An Orally Bioavailable Endothelin Antagonist
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 8 1983
mg, 0.20 mmol) in water (5 mL) was added sodium borohydride
(100 mg), and the mixture was stirred at room temperature
for 3 h. More sodium borohydride (200 mg) was added, and
the mixture was stirred for another 10 h. The reaction was
quenched by adding saturated NH4Cl, and the resulting
mixture was partitioned between saturated NH4Cl (150 mL)
and EtOAc (150 mL). The organic layer was shaken with
saturated NaHCO3, dried over Na2SO4, and concentrated to
give the sodium salt of 7v (67 mg, 67% yield) as a brown
3.29 (tt, J ) 11.6, 2.9 Hz, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 1.20-
1.90 (m, 10H).
1-(2-Am in o-3,5-d im et h ylp h en yl)-1-p h en ylm et h a n on e
(12c). 1H NMR (CDCl3) δ: 7.40-7.70 (m, 5H), 7.12 (s, 1H),
7.07 (s, 1H), 6.26 (br s, 2H), 2.21 (s, 3H), 2.15 (s, 3H).
1-(2-Am in o-3,5-dim eth ylph en yl)-2-ch lor oeth an on e (12d).
1H NMR (CDCl3) δ: 7.30 (s, 1H), 7.09 (s, 1H), 6.34 (br s, 2H),
4.71 (s, 2H), 2.24 (s, 3H), 2.16 (s, 3H).
1-(2-Am in o-3,5-d im et h ylp h en yl)-4-ch lor obu t a n -1-on e
(13). The title compound was essentially the exclusive product
when 2,4-dimethylaniline and cyclopropanecarbonitrile were
subjected to the literature procedure.23 1H NMR (CDCl3) δ:
7.48 (s, 1H), 7.07 (d, 1H), 3.67 (t, J ) 6.2 Hz, 2H), 3.16 (t, J )
7.0 Hz, 2H), 2.25 (s, 3H), 2.18 (s, 3H), 1.01 (m, 2H).
Compounds 15a and 15b were synthesized according to our
published procedure.23
1-(2-Am in o-3,5,6-tr im eth ylp h en yl)eth a n on e (15a ). 1H
NMR (DMSO-d6) δ: 6.81 (s, 1H), 4.49 (br s, 2H), 2.41 (s, 3H),
2.07 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H).
1-(2-Am in o-3,5,6-tr im eth ylp h en yl)p r op a n -1-on e (15b).
1H NMR (CDCl3) δ: 7.22 (s, 1H), 2.99 (q, J ) 7.3 Hz, 2H),
2.75 (s, 3H), 2.68 (s, 3H), 2.37 (s, 3H), 1.31 (t, J ) 7.3 Hz, 3H).
N-[2-(2-Ch lor oacetyl)-4,6-dim eth ylph en yl]-3-{[(4-ch lor o-
3-m et h ylisoxa zol-5-yl)a m in o]su lfon yl}t h iop h en e-2-ca r -
boxa m id e (16). Compound 16 was synthesized according to
our published procedure6 using acid chloride 4 and aniline 12d .
For 16 1H NMR (DMSO-d6) δ: 11.26 (s, 1H), 7.76 (d, J ) 5.1
Hz, 1H), 7.40 (d, J ) 5.1 Hz, 1H), 7.34 (s, 1H), 7.30 (s, 1H),
4.86 (s, 2H), 2.32(3) (s, 3H), 2.31(5) (s, 3H), 2.03 (s, 3H).
3,5-Dim eth ylp h en yl Meth yl Su lfon e (19). A mixture of
5-iodoxylene (12.0 g, 51.7 mmol), sodium methanesufinate
(20.8 g, 206.8 mmol), and cuprous iodide (14.8 g, 77.5 mmol)
in DMF (150 mL) was heated at 140 °C for 36 h under
nitrogen. To workup, the mixture was poured into water (300
mL), and the solids were filtered and washed with water (2 ×
100 mL). The solids were then washed with EtOAc (6 × 50
mL), and the combined washings dried over MgSO4 and
concentrated on a rotavap to give 19 (8.0 g, 84% yield). 1H
NMR (CDCl3) δ: 7.54 (s, 2H), 7.25 (s, 1H), 3.03 (s, 2H), 2.39
(s, 6H).
