2756 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Tamayo et al.
(8) (a) For recent reviews see the following: Szallasi, A.; Appendino, G.
Vanilloid receptor antagonists as the next generation of painkillers.
Are we putting the cart before the horse? J. Med. Chem. 2004, 47,
2717–2723. (b) Breitenbucher, J. G.; Chaplan, S. R.; Carruthers, N. I.
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0.64 mmol), (S)-3-amino-5-(6-iodo-2-(1-methoxypropan-2-ylami-
no)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (29; 0.20 g, 0.43 mmol),
CuI (33 mg, 0.13 mmol), Pd(PPh3)4 (50 mg, 0.06 mmol), and DMF
(5 mL). The reaction mixture was heated at 100 °C for 3 h and
then allowed to cool to room temperature. The mixture was diluted
with EtOAc, washed with 10% aqueous Na2CO3 (20 mL) and
saturated aqueous NaCl, and dried over MgSO4. Purification by
silica gel chromatography (20–60% EtOAc/hexanes) afforded 30
(0.14 g, 63%). MS (ESI positive ion) m/z: 522 (M + 1).
3-(6-(3-Amino-2-oxo-1,2-dihydroquinoxalin-5-yloxy)-2-((S)-
1-methoxypropan-2-ylamino)pyrimidin-4-yl)-6-(trifluoromethyl)-
pyridin-2-aminium trifluoroacetate (31). A 5 mL microwave tube
was charged with 3-amino-5-(6-(2-chloro-6-(trifluoromethyl)pyri-
din-3-yl)-2-((S)-1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)qui-
noxalin-2(1H)-one (0.13 g, 0.25 mmol), (3,4-dimethoxy-
phenyl)methanamine (83 mg, 0.50 mmol), and DMSO (2 mL). The
reaction mixture was stirred and heated at 120 °C for 40 min in a
microwave. Purification by preparative HPLC (10–100% CH3CN/
H2O, 0.1% TFA) afforded 5-(6-(2-(3,4-dimethoxybenzylamino)-6-
(trifluoromethyl)pyridin-3-yl)-2-((S)-1-methoxypropan-2-ylami-
no)pyrimidin-4-yloxy)-3-aminoquinoxalin-2(1H)-one (0.12 g, 77%)
as a TFA salt. MS (ESI positive ion) m/z: 653 (M + 1).
A 25 mL round-bottomed flask was charged with 5-(6-(2-(3,4-
dimethoxybenzylamino)-6-(trifluoromethyl)pyridin-3-yl)-2-(S)-1-
methoxypropan-2-ylamino)pyrimidin-4-yloxy)-3-aminoquinoxalin-
2(1H)-one (0.12 g, 0.18 mmol) and 80% TFA in CH2Cl2 (5 mL).
The reaction mixture was stirred at room temperature for 6 h and
concentrated under reduced pressure. Purification by preparative
HPLC (10–100% CH3CN/H2O, 0.1% TFA) afforded the title
compound as a TFA salt (80 mg, 87%). 1H NMR (400 MHz,
MeOH-d6): δ 8.17 (d, J ) 8.0 Hz, 1H), 8.12 (t, J ) 8.1 Hz, 1H),
7.15–7.09 (m, 2H), 7.03 (d, J ) 7.8 Hz, 1H), 6.75 (s, 1H), 3.33–3.30
(m, 2H), 3.20 (br s, 4H), 1.07 (br s, 3H). MS (ESI positive ion)
m/z: 503 (M + 1). HRMS calculated for C22H21F3N8O3 (M + H)+
503.17615, found 503.17759.
(9) (a) Norman, M. H.; Fotsch, C.; Doherty, E. M.; Bo, Y.; Chen, N.;
Chakrabarti, P.; Gavva, N. R.; Nishimura, N.; Nixey, T.; Ognyanov,
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(11) 60 min after drug administration, significant increases in body
temperature were observed from 0.1–3 mg/kg, po (Figure 1), and it
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Bannon, A. W.; Hovland, D. N.; Lehto, S. G.; Klionsky, L.;
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Kuang, R.; Le, A.; Tamir, R.; Wang, J.; Youngblood, B.; Zhu, D.;
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(19) Quantitative brain microdialysis would allow a more accurate deter-
mination of compound free fraction in the brain.
Acknowledgment. The authors thank Paul Reider, Randy
Hungate, Jean-Claude Louis, and Chris Fibiger for their support
of this research program. Thanks are also given to Rongzhen
Kuang, Jue Wang, Dawn Zhu, and Sonya Lehto for conducting
the in vivo pharmacology studies and to Wesley Barnhart for
his technical assistance in conducting the SFC chiral separations.
Finally, we acknowledge all our colleagues on the TRPV1
research team.
Supporting Information Available: Elemental analysis and
compound purity data for all the final compounds 7, 9, 13a–f, 18a,b,
19a,b, 24a–d, 28a–c, and 31; information on biological assays and
in vivo studies. This material is available free of charge via the
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(21) Unpublished results.
(22) Compound 9 was not progressed forward because of unavailability
of material at the time of the study.