Novel TRPV1 Receptor Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3 749
mmol) and 3-trifluoromethylthiophenyl isocyanate (0.37 g, 1.67
mmol) in toluene (30 mL) was stirred for 3 h at ambient
temperature. A precipitate collected by filtration was washed
with toluene and dried under vacuum to give 0.39 g (64%) of
acetate. Combined organic phases were washed with water,
separated, and concentrated. The solid residue was suspended
in ethyl acetate (5 mL), and the mixture was filtered to obtain
pure 13 (1.3 g, 65%) as a tan solid. 1H NMR (300 MHz, DMSO-
d6): δ 11.20 (broad s, 1H), 9.41, (s, 1H), 8.60 (d, J ) 6.0 Hz,
1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.66 (d, J ) 6.0 Hz, 1H). MS
(DCI/NH3) m/e: 289 (M + H)+.
General Procedure for the Preparation of Ureas from
Corresponding Trichloroacetamides: N-Isoquinolin-5-
yl-N′-(4-trifluoromethylbenzyl)-urea (14a). A solution of
2,2,2-trichloro-N-isoquinolin-5-yl-acetamide (13) (10.0 g, 34.7
mmol), 4-trifluoromethylbenzylamine (6.39 g, 36.6 mmol), and
DBU (13.0 mL, 86.75 mmol) in MeCN (250 mL) was refluxed
for 10 h. The mixture was cooled, concentrated, diluted with
ethyl acetate, and washed twice with aqueous ammonium
chloride. The organic layer was separated and concentrated
under vacuum The solid obtained was suspended in ethyl
acetate and filtered to obtain 4.9 g (41%) of 14a as a tan
solid.1H NMR (300 MHz, DMSO-d6): δ 9.26 (s, 1H), 8.82 (s,
1H), 8.52 (d, J ) 6.0 Hz, 1H), 8.26 (d, J ) 7.5 Hz, 1H), 7.94 (d,
J ) 6.0 Hz, 1H), 7.71 (m, 3H), 7.58 (m, 3H), 7.20 (t, J ) 6.0
Hz, 1H), 4.48 (d, J ) 6.0 Hz, 2H). MS (DCI/NH3) m/e: 346 (M
+ H)+. Anal. Calcd (C18H14F3N3O‚0.05H2O): C, H, N.
N-Isoquinolin-5-yl-N′-[2-(trifluoromethyl)benzyl]-
urea (14b). To CH2Cl2 (300 mL) at 0 °C were added phosgene
(20 mL, 20% solution in toluene) and solution of DMAP (10.0
g, 82 mmol) in CH2Cl2 (50 mL) dropwise. To the resulting
milky suspension was added dropwise a solution of 5-ami-
noisoquinoline (4) (5.0 g, 34.9 mmol) in CH2Cl2 (100 mL). The
mixture was allowed to warm to room temperature and then
stirred for 16 h. The solvent was removed under reduced
pressure. The solid residue was extracted with diethyl ether
(400 mL). The diethyl ether solution of the resulting isocyanate
was filtered, and a 20 mL aliquot (∼1.75 mmol) was used
directly for the next step. This solution was added to a solution
of 2-(2-trifluoromethyl-phenyl)-ethylamine (0.26 g, 1.5 mmol)
in diethyl ether (10 mL), the mixture was stirred for 2 h and
filtered, and the filter cake was washed with diethyl ether to
provide the title compound as an off-white solid (0.22 g, 42%).
1H NMR (300 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.88 (s, 1H),
8.58 (d, J ) 6.0 Hz, 1H), 8.30 (d, J ) 7.5 Hz, 1H), 7.99 (d, J )
6.0 Hz, 1H), 7.80-7.53 (m, 5H), 7.50 (t, J ) 7.5 Hz, 1H), 7.18
(t, J ) 4.5 Hz, 1H), 4.58 (d, J ) 6.0 Hz, 2H). MS(ESI): m/e:
346 (M + H)+.
N-Isoquinolin-5-yl-N′-[3-(trifluoromethyl)benzyl]-
urea (14c). This compound was synthesized from 13 and
3-(trifluoromethyl)benzylamine according to the procedure
described for the synthesis of 14a (32%). 1H NMR (300 MHz,
DMSO-d6): δ 9.27 (s, 1H), 8.82 (broad s, 1H), 8.53 (d, J ) 6.0
Hz, 1H), 8.25 (m, 1H), 7.94 (d, J ) 6.0 Hz, 1H), 7.55-7.79 (m,
6H), 7.18 (t, J ) 6.0 Hz, 1H), 4.47 (d, J ) 6.0 Hz, 2H); MS
(ESI-) m/e: 344 (M - H)-. Anal. Calcd (C18H14F3N3O): C, H,
N.
