CB1 Cannabinoid Receptor Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1833
13C NMR (150 MHz, DMSO-d6) δ 11.13, 14.71, 55.60, 59.85,
114.67, 127.33, 127.39, 128.42, 128.98, 129.04, 129.23, 134.41,
134.90, 135.50, 137.69, 143.42, 159.73, 163.35.
129.16, 129.65, 130.00 (q, JCF ) 32 Hz), 134.54, 134.66, 135.78,
136.92, 138.51, 142.72, 164.76.
1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-
1-yl)-1H-imidazole-4-carboxamide (60).34 To a magnetically
stirred suspension of 36 (1.10 g, 3.00 mmol) in anhydrous
CH3CN (50 mL) were successively added N,N-diisopropyl-
ethylamine (Hunig’s base) (1.15 mL, 6.6 mmol), O-benzotri-
azol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
(HBTU) (1.36 g, 3.6 mmol), and 1-aminopiperidine (0.39 mL,
3.6 mmol). After stirring for 16 h, the resulting mixture was
concentrated in vacuo. The residue was dissolved in EtOAc,
successively washed with aqueous NaHCO3 solution, water,
and brine, dried over Na2SO4, filtered, and concentrated to give
a crude solid. This solid was further purified by flash chro-
matography (EtOAc/petroleum ether ) 80/20 (v/v)), followed
by crystallization from CH3CN to give 60 (0.81 g, 62% yield),
mp 220-222 °C;1H NMR (600 MHz, DMSO-d6) δ 1.35-1.42
(m, 2H), 1.61-1.67 (m, 4H), 2.79-2.83 (m, 4H), 7.25 (d, J ) 8
Hz, 2H), 7.42 (d, J ) 8 Hz, 2H), 7.49 (dd, J ) 8 and 2 Hz, 1H),
7.54 (d, J ) 2 Hz, 1H), 7.68 (d, J ) 8 Hz, 1H), 8.08 (s, 1H),
8.80 (s, 1H); HRMS (C21H20Cl3N4O) [M + H]+: found m/z
449.0714, calcd 449.0703. Anal. (C21H19Cl3N4O) C, H, N.
1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-
(piperidin-1-yl)-1H-imidazole-4-carboxamide (61). 61 was
obtained from 37 (3.11 g, 7.88 mmol), HBTU (3.58 g, 9.46
mmol), DIPEA (3.0 mL, 17.0 mmol), and 1-aminopiperidine
(1.02 mL, 9.46 mmol) according to the procedure described for
60 in 69% yield, mp 133-136 °C; 1H NMR (600 MHz, DMSO-
d6) δ 0.97 (t, J ) 7 Hz, 3H), 1.34-1.41 (m, 2H), 1.61-1.66 (m,
4H), 2.77-2.82 (m, 4H), 2.84 (q, J ) 7 Hz, 2H), 7.33 (d, J ) 8
Hz, 2H), 7.39 (dd, J ) 8 and 2 Hz, 1H), 7.46 (d, J ) 8 Hz, 2H),
7.50 (d, J ) 2 Hz, 1H), 7.60 (d, J ) 8 Hz, 1H), 8.75 (s, 1H);
HRMS (C23H24Cl3N4O) [M + H]+: found m/z 477.1022, calcd
477.1016. Anal. (C23H23Cl3N4O‚H2O) C, H, N.
1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-
(piperidin-1-yl)-1H-imidazole-4-carboxamide (62). 62 was
obtained from 55 (3.81 g, 10.0 mmol), HBTU (4.20 g, 11.1
mmol), DIPEA (3.70 mL, 21.0 mmol), and 1-aminopiperidine
(1.20 mL, 11.1 mmol) according to the procedure described for
60 in 59% yield, mp 164-166 °C; 1H NMR (600 MHz, DMSO-
d6) δ 1.34-1.42 (m, 2H), 1.60-1.67 (m, 4H), 2.39 (s, 3H), 2.77-
2.82 (m, 4H), 7.29 (d, J ) 8 Hz, 2H), 7.40 (dd, J ) 8 and 2 Hz,
1H), 7.44 (d, J ) 8 Hz, 2H), 7.50 (d, J ) 2 Hz, 1H), 7.58 (d, J
) 8 Hz, 1H), 8.60 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ
10.53, 23.31, 25.65, 56.14, 127.45, 128.86, 129.09, 129.56,
129.63, 130.53, 133.80, 134.02, 134.34, 134.62, 134.76, 135.74,
141.87, 160.49; HRMS (C22H22Cl3N4O) [M + H]+: found m/z
463.0876, calcd 463.0859. Anal. (C22H21Cl3N4O) C, H, N.
