Pyrazolidine-3,5-diones as AT1 Ligands
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 14 2693
1.20-1.70 (m, 4H), 2.00 (m, 8H), 4.10 (t, J ) 7.25 Hz, 2H),
4.75 (s, 2H), 7.30 (m, 5H).
(t, J ) 7.05 Hz, 2H), 4.80 (s, 2H), 7.32 (m, 5H), 7.48 (m, 2H),
7.75 (d, J ) 8.05 Hz, 1H).
2-Bu tyl-3-[4-(2-car bom eth oxyben zoyl)ben zyl]-2,3-diaza-
sp ir o[4.4]n on a n e-1,4-d ion e (35): yield 39%; mp 81-82 °C
(cyclohexane); Rf 0.25 (hexane/EtOAc ) 7:3); IR (KBr) 1710,
1670 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, J ) 7.47 Hz,
3H), 1.22 (sextet, J ) 7.12 Hz, 2H), 1.42 (quintet, J ) 7.32
Hz, 2H), 1.95 (m, 8H), 3.47 (t, J ) 7.47 Hz, 2H), 3.62(s, 3H),
4.80 (s, 2H), 7.28 (d, J ) 8.00 Hz, 2H), 7.37 (d, J ) 7.95 Hz,
1H), 7.57 (t, J ) 7.50 Hz, 1H), 7.63 (t, J ) 7.99 Hz, 1H), 7.73
(d, J ) 8.30 Hz, 2H), 8.05 (d, J ) 8.54 Hz, 1H).
2-Ben zyl-4-p en t yloxy-2,3-d ia za sp ir o[4.4]n on -3-en -1-
on e (11b): Rf 0.79 (hexane/EtOAc ) 6:4); IR (KBr) 1700, 1600
cm-1; 1H NMR (300 MHz, CDCl3) δ 0.90 (t, J ) 7.20 Hz, 3H),
1.30 (m, 4H), 1.65 (m, 2H), 1.95 (m, 8H), 4.10 (t, J ) 7.23 Hz,
2H), 4.75 (s, 2H), 7.20 (m, 5H).
1-Ben zyl-3-b u t yloxy-4,4-d im et h ylp yr a zolid in -2-en -5-
on e (12b): Rf 0.52 (hexane/EtOAc ) 6:4); IR (KBr) 1700, 1600
1
cm-1; H NMR (80 MHz, CDCl3) δ 0.90 (t, J ) 7.22 Hz, 3H),
1.30 (m, 8H), 1.67 (m, 2H), 4.10 (t, J ) 7.22 Hz, 2H), 4.75 (s,
2-Bu tyl-3-[[2′-(N-ter t-bu tylam in osu lfon yl)(1,1′-biph en yl)-
4-yl]m eth yl]-2,3-diazaspir o[4.4]n on an e-1,4-dion e (38): yield
51%; mp 146-148 °C (EtOH); Rf 0.50 (hexane/EtOAc ) 6:4);
2H), 7.30 (m, 5H).
1-Ben zyl-4-bu tyl-3-bu tyloxy-4-m eth ylp yr a zolid in -2-en -
5-on e (13b): Rf 0.78 (hexane/EtOAc ) 6:4); IR (KBr) 1710,
IR (KBr) 3280, 1715, 1675, 1295, 1140 cm-1 1H NMR (300
;
1
1610 cm-1; H NMR (80 MHz, CDCl3) δ 0.79 (m, 6H), 0.84-
MHz, DMSO-d6) δ 0.80 (t, J ) 7.26 Hz, 3H), 0.95 (s, 9H), 1.17
(sextet, J ) 7.37 Hz, 2H), 1.40 (quintet, J ) 7.38 Hz, 2H), 1.80
(m, 8H), 3.50 (t, J ) 6.75 Hz, 2H), 4.84 (s, 2H), 6.50 (s, 1H),
7.30 (m, 3H), 7.38 (s, 1H), 7.42 (d, J ) 7.60 Hz, 1H), 7.50 (m,
2H), 8.20 (d, J ) 7.37 Hz, 1H); EI-MS [M.+] 511. Anal.
