Endothelin Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22 4497
5.11 (s, 2H), 2.31 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 2.02 (s,
3H), 2.00 (s, 3H).
NMR (400 MHz, CDCl3) δ 9.62 (br s, 1H), 7.43 (d, J ) 5.1 Hz,
1H), 7.35 (d, J ) 5.1 Hz, 1H), 6.92 (s, 2H), 6.04 (br t, 1H), 4.66
(d, J ) 4.8 Hz, 2H), 2.39 (s, 6H), 2.32 (s, 3H), 2.23 (s, 3H).
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N-[3-(cya n om eth yl)-2,4,6-tr im eth ylben zyl]-2-th iop h en e-
ca r boxa m id e (7ee): 1H NMR (400 MHz, CDCl3) δ 9.52 (br
s, 1H), 7.43 (d, J ) 5.1 Hz, 1H), 7.37 (d, J ) 5.1 Hz, 1H), 6.99
(s, 1H), 6.09 (br t, 1H), 4.69 (d, J ) 4.8 Hz, 2H), 3.66 (s, 2H),
2.43 (s, 3H), 2.39 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H); IR (KBr
pellet) 2240 cm-1 (CN).
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N-(2,4,6-tr im eth yl-5-p yr im id in yl)-2-th iop h en eca r boxa m -
id e (7ff): 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.77
(d, J ) 5.2 Hz, 1H), 7.43 (d, J ) 5.2 Hz, 1H), 2.55 (s, 3H), 2.35
(s and s, 6H), 1.99 (s, 3H).
Meth yl 2-(3-{[(3-{[(4-ch lor o-3-m eth yl-5-isoxa zolyl)a m i-
n o]su lfon yl}-2-t h ien yl)ca r b on yl]a m in o}-2,4,6-t r im et h -
ylp h en yl)a ceta te (7q): 1H NMR (400 MHz, DMSO-d6) δ
10.90 (br s, 1H), 7.71 (d, J ) 5.5 Hz, 1H), 7.40 (d, J ) 5.5 Hz,
1H), 6.94 (s, 1H), 3.70 (s, 2H), 3.60 (s, 3H), 3.22 (s, 3H), 3.12
(s, 3H), 3.11 (s, 3H), 2.01 (s, 3H); IR (KBr pellet) 1735 cm-1
.
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N-(3-m eth oxy-2,4,6-tr im eth ylph en yl)-2-th ioph en ecar box-
a m id e (7s): 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J ) 5.2
Hz, 1H), 7.48 (d, J ) 5.2 Hz, 1H), 7.45 (br s, 1H), 6.99 (s, 1H),
3.71 (s, 3H), 2.28 (s, 3H), 2.25 (s and s, 6H), 2.20 (s, 3H).
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N -[3-(cyclop r op ylm e t h oxy)-2,4,6-t r im e t h ylp h e n yl]-2-
th iop h en eca r boxa m id e (7t): 1H NMR (400 MHz, DMSO-
d6) δ 11.03 (s, 1H), 7.69 (d, J ) 5.2 Hz, 1H), 7.41 (d, J ) 5.2
Hz, 1H), 6.91 (s, 1H), 3.55 (d, J ) 6.96 Hz, 2H), 2.21 (s, 3H),
2.09(4) (s, 3H), 2.08(5) (s, 3H), 1.99 (s, 3H), 1.22 (m, 1H), 0.56
(m, 2H), 0.29 (m, 2H).
3-{[(4-Ch lor o-5-m et h yl-3-isoxa zolyl)a m in o]su lfon yl}-
N -[3-(c y a n o m e t h y l)-2,4,6-t r i m e t h y lp h e n y l]-2-t h i o -
p h en eca r boxa m id e (7gg): 1H NMR (400 MHz, DMSO-d6) δ
11.45 (s, 1H), 7.62 (d, J ) 5.1 Hz, 1H), 7.35 (d, J ) 5.1 Hz,
1H), 7.01 (s, 1H), 3.88 (s, 2H), 2.32 (s, 3H), 2.21 (s, 3H), 2.17
(s, 3H), 2.13 (s, 3H); IR (KBr pellet) 2262 cm-1 (CN).
3-{[(3-{[(4-Ch lor o-5-m et h yl-3-isoxa zolyl)a m in o]su lfo-
n yl}-2-th ien yl)car bon yl]am in o}-2,4,6-tr im eth ylben zyl ac-
eta te (7h h ): 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H),
7.62 (d, J ) 5.1 Hz, 1H), 7.35 (d, J ) 5.1 Hz, 1H), 6.97 (s, 1H),
5.11 (s, 2H), 2.30 (s, 3H), 2.17 (s, 6H), 2.02 (s, 3H); IR (KBr
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N-(3-h yd r oxy-2,4,6-tr im eth ylp h en yl)-2-th iop h en eca r box-
a m id e (7u ): 1H NMR (400 MHz, DMSO-d6) δ 10.74 (br s, 1H),
7.72 (d, J ) 5.48 Hz, 1H), 7.40 (d, J ) 5.48 Hz, 1H), 6.79 (s,
1H), 2.15 (s, 3H), 2.05 (s, 3H), 2.031 (s, 3H), 2.026 (s, 3H).