1-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-
(piperidin-1-yl)-1H-imidazole-4-carboxamide (63). 63 was
obtained from 56 (1.32 g, 3.10 mmol), HBTU (1.41 g, 3.72
mmol), DIPEA (1.19 mL, 6.82 mmol), and 1-aminopiperidine
(0.40 mL, 3.72 mmol) according to the procedure described for
60 in 69% yield, mp > 204 °C; 1H NMR (600 MHz, DMSO-d6)
δ 1.34-1.42 (m, 2H), 1.60-1.67 (m, 4H), 2.39 (s, 3H), 2.76-
2.82 (m, 4H), 7.20-7.24 (m, 2H), 7.39-7.42 (m, 1H), 7.50 (d,
J ) 2 Hz, 1H), 7.56-7.60 (m, 3H), 8.65 (s, 1H); HRMS (C22H22-
BrCl2N4O) [M + H]+: found m/z 507.0350, calcd 507.0354;
Anal. (C22H21BrCl2N4O‚H2O) C, H, N.
Ethyl 2-(2,4-Dichlorophenyl)-1-(4-(trifluoromethyl)-
phenyl)-5-methyl-1H-imidazole-4-carboxylate (53). 53 was
obtained from 46 (15.0 g, 0.0450 mol), NaHCO3 (7.6 g, 0.0905
mol), and 48 (20.8 g, 0.0995 mol) according to the procedure
1
described for 49 in 52% yield, mp 160-162 °C; H NMR (600
MHz, DMSO-d6) δ 1.34 (t, J ) 7 Hz, 3H), 2.40 (s, 3H), 4.31 (q,
J ) 7 Hz, 2H), 7.42 (dd, J ) 8 and 2 Hz, 1H), 7.51-7.56 (m,
3H), 7.59 (d, J ) 8 Hz, 1H) 7.80 (d, J ) 8 Hz, 2H); 13C NMR
(150 MHz, DMSO-d6) δ 11.16, 14.68, 60.02, 123.84 (q, JCF
)
273 Hz), 126.80 (q, JCF ) 3 Hz), 127.59, 128.60, 128.87, 129.00,
129.16, 130.08 (q, JCF ) 33 Hz), 134.56, 134.67, 135.87, 137.35,
138.37, 143.01, 163.21.
Ethyl 1-(5-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-
5-methyl-1H-imidazole-4-carboxylate (54). 54 was ob-
tained from 47 (30.05 g, 0.100 mol), NaHCO3 (9.24 g, 0.11 mol),
and 48 (23.0 g, 0.11 mol) according to the procedure described
for 49 in 31% yield, mp 123-126 °C; 1H NMR (600 MHz,
DMSO-d6) δ 1.34 (t, J ) 7 Hz, 3H), 2.50 (s, 3H), 4.32 (q, J )
7 Hz, 2H), 7.40 (d, J ) 8 Hz, 1H), 7.43 (dd, J ) 8 and 2 Hz,
1H), 7.50 (d, J ) 2 Hz, 1H), 7.53 (d, J ) 8 Hz, 1H), 8.04 (dd,
J ) 8 and 2 Hz, 1H), 8.56 (d, J ) 2 Hz, 1H); 13C NMR (150
MHz, DMSO-d6) δ 11.20, 14.66, 60.08, 123.40, 127.65, 128.68,
129.05, 129.19, 132.00, 134.29, 134.43, 135.73, 137.18, 139.14,
142.86, 146.74, 148.31, 163.13.
1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-
1H-imidazole-4-carboxylic Acid (55). 55 was obtained from
49 (16.4 g, 0.040 mol) and LiOH (2.5 g, 0.104 mol) according
to the procedure described for 36 in quantitative yield, mp
243-245 °C; 1H NMR (600 MHz, DMSO-d6) δ 2.33 (s, 3H), 7.27
(d, J ) 8 Hz, 2H), 7.36 (dd, J ) 8 and 2 Hz, 1H), 7.42 (d, J )
8 Hz, 2H), 7.47 (d, J ) 2 Hz, 1H), 7.49 (d, J ) 8 Hz, 1H), 12.20
(br s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 7.80, 124.16,
125.60, 125.80, 126.10, 126.31, 126.37, 130.52, 131.07, 131.20,
131.41, 132.33, 133.67, 139.51, 161.48.