1
the desired product 5. H NMR (DMSO-d6): δ 9.35 (s, 1 H),
8.97 (m, 2H), 8.50 (d, J ) 7.5 Hz, 1H), 8.00 (m, 2H), 7.80-
7.60 (m, 4H), 7.50 (t, J ) 7.5 Hz, 1H), 7.34 (d, J ) 7.5 Hz,
1H). MS (ESI+) m/e: 364 (M + H)+. Anal. Calcd (C17H12F3N3-
OS): C, H, N.
1-Quinoline-8-yl-3-(3-trifluoromethylsulfanyl-phenyl)-
urea (6). This compound was prepared from 8-aminoquinoline
(3) using the procedure described for the synthesis of 5 (yield
1
66%). NMR (DMSO-d6): δ 10.18 (s, 1 H), 9.77 (s, 1 H), 8.96
(m, 1 H), 8.59 (m, 1H), 8.40 (dd, J ) 1.0 and 7.5 Hz, 1H), 8.08
(s, 1H), 7.61 (m, 4H), 7.48 (t, J ) 7.5 Hz, 1 H), 7.32 (d, J ) 7.5
Hz, 1H). MS (ESI+) m/e: 364 (M + H)+. Anal. Calcd
(C17H12F3N3OS): C, H, N.
1-Isoquinoline-5-yl-3-(3-trifluoromethylsulfanyl-phen-
yl)-urea (7). This compound was prepared from 5-aminoiso-
quinoline (4) using the procedure described for the synthesis
1
of 5 (yield 53%). H NMR (DMSO-d6): δ 9.35 (s, 1H), 9.32 (s,
1H), 8.96 (s, 1H), 8.59 (d, J ) 6.0 Hz, 1H), 8.25 (d, J ) 7.0 Hz,
1H), 8.00-8.08 (m, 1 H), 7.95 (d, J ) 6.0 Hz, 1H), 7.86 (d, J )
8.0 Hz, 1H), 7.67 (t, J ) 8.0 Hz, 1H), 7.56-7.63 (m, 1 H), 7.49
(t, J ) 8.0 Hz, 1H), 7.34 (d, J ) 8.0 Hz, 1H). MS (ESI+) m/e:
364 (M + H)+. Anal. Calcd (C17H12F3N3OS): C, H, N.
5-Bromo-8-nitroisoquinoline (10). To a -10 °C solution
of isoquinoline (8) (11 g, 85 mmol) in concentrated H2SO4 (100
mL) was added N-bromosuccinimide (17.8 g, 100 mmol) by
portions. The reaction mixture was allowed to warm to room
temperature and stirred for 24 h. A 10 mL aliquot of the
reaction mixture was removed, poured onto ice, neutralized
with concentrated ammonium hydroxide (∼30 mL), and ex-
tracted with ether. The combined ether layers were dried over
MgSO4, and the solvent was removed under vacuum. This
yielded 1.51 g of 5-bromoisoquinoline (9), contaminated with
<10% of 5,8-dibromoisoquinoline. Potassium nitrate (10.1 g,
100 mmol) was added to the remaining reaction mixture. After
1 h, the reaction mixture was poured onto ice and neutralized
with concentrated NH4OH (∼300 mL). The crude product was
collected by filtration and allowed to dry. Recrystalization from
methanol gave 5-bromo-8-nitroisoquinoline (10) (8.83 g, 46%).
1H NMR (DMSO-d6): δ 9.81 (broad s, 1H), 8.87 (d, J ) 6.0
Hz, 1H), 8.38 (m, 2H), 8.17 (dd, J ) 1.0 and 6.0 Hz, 1H). MS
(DCI/NH3) m/e: 253 (M + H)+, Br pattern observed.
