Aryltriazoles as Novel CRF1 Receptor Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 5 1547
mL), and then water (8.0 mL) and stirred. The mixture was
dried, filtered, and evaporated to afford (S)-1-propylamino-1-
phenylbutane [(S)-20, 3.76 g, 86%] as a clear oil: 1H NMR
(CDCl3) δ 0.83 (t, J ) 6.9 Hz, 3H), 0.89 (t, J ) 7.2 Hz, 3H),
1.21 (m, 2H), 1.42 (m, 2H), 1.62 (m, 2H), 2.38 (m, 2H), 3.56
(dd, J ) 8.4, 6.2 Hz, 1H), 7.28 (m, 5H); MS (CI) m/e 192 (M +
(S)-1-Methyl-3-[N-{1-(4-fluorophenyl)pentyl}-N-propyl-
amino]-5-(2-methoxy-4-chlorophenyl)-1H-[1,2,4]triazole
hydrochloride [(S)-7r HCl]: white powder, 67% yield, 1H
NMR (CDCl3) δ 0.81 (t, J ) 7.2 Hz, 3H), 0.91 (t, J ) 7.2 Hz,
3H), 1.39 (m, 6H), 2.03 (m, 2H), 3.31 (m, 2H), 3.69 (s, 3H),
3.94 (s, 3H), 5.90 (t, J ) 7.6 Hz, 1H), 7.03 (dd, J ) 8.4, 8.4 Hz,
2H), 7.05 (d ) 1.8 Hz, 1H), 7.19 (dd, J ) 8.4, 1.8 Hz, 1H), 7.46
(dd, J ) 8.7, 5.4 Hz, 2H), 7.72 (d, J ) 8.1 Hz, 1H); MS (CI)
m/z 445 (M + H). Anal. (C24H31Cl2FN4O) C, H, N.
1-Methyl-3-[N-{1-(4-trifluoromethylphenyl)propyl}-N-
propylamino]-5-(2-methyl-4-methoxyphenyl)-1H-[1,2,4]-
triazole (7s) was prepared in a manner similar to the
procedure described for 7e using 2-methyl-4-methoxybenzoic
acid and N-[1-(4-trifluoromethylphenyl)propyl]-N-propylamine:
28.6 mg; 1H NMR (CDCl3) δ 0.83 (t, J ) 7.5 Hz, 3H), 1.06 (t,
J ) 7.5 Hz, 3H), 1.36 (m, 1H), 1.54 (m, 1H), 2.12 (m, 2H), 2.40
(s, 3H), 3.35 (m, 2H), 3.70 (s, 3H), 3.86 (s, 3H), 5.64 (t, J ) 7.2
Hz, 1H), 6.89 (m, 2H), 7.37 (d, J ) 8.0 Hz, 1H), 7.61 (s, 4H);
MS (CI) m/z 447 (M + H); HPLC purity 98%, 100%.
The corresponding S- and R-enantiomers were separated
by chiral HPLC and the S-isomer was converted to the
hydrochloride salt in a manner similar to the procedure
described for 7l.
(S)-1-Methyl-3-[N-{1-(4-trifluoromethylphenyl)propyl}-
N-propylamino]-5-(2-methyl-4-methoxyphenyl)-1H-[1,2,4]-
triazole hydrochloride [(S)-7s HCl]: white powder, 69%
yield; 1H NMR (CDCl3) δ 0.83 (t, J ) 7.2 Hz, 3H), 1.06 (t, J )
7.2 Hz, 3H), 1.38 (m, 1H), 1.55 (m, 1H), 2.13 (m, 2H), 2.40 (s,
3H), 3.23-3.39 (m, 2H), 3.69 (s, 3H), 3.86 (s, 3H), 5.67 (t, J )
7.3 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 1H), 6.90 (s, 1H), 7.35 (d, J
) 8.7 Hz, 1H), 7.61 (4H, br s); MS (CI) m/z 447 (M + H). Anal.
(C24H30ClF3N4O‚0.5H2O) C, H, N.
H); [R]20 ) -46 (c 0.77, CH2Cl2).
D
The corresponding (R)-1-propylamino-1-phenylbutane [(R)-
20; 1.65 g, 51% overall yield) was prepared in a similar manner
starting from (S)-(-)-1-phenylbutanol: 1H NMR (CDCl3) δ 0.84
(t, J ) 6.9 Hz, 3H), 0.88 (t, J ) 7.2 Hz, 3H), 1.21 (m, 2H), 1.42
(m, 2H), 1.62 (m, 2H), 2.39 (m, 2H), 3.55 (dd, J ) 8.4, 6.2 Hz,
1H), 7.28 (m, 5H); MS (CI) m/e 192 (M + H); [R]20 ) -50 (c
D
0.6, CH2Cl2).
