Potassium Channel Openers Targeted for UUI. 1
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1197
1
compound 20: mp 257-260 °C; H NMR (DMSO-d6) δ 10.00
at room temperature, diluted with diethyl ether, and filtered
to give 1.22 g (80%) of monoadduct of sufficient purity for the
second step. The compound (0.50 g, 1.90 mmol) was added to
a solution of (()-2-amino-3,3-dimethylbutane (0.51 mL, 3.80
mmol) in ethanol (10 mL) and was stirred at room temperature
overnight. Filtration afforded 0.536 g (89%) of title compound
as a yellow solid: mp 285-286 °C; 1H NMR (DMSO-d6) δ 9.55
(s, 1H), 7.57 (d, 1H), 7.41 (d, 2H), 7.25 (d, 2H), 3.95 (m, 1H),
2.44 (s, 3H), 1.17 (d, 3H), 0.91 (s, 9H); IR (KBr) 3400, 3200,
2920, 1800, 1660, 1575, 1525, 1450 cm-1; MS (m/z) 318 (M+).
(br d, 1H), 8.9 (d, 1H), 8.4 (m, 1H), 8.02 (d, 1H), 7.96 (br d,
1H), 7.86 (dd, 1H), 7.66-7.54 (m, 2H), 1.45 (s, 9H); IR (KBr)
3400, 3200, 2980, 1785, 1680 cm-1; MS (m/z) 296 (MH+).
3-ter t-Bu tyla m in o-4-(qu in olin -6-yla m in o)-cyclobu t-3-
en e-1,2-dion e (22). To a solution of 3,4-diethoxy-3-cyclobutene-
1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was
added a suspension of 6-aminoquinoline (4.24 g, 29.4 mmol)
in ethanol (50 mL). The mixture was heated at reflux for 18
h, cooled, and vacuum filtered to afford 6.64 g (84%) of
monoadduct (mp: 185-187, dec) which was used without
further purification. An aliquot (3.00 g, 11.2 mmol) was
dissolved in tert-butylamine (50 mL). The solution was refluxed
for 3 h, cooled, and concentrated. The residue was recrystal-
lized twice from ethanol and then triturated with diethyl ether
to give 1.05 g (31%) of the title compound as a pale yellow
solid: mp 234-236 °C; 1H NMR (DMSO-d6) δ 9.92 (s, 1H), 8.76
(d, 1H), 8.24 (d, 1H), 8.01 (d, 1H), 7.98 (s, 1H), 7.97 (d, 1H),
7.88 (d, 1H), 7.48 (m, 1H), 1.45 (s, 9H). IR (KBr) 1780, 1665,
1610 cm-1; MS (m/z) 295 (M+).
(()-3-(4-Tr iflu or om et h oxy-p h en yla m in o)-4-(1,2,2-t r i-
m eth yl-p r op yla m in o)-cyclobu t-3-en e-1,2-d ion e (32). Pre-
pared in the manner described for compound 34: mp 282-
1
285 °C; H NMR (DMSO-d6) δ 9.66 (s, 1H), 7.60 (d, 1H), 7.53
(d, 2H), 7.33 (d, 2H), 3.99 (m, 1H), 1.17 (d, 3H), 0.91 (s, 9H);
MS (m/z) 357 (M + H)+.
(()-4-[3,4-Dioxo-2-(1,2,2-t r im et h yl-p r op yla m in o)-cy-
clobu t-1-en yla m in o]-ben zon itr ile (34). 4-Aminobenzoni-
trile (17.58 g, 149 mmol) was added to a solution of 3,4-
diethoxy-3-cyclobutene-1,2-dione (25.31 g, 149 mmol) in absolute
ethanol (450 mL). The mixture was heated at reflux overnight
and the resulting suspension was filtered hot to remove a small
amount of bis-adduct. The filtrate was gradually concentrated
to afford several crops of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-
enylamino)-benzonitrile, as a bright yellow solid, which were
(()-3-(Qu in olin -8-yla m in o)-4-(1,2,2-t r im et h yl-p r op yl-
a m in o)-cyclobu t-3-en e-1,2-d ion e (23). To a solution of
8-aminoquinoline (1.00 g, 6.94 mmol) in ethanol (20 mL) was
added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.03 mL, 6.94
mmol), and the resulting mixture was heated to reflux for 24
h. The mixture was cooled, diluted with ethanol, and filtered.