(C28H37N3O4S) C, H, N.
1.00 (m, 8H), 1.25 (s, 3H), 1.59 (m, 2H), 4.12 (t, J ) 7.32 Hz,
2H), 4.75 (s, 2H), 7.31 (m, 5H).
Gen er a l P r oced u r e for Alk yla tion of P yr a zolid in e-3,5-
d ion es 4-6 a n d 14-18 w ith th e Desir ed Alk yl Br om id e
Der iva tives. K2CO3 (60 mmol) was added portionwise to a
solution of compounds 4-6 and 14-18 (30 mmol) in DMF (10
mL). The desired alkyl bromide (45 mmol) was then added to
the reaction mixture, which was allowed to stir for 20 h at
room temperature. Water (80 mL) was added and the resulting
suspension was extracted with Et2O. The combined organic
extracts were washed with water and dried (MgSO4), and the
solution was concentrated. The resulting precipitate was
collected by filtration, washed with Et2O and further purified
by crystallization.
2-P h en yl-3-[[2′-[1-(tr ip h en ylm eth yl)-1H-tetr a zol-5-yl]-
(1,1′-b ip h en yl)-4-yl]m et h yl]-2,3-d ia za sp ir o[4.4]n on a n e-
1,4-d ion e (20): yield 35%; mp 152-154 °C (EtOH); Rf 0.51
(hexane/EtOAc ) 6:4); IR (KBr) 1740, 1650 cm-1; 1H NMR (80
MHz, CDCl3) δ 1.80 (m, 8H), 4.60 (s, 2H), 6.60-7.90 (m, 28H).
2-(p-Tolyl)-3-[[2′-[1-(tr ip h en ylm eth yl)-1H-tetr a zol-5-yl]-
(1,1′-b ip h en yl)-4-yl]m et h yl]-2,3-d ia za sp ir o[4.4]n on a n e-
1,4-d ion e (21): yield 30%; mp 165-168 °C (acetonitrile); Rf
0.83 (CH2Cl2); IR (KBr) 1720, 1690 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.91-1.97 (m, 8H), 2.40 (s, 3H), 4.56 (s, 2H), 6.75 (d,
J ) 6.87 Hz, 2H), 6.89 (m, 6H), 7.00 (d, J ) 7.03 Hz, 2H), 7.10
(d, J ) 7.10 Hz, 2H), 7.21 (m, 12H), 7.39 (t, J ) 7.67 Hz, 1H),
7.50 (t, J ) 7.67 Hz, 1H), 7.88 (d, J ) 7.67 Hz, 1H).
2-Ben zyl-3-[[2′-[1-(tr ip h en ylm eth yl)-1H-tetr a zol-5-yl]-
(1,1′-b ip h en yl)-4-yl]m et h yl]-2,3-d ia za sp ir o[4.4]n on a n e-
1,4-d ion e (22): yield 42%; mp 198-200 °C (EtOAc); Rf 0.59
(hexane/EtOAc ) 6:4); IR (KBr) 1725, 1690 cm-1; 1H NMR (300
MHz, DMSO-d6) δ 1.80 (m, 8H), 4.61 (s, 2H), 4.68 (s, 2H), 6.85
(s, 1H), 6.90 (m, 5H), 7.05 (d, J ) 8.11 Hz, 2H), 7.11 (d, J )
8.11 Hz, 2H), 7.20 (d, J ) 7.89 Hz, 2H), 7.30 (m, 12H), 7.50 (d,
J ) 7.89 Hz, 1H), 7.55 (t, J ) 7.89 Hz, 1H), 7.64 (t, J ) 7.89
Hz, 1H), 7.80 (d, J ) 7.89 Hz, 1H).