1
solid: mp 147-154 °C; H NMR (DMSO-d6) δ: 10.92 (s, 1H),
7.69 (d, J ) 5.5 Hz, 1H), 7.40 (d, J ) 5.5 Hz, 1H), 7.21 (s, 1H),
6.94 (s, 1H), 4.86 (br s, 1H), 2.29 (s, 3H), 2.11 (s, 3H), 1.99 (s,
3H), 1.20 (d, J ) 6.2 Hz, 3H); IR (KBr pellet): 3437, 3237,
1634, 1603, 1537, 1496 cm-1. HRMS Calcd for C19H20
ClN3O5S2: 469.0533. Found: 469.0516.
-
3-{[(4-Ch lor o-3-m et h ylisoxa zol-5-yl)a m in o]su lfon yl}-
N-[2-(1-h yd r oxyim in o)e t h yl-4,6-d im e t h ylp h e n yl]t h io-
p h en e-2-ca r boxa m id e (7w ). To a solution of the sodium salt
of 3a (500 mg, 1.02 mmol) in 2 N NaOH (40 mL) and EtOH (4
mL) was added hydroxylamine hydrochloride (4 g). The reac-
tion was heated at 60 °C for 3 h before it was quenched with
2 N HCl (45 mL) at 0 °C. The precipitate was filtered, washed
with dilute HCl, and partitioned between EtOAc and saturated
NaHCO3. The organic layer was dried (Na2SO4) and concen-
trated to afford the sodium salt of 7w (275 mg, 53% yield) as
an off-white solid: mp 136-142 °C; 1H NMR (DMSO-d6) δ:
10.98 (s, 1H), 10.82 (s, 1H), 7.68 (d, J ) 5.3 Hz, 1H), 7.39 (d,
J ) 5.3 Hz, 1H), 7.10 (s, 1H), 6.98 (s, 1H), 2.30 (s, 3H), 2.20 (s,
3H), 1.99(1) (s, 3H), 1.98(6) (s, 3H); IR (KBr pellet): 3434, 1727,
1632, 1601, 1533 cm-1. HRMS Calcd for C19H19ClN4O5S2:
482.0485. Found: 482.0462.
3-{[(4-Ch lor o-3-m et h ylisoxa zol-5-yl)a m in o]su lfon yl}-
N-[2-(1-m et h oxyim in oet h yl)-4,6-d im et h ylp h en yl]t h io-
p h en e-2-ca r boxa m id e (7x). Compound 7x was synthesized
in the same fashion as for 7w from 3a except that O-
methylhydroxylamine hydrochloride (25% w/w in water) and
Na2CO3 were used instead of hydroxylamine hydrochloride and
2 N NaOH, respectively. It was a mixture of two isomers in
the ratio of 4.5:1, and the sodium salt is a gray solid (38%
1
yield): mp 140-145 °C; H NMR (DMSO-d6) major isomer δ:
Eth yl (3,5-Dim eth ylp h en yl) Su lfon e (20). To a solution
of 19 (200 mg, 1.09 mmol) in anhydrous THF (1 mL) at -78
11.03 (s, 1H), 7.69 (d, J ) 5.3 Hz, 1H), 7.39 (d, J ) 5.3 Hz,
1H), 7.12 (s, 1H), 7.01 (s, 1H), 3.73 (s, 3H), 2.30 (s, 3H), 2.19
(s, 3H), 1.98(7) (s, 3H), 1.95 (s, 3H); minor isomer δ: 10.76 (s,
1H), 7.66 (d, J ) 5.1 Hz, 1H), 7.36 (d, J ) 5.1 Hz, 1H), 7.07 (s,
1H), 6.83 (s, 1H), 3.53 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 1.99
(5) (s, 3H), 1.97 (s, 3H); IR (KBr pellet): 3456, 1634, 1533,
1497 cm-1. HRMS Calcd for C20H21ClN4O5S2: 496.0462.
Found: 496.0630.
n
°C under nitrogen was added BuLi (1 M in hexanes, 0.52 mL,
1.30 mmol). The mixture was stirred for 15 min before the
addition of iodomethane (616 mg, 4.34 mmol). The reaction
was allowed to warm to room temperature and then poured
into iced water (50 g). The aqueous mixture was extracted with
EtOAc (2 × 25 mL), and the combined organic layers were
dried over MgSO4 and concentrated to give 20 (150 mg, 70%
N-(2-Acetyl-4,6-d im eth ylp h en yl)-3-{[(4-ch lor o-3-m eth -
ylisoxa zol-5-yl)a m in o]su lfon yl}-5-m et h ylt h iop h en e-2-
ca r boxa m id e (7y). Compound 7y (sodium salt) is an off-white
1
yield). H NMR (DMSO-d6) δ: 7.50 (s, 2H), 7.37 (s, 1H), 3.24
(q, J ) 7.4 Hz, 2H), 2.38 (s, 6H), 1.10 (t, J ) 7.3 Hz, 3H).
