BMS-191011: Opener of Maxi-K Channels
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 537
described above for 10b was followed starting from 5-[3,4-
dichlorophenyl]-1,3,4-oxadiazol-2-amine: mp 290-293 °C; IR
7.96 (d, J ) 8.2 Hz, 2H), 10.28 (s, 1H), 10.42 (s, 1H), 10.55 (s,
1H); MS m/z 471 (MH+); Anal. (C20H18ClF3N4O3) C, H, N.
N-[2-Chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phe-
nyl]-1,2,4-oxadiazol-1-yl]methyl]-5-hydroxyphenyl]-4-morpho-
lineacetamide (14b). (a) 3-[(4-Amino-5-chloro-2-methoxyphenyl)-
methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (13;
3 g, 7.5 mmol) and pyridine (0.68 mL, 8.41 mmol) were dissolved
in THF (35 mL) under N2 and cooled to 0 °C. Bromoacetyl bromide
(0.72 mL, 8.26 mmol) was added dropwise, and the reaction mixture
was stirred for 18 h before being partitioned between EtOAc (400
mL) and 0.1 N HCl solution (50 mL). The organic phase was
washed with satd NaHCO3 solution and brine and dried over
MgSO4. Active carbon (500 mg) was added, and the solution was
filtered through a plug of celite and concentrated to give 2-bromo-
N-[2-chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)-phenyl]-
1,2,4-oxadizol-1-yl]methyl]-5-methoxyphenyl] acetamide 3.8 g
(98%): mp 140-182 °C (dec); IR (KBr) 3348, 2972, 1784, 1672,
1
(KBr) 3387, 1688, 1626, 1427, 1269, 1160 cm-1; H NMR (300
MHz, DMSO-d6) δ 4.72 (s, 2H), 5.23 (s, 2H), 6.30 (s, 1H), 6.84
(s, 1H), 7.75 (s, 2H), 7.96 (s, 1H), 9.48 (s, 1H), 12.39 (s, 1H); MS
m/z 383 (MH-); Anal. (C15H11Cl3N4O2) C, H, N.
1-[(5-Chloro-2-hydroxyphenyl)methyl]-1,3-dihydro-3-[4-(tri-
fluoromethyl) phenyl]-2H-imidazol-2-one (11). (a) The sequence
described above for 8a, step c, was followed starting from 1,3-
dihydro-3-[4-(trifluoromethyl)phenyl]-2H-imidazol-2-one and alky-
lating with 5-chloro-2-methoxybenzylbromide: mp 122-123 °C;
IR (KBr) 1692, 1318, 1139, 1063 cm-1 1H NMR (300 MHz,
;
DMSO-d6) δ 3.84 (s, 3H), 4.75 (s, 2H), 6.83 (d, J ) 3.3 Hz, 1H),
7.05-7.09 (m, 2H), 7.24 (d, J ) 3.3 Hz, 1H), 7.35 (dd, J ) 8.8,
2.6 Hz, 1H), 7.80 (d, J ) 8.9 Hz, 2H), 8.03 (d, J ) 8.8 Hz, 2H);
MS m/z 383 (MH+); Anal. (C18H14ClF3N2O2) C, H, N.
(c) Demethylation of 1-[(5-chloro-2-methoxyphenyl)methyl]-1,3-
dihydro-3-[4-(trifluoromethyl) phenyl]-2H-imidazol-2-one was per-
formed as described for 8l, step c: mp 169-170 °C; 1H NMR (300
MHz, DMSO-d6) δ 4.72 (s, 2H), 6.83 (d, J ) 2.9 Hz, 1H), 6.87 (d,
J ) 8.4 Hz, 1H), 7.03 (d, J ) 2.6 Hz, 1H), 7.18 (dd, J ) 8.8, 2.9
Hz, 1H), 7.24 (d, J ) 3.3 Hz, 1H), 7.82 (d, J ) 8.4 Hz, 2H), 8.04
(d, J ) 8.4 Hz, 2H), 10.13 (s, 1H); MS m/z 367 (MH-); Anal.
(C17H12ClF3N2O2) C, H, N.
