High Affinity TRPV1 (VR1) Vanilloid Receptor Antagonist
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1867
Anal. (C18H19F3N4O) C, H, N: calcd. C: 52.78, H: 4.20, N:
12.96; found C: 53.01, H: 4.25, N: 12.94
ran (150 mL) was added dropwise to the flask and stirred for
1 h at -78 °C. A solution of 1-benzyl-4-piperidone (10.8 mL,
0.06 mol) dissolved in tetrahydrofuran was then added drop-
wise to the cold solution. The reaction mixture was stirred for
18 h, warmed to room temperature, and treated with saturated
NH4Cl solution (20 mL). The solvent was removed under
reduced pressure and the residue diluted with 1 N NaHCO3
and extracted with ethyl acetate (3 × 50 mL). The organic
layers were combined, dried (Na2SO4), and evaporated. Chro-
matography of the residue (2-6% 2 M ammonia in methanol:
dichloromethane) gave the title compound (10 g, 61%). 1H NMR
(CD3OD) δ 8.31 (d, J ) 4.7 Hz, 1H), 7.55 (d, J ) 7.6 Hz, 1H),
7.39-7.27 (m, 5H), 7.17 (dd, J ) 7.6, 4.7, 1H), 3.61 (s, 2H),
2.82-2.79 (m, 2H), 2.65-2.59 (m, 5H), 2.45-2.37 (m, 2H),
1.76-1.72 (m, 2H), MS m/z 283.3 [MH+].
Step B: 1′-Benzyl-3-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]-
bipyridinyl. A solution of thionyl chloride (20 mL) was cooled
to 0 °C and stirred for 30 min. 1′-Benzyl-3-methyl-2′,3′,5′,6′-
tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol (1.5 g, 5.3 mmol) was
added dropwise and the reaction warmed to room temperature.
After 18 h excess thionyl chloride was evaporated and the
residue chromatographed (2-6% 2 M ammonia in methanol:
dichloromethane) to afford the title compound (0.503 g, 35%).
1H NMR (CD3OD) δ 8.29-8.28 (m, 1H), 7.65 (d, J ) 6.9 Hz,
1H), 7.42-7.26 (m, 5H), 7.19 (dd, J ) 7.7, 4.9 Hz, 1H), 5.75-
5.74 (m, 1H), 3.69 (s, 2H), 3.20-3.18 (m, 2H), 2.80-2.77 (m,
2H), 2.51-2.48 (m, 2H), 2.37 (s, 3H), MS m/z 265.2 [MH+].
Step C: 3-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipy-
ridinyl. 10% Pd/C (280 mg) in ethanol was added to a solution
of 1′-benzyl-3-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl (480
mg, 1.80 mmol) in ethanol. Nitrogen was bubbled through the
solution, and the reaction was hydrogenated (H2) at 60 psi.
After 18 h the reaction mixture was filtered through Celite
and washed with methanol, and the solvent was evaporated.
Chromatography of the residue (4-9% 2 M ammonia in
methanol) gave the title compound (60 mg, 20%). 1H NMR
(CD3OD) δ 8.30 (d, J ) 4.8 Hz, 1H), 7.56 (d, J ) 7.6 Hz, 1H),
7.13 (dd, J ) 7.6, 4.8 Hz, 1H), 3.25-3.22 (m, 2H), 3.17-3.13
(m, 1H), 2.38 (s, 3H), 1.97-1.85 (m, 2H), 1.79-1.75 (m, 2H),
MS m/z 177.3 [MH+].
Step D: The title compound (27) was prepared in a similar
fashion as 4 using 3-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]-
bipyridinyl and 4-trifluoromethyl phenyl isocyanate (10) 1H
NMR (CD3OD) δ 8.30 (dd, J ) 4.8, 1.1 Hz, 1H), 7.60-7.53 (m,
5H), 7.14 (dd, J ) 7.6, 4.8 Hz, 1H), 4.37-4.33 (m, 2H), 3.27-
3.23 (m, 1H), 2.42 (s, 3H), 1.95-1.88 (m, 2H), 1.82-1.79 (m,
2H), MS m/z 364.2 [MH+], Anal. (C19H20F3N3O) C, H, N.