(S)-1-methyl-3-[N-(1-phenylbutyl)-N-propylamino]-5-
(2-methoxy-4-chlorophenyl)-1H-[1,2,4]triazole [(S)-7q HCl].
To a solution of 2-methoxy-4-chlorobenzoyl thioisocyanate (0.60
g, 2.64 mmol) in THF (5 mL) was added dropwise a solution
of (S)-1-propylamino-1-phenylbutane (0.53 g, 2.77 mmol) in
THF (5 mL). The mixture was stirred at room temperature
for 10 min, after which time TLC (20% EtOAc/hexanes)
indicated disappearance of the starting material. Powdered
sodium carbonate (0.29 g, 2.77 mmol) was added, followed by
methyl iodide (0.31 mL, 5.54 mmol), and the mixture was
heated at 70 °C for 6 h. Following evaporation of the solvent,
silica gel chromatography (50% EtOAc/hexanes to 80% EtOAc/
hexanes) afforded the S-methylated thiourea (1.12 g, 98%) as
an oil. Methyl hydrazine (1.0 mL) was added and the mixture
was heated at 100 °C for 2 h, after which time HPLC-MS
indicated disappearance of the starting material. The reaction
mixture was cooled and then poured onto water. The aqueous
layer was extracted twice with EtOAc and the organic layer
was washed with brine, dried, and evaporated. Silica
gel chromatography (20% EtOAc/hexanes) afforded (S)-1-
methyl-3-[N-(1-phenylbutyl)-N-propylamino]-5-(2-methoxy-4-
chlorophenyl)-1H-[1,2,4]triazole as an oil [(S)-7q; 0.74 g, 70%
from the benzoyl thioisocyanate].
1-Methyl-3-[N-(1-phenylbutyl)-N-propylamino]-5-(2-
methyl-4-methoxyphenyl)-1H-[1,2,4]triazole (7t) was pre-
pared in a manner similar to the procedure described for 7e
using 2-methyl-4-methoxybenzoic acid and N-(1-phenylbutyl)-
1
N-propylamine: 4.0 mg; H NMR (CDCl3) δ 0.75 (t, J ) 7.2
The above free base was dissolved in diethyl ether and a
solution of 1.0 M HCl in diethyl ether (1.8 mL, 1.8 mmol) was
added. The precipitate was filtered and washed with diethyl
ether to afford the title compound (0.63 g, 78%) as a white
powder: 1H NMR (CDCl3) δ 0.82 (t, J ) 7.2 Hz, 3H), 0.99 (t,
J ) 7.2 Hz, 3H), 1.26 (m, 1H), 1.46 (m, 3H), 2.02 (m, 2H), 3.32
(m, 2H), 3.69 (s, 3H), 3.69 (s, 3H), 3.93 (s, 3H), 5.58 (t, J ) 7.6
Hz, 1H), 7.05 (d, J ) 1.8 Hz, 1H), 7.19 (dd, J ) 8.4, 1.8 Hz,
1H), 7.31 (m, 3H), 7.45 (m, 2H), 7.73 (d, J ) 8.1 Hz, 1H); MS
(CI) m/z 413 (M + H). Anal. (C23H30Cl2N4O‚H2O) C, H, N.
1-Methyl-3-[N-{1-(4-fluorophenyl)pentyl}-N-propylami-
no]-5-(2-methoxy-4-chlorophenyl)-1H-[1,2,4]triazole (7r)
was prepared in a manner similar to the procedure described
for 7e using N-[1-(4-fluorophenyl)pentyl]-N-propylamine: 12.4
Hz, 3H), 0.97 (t, J ) 7.4 Hz, 3H), 1.48 (m, 4H), 2.00 (m, 2H),
2.29 (s, 3H), 3.04 (t, J ) 8.4 Hz, 2H), 3.57 (s, 3H), 3.83 (s, 3H),
5.50 (t, J ) 7.3 Hz, 1H), 6.80 (m, 2H), 7.26 (m, 4H), 7.40 (d, J
) 7.8 Hz, 2H); MS (CI) m/z 393 (M + H); HPLC purity 100%,
100%.
(S)-1-Methyl-3-[N-(1-phenylbutyl)-N-propylamino]-5-
(2-methyl-4-methoxyphenyl)-1H-[1,2,4]triazole [(S)-7t] was
prepared in a manner similar to the procedure described for
(S)-7q using 2-methyl-4-methoxybenzoic acid and (S)-1-pro-
pylamino-1-phenylbutane 20 (formation of the HCl salt was
not successful): colorless solid, 74% yield; 1H NMR (CDCl3) δ
0.75 (t, J ) 7.2 Hz, 3H), 0.97 (t, J ) 7.4 Hz, 3H), 1.48 (m, 4H),
2.00 (m, 2H), 2.29 (s, 3H), 3.04 (t, J ) 8.4 Hz, 2H), 3.57 (s,
3H), 3.83 (s, 3H), 5.50 (t, J ) 7.3 Hz, 1H), 6.81 (m, 2H), 7.26
(m, 4H), 7.40 (d, J ) 7.8 Hz, 2H); MS (CI) m/z 393 (M + H);
1
mg; H NMR (CDCl3) δ 0.76 (t, J ) 7.5 Hz, 3H), 0.91 (t, J )
HPLC purity 100%, 100%; [R]20 ) -149.1 (c 0.48, CH2Cl2).