4-[(5-Chloro-2-hydroxyphenyl)methyl-2-[4-(trifluoromethyl)-
phenyl]-4H-1,3,4-oxadiazin-5(6H)-one (12). (a) The sequence
described above for 8a, step c, was followed starting from 4,6-
dihydro-2-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazin-5(6H)-
one and alkylating with 5-chloro-2-methoxybenzyl bromide gave
4-[(5-chloro-2-hydroxyphenyl)methyl-2-[4-(trifluoromethyl)phenyl]-
4H-1,3,4-oxadiazin-5(6H)-one: mp 122-123 °C; IR (KBr) 1685,
1320, 1129 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 3.83 (s, 3H),
4.86 (s, 2H), 5.01 (s, 2H), 7.06 (d, J ) 8.8 Hz, 1H), 7.22 (d, J )
2.6 Hz, 1H), 7.33 (dd, J ) 8.8, 2.9 Hz, 1H), 7.84 (d, J ) 8.4 Hz,
2H) 7.94 (d, J ) 8.4 Hz, 2H); MS m/z 399 (MH+); Anal. (C18H14-
ClF3N2O3) C, H, N.
1
1594, 1234, 1168, 1066 cm-1; H NMR (300 MHz, DMSO-d6) δ
3.77 (s, 3H), 4.15 (s, 2H), 4.90 (s, 2H), 7.47-7.48 (m, 2H), 7.86
(d, J ) 8.4 Hz, 2H), 7.96 (d, J ) 8.3 Hz, 1H), 9.30 (s, 1H); MS
m/z 520 (MH+); Anal. (C18H14BrClF3N3O4) C, H, N.
(b) 2-Bromo-N-[2-chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluorom-
ethyl)-phenyl]-1,2,4-oxadizol-1-yl]methyl]-5-methoxyphenyl] ac-
etamide (1 g, 1.9 mmol), morpholine (167 mg, 1.9 mmol),
potassium carbonate (262 mg, 1.9 mmol), and KI (78 mg) were
dissolved in CH3CN (100 mL) and heated at reflux for 3.5 h. The
reaction mixture was filtered and concentrated, and the residue was
taken up in EtOAc and washed with water and brine. Recrystalli-
zation from CH3CN gave N-[2-chloro-4-[[1,5-dihydro-5-oxo-3-[4-
(trifluoromethyl)phenyl]-1,2,4-oxadiazol-1-yl]methyl]-5-methox-
yphenyl]-4-morpholineacetamide 900 mg (90%): mp 178-179 °C;
IR (KBr) 3434, 2848, 1772, 1696, 1528, 1324, 1118 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 2.56 (br s, 4H), 3.18 (s, 2H,), 3.65 (t, J )
4.3 Hz, 4H), 3.78 (s, 3H), 4.88 (s, 2H), 7.50 (s, 1H), 7.88 (d, J )
8.5 Hz, 2H), 7.96 (d, J ) 8.4 Hz, 2H), 8.04 (s, 1H), 9.94 (s, 1H);
MS m/z 528 (MH+); Anal. (C23H22ClF3N4O5) C, H, N.
(b) Demethylation of 4-[(5-chloro-2-hydroxyphenyl)methyl-2-
[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazin-5(6H)-one was per-
formed as described for 8l, step c, to give 12: mp 176-177 °C;
IR (KBr) 3284, 1665, 1329, 1321, 1110 cm-1; 1H NMR (300 MHz,
DMSO-d6) δ 4.84 (s, 2H), 5.00 (s, 2H), 6.85 (d, J ) 9.1 Hz, 1H),
7.13-7.16 (m, 2H), 7.84 (d, J ) 8.4, 2H), 7.95 (d, J ) 8.0 Hz,
2H), 9.98 (s, 1H); MS m/z 382.99 (MH-); Anal. (C17H12ClF3N2O3)
C, H, N.
(c) Demethylation was performed as in 8l, step c, giving 14b:
mp 240-241 °C; IR (KBr) 3428, 1786, 1664, 1422, 1326, 1118
1
cm-1; H NMR (300 MHz, DMSO-d6) δ 2.54 (br s, 4H), 3.05 (br
s, 2H,), 3.69 (br s, 4H), 4.84 (s, 2H), 7.13 (s, 1H), 7.88 (d, J ) 8.5
Hz, 2H), 7.96 (d, J ) 8.4 Hz, 2H), 8.06 (s, 1H), 9.61 (br s, 1H),
9.81 (br s, 1H); MS m/z 513 (MH+); Anal. (C22H20ClF3N4O5) C,
H, N.