2,6-Dimethyl-4-(3-trifluoromethylpyridin-2-yl)pipera-
zine-1-carboxylic Acid (4-Trifluoromethylphenyl)amide
(21). The title compound was prepared in a similar manner
as 4 using 5t and 4-(trifluoromethyl)phenyl isocyanate (10)
1
(67%). H NMR ((CD3)2SO)) δ 8.74 (s, 1H), 8.65 (dd, J ) 4.8,
1.2 Hz, 1H), 8.18 (dd, J ) 7.8, 1.8 Hz, 1H), 7.75 (d, J ) 8.4 Hz,
2H), 7.59 (d, J 8.6 Hz, 2H), 7.38 (dd, J ) 7.1, 4.8 Hz, 1H),
4.41-4.38 (m, 2H), 3.20 (d, J ) 11.9 Hz, 2H), 3.05 (dd, J )
12.4, 4.3 Hz, 2H), 1.36 (d, J ) 6.8 Hz, 6H), MS m/z 447.3
[MH+], Anal. (C20H20F6N4O) C, H, N.
2,5-Dimethyl-4-(3-trifluoromethylpyridin-2-yl)pipera-
zine-1-carboxylic Acid (4-Trifluoromethylphenyl)amide
(22). The title compound was prepared in a similar manner
as 4 using 5u and 4-(trifluoromethyl)phenyl isocyanate (10)
1
(30%). H NMR ((CD3)2SO)) δ 8.84 (s, 1H), 8.52 (dd, J ) 4.8,
1.2 Hz, 1H), 8.08 (dd, J ) 7.8, 1.6 Hz, 1H), 7.71 (d, J ) 8.6 Hz,
2H), 7.59 (d, J ) 8.6 Hz, 2H), 7.17 (dd, J ) 7.1, 4.8 Hz, 1H),
4.46 (bs, 1H), 4.05-4.02 (m, 1H), 3.82 (dd, J ) 13.2, 2.6 Hz,
1H), 3.65 (dd, J ) 13.3, 3.9 Hz, 1H), 3.53 (dd, J ) 13.2, 3.6
Hz, 1H), 3.08 (d, J ) 12.2 Hz, 1H), 1.70 (d, J ) 6.6 Hz, 3H),
1.02 (d, J ) 6.5 Hz, 3H), MS m/z 447.3 [MH+], Anal.
(C20H20F6N4O) C, H, N.
5-(3-Trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]-
heptane-2-carboxylic Acid (4-Trifluoromethylphenyl)-
amide (23). The title compound was prepared in a similar
manner as 4 using 5v and 4-(trifluoromethyl)phenyl isocyanate
1
(10) (46%). H NMR ((CD3)2SO) δ 8.66 (s, 1H), 8.37 (dd, J )
4.7, 1.5 Hz, 1H), 7.95 (dd, J ) 7.8, 1.7 Hz, 1H), 7.70 (d, J )
8.6 Hz, 2H), 7.55 (d, J ) 8.8 Hz, 2H), 6.87 (dd, J ) 7.8, 4.7 Hz,
1H), 4.91 (s, 1H), 4.78 (s, 1H), 3.76 (d, J ) 9.3 Hz, 1H), 3.60-
3.57 (m, 2H), 3.16 (d, J ) 5.2 Hz, 1H), 1.95 (bs, 2H), MS m/z
431.3 [MH+], Anal. (C19H16F6N4O) C, H, N.
4-(3-Trifluoromethylpyridin-2-yl)-[1,4]diazepane-1-car-
boxylic Acid (4-Trifluoromethylphenyl)amide (24). The
title compound was prepared according to the library synthesis
procedure using 5d and 4-(trifluoromethyl)phenyl isocyanate
(10). 1H NMR ((CD3)2SO)) δ 8.67 (s, 1H), 8.38 (dd, J ) 4.7, 1.8
Hz, 1H), 7.97 (dd, J ) 7.8, 1.9 Hz, 1H), 7.64 (d, J ) 8.6 Hz,
2H), 7.55 (d, J ) 8.8 Hz, 2H), 6.98 (dd, J ) 7.6, 4.3 Hz, 1H),
3.74-3.70 (m, 2H), 3.60-3.50 (m, 6H), 1.97-1.90 (m, 2H), MS
m/z 433.1 [MH+], Anal. (C19H18F6N4O) C, H, N.
