Urea TRPV1 Antagonists
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3659
References
water and brine, dried (Na2SO4), and concentrated in vacuo. The
crude product was triturated with Et2O and the solid collected by
vacuum filtration to give 0.85 g (47%) of 4-(8-azabicyclo[3.2.1]-
octan-8-yl)-2-bromobenzonitrile (17, R4 ) tropanyl) as a light-
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1
yellow solid. H NMR (DMSO-d6): δ 7.57 (d, J ) 8.8 Hz, 1H),
7.11 (d, J ) 2.4 Hz, 1H), 6.84 (dd, J ) 8.8, 2.37 Hz, 1H), 4.36 (m,
2H), 1.76-2.03 (m, 5H), 1.64 (m, 2H), 1.31-1.50 (m, 3H). MS
(ESI+) m/z 291/293 (M + H)+.
A 2 M solution of benzylmagnesium bromide in THF (2.30 mL,
4.60 mmol) was added dropwise to a mixture of ZnCl2 (2.30 mmol)
in dioxane (15 mL) at ambient temperature. The mixture was stirred
for 30 min followed by addition of solid bromonitrile 17 (335 mg,
1.15 mmol) and Pd(dppf)2Cl2. The mixture was heated to reflux
for 3 h, then cooled to ambient temperature, quenched with
methanol, and diluted by EtOAc and 3 M NaOH solution. The
mixture was poured into water, and the separated organic phase
was washed with water and brine, dried (Na2SO4), and concentrated
in vacuo. Flash chromatography (20% EtOAc/hexane) yielded 316
mg (91%) of 2-benzyl-4-(8-azabicyclo[3.2.1]octan-8-yl)benzonitrile
(18, R3 ) benzyl, R4 ) tropanyl) as a colorless oil. 1H NMR
(DMSO-d6): δ 7.47 (d, J ) 8.82 Hz, 1H), 7.15-7.34 (m, 5H),
6.84 (d, J ) 2.4 Hz, 1H), 6.71 (dd, J ) 8.7, 2.5 Hz, 1H), 4.30 (m,
2H), 4.00 (s, 2H), 1.76-2.02 (m, 5H), 1.64 (m, 2H), 1.44 (m, 1H),
1.32 (m, 2H). MS (ESI+) m/z 303 (M + H)+.
The intermediate benzylnitrile 18 from above (310 mg, 1.03
mmol) was hydrogenated at 60 psi in the presence of Raney nickel
(3 g) in 30 mL of MeOH/NH3 at ambient temperature. After 2 h
the catalyst was filtered and the filtrate concentrated in vacuo. The
residue was purified by flash chromatography (5-10% CH3OH/
CH2Cl2) to give 243 mg (76%) of (2-benzyl-4-(8-azabicyclo[3.2.1]-
octan-8-yl)phenyl)methanamine as a pale-brown oil. 1H NMR
(DMSO-d6): δ 7.26 (m, 2H), 7.16 (m, 4H), 6.60 (m, 2H), 4.10 (m,
2H), 3.95 (s, 2H), 3.55 (s, 2H), 2.08 (br s, 2H), 1.94 (m, 2H), 1.68-
1.87 (m, 5H), 1.36 (m, 1H), 1.20 (m, 2H). MS (ESI+) m/z 307 (M
+ H)+.
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(16) Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner,
R. J.; DiDomenico, S.; Koenig, J. R.; Turner, S.; Jinkerson, T.; Drizin,
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Compound 73 was synthesized using (2-benzyl-4-(8-azabicyclo-
[3.2.1]octan-8-yl)phenyl)methanamine and methyl 4-amino-1H-
indazole-1-carboxylate17 and the process described for compound
1
65 (yield 87%). H NMR (DMSO-d6): δ 12.87 (s, 1H), 8.53 (s,
1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.66 (d, J ) 6.8 Hz, 1H), 7.10-
7.29 (m, 6H), 7.03 (d, J ) 9.0 Hz, 1H), 6.63 (m, 2H), 6.46 (t, J )
5.1 Hz, 1H), 4.21 (d, J ) 5.1 Hz, 2H), 4.13 (m, 2H), 3.99 (s, 2H),
1.99 (m, 2H), 1.81 (m, 5H), 1.41 (m, 1H), 1.21 (m, 2H). MS (ESI+)
m/z 466 (M + H)+. Anal. (C29H31N5O) C, H, N.
1-(2-Benzyl-4-(8-azabicyclo[3.2.1]octan-8-yl)benzyl)-3-(1-methyl-
1H-indazol-4-yl)urea (74). To a solution of compound 73 (292
mg, 0.627 mmol) in DMSO (5 mL) was added NaH (60% in oil,
28 mg, 0.70 mmol) at ambient temperature. After 1.5 h, dimethyl
sulfate (66 µL, 0.69 mmol) was added. The reaction was allowed
to proceed for 1 h, and then the mixture was partitioned between
EtOAc and half-saturated NaCl solution. The separated organic
phase was washed with water and brine, dried (Na2SO4), and
concentrated in vacuo. Flash chromatography (40-75% EtOAc/
hexane) gave 122 mg (69%) of the title compound as a white solid.
1H NMR (DMSO-d6): δ 8.61 (s, 1H), 8.00 (s, 1H), 7.68 (d, J )
7.5 Hz, 1H), 7.09-7.31 (m, 8H), 6.65 (m, 2H), 6.50 (t, J ) 5.1
Hz, 1H), 4.18 (d, J ) 5.1 Hz, 2H), 4.12 (m, 2H), 3.99 (m, 5H),
1.95 (m, 2H), 1.66-1.86 (m, 5H), 1.38 (m, 1H), 1.20 (m, 2H). MS
(ESI+) m/z 480 (M + H)+. Anal. (C30H33N5O) C, H, N.
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Z.; Perner, R. J.; DiDomenico, S.; Koenig, J. R.; Turner, S. C.;
Jinkerson, T. K.; Brown, B. S.; Keddy, R. G.; McDonald, H. A.;
Honore, P.; Wismer, C. T.; Marsh, K. C.; Wetter, J. M.; Polakowski,
J. S.; Segreti, J. A.; Jarvis, M. F.; Faltynek, C. R.; Lee, C.-H.
Structure-activity studies of a novel series of 5,6-fused heteroaro-
matic ureas as TRPV1 antagonists. Bioorg. Med. Chem. 2006, 14,
4740-4749.
Acknowledgment. We thank the Abbott Structural Chem-
istry group for excellent NMR and mass spectrometry support.
We also thank the High Pressure and Process Research labs for
assistance with the scale-up of intermediates.
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Supporting Information Available: Experimental procedures
for synthesis of 31-39, 41-49, 51-64, 66, 68-70, 72, 75, and
76; details of the Ca2+ influx functional in vitro assay and complete
Freund’s adjuvant in vivo assay; and results from elemental analysis.
This material is available free of charge via the Internet at http://
pubs.acs.org.