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N -[3-(h yd r oxym e t h yl)-2,4,6-t r im e t h ylp h e n yl]-2-t h io-
pellet) 1733 cm-1
.
1
p h en eca r boxa m id e (7v): H NMR (400 MHz, DMSO-d6) δ
3-{[(4-Ch lor o-5-m et h yl-3-isoxa zolyl)a m in o]su lfon yl}-
N -[3-(h yd r oxym e t h yl)-2,4,6-t r im e t h ylp h e n yl]-2-t h io-
p h en eca r boxa m id e (7ii): 1H NMR (400 MHz, DMSO-d6) δ
10.30 (br s, 1H), 7.80 (d, J ) 5.1 Hz, 1H), 7.43 (d, J ) 5.1 Hz,
1H), 6.92 (s, 1H), 4.48 (s, 2H), 2.33 (s, 3H), 2.30 (s, 3H), 2.24
(s, 3H), 2.15 (s, 3H).
3-{[(3,4-Dim et h yl-5-isoxa zolyl)a m in o]su lfon yl}-N-[3-
(cya n om et h yl)-2,4,6-t r im et h ylp h en yl]-2-t h iop h en eca r -
boxa m id e (7jj): 1H NMR (400 MHz, DMSO-d6) δ 10.24 (br
s, 1H), 7.85 (d, J ) 5.1 Hz, 1H), 7.35 (d, J ) 5.1 Hz, 1H), 7.04
(s, 1H), 3.90 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.17 (s, 3H),
2.08 (s, 3H), 1.66 (s, 3H); IR (KBr pellet) 2243 cm-1 (CN).
3-{[(3-{[(3,4-Dim eth yl-5-isoxa zolyl)a m in o]su lfon yl}-2-
th ien yl)ca r bon yl]a m in o}-2,4,6-tr im eth ylben zyl a ceta te
(7k k ): 1H NMR (400 MHz, DMSO-d6) δ 10.22 (br s, 1H), 7.85
(d, J ) 5.1 Hz, 1H), 7.34 (d, J ) 5.1 Hz, 1H), 7.00 (s, 1H), 5.12
(s, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H),
2.02 (s, 3H), 1.65 (s, 3H).
3-{[(3,4-Dim et h yl-5-isoxa zolyl)a m in o]su lfon yl}-N-[3-
(h yd r oxym eth yl)-2,4,6-tr im eth ylp h en yl]-2-th iop h en eca r -
boxa m id e (7ll): 1H NMR (400 MHz, DMSO-d6) δ 10.20 (br
s, 1H), 7.84 (d, J ) 5.1 Hz, 1H), 7.35 (d, J ) 5.1 Hz, 1H), 6.92
(s, 1H), 4.48 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H),
2.07 (s, 3H), 1.65 (s, 3H).
Eth yl N-[(3-{[(4-ch lor o-3-m eth yl-5-isoxa zolyl)a m in o]-
su lfon yl}-2-th ien yl)ca r bon yl]-N-(3-h yd r oxy-2,4,6-tr im e-
th ylp h en yl)ca r ba m a te (67): 1H NMR (400 MHz, D2O) δ 8.05
(d, J ) 3.8 Hz, 1H), 7.84 (d, J ) 3.8 Hz, 1H), 7.47 (s, 1H), 5.86
(s, 1H), 4.44 (m, 2H), 2.66 (s, 3H), 2.54 (s and s, 6H), 2.52 (s,
3H), 1.36 (t, J ) 7.0 Hz, 3H).
10.98 (br s, 1H), 7.69 (d, J ) 5.5 Hz, 1H), 7.41 (d, J ) 5.5 Hz,
1H), 6.90 (s, 1H), 4.47 (s, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 2.11
(s, 3H), 1.99 (s, 3H).
3-{[(3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfo-
n yl}-2-t h ien yl)ca r b on yl]a m in o}-2,4,6-t r im et h ylp h en yl
m eth yl ca r bon a te (7w ): 1H NMR (400 MHz, DMSO-d6) δ
11.18 (s, 1H), 7.71 (d, J ) 5.5 Hz, 1H), 7.41 (d, J ) 5.5 Hz,
1H), 7.04 (s, 1H), 3.86 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.99-
(1) (s, 3H), 1.98(8) (s, 3H); IR (KBr pellet) 1754 cm-1
.
3-{[(3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfo-
n yl}-2-th ien yl)car bon yl]am in o}-2,4,6-tr im eth ylph en yl car -
1
bon a te (7x): H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H),
7.71 (d, J ) 5.1 Hz, 1H), 7.41 (d, J ) 5.1 Hz, 1H), 7.10 (s, 1H),
2.23 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H), 1.98 (s, 3H); IR (KBr
pellet) 1752 cm-1
.
