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6727
9. (a) Rahman, S. S.; Smith, I. E. D. WO Patent 2005/
016867; (b) Campbell, M.; Hatley, R. J. D.; Heer, J. P.;
Mason, A. M.; Nicholson, N. H.; Pinto, I. L.; Rahman, S.
S.; Smith, I. E. D. WO Patent 2005/016870.
10. Dehmlow, H.; Grether, U.; Kratochwil, N. A.; Narquiz-
ian, R.; Panousis, C.; Peters, J.-U. US Patent 0,281,810,
2006.
11. (a) Pinto, I. L.; Rahman, S. S.; Nicholson, N. H. WO
Patent 2005/077950; (b) Hatley, R. J. D.; Pinto, I. L. WO
Patent 2006/045564; (c) Hatley, R. J. D.; Pinto, I. L. WO
Patent 2006/045565; (d) Hatley, R. J. D.; Mason, A. M.;
Pinto, I. L. WO Patent 2007/017261; (e) Hatley, R. J. D.;
Heer, J. P.; Liddle, J.; Mason, A. M.; Pinto, I. L.;
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where we measured the extent of flushing by the change
in blood perfusion of the mouse ear via laser Doppler.
In this study, 1a did not induce any flushing at either
30 mg/kg or 100 mg/kg (ip), in contrast to the intense
flushing caused by the niacin control at these doses
(Fig. 4). As a balanced compound regarding its activity
and PK, 1a was selected for study in the mouse vasodi-
lation model. It is unclear to us whether the lack of vaso-
dilation effect of 1a is a class effect until more
compounds have been tested.
In conclusion, we have identified a novel urea class of
anthranilic acid derivatives which bound and activated
the niacin receptor GPR109A. The SAR established
the importance of the piperazine and quinoxaline moie-
ties. Compound 1q bearing a terminal hydroxyl group
matched the potency of niacin indicating the added
favorable interaction of the hydroxyl group with the
receptor. Compound 1a had a good PK profile and bet-
ter efficacy in reducing FFA devoid of any flushing at
100 mg/kg in the mouse model. These data suggested
the possibility of developing niacin-like compounds with
reduced or no flushing.
13. Dehmlow, H.; Grether, U.; Kratochwil, N.A.; Narquizian,
R.; Panousis, C. U.S. Patent 2007/0072873.
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A. M.; Ijzerman, A. P.; Stannek, C.; Brumeister, A.;
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References and notes
16. The structures of 5 and 6 can be assigned by comparison
with known compound 6 obtained from a different
synthetic route, see: Hazeldine, S. T.; Polin, L.; Kushner,
J.; Paluch, J.; White, K.; Edelstein, M.; Palomino, E.;
Corbett, T. H.; Horwitz, J. P. J. Med. Chem. 2001, 44,
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18. The corresponding experimental procedures to Scheme 1
are shown below: To a suspension of diaminomethoxy-
benzene bis-HCl salt (2.1 g, 10 mmol) in 25 mL of water
and 10 mL of ethanol was added sodium bicarbonate
(1.7 g, 20 mmol). To the resulting mixture was added ethyl
glyoxylate (2.04 g, 2 mL, 11 mmol) and the mixture was
then under reflux for 2 h. The mixture was cooled and
filtered. The collected solid was dissolved in DMSO and
purified by RP-HPLC to afford a mixture of alcohols
(1.76 g). To this mixture of alcohols was added 40 mL of
POCl3.The resulting mixture was under reflux for 1 h. The
mixture was concentrated by distilling off the solvent. The
residue was poured into ice and basified with a saturated
sodium carbonate solution. The mixture was then
extracted with ethyl acetate. The organic layer was washed
with brine, dried with sodium sulfate, and concentrated in
vacuo. The residue was purified by flash chromatography
eluting with 5% of ethyl acetate in hexanes to obtain 5
(220 mg, 1.13 mmol, 11% over 2 steps). A mixture of 5
(220 mg, 1.13 mmol), piperazine (440 mg, 5.1 mmol), and
4 mL of butanol was heated at 150 °C in microwave for
15 min, then at 170 °C in microwave for additional 15 min.
The mixture was purified by RP-HPLC to give 8 (300 mg,
0.84 mmol, 74%) as a yellow oil. A solution of 8 (300 mg,
0.84 mmol) in 4 mL of dichloromethane was treated with a
stock solution of isocyanate 3 (0.2 M, 2 mL, 0.40 mmol).
After 1 h, the solution was concentrated and purified by
RP-HPLC to afford 9 (119 mg, 0.28 mmol, 34%) as a
yellow oil. To 9 (42 mg, 0.1 mmol) in 4 mL of THF/water/
methanol (3:1:1) was added 1 mL of LiOH (1 N) at rt. The
mixture was stirred at rt for 1 h, and concentrated. To this