N. E. Austin et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1627–1629
1629
Scheme 1. Synthesis of compounds 2–8. Reagents and conditions: (i) ArCOCl, Et3N, CH2Cl2, 6 h, 25 ꢀC (70–94%); (ii) ACE-Cl, CH2Cl2, 18 h,
50 ꢀC, then MeOH, 1–24 h (36–97%).
Scheme 2. Synthesis of compounds 9 to 14. Reagents and conditions: (i) HCHO, BnNH2, EtOH, c.HCl; (ii) 10% Pd/C, H2, (Boc) 2O EtOH; (iii) 3,5-
dinitro-2-pyridone, NH3, MeOH; (iv) 10% Pd/C, H2, EtOH, 4 h (25% from 17); (v) ArCOCl, Et3N, CH2Cl2, 6 h, 25 ꢀC (75–89%); (vi) TFA, CH2Cl2
18 h, 25 ꢀC (89–99%).
2. Upton, N. Trends Pharmacol. Sci. 1994, 15, 456.
3. Hovinga, C. A. Exp. Opin. Invest. Drugs 2002, 11, 1387.
4. Upton, N.; Thompson, M. In Progress in Medicinal Chem-
istry, Vol. 37; King, F. D., Oxford, A. W, Eds.; Elsevier
Science: Oxford, 2000; p 177.
5. Chan, W. N.; Hadley, M. S.; Harling, J. D.; Herdon, H. J.;
Orlek, B. S.; Riley, G. J.; Stead, R. E. A.; Stean, T. O.;
Thompson, M.; Upton, N.; Ward, R. W. Bioorg. Med. Chem.
2000, 8, 2085.
6. Austin, N. E., Jeffrey, P. Unpublished observations.
7. (a) Preliminary results are in: Herdon, H.; Jerman, J.;
Stean, T. O.; Chan, W.; Middlemiss, D. N.; Upton, N. Eur. J.
Pharmacol. 1996, 314, R7. (b) Herdon, H. J.; Jerman, J. C.;
Stean, T. O.; Middlemiss, D. N.; Chan, W. N.; Vong, A. K.;
Evans, J. M.; Thompson, M.; Upton, N. Brit. J. Pharmacol.
1997, 121, 1687.
reproducibility. As it became apparent that the N-H
analogues showed superior pharmacokinetic parameters
to the N-Me derivatives, the synthesis of larger quan-
tities of key compounds became a requirement. The
unpredictable and toxic nature of the demethylation
step meant that an alternative synthetic strategy was
required. Route optimisation work produced an alter-
native intermediate 16 which was prepared via 18 and 3,5-
dinitro-2-pyridone15 (Scheme 2). The overall yield to 9–14
was high (20%) compared with using the original pub-
lished route to such benzamides (<4% over nine steps).
Conclusions
8. Upton, N.; Blackburn, T. P.; Campbell, C. A.; Cooper, D.;
Evans, M. L.; Herdon, H. J.; King, P. D.; Ray, A. M.; Stean,
T. O.; Chan, W. N.; Evans, J. M.; Thompson, M. Brit. J.
Pharmacol. 1997, 121, 1679.
9. Litchfield, J. T.; Wilcoxon, F. J. Pharmacol. Exp. Ther.
1949, 96, 99.
10. For 12, human CYP’s all IC50>35 mM at 1A2, 2C9, 2C19,
2D6 and 3A4). Intrinsic clearance rates in microsomes were
mouse <0.5, rat 1.1, dog <0.5 and human <0.5 mL/min/g liver.
11. De Lean, A.; Munson, P. J.; Rodbard, D. Am. J. Physiol.
235, E97. 1978.
A series of novel 8,8-dimethyl[1,6]naphthyridines has
been prepared with high affinity in the [3H]-SB-204269
binding assay. Compound 1216 has excellent aqueous
solubility (>1 mg/mL) and has been shown to have an
encouraging pharmacokinetic profile and good in vivo
activity in preclinical anticonvulsant models in the rat.
A modified synthesis of the naphthyridine core has also
been developed allowing this particular series to be
amenable to high throughput chemistry and scale-up.
12. All data reported herein reflect characterized samples.
Compounds 2–14 were purified by crystallization as mono-
hydrochlorides. All compounds were >95% purity as mea-
sured using a VG micromass OpenLynx LCMS system and a
Bruker AC 250MHz 1H NMR.
This group of investigational anticonvulsants, from a
new structural class, possesses an improvement in drug
chemical structure, improved pharmacokinetic proper-
ties and as such represents an exciting potential for the
treatment of epilepsy and related disorders.
13. Harling, J. D.; Harrington, F. P.; Thompson, M. Synth.
Commun. 2001, 31, 787.
14. Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.;
Malfroot, M. J. Org. Chem. 1984, 49, 2081.
15. Takada, S.; Sasatani, T.; Chomei, N.; Adachi, M.;
Fujishita, T.; Eigyo, M.; Murata, S.; Kawasaki, K.; Matsush-
ita. J. Med. Chem. 1996, 39, 2844.
16. Spectroscopic data for 12. N-(8,8-Dimethyl-5,6,7,8-tetra-
hydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethyl-
benzamide, hydrochloride. 1H NMR (250 MHz; CD3OD) [free
base] d:1.37 (6H, s), 3.35 (2H, s), 4.35 (2H, s), 7.25 (1H, d,
J=9 Hz), 8.07 (1H, d, J=2 Hz), 8.15–8.18 (2H, m), 8.70 (1H,
d, J=2 Hz); m/z (API)+: 378.1 (MH+; 100%); aqueous
solubility >1 mg/mL.
Acknowledgements
The authors would like to thank Ms. G. Espasa-Bosch
and Mr. S. P Wright for technical assistance.
References and Notes
1. (a) Nicolson, A.; Leach, J. P. CNS Drugs 2001, 15, 955.
(b) Chadwick, D. Arch Neurol. 1998, 55, 1140.