Imidazoles as CCK2 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6809
ethanol to afford 2-adamantan-1-ylethyl-5-phenyl-1H-pyrrole-
3-carboxylic acid ethyl ester as a white solid (1.12 g, 62%). 1H
NMR (CDCl3) δ 8.40 (1H, br s), 7.48 (2H, m), 7.37 (2H, m),
7.25 (1H, m), 6.85 (1H, d), 4.32 (2H, q), 2.97 (2H, m), 2.00 (3H,
br s), 1.70 (6H, m), 1.58 (6H, s), 1.46 (2H, m), 1.38 (3H, t).
Step b. To a solution of 5-adamantan-1-yl-3-oxo-2-(triphen-
yl-λ5-phosphanylidene)pentanoic acid ethyl ester (35.6 g, 66
mmol) in THF (500 mL) and H2O (250 mL) was added OXONE
(60.9 g, 99 mmol) at 0 °C. The solution was stirred at room
temperature for 16 h and diluted with H2O (300 mL), and the
product was extracted with EtOAc (2 × 200 mL). The organic
phase was dried (MgSO4) and filtered, and the solvent was
evaporated. The crude product was purified by chromatogra-
phy on silica gel using CH2Cl2-EtOAc (9:1) as eluant, affording
5-adamantan-1-yl-2,3-dioxopentanoic acid ethyl ester hydrate
as a pale-yellow oil (14.3 g, 70%). 1H NMR (CDCl3) δ 5.02 (2H,
br s), 4.30 (2H, m), 2.54 (2H, m), 1.94 (3H, br s), 1.58 (6H, m),
1.39 (8H, m), 1.25 (3H, m).
Step c. To a slurry of ammonium acetate (2.25 g, 30 mmol)
in acetic acid (15 mL) was added 5-adamantan-1-yl-2,3-
dioxopentanoic acid ethyl ester hydrate (930 mg, 3 mmol)
followed by o-tolualdehyde (0.7 mL, 6 mmol). The mixture was
heated at 70 °C for 2 h. The solution was cooled to room
temperature, and the acetic acid was evaporated. The residue
was dissolved in EtOAc (50 mL) and washed with saturated
NaHCO3 (2 × 50 mL), water (20 mL), and brine (20 mL). The
organic phase was dried (MgSO4), and the solvent was
evaporated. The crude product was purified by chromatogra-
phy on silica gel using CH2Cl2-EtOAc (19:1) as eluant to afford
5-(2-adamantan-1-ylethyl)-2-o-tolyl-1H-imidazole-4-carboxyl-
ic acid ethyl ester as a white amorphous solid (665 mg, 56%).
1H NMR (CDCl3) δ 10.0 (1H, br s), 7.52 (1H, m), 7.25 (3H, m),
4.32 (2H, m), 2.91 (2H, m), 2.49 (3H, s), 1.97 (3H, br s), 1.74-
1.34 (17H, m).
Step c. To a solution of 2-adamantan-1-ylethyl-5-phenyl-
1H-pyrrole-3-carboxylic acid ethyl ester (1.12 g, 3 mmol) in
ethanol (80 mL) was added 6 M sodium hydroxide (9 mL). The
mixture was heated at reflux for 16 h. It was allowed to cool
to room temperature and was concentrated to a small volume
under reduced pressure. The concentrated solution was diluted
with 2 M hydrochloric acid (40 mL), and the precipitated solid
was filtered, washed with water, and dried to afford 2-ada-
mantan-1-ylethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (980
1
mg, 94%). H NMR (CDCl3) δ 11.50 (1H, br s), 11.40 (1H, s),
7.60 (2H, m), 7.35 (2H, m), 7.16 (1H, m), 6.70 (1H, d), 2.85
(2H, m), 1.94 (3H, br s), 1.66 (6H, m), 1.52 (6H, s), 1.35 (2H,
m).
Step d. To a suspension of 2-adamantan-1-ylethyl-5-phenyl-
1H-pyrrole-3-carboxylic acid (274 mg, 0.79 mmol) in CH2Cl2
(5 mL) was added thionyl chloride (180 µL, 2.5 mmol) and DMF
(20 µL). The mixture was stirred at room temperature for 30
min, and the solvent was evaporated. The residue was dis-
solved in CH2Cl2 (5 mL), and the solvent was evaporated.