8-Aminoisoquinoline (11). A mixture of 5-bromo-8-ni-
troisoquinoline (10) (8.83 g, 34.9 mmol) and 10% Pd/C (600
mg) in DMF (200 mL) and Et3N (5.3 mL) was hydrogenated
at 60 psi for 1 h. The catalyst was removed by filtration, and
the solvent was evaporated under vacuum. The residue was
taken into water, the aqueous solution was extracted with
ether, and the combined organic extracts were dried over
MgSO4. The ether was removed under vacuum to give 8-ami-
1
noisoquinone (11) (3.6 g, 72%). H NMR (DMSO-d6): δ 9.45
N-Isoquinolin-5-yl-N′-[2-(4-trifluoromethyl-phenyl)-
ethyl]-urea (14d). This compound was synthesized from 13
and 2-[4-(trifluoromethyl)phenyl]ethylamine according to the
(s, 1H), 8.34 (d, J ) 6.0 Hz, 1H), 7.56 (d, J ) 6.0 Hz, 1H), 7.41
(t, J ) 7.5 Hz, 1H), 7.01 (d, J ) 7.5 Hz, 1H), 6.75 (d, J ) 7.5
Hz, 1H), 6.20 (broad s, 2H). MS (DCI/NH3) m/e: 145 (M + H)+.
1
procedure described for the synthesis of 14a (yield 48%). H
NMR (DMSO-d6): δ 9.26 (s, 1H), 8.64 (s, 1H), 8.51 (d, J ) 6.0
Hz, 1H), 8.23 (d, J ) 7.5 Hz, 1H), 7.87 (d, J ) 6.0 Hz, 1H),
7.73 (d, J ) 7.5 Hz, 1H), 7.64 (s, 1H), 7.59 (m, 4H), 6.62 (t, J
) 4.5 Hz, 1H), 3.46 (m, 2H), 2.91 (t, J ) 6.0 Hz, 2H). MS
(ESI+) m/e: 360 (M + H)+. Anal. Calcd (C19H16F3N3O): C, H,
N.
1-Isoquinolin-8-yl-3-(3-trifluoromethylsulfanyl-phen-
yl)-urea (12). This compound was prepared from 8-aminoiso-
quinoline (11) using the procedure described for the synthesis
1
of 5 (yield 48%). H NMR (DMSO-d6): δ 9.53 (s, 1H), 9.35 (s,
1H), 9.20 (s, 1H), 8.52 (d, J ) 6.0 Hz, 1H), 8.12 (m, 1H), 8.05
(m, 1 H), 7.83 (d, J ) 6.0 Hz, 1H), 7.78 (t, J ) 7.5 Hz, 1H),
7.70-7.58 (m, 2H), 7.50 (t, J ) 7.5 Hz, 1H), 7.35 (d, J ) 7.5
Hz, 1H). MS (ESI+) m/e: 364 (M + H)+. Anal. Calcd
(C17H12F3N3OS): C, H, N.
2,2,2-Trichloro-N-isoquinolin-5-yl-acetamide(13)(Scheme
1). To a +5 °C solution of 5-aminoisoquinoline (4) (1.0 g, 6.9
mmol) in dichloromethane (40 mL) and Et3N (1 mL) was added
dropwise trichloroacetyl chloride (1.38 g, 7.6 mmol). The
reaction mixture was stirred at ambient temperature for 14
h, concentrated, and diluted with ethyl acetate. The solution
was washed with 1 N HCl, the aqueous layer was separated,
treated with aqueous NaHCO3, and extracted with ethyl
N-Isoquinolin-5-yl-N′-[2-(3-trifluoromethyl-phenyl)-
ethyl]-urea (14e). This compound was synthesized from 13
and 2-[3-(trifluoromethyl)phenyl]ethylamine according to the
1
procedure described for the synthesis of 14a (yield 62%). H
NMR (DMSO-d6): δ 9.26 (s, 1H), 8.62 (s, 1H), 8.52 (d, J ) 6.0
Hz, 1H), 8.22 (d, J ) 7.5 Hz, 1H), 7.87 (d, J ) 6.0 Hz, 1H),
7.73 (d, J ) 7.5 Hz, 1H), 7.64 (s, 1H), 7.59 (m, 4H), 6.60 (t, J
) 4.5 Hz, 1H), 3.45 (m, 2H), 2.91 (t, J ) 6.0 Hz, 2H). MS
(ESI+) m/e: 360 (M + H)+.
8-Nitro-quinazolin-4-ol (16) (Scheme 2). A solution of
2-amino-3-nitro-benzoic acid (15) (5.12 g, 28 mmol) in meth-