3-[[2′-(N-ter t-Bu tyla m in osu lfon yl)(1,1′-bip h en yl)-4-yl]-
m eth yl]-2-pr opyl-2,3-diazaspir o[4.4]n on an e-1,4-dion e (39):
yield 42%; mp 151-154 °C (EtOH); Rf 0.47 (hexane/EtOAc )
6:4); IR (KBr) 3300, 1725, 1680, 1300, 1145 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 0.83 (t, J ) 7.30 Hz, 3H), 0.97 (s, 9H),
1.61 (m, 2H), 2.00 (m, 8H), 3.50 (t, J ) 7.35 Hz, 2H), 4.87 (s,
2H), 7.34 (m, 4H), 7.55 (m, 4H), 8.16 (d, J ) 8.02 Hz, 1H).
3-[[2′-(N-ter t-Bu tyla m in osu lfon yl)(1,1′-bip h en yl)-4-yl]-
m eth yl]-2-pen tyl-2,3-diazaspir o[4.4]n on an e-1,4-dion e (40):
yield 47%; mp 144-145 °C (acetonitrile); Rf 0.32 (hexane/
EtOAc ) 7:3); IR (KBr) 3300, 1720, 1680, 1300, 1150 cm-1; 1H
NMR (300 MHz, DMSO-d6) δ 0.80 (t, J ) 7.25 Hz, 3H), 0.95
(s, 9H), 1.20 (m, 4H), 1.42 (m. 2H), 1.83 (m, 8H), 3.50 (t, J )
7.25 Hz, 2H), 4.85 (s, 2H), 6.57 (s, 1H), 7.30 (m, 5H), 7.58 (m,
2H), 8.02 (d, J ) 8.05 Hz, 1H).
1,4-Dib u t yl-2-[[2′-(N-ter t-b u t yla m in osu lfon yl)(1,1′-b i-
ph en yl)-4-yl]m eth yl]-4-m eth ylpyr azolidin e-3,5-dion e (41):
yield 35%; mp 148-152 °C (EtOH); Rf 0.61 (hexane/EtOAc )
6:4); IR (KBr) 3300, 1730, 1690, 1300, 1140 cm-1 1H NMR
;
(300 MHz, DMSO-d6) δ 0.78 (t, J ) 7.33 Hz, 3H), 0.82 (t, J )
7.17 Hz, 3H), 0.96 (s, 9H), 1.02 (m, 2H), 1.15 (s, 3H), 1.20 (m,
4H), 1.39 (m, 2H), 1.60 (m, 2H), 3.58 (m, 2H), 4.81 (d, J )
16.01 Hz, 1H), 4.96 (d, J ) 16.01 Hz, 1H), 6.61 (s, 1H), 7.28
(d, J ) 7.15 Hz, 1H), 7.35 (d, J ) 8.15 Hz, 2H), 7.40 (d, J )
8.15 Hz, 2H), 7.60 (m, 2H), 8.03 (d, J ) 7.78 Hz, 1H).
1-Bu tyl-2-[[2′-(N-ter t-bu tylam in osu lfon yl)(1,1′-biph en yl)-
4-yl]m eth yl]-4,4-dim eth ylpyr azolidin e-3,5-dion e (42): yield
50%; mp 133-135 °C (EtOH); Rf 0.38 (hexane/EtOAc ) 6:4);
IR (KBr) 3300, 1730, 1690, 1300, 1140 cm-1 1H NMR (300
;
MHz, DMSO-d6) δ 0.82 (t, J ) 7.02 Hz, 3H), 0.96 (s, 9H), 1.20
(m, 8H), 1.50 (m, 2H), 3.53 (t, J ) 7.02 Hz, 2H), 4.85 (s, 2H),
6.56 (s, 1H), 7.31 (m, 3H), 7.40 (d, J ) 7.95 Hz, 2H), 7.59 (m,
2H), 8.05 (d, J ) 7.95 Hz, 1H).
2-Bu tyl-3-[[2′-cya n o(1,1′-bip h en yl)-4-yl]m eth yl]-2,3-d i-
a za sp ir o[4.4]n on a n e-1,4-d ion e (24): yield 33%; mp 120-
122 °C (toluene/cyclohexane ) 1:5); Rf 0.80 (EtOAc); IR (KBr)
Gen er a l P r oced u r e for Dep r otection of th e ter t-Bu tyl-
su lfon a m id e Moiety. A few drops of anisole were added to a
solution of compounds 38-42 (10 mmol) in TFA (400 mmol).
