Piperazinylbenzimidazoles as TRPV1 antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3739
(R)-2-(4-(3-Bromopyridin-2-yl)-2-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51a). Following the procedure described for compound 47a,
2-chlorobenzoimidazole 20n and piperazine 8q provided the title
compound (73%) as a white amorphous solid. MS (ESI, pos. ion)
cedure described for compound 47a, piperazine 8f and 2-chloro-
benzimidazole 20n provided the title compound (68%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 416 (M + 1). 1H NMR
(CDCl3): δ 3.64-3.74 (m, 4 H), 3.78-3.88 (m, 4 H), 6.85 (d, J )
8.0 Hz, 1 H), 7.02 (d, J ) 8.0 Hz, 1 H), 7.37 (br s, 2 H), 7.58 (br
s, 1 H), 7.64 (t, J ) 8.0 Hz, 1 H). Anal. (C18H15F6N5): C, H, N.
2-(4-(3-Chloropyridin-2-yl)piperazin-1-yl)-6-(trifluorometh-
yl)-1H-benzo[d]imidazole (52e). Following the procedure described
for compound 47a, piperazine 8b and 2-chlorobenzimidazole 20n
provided the title compound (41%) as a white solid. Mp: 208-
210 °C. MS (ESI, pos. ion) m/z: 382 (M + 1). 1H NMR (DMSO-
d6): δ 3.37-3.43 (m, 4 H), 3.65-3.75 (m, 4 H), 7.06 (dd, J )
7.8, 4.7 Hz, 1 H), 7.28 (br s, 1 H), 7.32-7.42 (m, 1 H), 7.48 (br
s, 1 H), 7.86 (d, J ) 7.8 Hz, 1 H), 8.26 (d, J ) 4.7 Hz, 1 H), 11.89
(br s, 1 H). Anal. (C17H15ClF3N5‚0.25H2O): C, H, N.
2-(4-(3-Iodopyridin-2-yl)piperazin-1-yl)-6-(trifluoromethyl)-
1H-benzo[d]imidazole (52f). Following the procedure described
for compound 47a, piperazine 8c and 2-chlorobenzimidazole 20n
provided the title compound (58%) as a white amorphous solid.
MS (ESI, pos. ion) m/z: 474 (M + 1). 1H NMR (CDCl3): δ 3.00-
3.10 (m, 4 H), 3.18-3.28 (m, 4 H), 6.64 (d, J ) 7.6 Hz, 1 H), 6.66
(d, J ) 7.6 Hz, 1 H), 8.06 (d, J ) 7.6 Hz, 1 H), 8.07 (d, J ) 7.6
Hz, 1 H), 8.27 (d, J ) 4.4 Hz, 1 H), 8.28 (d, J ) 4.8 Hz, 1 H).
Anal. (C17H15F3IN5‚0.2H2O): C, H, N.
2-(4-(3-Methylpyridin-2-yl)piperazin-1-yl)-6-(trifluorometh-
yl)-1H-benzo[d]imidazole, Trifluoroacetic Acid Salt (52g). Fol-
lowing the procedure described for compound 47a, piperazine 30a
and 2-chloro-3-methylpyridine provided the crude product, which
was purified by preparative HPLC (gradient 0.1% trifluoroacetic
acid in acetonitrile) to give the title compound (73%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 362 (M + 1). 1H NMR
(CDCl3): δ 3.48-3.52 (m, 4 H), 3.94 (br s, 4 H), 7.19 (dd, J )
8.0 Hz, 4.0 Hz, 1 H), 7.40-7.48 (m, 2 H), 7.60 (s, 1 H), 7.84 (d,
J ) 8.0 Hz, 1 H), 8.11 (d, J ) 4.0 Hz, 1 H). Anal. (C18H18F3N5‚
2.3TFA‚1.4H2O): C, H, N.
2-(4-(6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)piperazin-
1-yl)nicotinonitrile (52h). Following the procedure described for
compound 47a, 2-piperazin-1-ylnicotinonitrile and 2-chlorobenz-
imidazole 20n provided the title compound (56%) as a white
amorphous solid. MS (ESI, pos. ion) m/z: 373 (M + 1). 1H NMR
(DMSO-d6): δ 3.75 (m, 8 H), 6.98 (dd, J ) 7.4, 4.7 Hz, 1 H),
7.20-7.60 (m, 3 H), 8.12 (d, J ) 7.8 Hz, 1 H), 8.45 (d, J ) 4.0
Hz, 1 H), 11.90 (s, 1 H). LC/MS retention time: A, 8.87 min; B,
5.71 min.