3-Aminobenzoic acid benzyl ester (5a) (197 mg, 0.87 mmol)
was added to the residue followed by anhydrous pyridine (3
mL). The solution was kept at room temperature for 16 h and
diluted with CH2Cl2 (30 mL). The organic phase was washed
with 2 M hydrochloric acid (2 × 20 mL) and brine (20 mL)
and dried (MgSO4), and the solvent was evaporated. The
residue was purified by chromatography on silica gel using
CH2Cl2-hexanes-EtOAc (95:95:10) as eluant to afford 3-{[2-
(2-adamantan-1-ylethyl)-5-phenyl-1H-pyrrole-3-carbonyl]amino}-
benzoic acid benzyl ester as a pale-yellow solid (157 mg, 56%).
1H NMR (CDCl3) δ 8.50 (1H, br s), 8.15 (1H, m), 8.01 (1H, d),
7.81 (1H, d), 7.59 (1H, br s), 7.51-7.37 (10H, m), 7.27 (1H, t),
6.64 (1H, d), 5.38 (2H, s), 3.07 (2H, m), 1.98 (3H, br s), 1.75-
1.46 (14H, m).
Step e. A mixture of 3-{[2-(2-adamantan-1-ylethyl)-5-phen-
yl-1H-pyrrole-3-carbonyl]amino}benzoic acid benzyl ester (157
mg, 0.27 mmol), 10% palladium on charcoal (50 mg) and THF-
methanol (1:1, 20 mL) was evacuated and flushed with
hydrogen three times. The mixture was vigorously stirred
overnight under an atmosphere of hydrogen. The catalyst was
removed by filtration and the filtrate was evaporated to afford
13 as a white solid (123 mg, 93%). 1H NMR (DMSO-d6) δ 11.38
(1H, s), 9.42 (1H, s), 8.22 (1H, s), 7.91 (1H, d), 7.63 (2H, d),
7.56 (1H, d), 7.37 (2H, t), 7.28 (1H, t), 7.17 (2H, m), 2.96 (2H,
m), 1.94 (3H, br s), 1.65 (6H, m), 1.54 (6H, s), 1.38 (2H, m).
The product was further characterized as the N-methyl-D-
glucamine salt. Anal. (C30H32N2O3‚C7H17NO5‚1.6H2O) C, H, N.
3-{[2-(2-Adamantan-1-ylethyl)-5-o-tolyl-1H-pyrrole-3-
carbonyl]amino}benzoic Acid (14). 14 was prepared by a
similar sequence used to obtain 13 except that 2-bromo-1-o-
tolyethanone replaced 2-bromo-1-phenylethanone in step a. 1H
NMR (DMSO-d6) experiments were conducted. The product
was further characterized as the N-methyl-D-glucamine salt.
Anal. (C31H34N2O3‚C7H17NO5‚1.5H2O) C, H, N.
3-{[5-(2-Adamantan-1-ylethyl)-2-o-tolyl-1H-imidazole-
4-carbonyl]amino}benzoic Acid (22). Step a. To a solution
of 3-(adamantan-1-yl)propionic acid26 (14.6 g, 70 mmol) and
(carbethoxymethylene)triphenylphosphorane (24.4 g, 70 mmol)
in CH2Cl2 (300 mL) were added EDC (12.25 g, 64 mmol) and
DMAP (5 mg) at 0 °C. The solution was stirred at this
temperature for 1 h, then at room temperature for 16 h. The
reaction mixture was washed with saturated NaHCO3 (2 ×
100 mL) and dried (MgSO4). Filtration and evaporation of the
solvent gave the crude product, which was purified by chro-
matography on silica gel using CH2Cl2-EtOAc (9:1) as eluant
to afford 5-adamantan-1-yl-3-oxo-2-(triphenyl-λ5-phospha-
nylidene)pentanoic acid ethyl ester (35.6 g, 94%). 1H NMR
(CDCl3) δ 7.65 (6H, m), 7.43 (9H, m), 3.73 (2H, m), 2.85 (2H,
m), 1.92 (3H, br s), 1.66 (6H, m), 1.50 (6H, s), 1.39 (2H, m),
0.67 (3H, m).