6.2 Hz, 3H), 1.40 (m, 6H), 1.98 (m, 2H), 2.99 (t, J ) 6.2 Hz,
2H), 3.57 (s, 3H), 3.83 (s, 3H), 5.41 (t, J ) 6.3 Hz, 1H), 6.98
(m, 3H), 7.04 (d, J ) 8.1 Hz, 1H), 7.39 (m, 3H); MS (CI) m/z
445 (M + H); HPLC purity 98%, 100%.
The hydrochloride salt of 7r was also prepared in a manner
similar to the procedure described for 7l.
1-Methyl-3-[N-{1-(4-fluorophenyl)pentyl}-N-propylami-
no]-5-(2-methoxy-4-chlorophenyl)-1H-[1,2,4]triazole hy-
drochloride [7r HCl]: white powder, 68% yield; 1H NMR
(CDCl3) δ 0.81 (t, J ) 7.5 Hz, 3H), 0.90 (t, J ) 6.9 Hz), 1.38
(m, 4H), 1.48 (m, 2H), 2.03 (m, 2H), 3.29 (m, 2H), 3.69 (s, 3H),
3.93 (s, 3H), 5.84 (t, J ) 6.3 Hz, 1H), 7.02 (m, 2H), 7.19 (dd, J
) 8.4, 1.8 Hz, 1H), 7.45 (m, 1H), 7.71 (d, J ) 8.1 Hz); 13C
(CDCl3) δ 164.1, 160.9, 157.9, 156.1, 146.1, 141.0, 135.3, 133.7,
130.0, 129.9, 122.0, 115.6, 115.3, 112.9, 61.0, 56.6, 46.4, 37.6,
31.3, 28.7, 22.8, 21.5, 14.0, 11.1; MS (CI) m/z 445.2 (M + H).
Anal. C24H30ClFN4O·HCl.
D
Anal. (C24H32N4O) C, H, N.
(R)-1-Methyl-3-[N-(1-phenylbutyl)-N-propylamino]-5-
(2-methyl-4-methoxyphenyl)-1H-[1,2,4]triazole [(R)-7t]
was prepared in a manner similar to the procedure described
for (S)-7q using 2-methyl-4-methoxybenzoic acid and (R)-1-
1
propylamino-1-phenylbutane 20: colorless oil, 72% yield; H
NMR (CDCl3) δ 0.75 (t, J ) 7.2 Hz, 3H), 0.97 (t, J ) 7.4 Hz,
3H), 1.48 (m, 4H), 2.01 (m, 2H), 2.29 (s, 3H), 3.04 (t, J ) 8.4
Hz, 2H), 3.57 (s, 3H), 3.83 (s, 3H), 5.50 (t, J ) 7.3 Hz, 1H),
6.81 (m, 2H), 7.26 (m, 4H), 7.40 (d, J ) 7.8 Hz, 2H); MS (CI)
m/z 393 (M + H); HPLC purity 100%, 100%; [R]20 ) +149.7
D
(c 0.52, CH2Cl2).
1-Methyl-3-[N-(1-phenylpentyl)-N-propylamino]-5-(2-
methyl-4-methoxyphenyl)-1H-[1,2,4]triazole (7u) was pre-
pared in a manner similar to the procedure described for 7e
using 2-methyl-4-methoxybenzoic acid and N-(1-phenylpentyl)-
1
The corresponding S- and R-enantiomers of 7r were sepa-
N-propylamine: 24.7 mg; H NMR (CDCl3) δ 0.74 (t, J ) 7.5
rated by chiral HPLC: (S)-7r [R]20D ) -128.9 (c 0.66, CH2Cl2);
Hz, 3H), 0.89 (t, J ) 7.5 Hz, 3H), 1.42 (m, 6H), 1.95 (m, 2H),
2.29 (s, 3H), 3.04 (t, J ) 7.5 Hz, 2H), 3.57 (s, 3H), 3.84 (s, 3H),
5.48 (t, J ) 7.3 Hz, 1H), 6.77 (m, 2H), 7.27 (m, 4H), 7.40 (m,
2H); MS (CI) m/z 407 (M + H); HPLC purity 100%, 100%.
(R)-7r [R]20 ) +124.6 (c 0.70, CH2Cl2).
D
The S-isomer was converted to the hydrochloride salt in a
manner similar to the procedure described for 7l.