The crude product was triturated with chloroform/hexanes and
then purified by flash chromatography (ethyl acetate/hexane)
to give 1.31 g (70%) of monoadduct: 1H NMR (DMSO-d6) δ
9.75 (br m, 1 H), 8.86 (dd, 1 H), 8.26 (br m, 1H), 8.20 (dd, 1H),
7.57 (m, 2H), 7.53 (dd, 1H), 4.95 (q, 2H), 1.59 (t, 3H). To the
compound (0.300 g, 1.12 mmol) in ethanol (5 mL) was added
(()-2-amino-3,3-dimethylbutane (0.18 mL, 1.34 mmol), and the
resulting mixture was heated at 45 °C overnight, diluted with
hexanes, and filtered to give 0.294 g (81%) of title compound
1
collected by filtration and combined: yield 29.11 g (81%); H
NMR (DMSO-d6) δ 11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d, 2H),
4.79 (q, 2H), 1.46 (t, 3H). To this product (13.00 g, 53.7 mmol)
in ethanol (360 mL) was added (()-2-amino-3,3-dimethylbu-
tane (7.2 mL, 54 mmol). The mixture was heated at reflux
overnight. Gradual concentration of the reaction solution
afforded two crops of 4-[3,4-dioxo-2-(1,2,2-trimethyl-propyl-
amino)-cyclobut-1-enylamino]-benzonitrile, as a yellow pre-
cipitate, which were collected by filtration and combined: yield
11.34 g (71%); mp 241-243 °C; 1H NMR (DMSO-d6) δ 9.89 (s,
1H), 7.78 (d, 2H), 7.72 (d, 1H), 7.60 (d, 2H), 3.96 (m, 1H), 1.18
(d, 3H), 0.91 (s, 9H).
1
as a yellow solid: mp 244-245; H NMR (DMSO-d6) δ 10.45
(s, 1H), 8.97 (dd, 1H), 8.62 (d, 1H), 8.41 (dd, 1H), 8.29 (dd,
1H), 7.6 (m, 3H), 4.10 (m, 1H), 1.21 (d, 3H), 0.94 (s, 9H); IR
(KBr) 3280, 2960, 1790, 1670 cm-1; MS (m/z) 323 (MH+).
(+)-(R)-4-[3,4-Dioxo-2-(1,2,2-t r im et h yl-p r op yla m in o)-
cyclobu t-1-en yla m in o]-ben zoic Acid Meth yl Ester (36).
3-ter t-Bu tyla m in o-4-(isoqu in olin -5-yla m in o)-cyclobu t-
3-en e-1,2-d ion e (24). To a solution of 3,4-diethoxy-3-cy-
clobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol
(100 mL) was added a suspension of 5-aminoisoquinoline (4.24
g, 29.4 mmol) in ethanol (50 mL). The mixture was heated to
reflux overnight and then filtered to yield 2.30 g (29%) of
monoadduct as a solid: mp 182 (dec) °C. The compound (0.300
g, 1.12 mmol) was dissolved in tert-butylamine (50 mL) and
refluxed for 3 h. The mixture was cooled, concentrated, and
triturated with diethyl ether to afford 0.120 g (39%) of the title
compound as a white solid, one-eighth hydrate: mp 268-270
°C (dec); 1H NMR (DMSO-d6) δ 9.75 (s, 1H), 9.35 (s, 1H), 8.62
(d, 1H), 8.19 (s, 1H), 8.01 (d, 1H), 7.88 (d, 1H), 7.80 (d, 1H),
Prepared in the manner described for compound 34: mp 279-
1
280 °C; [R]25 ) +7.54° (DMSO); H NMR (DMSO-d6) δ 9.87
D
(s, 1H), 7.93 (d, 2H), 7.68 (d, 1H), 7.56 (d, 2H), 4.99 (m, 1H),
3.82 (s, 3H), 1.18 (d, 3H), 0.92 (s, 9H); MS (m/z) 331 (M + H)+.