Step d. To a suspension of 5-(2-adamantan-1-ylethyl)-2-o-
tolyl-1H-imidazole-4-carboxylic acid ethyl ester (660 mg, 1.68
mmol) in ethanol (10 mL) was added a solution of sodium
hydroxide (340 mg, 8.4 mmol) in water (2 mL). The reaction
mixture was heated under reflux for 24 h, allowed to cool to
room temperature, and concentrated under reduced pressure.
The aqueous solution was diluted with water (30 mL) and
acidified to pH 2 by the addition of 1 M hydrochloric acid. The
precipitate formed was collected by filtration, washed with
water, and dried to afford 5-(2-adamantan-1-ylethyl)-2-o-tolyl-
1H-imidazole-4-carboxylic acid as an off-white solid (490 mg,
1
80%). H NMR (DMSO-d6) δ 7.55 (2H, m), 7.40 (2H, m), 7.64
(2H, m), 2.90 and 2.66 (2H, 2 × m), 2.43 and 2.40 (3H, 2 × s),
1.95 (3H, s), 1.70-1.39 (14H, m).
Step e. To a solution of 5-(2-adamantan-1-yethyl)-2-o-tolyl-
1H-imidazole-4-carboxylic acid (290 mg, 0.8 mmol) and 3-ami-
nobenzoic acid benzyl ester (5a) (180 mg, 0.8 mmol) in DMF
(3 mL) were added HOBt (110 mg, 0.8 mmol), DMAP (5 mg),
and EDC (150 mg, 0.8 mmol). The solution was kept at room
temperature for 72 h, diluted with water (20 mL), and
extracted with EtOAc (2 × 20 mL). The organic phase was
washed with 5% KHSO4 solution (20 mL), saturated NaHCO3
(20 mL), and brine (2 × 20 mL). The solution was dried over
MgSO4 and filtered, and the solvent was evaporated. The crude
product was purified by chromatography on silica gel using
CH2Cl2-EtOAc (9:1) as eluant to afford 3-{[5-(2-adamantan-
1-ylethyl)-2-o-tolyl-1H-imidazole-4-carbonyl]amino}benzoic acid
benzyl ester as a white amorphous solid (246 mg, 54%). 1H
NMR (CDCl3) δ 9.35 (1H, br s), 9.27 (1H, s), 8.16 (2H, m), 7.80
(1H, d), 7.55 (1H, d), 7.47-7.27 (10H, m), 5.37 (2H, s), 3.13
(2H, m), 2.59 (3H, s), 1.98 (3H, s), 1.74-1.45 (14H, m).
Step f. 3-{[5-(2-Adamantan-1-ylethyl)-2-o-tolyl-1H-imida-
zole-4-carbonyl]amino}benzoic acid benzyl ester (240 mg, 0.42
mmol) was deprotected using the same procedure as in step e
in the preparation of 13 to afford 22 as a white solid (168 mg,
84%). 1H NMR (DMSO-d6) δ 12.70 (1H, br s), 12.55 (1H, br s),
9.76 (1H, s), 8.49 (1H, s), 7.95 (1H, d), 7.61 (2H, m), 7.43 (1H,
d), 7.30 (3H, m), 2.98 (2H, m), 2.55 (3H, s), 1.95 (3H, s), 1.71-
1.41 (14H, m). The product was further characterized as the
N-methyl-D-glucamine salt. Anal. (C30H33N3O3‚C7H17NO5‚
2.1H2O) C, H, N.
3-{[5-(2-Adamantan-1-ylethyl)-2-phenyl-1H-imidazole-
4-carbonyl]amino}benzoic Acid (21). 21 was prepared by
similar sequence used to prepare 22 except that benzaldehyde
was used in place of o-tolualdehyde in step c. 1H NMR (DMSO-
Buck, Ildiko M.
