Curr. Opin. Drug
Discov. Devel. 2007, 10, 597.
Benzylic alcohol 19 was converted to bromide 27 which
underwent in situ reaction with zinc and subsequent
Negishi coupling with thiazole 28 or thiophene 29 to
give 6f and 6m, respectively, upon ester hydrolysis
(Scheme 5). Picolinate 6p and pyridyl isomers 6q and
6r were prepared in a similar manner.15
5. (a) Hall, A.; Atkinson, S. A.; Brown, S. H.; Chessell, I. P.;
Chowdhury, A.; Coleman, T.; Giblin, G. M. P.; Gleave,
R. J.; Hammond, B.; Healy, M. P.; Johnson, M. R.;
Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.;
Tang, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 3657; (b)
Hall, A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.;
Clayton, N. M.; Coleman, T.; Giblin, G. M. P.; Ham-
mond, B.; Healy, M. P.; Johnson, M. R.; Metcalf, A.;
Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.;
Sweeting, J.; Winyard, L. Bioorg. Med. Chem. Lett. 2007,
17, 732; (c) Hall, A.; Brown, S. H.; Chessell, I. P.;
Chowdhury, A.; Clayton, N. M.; Coleman, T.; Giblin, G.
M. P.; Hammond, B.; Healy, M. P.; Johnson, M. R.;
Metcalf, A.; Michel, A. D.; Naylor, A.; Novelli, R.;
Spalding, D. J.; Sweeting, J.; Winyard, L. Bioorg. Med.
Chem. Lett. 2007, 17, 916.
6. Giblin, G. M. P.; Bit, R. A.; Brown, S. H.; Chaignot, H.
M.; Chowdhury, A.; Chessell, I. P.; Clayton, N. M.;
Coleman, T.; Hall, A.; Hammond, B.; Hurst, D. N.;
Michel, A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.;
Tang, S. P.; Wilson, A. W.; Wilson, R. Bioorg. Med.
Chem. Lett. 2007, 17, 385.
7. McKeown, S. C.; Hall, A.; Giblin, G. M. P.; Lorthioir, O.;
Blunt, R.; Lewell, X. Q.; Wilson, R. J.; Brown, S. H.;
Chowdhury, A.; Coleman, T.; Watson, S. P.; Chessell, I.
P.; Pipe, A.; Clayton, N. M.; Goldsmith, P. Bioorg. Med.
Chem. Lett. 2006, 16, 4767.
Imidazole 6h was prepared from nitrile derivative 20, via
amidoxime 34 (Scheme 6). The methyl imidazoles were
prepared via alkylation of 35 followed by ester hydroly-
sis (Scheme 6).
Furan 6k was prepared by Friedel–Crafts alkylation of
4-chloro anisole (36) (Scheme 7). Selective demethyla-
tion of the phenolic ether 37 followed by alkylation
and ester hydrolysis delivered the final acids. Furan 6l
was prepared in an analogous fashion.
Wittig reaction with 5-chlorosalicyaldehyde (38) fol-
lowed by benzylation of the phenolic hydroxyl, double
bond and ester reduction then oxidation of the alco-
hol gave aldehyde 39 (Scheme 8). Gewald reaction17
with ethyl cyanoacetate and sulfur in the presence of
triethylamine gave aminothiophene 40 which under-
went deamination and ester hydrolysis to give thio-
phene 6n (Scheme 8).
8. Hall, A.; Bit, R. A.; Brown, S. H.; Chaignot, H. M.;
Chessell, I. P.; Coleman, T.; Giblin, G. M. P.; Hurst, D. N.;
Kilford, I. R.; Lewell, X. Q.; Michel, A. D.; Mohamed, S.;
Naylor, A.; Novelli, R.; Skinner, L.; Spalding, D. J.; Tang,
S. P.; Wilson, R. J. Bioorg. Med. Chem. Lett. 2006, 16, 2666.
9. Logarithm (base 10) of the distribution coefficient
(D), where D is the ratio of equilibrium concentrations
of all species of a compound between n-octanol and water
(buffered to pH 7.4). All values are measured.
Commercially available amino thiazole 41 underwent
deprotection and re-esterification to give phenol 42
which was alkylated with benzyl bromide (Scheme 9).
Ester hydrolysis delivered aminothiazole 9a (Scheme 9)
In summary, we have explored several aromatic het-
erocycles as replacements for the original pyrazole
lead (6a). The SAR generated has shown that the pyr-
azole, thiazole and furan derivatives demonstrated the
highest EP1 affinity and therefore merit further
investigation.
10. Active compounds behaved as antagonists in a functional
assay (FLIPR). For assay details, see Ref. 8.
11. Molecular overlays conducted using MOE (Molecular
Operating Environment), Chemical Computing Group
12. Giblin, G. M. P.; Hall, A.; Hurst, D. N.; Lewell, X. Q.;
Lorthioir, O. E.; McKeown, S. C.; Scoccitti, T.; Watson,
S. P. 2005, WO2005/040128A1.
Acknowledgments
13. Bit, R. A.; Hall, A.; Hurst, D. N.; Scoccitti, T. 2006,
WO2006/114274A1.
14. Bit, R. A.; Giblin, G. M. P.; Hall, A.; Hurst, D.
N.; Kilford, I. R.; Scoccitti, T. 2006, WO2006/
114272A1.
We thank Helen Price, Thomas Hayhow, Edward Mil-
ton and Anne-Marie D’Souza for the synthesis of se-
lected compounds.
15. Giblin, G. M. P.; Hall, A.; Hurst, D. N.; Rawlings, D. A.;
Scoccitti, T. 2006, WO2006/066968A1.
References and notes
16. Higgins, S. D.; Thomas, C. B. J. Chem. Soc., Perkin Trans.
1 1982, 235.
17. Gewald, K. Chem. Ber. 1965, 98, 3571.
1. Chadwick, D. J.; Goode, J. Osteoarthritic Joint Pain;
Wiley Interscience, 2004.