Ethyl 2-(4-(6-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-
piperazin-1-yl)nicotinate Hydrochloride (52i). Following the
procedure described for compound 47a, piperazine 8e and 2-
chlorobenzimidazole 20n provided the crude reaction product. A
solution of the product in EtOAc was treated with a 1 M solution
of hydrogen chloride in Et2O and the mixture was evaporated under
reduced pressure. The residue was dried in vacuo to give the title
compound title compound (71%) as a white amorphous solid. MS
(ESI, pos. ion) m/z: 420 (M + 1). 1H NMR (CDCl3): δ 1.34 (t, J
) 7.2 Hz, 3 H), 3.45-3-55 (m, 4 H), 3.69-3.81 (m, 4 H), 4.32
(q, J ) 7.0 Hz, 2 H), 6.83 (dd, J ) 7.6, 4.9 Hz, 1 H), 7.26-7.36
(m, 2 H), 7.49 (br s, 1 H), 8.06 (dd, J ) 7.8, 2.0 Hz, 1 H), 8.28
(dd, J ) 4.7, 2.0 Hz, 1 H). Anal. (C20H20N5F3O2): C, H, N.
(5-Chloro-6-(4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-
yl)piperazin-1-yl)pyridin-3-yl)methanol (52j). Following the pro-
cedure described for compound 31a, piperazine 8h and 2-chloro-
benzimidazole 20n provided the title compound (42%) as a solid.
Mp: 162-165 °C. MS (ESI, pos. ion) m/z: 412 (M + 1). 1H NMR
(DMSO-d6): δ 3.30-3.40 (m, 4 H), 3.65-3.75 (m, 4 H), 4.47 (d,
J ) 5.8 Hz, 2 H), 5.30 (t, J ) 5.5 Hz, 1 H), 7.20-7.50 (m, 3 H),
7.78 (d, J ) 2.0 Hz, 1 H), 8.19 (d, J ) 2.0 Hz, 1 H). Anal. (C18H17-
ClN5F3O): C, H, N.
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m/z: 570 (M + 1). H NMR (CD3OD): δ 1.53 (d, J ) 6.8 Hz, 3
H), 3.09 (dt, J ) 12.4, 3.6 Hz, 1 H), 3.21 (dd, J ) 12.8, 3.4 Hz, 1
H), 3.60-3.98 (m, 3 H), 4.10 (d, J ) 11.2 Hz, 1 H), 4.51 (br s, 1
H), 6.97 (dd, J ) 8.0, 4.8 Hz, 1 H), 7.47 (br s, 2 H), 7.92 (br s, 2
H), 7.98 (dd, J ) 8.0, 1.2 Hz, 1 H) 8.28 (d, J ) 4.8 Hz, 1 H).
Anal. (C24H18BrF6N5): C, H, N.
(S)-2-(4-(3-Bromopyridin-2-yl)-2-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51b). Following the procedure described for compound 47a,
2-chlorobenzoimidazole 20i and piperazine 8r provided the title
compound (84%) as a white amorphous solid. MS (ESI, pos. ion)
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m/z: 570 (M + 1). H NMR (CD3OD): δ 1.51 (d, J ) 6.4 Hz, 3
H), 3.00-3.05 (m, 1 H), 3.19 (dd, J ) 12.0, 3.2 Hz, 1 H), 3.60-
3.86 (m, 3 H), 4.07 (d, J ) 11.2 Hz, 1 H), 4.49 (br s, 1 H), 6.94
(dd, J ) 8.0, 4.8 Hz, 1 H), 7.36-7.60 (m, 2 H), 7.80-7.90 (m, 2
H), 7.96 (d, J ) 8.0 Hz, 1 H), 8.25 (dd, J ) 4.8, 1.6 Hz, 1 H). MS
m/z: 571 (M + 1). Anal. (C24H18BrF6N5): C, H, N.
(R)-2-(4-(3-Bromopyridin-2-yl)-3-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51c). Following the procedure described for compound 47a,
2-chlorobenzoimidazole 20i and piperazine 9 provided the title
compound (64%) as white amorphous solid. MS (ESI, pos. ion)
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m/z: 570 (M + 1). H NMR (CD3OD): δ 1.12 (d, J ) 6.0 Hz, 3
H), 3.10-3.30 (m, 1 H), 3.50-3.65 (m, 2 H), 3.70-3.90 (m, 3 H),
4.05 (br s, 1H), 6.98 (dd, J ) 8.0, 4.8 Hz, 1 H), 7.47 (s, 2 H), 7.86
(br s, 2 H), 7.99 (dd, J ) 7.6, 1.6 Hz, 1 H), 8.29 (dd, J ) 4.4, 1.6
Hz, 1 H). LC/MS retention time: A, 12.89 min; B, 6.82 min.