The mixture was allowed to stir at room temperature for 12
h. After removal of the solvent under reduced pressure, water
was added and the suspension was made basic with NaHCO3.
The resulting precipitate was collected by filtration, washed
with water and Et2O and further purified by crystallization.
3-[[2′-(Am in osu lfon yl)(1,1′-b ip h en yl)-4-yl]m et h yl]-2-
bu tyl-2,3-d ia za sp ir o[4.4]n on a n e-1,4-d ion e (43): yield 83%;
mp 98-100 °C (toluene); Rf 0.47 (hexane/EtOAc ) 4:6); IR
(KBr) 3350, 3200, 3060, 1720, 1670, 1335, 1160 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 0.82 (t, J ) 7.37 Hz, 3H), 1.17 (sextet,
J ) 7.23 Hz, 2H), 1.40 (quintet, J ) 7.23 Hz, 2H), 1.80 (m,
8H), 3.52 (t, J ) 7.37 Hz, 2H), 4.87 (s, 2H), 7.20 (s, 2H), 7.25
(m, 3H), 7.40 (d, J ) 8.14 Hz, 2H), 7.60 (m, 2H), 8.02 (dd, J )
7.37 Hz, 1.47 Hz, 1H); EI-MS [M.+] 455. Anal. (C24H29N3O4S)
C, H, N.
1
2210, 1715, 1675 cm-1; H NMR (300 MHz, CDCl3) δ 0.88 (t,
J ) 7.27 Hz, 3H), 1.24 (m, 2H), 1.46 (m, 2H), 1.96-2.03 (m,
8H), 3.54 (t, J ) 7.53 Hz, 2H), 4.85 (s, 2H), 7.35 (s, 1H), 7.38
(s, 1H), 7.48 (m, 3H), 7.51 (t, J ) 8.20 Hz, 1H), 7.66 (t, J )
8.20 Hz, 1H), 7.80 (d, J ) 8.20 Hz, 1H); EI-MS [M.+] 401. Anal.
(C25H27N3O2‚0.5H2O) C, H, N.
3-[[(1,1′-Bip h en yl)-4-yl]m eth yl]-2-bu tyl-2,3-d ia za sp ir o-
[4.4]n on a n e-1,4-d ion e (30): yield 60%; mp 104-107 °C
(EtOH); Rf 0.62 (hexane/EtOAc ) 6:4); IR (KBr) 1730, 1680
1
cm-1; H NMR (300 MHz, DMSO-d6) δ 0.90 (t, J ) 7.17 Hz,
3H), 1.15 (sextet, J ) 7.17 Hz, 2H), 1.40 (quintet, J ) 7.15
Hz, 2H), 1.82 (m, 8H), 3.50 (t, J ) 7.15 Hz, 2H), 4.80 (s, 2H),
7.30 (m, 3H), 7.43 (m, 2H), 7.67 (m, 4H); EI-MS [M.+] 376.5.
Anal. (C24H28N2O2) C, H, N.
2-Bu tyl-3-[[2′-(ter t-bu tyloxyca r bon yl)(1,1′-bip h en yl)-4-
yl]m eth yl]-2,3-d ia za sp ir o[4.4]n on a n e-1,4-d ion e (32): yield
35%; mp 96-97 °C (hexane); Rf 0.50 (hexane/EtOAc ) 7:3);
1
IR (KBr) 1710, 1670 cm-1; H NMR (80 MHz, CDCl3) δ 0.90
3-[[2′-(Am in osu lfon yl)(1,1′-b ip h en yl)-4-yl]m et h yl]-2-
pr opyl-2,3-diazaspir o[4.4]n on an e-1,4-dion e (44): yield 95%;
(t, J ) 7.20 Hz, 3H), 1.10-1.15 (m, 13H), 2.00 (m, 8H), 3.50