3,5-Dim et h ylp h en yl (2-p r op yl) su lfon e (21). 1H NMR
(DMSO-d6) δ: 7.47 (s, 2H), 7.38 (s, 1H), 3.36 (septet, J ) 6.7
Hz, 1H), 2.38 (s, 6H), 1.15 (d, J ) 6.7 Hz, 6H).
1
solid: mp 158-162 °C; H NMR (DMSO-d6) δ: 11.35 (s, 1H),
7.24 (s, 1H), 7.20 (s, 1H), 7.15(1) and 7.16(4) (s and s, 1H),
2.44 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 1.99 (s,
3H); IR (KBr pellet): 3447, 3243, 2966, 2925, 1680, 1639, 1603,
1501 cm-1. HRMS Calcd for C20H20ClN3O5S2: 481.0533.
Found: 481.0505.
3,5-Dim et h ylp h en yl (1-p r op yl) su lfon e (22). 1H NMR
(DMSO-d6) δ: 7.50 (s, 2H), 7.36 (s, 1H), 3.16-3.28 (m, 2H),
2.38 (s, 6H), 1.50-1.62 (m, 2H), 0.92 (t, J ) 7.7 Hz, 3H).
Gen er a l P r oced u r e for Nitr a tion of Alk yl Ar yl Su l-
fon es. To a mixture of 22 (5.06 g, 23.8 mmol) and concentrated
H2SO4 (17 mL) at 0 °C was added KNO3 (2.40 g, 23.8 mmol).
The reaction was stirred at room-temperature overnight before
the mixture was poured onto ice (150 g). The precipitate was
collected via filtration and washed with water (200 mL) to give
23b (5.60 g, 95% yield).
N-(2-Acetyl-4,6-d im eth ylp h en yl)-3-{[(3,4-d im eth ylisox-
a zol-5-yl)a m in o]su lfon yl}th iop h en e-2-ca r boxa m id e (7z).
Compound 7z is a yellow solid. Its sodium salt: mp 158-160
°C; 1H NMR (DMSO-d6) δ: 11.99 (s, 1H), 7.68 (d, J ) 5.3 Hz,
1H), 7.35 (d, J ) 5.3 Hz, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 2.35
(s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 1.92 (s, 3H), 1.53 (s, 3H); IR
(KBr pellet): 3455, 3245, 1685, 1627, 1540 cm-1. HRMS Calcd
for C20H21N3O5S2: 447.0922. Found: 447.0899.
1-Meth a n esu lfon yl-3,5-d im eth yl-2-n itr oben zen e (23a ).
1H NMR (DMSO-d6) δ: 7.77 (s, 1H), 7.70 (s, 1H), 3.24 (q, J )
7.4 Hz, 2H), 2.38 (s, 6H), 1.10 (t, J ) 7.3 Hz, 3H).
Compounds 12a -d were synthesized according to our
published procedure.23
1,5-Dim et h yl-2-n it r o-3-(p r op a n e-1-su lfon yl)b en zen e
1-(2-Am in o-3,5-d im eth ylp h en yl)p r op a n -1-on e (12a ). 1H
NMR (CDCl3) δ: 7.46 (d, J ) 0.7 Hz, 1H), 7.04 (d, J ) 0.7 Hz,
1H), 6.40 (br s, 2H), 2.98 (q, J ) 7.3 Hz, 2H), 2.24 (s, 3H), 2.15
(s, 3H), 1.20 (t, J ) 7.3 Hz, 3H).
1
(23b). H NMR (DMSO-d6) δ: 7.73 (s, 1H), 7.70 (s, 1H), 3.34
(s, 3H), 2.45 (s, 3H), 2.29 (s, 3H).
1,5-Dim et h yl-2-n it r o-3-(p r op a n e-2-su lfon yl)b en zen e
1
(23c). H NMR (DMSO-d6) δ: 7.71(2) (s, 1H), 7.70(5) (s, 1H),
1-(2-Am in o-3,5-d im et h ylp h en yl)-1-cycloh exylm et h a -
3.58 (septet, J ) 6.6 Hz, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 1.23
(d, J ) 6.6 Hz, 6H).
n on e (12b). 1H NMR (CDCl3) δ: 7.47 (s, 1H), 7.07 (d, 1H),