1-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-5-methyl-
1H-imidazole-4-carboxylic Acid (56). 56 was obtained from
50 (1.36 g, 3.0 mmol) and LiOH (0.13 g, 6.0 mmol) according
to the procedure described for 36 in 93% yield, mp 236-238
1
°C; H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 7.00 (d, J ) 8
Hz, 2H), 7.24 (dd, J ) 8 and 2 Hz, 1H), 7.30 (d, J ) 8 Hz, 1H),
7.34 (d, J ) 2 Hz, 1H), 7.53 (d, J ) 8 Hz, 2H), OH proton
invisible;13C NMR (100 MHz, DMSO-d6) δ 11.42, 123.19,
127.73, 129.22, 129.42, 129.81, 130.15, 132.93, 134.61, 134.75,
135.07, 135.99, 137.21, 143.08, 165.06.
2-(2,4-Dichlorophenyl)-1-(4-fluorophenyl)-5-methyl-
1H-imidazole-4-carboxylic Acid (57). 57 was obtained from
51 (5.00 g, 0.0127 mol) and LiOH (0.61 g, 0.0254 mol) according
to the procedure described for 36 in 74% yield, mp 220-221
1
°C; H NMR (600 MHz, DMSO-d6) δ 2.36 (s, 3H), 7.21-7.25
(m, 2H), 7.33-7.37 (m, 2H), 7.40 (dd, J ) 8 and 2 Hz, 1H),
7.51 (d, J ) 2 Hz, 1H), 7.53 (d, J ) 8 Hz, 1H), 12.20 (br s, 1H);
13C NMR (150 MHz, DMSO-d6) δ 11.12, 116.55 (d, JCF ) 23
Hz), 127.42, 129.03, 129.08, 129.27, 130.10 (d, JCF ) 8 Hz),
131.28, 134.50, 134.79, 135.58, 137.11, 142.97, 162.20 (d, JCF
) 248 Hz), 164.84.
2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-5-methyl-
1H-imidazole-4-carboxylic Acid (58). 58 was obtained from
52 (5.00 g, 0.0123 mol) and LiOH (0.59 g, 0.0246 mol) according
to the procedure described for 36 in 87% yield, mp 189-191
°C; 1H NMR (600 MHz, DMSO-d6) δ 2.32 (s, 3H), 3.74 (s, 3H),
6.91 (d, J ) 8 Hz, 2H), 7.17 (d, J ) 8 Hz, 2H), 7.36 (dd, J ) 8
and 2 Hz, 1H), 7.46-7.51 (m, 2H), 12.20 (br s, 1H).
2-(2,4-Dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)-
phenyl)-1H-imidazole-4-carboxylic Acid (59). 59 was ob-
tained from 53 (5.00 g, 0.0113 mol) and LiOH (0.54 g, 0.0225
mol) according to the procedure described for 36 in 84% yield,
mp 224-226 °C; 1H NMR (600 MHz, DMSO-d6) δ 2.40 (s, 3H),
7.42 (d, J ) 8 Hz, 1H), 7.51 (d, J ) 2 Hz, 1H), 7.54 (d, J ) 8
Hz, 2H), 7.58 (d, J ) 8 Hz, 1H), 7.79 (d, J ) 8 Hz, 2H), 12.25
(br s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 11.17, 123.83 (q,
JCF ) 273 Hz), 126.78 (q, JCF ) 3 Hz), 127.55, 128.73, 128.84,
2-(2,4-Dichlorophenyl)-1-(4-fluorophenyl)-5-methyl-N-
(piperidin-1-yl)-1H-imidazole-4-carboxamide (64). 64 was
obtained from 57 (1.00 g, 2.74 mmol), HBTU (1.25 g, 3.30
mmol), DIPEA (1.05 mL, 6.01 mmol), and 1-aminopiperidine
(0.35 mL, 3.26 mmol) according to the procedure described for
60 in 58% yield, mp 223-224 °C; 1H NMR (600 MHz, DMSO-
d6) δ 1.35-1.41 (m, 2H), 1.60-1.66 (m, 4H), 2.38 (s, 3H), 2.77-
2.82 (m, 4H), 7.18-7.24 (m, 2H), 7.30-7.34 (m, 2H), 7.39 (dd,
J ) 8 and 2 Hz, 1H) 7.49 (d, J ) 2 Hz, 1H), 7.57 (d, J ) 8 Hz,
1H), 8.60 (s, 1H); HRMS (C22H22Cl2FN4O) [M + H]+: found
m/z 447.1152, calcd 447.1155; Anal. (C22H21Cl2FN4O‚0.5H2O)
C, H, N.
2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-5-methyl-
N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (65). 65
was obtained from 58 (1.00 g, 2.65 mmol), HBTU (1.21 g, 3.19