1-(4-Trifluoromethylphenyl)-3-[1-(3-trifluoromethylpy-
ridin-2-yl)pyrrolidin-3-yl]-urea (25). The title compound
was prepared in a similar manner as 4 using 5w and
4-(trifluoromethyl)phenyl isocyanate (10) (88%). 1H NMR
((CD3)2SO)) δ 8.29 (d, J ) 4.6 Hz, 1H), 7.90 (dd, J ) 7.6, 1.5
Hz, 1H), 7.56-7.51 (m, 4H), 6.78 (dd, J ) 7.8, 4.8 Hz, 1H),
4.41-4.38 (m, 1H), 3.90-3.86 (m, 1H), 3.80-3.75 (m, 1H),
3.70-3.67 (m, 1H), 3.50 (dd, J ) 10.4, 3.8 Hz, 1H), 2.28-2.24
(m, 1H), 2.02-1.99 (m, 1H), MS m/z 419.2 [MH+], Anal.
(C18H16F6N4O) C, H, N.
1-(4-Trifluoromethylphenyl)-3-(3′-trifluoromethyl-
3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)urea (26). A
solution of (5x) (0.245 g, 1.0 mmol) in dichloromethane (20 mL)
was treated with 4-trifluoromethyl phenyl isocyanate (10) (0.16
mL, 1.1 mmol) and stirred at room temperature for 5 h. The
reaction mixture was diluted with saturated NaHCO3 solution
(20 mL) and the organic layer separated, washed with brine
(20 mL), dried over Na2SO4 and evaporated to afford an oil.
Trituration with 60:40 hexane:ethyl acetate precipitated the
title compound as a cream-colored powder (0.349 g, 81%): 1H
NMR ((CD3)2SO)) 8.8 (s, 1H), 8.5 (d, J ) 3.6 Hz, 1H), 8.0 (d, J
) 7.7 Hz, 1H), 7.7 (m, 2H), 7.2 (d, J ) 4.9 Hz, 1H), 6.4 (d, J )
7.7 Hz, 1H), 3.7 (m, 1H), 3.4-3.5 (bd, J ) 12.7 Hz, 2H), 2.9 (t,
J ) 10.7 Hz, 2H), 2.0 (bd, J ) 9.7 Hz, 2H), 1.5 (bq, J ) 9.9 Hz,
2H). MS(CI) m/z 433 (MH+). Anal. (C19H18F6N4O): C, H, N.
3-Methyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-
carboxylic Acid (4-Trifluoromethylphenyl)amide (27).
Step A: 1′-Benzyl-3-methyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]-
bipyridinyl-4′-ol. 2.5 M n-BuLi in hexanes (25 mL, 0.06 mol)
was placed in a dry flask and cooled to -78 °C. 2-Bromo-3-
methyl pyridine (0.06 mol, 6.5 mL) dissolved in tetrahydrofu-
3′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrid-
inyl-4-carboxylic Acid (4-Trifluoromethylphenyl)amide
(28). Step A: 3′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-
[1,2′]bipyridinyl-4-carboxylic Acid. To a solution of 2-chloro-
3-trifluoromethylpyridine (1.81 g, 10.0 mmol) in 100 mL of
acetonitrile was added piperidin-4-carboxylic acid (1.29 g, 11.0
mmol), and the reaction mixture was heated at reflux tem-
perature for 16 h. The solvent was evaporated, and the residue
was stirred with saturated NaHCO3 solution (50 mL). The
precipitated solid (2.05 g, 75%) was collected by vacuum
1
filtration and used, Step B, without further purification. H
NMR ((CD3)2SO)) δ 11.0 (bs, 1H), 8.1 (d, J ) 4 Hz, 1H), 7.6 (d,
J ) 9 Hz, 1H), 6.5(dd, J ) 4, 9 Hz, 1H), 3.3-3.5 (m, 2H), (2.8-
3.1,m, 3H), 1.4-1.6 (m, 4H), MS m/z 275.0 [MH+].
Step B: To a solution of 3′-trifluoromethyl-3,4,5,6-tetrahy-
dro-2H-[1,2′]bipyridinyl-4-carboxylic acid (0.413 g, 1.5 mmol)
in dichloromethane (20 mL) were added diisopropylethylamine
and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
hexafluorophosphate (0.456 g, 1.0 mmol). The reaction mixture
was then stirred at room temperature for 10 min. 4-Trifluo-
romethylaniline (0.177 g, 1.1 mmol) was added and the
reaction mixture stirred for an additional 16 h. The reaction
mixture was diluted with saturated NaHCO3 (20 mL), and the
organic layer was separated, washed with brine (20 mL), dried
over Na2SO4, and evaporated. The product was chromato-
graphed on silica gel eluting with CH2Cl2:2% MeOH to afford
the title compound 28, as a white solid (0.283 g, 68%): 1H NMR