N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phe-
nyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-thiomor-
pholineacetamide (14c). The sequence described above for 14b
was followed, alkylating with thiomorpholine and demethylation
according to 8l, step c: mp 250-252 °C; IR (KBr) 3174, 1782,
[3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluo-
romethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (13). (a) The se-
quence described above to 8a was followed was starting from
4-(trifluoromethyl)benzoic acid and alkylating with N-[4-(bromom-
ethyl)-2-chloro-5-methoxyphenyl]acetamide to give [3-[(4-acety-
lamino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)-
phenyl]-1,3,4-oxadiazol-2(3H)-one: mp 202-202.5 °C; IR (KBr)
3254, 1788, 1664, 1328, 1128 cm-1; 1H NMR (300 MHz, DMSO-
d6) δ 2.09 (s, 3H), 3.75 (s, 3H), 4.88(s, 2H), 7.43 (s, 1H), 7.48 (s,
1H), 7.86 (d, J ) 8.2 Hz, 2H), 7.95 (d, J ) 8.0 Hz, 2H), 9.50 (s,
1H); MS m/z 442 (MH+); Anal. (C19H15ClF3N3O4) C, H, N.
(b) Hydrolysis of [3-[(4-acetylamino-5-chloro-2-methoxyphenyl)-
methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one
was performed as described above for compound 8l, step b, to give
the HCl salt: mp > 190 °C (dec). IR (KBr) 3450, 2813, 1776,
1
1662, 1416, 1320, 1132 cm-1; H NMR (300 MHz, DMSO-d6) δ
2.68 (br s, 4H), 2.77 (br s, 4H), 3.15 (s, 2H), 4.84 (s, 2H), 7.38 (s,
1H), 7.86 (d, J ) 8.4 Hz, 2H), 7.95 (d, J ) 8.3 Hz, 2H), 7.99 (s,
1H), 9.78 (s, 1H), 10.22 (s, 1H); MS m/z 527 (MH-); Anal. (C22H20-
ClF3N4O4S) C, H, N.
N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phe-
nyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-methyl-1-
piperazineacetamide, dihydrochloride salt (14d). The sequence
described above for 14b was followed, alkylating with N-meth-
ylpiperazine and demethylation according to 8l, step c, isolated as
HCl salt: mp > 220 °C (dec); IR (KBr) 3164, 2494, 1798, 1696,
1324, 1176, 1108 cm-1; H NMR (300 MHz, DMSO-d6) δ 3.71
1544, 1326, 1064 cm-1; H NMR (300 MHz, DMSO-d6) δ 2.80
1
1
(s, 3H), 4.79 (s, 2H), 6.80 (s, 1H), 7.28 (s, 1H), 7.84 (d, J ) 8.4
Hz, 2H), 7.93 (d, J ) 8.3 Hz, 2H), 8.43 (br s, 3H); MS m/z 400
(MH-); Anal. (C17H13ClF3N3O3) C, H, N, Cl.
(s, 3H), 3.40 (br s, 4H), 3.59 (br s, 4H), 4.09 (br s, 2H), 4.86 (s,
2H), 7.38 (s, 1H), 7.52 (s, 1H), 7.86 (d, J ) 8.4 Hz, 2H), 7.96 (d,
J ) 8.3 Hz, 2H), 10.11 (br s, 1H), 10.46 (br s, 1H), 11.91 (br s,
1H); MS m/z 526 (MH+); Anal. (C23H23ClF3N5O4) C, H, N.
N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phe-
nyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-phenyl-1-
piperazineacetamide, Dihydrochloride Salt (14e). The sequence
described above for 14b was followed, alkylating with N-phe-
nylpiperazine and demethylation according to 8l, step c, isolated
as HCl salt: mp 220-235 °C; IR (KBr) 2966, 1786, 1700, 1542,
N-[2-Chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phe-
nyl]-1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-2-(dimethy-
lamino)acetamide, Hydrochloride Salt (14a). The sequence
described below for 14b was followed (alkylation with dimethy-
lamine) and demethylation according to 8l, step c, isolated as HCl
salt: mp > 233 °C (dec); IR (KBr) 3410, 1780, 1326, 1170, 1066
cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.86 (s, 6H), 4.23 (s, 2H),
4.87 (s, 2H), 7.36 (s, 1H), 7.39 (s, 1H), 7.86 (d, J ) 8.4 Hz, 2H),
1
1418, 1324 cm-1; H NMR (300 MHz, DMSO-d6) δ 3.22 (br s,