N. Garton et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1049–1054
1053
O
H
O
Me
H
N
H
Br
Me NH2
+
NaBH(OAc)3
Me
Me
Me
Me
B(OH)2
Me
Me
Scheme 6. Reagents and conditions: methylamine (2 equiv), NaBH(OAc)3 (2 equiv), AcOH (cat), DCM, 20 °C, 16 h.
CO2Me
O
CO2R
O
CO2R
O
B(OH)2
Me
CO2R
O
O
Me
N
N
N
H
i)
N
H
N
H
N
H
ii)
Br
Br
Me
Me
Me
Me
R=H, NH2
R=Me, NH2
R=H, NH2
Scheme 7. Reagents and conditions: (i) oxalyl chloride (1.1 equiv), DCM, 20 °C, 2 h; (ii) methanol or 2 M methanolic ammonia.
OH
Cl
Cl
O
NH2
N
N
OR
N
CHO
i)
ii)
iii)
N
N
H
N
N
H
N
Ph
Ph
Ph
Ph
Ph
Scheme 8. Reagents and conditions: (i) PCl5 (1 equiv), diethyl ether, 20 °C, 5 h; (ii) POCl3 (8 equiv), DMF (12 equiv), 90 °C, 6 h; (iii) NaOR (10 equiv), methanol, 65 °C, 24 h.
amination with methylamine using sodium triacetoxyboro-
hydride as the reducing agent (Scheme 6).
Compounds (4a–e, g–i, l–m, o, 5a–d) were synthesised using
the same methodology outlined in Scheme 1. The phenolic ana-
logue (4f) was generated from the benzyl derivative (4h) using
the hydrogenation conditions for (2h) above.
The carboxylate compounds (4j–k) were made from the start-
ing methyl ester following conditions outlined in Scheme 1. The
ester was transformed into a mixture of carboxylic acid and
amide during imidazole formation and the desired compounds
were obtained after treatment with oxalyl chloride and quench-
ing in methanol or methanolic ammonia as appropriate (Scheme
7).
Alkoxypyridine compound (4n) was synthesised by building up
the core pyridine ring, imidazole formation as described in the lit-
erature and subsequent alkoxide displacement of a chloropyridine
(Scheme 8).
References and notes
1. Sachs, G.; Shin, J. M.; Vagin, O.; Lambrecht, N.; Yakubov, I.; Munson, K. J. Clin.
Gastroenterol. 2007, 41, S226.
2. Scarpignato, C.; Pelosini, I.; Di Mario, F. Dig. Dis. 2006, 24, 11.
3. Parsons, M. E.; Keeling, D. J. Expert Opin. Investig. Drugs 2005, 14, 411.
4. Andersson, K.; Carlsson, E. Pharmacol. Ther. 2005, 108, 294.
5. Kaminski, J. J.; Bristol, J. A.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn, D. J.;
Elliott, A. J.; Lovey, R. G.; Guzik, H.; Chiu, P. J. S.; Long, J. F.; McPhail, A. T. J. Med.
Chem. 1989, 32, 1686.
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533.
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Solomon, D. M.; Conn, D. J.; Domalski, M. S.; Wong, S. C.; Gold, E. H.; Long, J. F.;
Chiu, P. J. S.; Steinberg, M.; McPhail, A. T. J. Med. Chem. 1985, 28, 876.
8. Andersson, K.; Carlsson, E. Pharmacol. Ther. 2005, 108, 294.
9. Bailey, N.; Bamford, M. J.; Demont, E.; Elliott, R.; Garton, N.; Farre-Gutierrez, I.;
Hayhow, T.; Hutley, G.; Naylor, A.; Panchal, T. A. Bioorg. Med. Chem. Lett. 2009,
19, 3602.
10. Bailey, N.; Bamford, M. J.; Brissy, D.; Brookfield, J.; Demont, E.; Elliott, R.;
Garton, N.; Farre-Gutierrez, I.; Hayhow, T.; Hutley, G.; Naylor, A.; Panchal, T. A.;
Seow, H. X.; Spalding, D.; Takle Bioorg. Med. Chem. Lett. 2009, 19, 6813.
11. Bristol, J. A.; Lovey, R. G. Imidazo[1,2-b]pyridazines. U.S. (1984), 12 pp. US
4464372.
12. Amin, K.; Dahlstrom, M.; Nordberg, P.; Starke, I. Preparation of heterocyclic
compounds for inhibition of gastric acid secretion. PCT Int. Appl. (1999), 34 pp.
WO 9928322.
13. Berg, A. L.; Bottcher, G.; Andersson, K.; Carlsson, E.; Lindstrom, A. K.; Huby, R.;
Hakansson,H.;Skanberg-Wilhelmsson,I.;Hellmold,H.Toxicol.Pathol.2008,36, 727.
14. Andersson, K. Society for Medicines Research Symposium, September 21, 2006,
London, U.K.
(N1)-Alkylated methoxy derivative (4p) was synthesised using
conditions outlined in Scheme 4.
Acknowledgements
The authors acknowledge the assistance of GlaxoSmithKline
colleagues from the departments of Gene Expression and Protein
Biochemistry for the pig gastric membranes and Assay Develop-
ment & Compound Profiling for assay of the compounds.20
15. A search of the Cambridge crystallography database with the following query
retrieved a total of 43 hits where the twist between the two rings is more
pronounced with R = Me than R = H.