(S)-2-(4-(3-Bromopyridin-2-yl)-3-methylpiperazin-1-yl)-6-(tri-
fluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole
(51d). Following the procedure described for compound 47a,
piperazine 30b and 2-chloropyridine 6b provided the title compound
(18%) as a white amorphous solid. MS (ESI, pos. ion) m/z: 570
(M + 1). 1H NMR (CD3OD): δ 1.12 (d, J ) 6.0 Hz, 3 H), 3.10-
3.30 (m, 1 H), 3.50-3.65 (m, 2 H), 3.70-3.90 (m, 3 H), 4.05 (br
s, 1H), 6.98 (dd, J ) 8.0, 4.8 Hz, 1 H), 7.47 (s, 2 H), 7.86 (br s,
2 H), 7.98 (dd, J ) 7.6, 1.6 Hz, 1 H), 8.28 (dd, J ) 4.4, 1.6 Hz,
1 H). LC/MS retention time: A, 12.81 min; B, 7.86 min.
2-(4-Pyridin-2-ylpiperazin-1-yl)-6-(trifluoromethyl)-1H-ben-
zo[d]imidazole (52a). Following the procedure described for
compound 5, 2-chlorobenzimidazole 20n and 1-(pyridin-2-yl)-
piperazine provided the title compound (19%) as amorphous solid.
MS (ESI, pos. ion) m/z: 570 (M + 1).1H NMR (DMSO-d6): δ
3.52-3.86 (m, 8 H), 6.62-6.72 (m, 1 H), 6.93 (d, J ) 8.6 Hz, 1
H), 7.28 (s, 1 H), 7.36 (d, J ) 8.2 Hz, 1 H), 7.47 (br s, 1 H), 7.58
(t, J ) 7.2 Hz, 1 H), 8.15 (d, J ) 3.5 Hz, 1 H), 11.89 (br s, 1 H).
Anal. (C17H16F3N5): C, H, N.
6-(Trifluoromethyl)-2-(4-(4-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazole (52b). Following the pro-
cedure described for compound 31a, 2-chloro-4-(trifluoromethyl)-
pyridine and piperazine 30a provided the title compound (66%) as
a white amorphous solid. MS (ESI, pos. ion) m/z: 416 (M + 1).
1H NMR (CD3OD): δ 3.66-3.76 (m, 4 H), 3.78-3.88 (m, 4 H),
6.88 (d, J ) 5.2 Hz, 1 H), 7.10 (s, 1 H), 7.30 (d, J ) 8.2 Hz, 1 H),
7.36 (d, J ) 8.2 Hz, 1 H), 7.50 (s, 1 H), 8.32 (d, J ) 5.2 Hz, 1 H).
Anal. (C18H15F6N5): C, H, N.
6-(Trifluoromethyl)-2-(4-(5-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1 H-benzo[d]imidazole (52c). Following the pro-
cedure described for compound 47a, 1-(5-(trifluoromethyl)pyridin-
2-yl)piperazine and 2-chlorobenzimidazole 20n provided the title
compound (98%) as a white solid. Mp: 214 °C. MS (ESI, pos.
ion) m/z: 416 (M + 1). 1H NMR (CDCl3): δ 3.74 (d, J ) 7.2 Hz,
2 H), 3.76-3.86 (m, 4 H), 3.86-3.96 (m, 4 H), 6.74 (d, J ) 9.2
Hz, 2 H), 7.39 (br s, 1 H), 7.66 (br s, 1 H), 7.72 (dd, J ) 8.8, 2.0
Hz, 1 H), 8.45 (s, 1 H). Anal. (C18H15F6N5): C, H, N.
5-Chloro-6-(4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-
piperazin-1-yl)nicotinamide (52k). Following the procedure de-
scribed for compound 31a, piperazine 8p and 2-chlorobenzimid-
azole 20n provided the title compound (81%) as a white amorphous
6-(Trifluoromethyl)-2-(4-(6-(trifluoromethyl)pyridin-2-yl)-
piperazin-1-yl)-1H-benzo[d]imidazole (52d). Following the pro-
1
solid. MS (ESI, pos. ion) m/z: 425 (M + 1). H NMR (DMSO-