O-(3-{[(3-{[(4-Ch lor o-3-m eth yl-5-isoxa zolyl)a m in o]su l-
fon yl}-2-t h ien yl)ca r b on yl]a m in o}-2,4,6-t r im et h ylp h e-
n yl) N,N-d im eth ylca r ba m oth ioa te (7y): 1H NMR (400
MHz, DMSO-d6) δ 11.14 (s, 1H), 7.70 (d, J ) 5.1 Hz, 1H), 7.41
(d, J ) 5.1 Hz, 1H), 6.98 (s, 1H), 3.39 (s, 3H), 3.35 (s, 3H),
2.15 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.95 (s, 3H).
O-(3-{[(3-{[(4-Ch lor o-3-m eth yl-5-isoxa zolyl)a m in o]su l-
fon yl}-2-t h ien yl)ca r b on yl]a m in o}-2,4,6-t r im et h ylb en -
zyl) N,N-d im eth ylca r ba m oth ioa te (7z): 1H NMR (400 MHz,
DMSO-d6) δ 11.09 (s, 1H), 7.71 (d, J ) 5.1 Hz, 1H), 7.42 (d, J
) 5.1 Hz, 1H), 7.01 (s, 1H), 5.43 (s, 2H), 3.28 (s, 6H), 2.33 (s,
3H), 2.19 (s, 3H), 2.15 (s, 3H), 1.99 (s, 3H).
3-{[(3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfo-
n yl}-2-t h ien yl)ca r b on yl]a m in o}-2,4,6-t r im et h ylp h en yl
N,N-d im eth ylsu lfa m a te (7a a ): 1H NMR (400 MHz, DMSO-
d6) δ 11.20 (s, 1H), 7.71 (d, J ) 5.2 Hz, 1H), 7.41 (d, J ) 5.2
Hz, 1H), 7.05 (s, 1H), 3.03 (s, 6H), 2.32 (s, 3H), 2.19 (s, 3H),
2.15 (s, 3H), 1.99 (s, 3H).
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N-(2,3,4,5,6-p en ta m eth ylp h en yl)-2-th iop h en eca r boxa m -
id e (7bb): 1H NMR (400 MHz, CDCl3) δ 9.53 (br s, 1H), 7.52
(d, J ) 5.5 Hz, 1H), 7.48 (br s, 1H), 7.47 (d, J ) 5.5 Hz, 1H),
2.25 (s, 6H), 2.24 (s and s, 9H), 2.21 (s, 3H).
N-(4-Ch lor o-3-m eth yl-5-isoxa zolyl)-2-[2-(6-m eth yl-1,3-
b en zod ioxol-5-yl)p r op a n oyl]-3-t h iop h en esu lfon a m id e
(70): 1H NMR (400 MHz, DMSO-d6) δ 7.69 (m, 1H), 7.31 (m,
1H), 6.73 (s, 1H), 6.54 (s, 1H), 5.92 (d, J ) 3.0 Hz, 2H), 4.92
(m, 1H), 2.20 (s, 3H), 2.08 (s, 3H), 1.32 (d, J ) 6.6 Hz, 3H).
2-[4-Br om o-2-(6-m eth yl-1,3-ben zodioxol-5-yl)bu tan oyl]-
N-(4-ch lor o-3-m et h yl-5-isoxa zolyl)-3-t h iop h en esu lfon a -
m id e (71): 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J ) 5.1
Hz, 1H), 7.31 (d, J ) 5.1 Hz, 1H), 6.76 (s, 1H), 6.56 (s, 1H),
5.94 (s, 2H), 4.92 (t, J ) 5.8 Hz, 1H), 3.41 (t, J ) 7.7 Hz, 2H),
2.21 (s, 3H), 2.16 (m, 2H), 2.09 (s, 3H).
N-[3,5-Bis(cya n om eth yl)-2,4,6-tr im eth ylp h en yl]-3-{[(4-
ch lor o-3-m e t h yl-5-isoxa zolyl)a m in o]su lfon yl}-2-t h io-
p h en eca r boxa m id e (7cc): 1H NMR (400 MHz, DMSO-d6) δ
11.20 (br s, 1H), 7.75 (d, J ) 5.1 Hz, 1H), 7.42 (d, J ) 5.1 Hz,
1H), 4.00 (s, 4H), 2.45 (s, 3H), 2.25 (s, 6H), 2.01 (s, 3H); IR
(KBr pellet) 2250 cm-1 (CN).
4-(3-{[(4-Ch lor o-3-m eth yl-5-isoxazolyl)am in o]su lfon yl}-
2-th ien yl)-3-(6-m eth yl-1,3-ben zod ioxol-5-yl)-4-oxobu ta n o-
ic a cid (73): 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J )
5.1 Hz, 1H), 7.30 (d, J ) 5.1 Hz, 1H), 6.72 (s, 1H), 6.57 (s,
1H), 5.92 (s, 2H), 5.06 (m, 1H), 2.93 (dd, 1H), 2.70 (dd, 1H),
3-{[(4-Ch lor o-3-m et h yl-5-isoxa zolyl)a m in o]su lfon yl}-
N-(m esitylm eth yl)-2-th iop h en eca r boxa m id e (7d d ): 1H
2.22 (s, 3H), 2.06 (s, 3H); IR (KBr pellet) 1711, 1680 cm-1
.