(()-3-(4-Met h a n esu lfon yl-p h en yla m in o)-4-(1,2,2-t r i-
m eth yl-p r op yla m in o)-cyclobu t-3-en e-1,2-d ion e (37). To a
suspension of 3-(4-methylsulfanyl-phenylamino)-4-(1,2,2-tri-
methyl-propylamino)-cyclobut-3-ene-1,2-dione (31, 0.100 g,
0.314 mmol) in ethanol (3 mL) was added potassium peroxy-
monosulfate (OXONE, 0.77 g, 1.26 mmol) as a solution in water
(2 mL). The mixture was stirred overnight at room tempera-
ture and filtered, and the solid was washed with water and
dried in vacuo. The solid was triturated with methanol/ethyl
acetate to afford 0.05 g (45%) of sulfone as an off-white solid:
7.68 (t, 1H), 1.47 (s, 9H); IR (KBr) 3200, 1785, 1670, 1600 cm-1
;
MS (m/z) 295 (M+).
1
mp 307-310 °C; H NMR (DMSO-d6) δ 9.91 (s, 1H), 7.85 (d,
(()-3-(6-Meth oxy-qu in olin -8-ylam in o)-4-(1,2,2-tr im eth yl-
p r op yla m in o)-cyclobu t-3-en e-1,2-d ion e (25). Prepared in
the manner described for compound 23 utilizing 8-amino-6-
methoxyquinoline: mp 243-245 °C; 1H NMR (DMSO-d6) δ
10.43 (br s, 1H), 8.78 (dd, 1H), 8.64 (d, 1H), 8.28 (dd, 1H), 8.13
(d, 1H), 7.56 (dd, 1H), 7.02 (d, 1H), 4.11 (m, 1H), 3.88 (s, 3H),
2H), 7.71 (d, 1H), 7.65 (d, 2H), 3.99 (m, 1H), 3.17, (s, 3H), 1.20
(d, 3H), 0.91 (s, 9H); IR (KBr) 3400, 3150, 2925, 1800, 1680,
1575, 1530, 1450 cm-1; MS (m/z) 351 (M + H)+.
(+)-(R)-3-(4-Tr iflu or om eth yl-p h en yla m in o)-4-(1,2,2-tr i-
m eth yl-p r op yla m in o)-cyclobu t-3-en e-1,2-d ion e (40). Pre-
pared in the manner described for compound 34: mp 296-
1.20 (d, 3H), 0.94 (s, 9H); IR (KBr) 3400, 3220, 2950, 1780 cm-1
;
1
299 °C; [R]25 ) +4.20° (DMSO); H NMR (DMSO-d6) δ 9.81
D
MS (m/z) 353 (M+).
(s, 1H), 7.63 (m, 5H), 4.00 (m, 1H), 1.17 (d, 3H), 0.91 (s, 9H);
Rep r esen ta tive Ar yl An a logu es in Ta ble 3: (+)-(R)-3-
P h en yla m in o-4-(1,2,2-tr im eth yl-p r op yla m in o)-cyclobu t-
3-en e-1,2-d ion e (28). Prepared in the manner described for
MS (m/z) 341 (M + H)+.
Rep r esen ta tive Ben zon itr ile An a logu es in Ta ble 5:
(+)-(R)-4-[3,4-Dioxo-2-(1,2,2-tr im eth yl-p r op yla m in o)-cy-
clobu t-1-en yla m in o]-ben zon itr ile (42). Prepared in the
compound 34: mp 279-280 °C; [R]25 ) +6.96; 1H NMR
D
manner described for compound 34: mp 273-274 °C; [R]25
)
(DMSO-d6) δ 9.55 (s, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.33 (m,
2H), 7.01 (m, 1H), 3.99 (m, 1H), 1.17 (d, 3H), 0.91 (s, 9H); MS
(m/z) 273 (M + H)+.
D
1
+5.88° (DMSO); H NMR (DMSO-d6) δ 9.88 (s, 1H), 7.79 (d,
2H), 7.71 (d, 1H), 7.61 (d, 2H), 3.99 (m, 1H), 1.17 (d, 3H), 0.91
(s, 9H); MS (m/z) 298 (M + H)+. The chiral purity of 42 was
determined using a Chiralpak AS column with an 80:20
isocratic hexane:ethanol mobile phase at a flow rate of 1.0 mL/
min. Under these conditions, compound 42 possessed a reten-
tion time of 9.40 min (>99% ee).
(()-3-(4-Meth ylsu lfan yl-ph en ylam in o)-4-(1,2,2-tr im eth yl-
pr opylam in o)-cyclobu t-3-en e-1,2-dion e (31). 4-(Methylthio)-
aniline (0.722 mL, 5.80 mmol) was added to a stirring solution
of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.29 mL, 8.70 mmol)
in absolute ethanol (29 mL). The mixture was stirred overnight