Substituted Analogues of GV150526
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18 3491
aminophenyl)ethylurea (1.2 equiv), easily prepared by reaction
of the commercially available R-methyl-4-nitrobenzylamine
hydrochloride with trimethylsilyl isocyanate followed by hy-
drogenation with palladium on carbon, was then added, and
the reaction mixture was refluxed for 5 h. After cooling to room
temperature the precipitate obtained was filtered giving the
title compounds 5b in 52% yield.
Gen er a l P r oced u r e for th e Ba sic Hyd r olysis of Eth yl
Ester s: P r oced u r e D. A solution of ester (0.14 mmol, 1 equiv)
and lithium hydroxide monohydrate (3-4 equiv) in ethanol
(2 mL) was stirred at 50 °C over a range of 2.5-4 h. After
cooling to room temperature the solution was acidified with a
2 N solution of hydrochloric acid until a solid precipitated. The
precipitate was filtered to give carboxylic acids in 58-84%
yields with the exception of the 3-pyridino derivative 16 (26%)
and the ethylthio derivative 10 (27%). The sodium salts were
obtained in quantitative yields by freeze-drying the carboxylic
acids with 1 equiv of sodium hydroxide (0.1 N).
(E)-4,6-Dich lor o-3-{2-[[4-(m et h ylu r eid ocyclop r op yl)-
ph en yl]car bam oyl]vin yl}-1H-in dole-2-car boxylic Acid So-
d iu m Sa lt (12). Prepared starting from cyclopropyl isocyanate
according to the general procedures A, B, and D: mp >250
°C; IR (Nujol) νmax 3327, 1700, 1661, 1601 cm-1 1H NMR
;
(DMSO-d6) δ 11.80 (bs, 1H), 9.99 (bs, 1H), 8.57 (d, 1H), 7.67
(d, 2H), 7.40 (d, 1H), 7.18 (d, 1H), 7.14 (d, 2H), 7.09 (d, 1H),
6.30 (bt, 1H), 6.18 (bd, 1H), 4.13 (d, 2H), 2.41 (m, 1H), 0.55
(m, 2H), 0.33 (m, 2H); MS m/e 509. Anal. (C23H19Cl2N4O4Na)
C, H, N.
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylu r eid o(tetr a h yd r op y-
r a n -4-yl))p h en yl]ca r ba m oyl]vin yl}-1H-in d ole-2-ca r boxy-
lic Acid Sod iu m Sa lt (13). Prepared starting from 4-tetrahy-
dropyranyl isocyanate according to the general procedures A,
1
B, and D: mp >250 °C; IR (Nujol) νmax 3312, 1622 cm-1; H
NMR (DMSO-d6) δ 11.75 (b, 1H), 9.94 (s, 1H), 8.59 (d, 1H),
7.67 (d, 2H), 7.37 (d, 1H), 7.18 (d, 1H), 7.14 (d, 2H), 7.09 (bs,
1H), 6.14 (t, 1H), 5.92 (d, 1H), 4.12 (d, 2H), 3.77 (m, 2H), 3.58
(m, 1H), 3.3 (m, 2H), 1.72 (m, 2H), 1.29 (m, 2H); MS m/e 553.
Anal. (C25H23Cl2N4O5Na) C, H, N.
(E)-4,6-Dich lor o-3-[2-[(4-u r eid op h en yl)ca r b a m oyl]vi-
n yl]-1H-in d ole-2-ca r boxylic Acid Sod iu m Sa lt (6). Pre-
pared starting from the commercially available trimethylsilyl
isocyanate according to general procedures A, B, and D: mp
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylu r eid op h en yl)p h en yl]-
ca r ba m oyl]vin yl}-1H-in d ole-2-ca r boxylic Acid Sod iu m
Sa lt (14). Prepared starting from the commercially available
phenyl isocyanate according to the general procedures A, B,
and D: mp >250 °C; IR (Nujol) νmax 3500-2500, 1657, 1590
cm-1; 1H NMR (DMSO-d6) δ 11.81 (bs, 1H), 9.99 (bs, 1H), 8.61
(bs, 1H), 8.57 (d, 1H), 7.70 (d, 2H), 7.40 (m, 3H), 7.26-7.14
(m, 5H), 7.11 (d, 1H), 6.87 (m, 1H), 6.66 (bt, 1H), 4.23 (d, 2H);
MS m/e 545. Anal. (C26H19Cl2N4O4Na‚1.5H2O) C, H, N.
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylu r eid o(4-m eth oxyp h e-
n yl))ph en yl]car bam oyl]vin yl}-1H-in dole-2-car boxylic Acid
(15). Prepared starting from the commercially available
4-methoxyphenyl isocyanate according to the general proce-
dures A, B, and D: mp 220 °C; IR (Nujol) νmax 3400-3200,
1650 cm-1; 1H NMR (DMSO-d6) δ 13.73 (bs, 1H), 12.55 (s, 1H),
10.19 (s, 1H), 8.32 (s, 1H), 8.26 (d, 1H), 7.67 (d, 2H), 7.48 (m,
1H), 7.31 (m, 1H), 7.29 (d, 2H), 7.24 (d, 2H), 6.80 (d, 2H), 6.78
(d, 1H), 6.44 (t, 1H), 4.23 (d, 2H), 3.68 (s, 3H); MS m/e 553.
Anal. (C27H22Cl2N4O5‚H2O) C, H, N.
1
>250 °C; H NMR (DMSO-d6) δ 11.86 (bs, 1H), 9.96 (bs, 1H),
9.77 (s, 1H), 8.76 (d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 7.41 (d,
1H), 7.13 (d, 1H), 7.00 (d, 1H), 6.36 (bs, 2H); MS m/e 455. Anal.
(C19H13Cl2N4O4Na) C, H, N.
(E)-4,6-Dich lor o-3-[2-[(4-m eth ylu r eid op h en yl)ca r ba m -
oyl]vin yl]-1H-in d ole-2-ca r boxylic Acid Sod iu m Sa lt (7).
Prepared starting from the commercially available trimeth-
ylsilyl isocyanate according to the general procedures A, B,
and D: mp >250 °C; IR (Nujol) νmax 3408, 3360, 3192, 1645,
1
1620 cm-1; H NMR (DMSO-d6) δ 11.8 (b, 1H), 9.97 (s, 1H),
8.58 (d, 1H, 15.2 Hz), 7.68 (d, 2H), 7.39 (d, 1H), 7.19 (d, 1H,
15.2 Hz), 7.15 (d, 2H), 7.10 (d, 1H), 6.32 (t, 1H), 5.47 (bs, 2H),
4.10 (d, 2H); MS m/e 469. Anal. (C20H15Cl2N4O4Na‚0.5H2O) C,
H, N.
(E)-4,6-Dich lor o-3-[2-[(4-eth ylu r eidoph en yl)car bam oyl]-
vin yl]-1H-in d ole-2-ca r boxylic Acid Sod iu m Sa lt (8). Pre-
pared starting from the commercially available trimethylsilyl
isocyanate according to the general procedures A, B, and D:
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylu r eid o(3-p yr id in yl))-
p h en yl]ca r b a m oyl]vin yl}-1H -in d ole-2-ca r b oxylic Acid
(16). Prepared starting from 3-pyridinyl isocyanate according
to the general procedures A, B, and D: mp >250 °C; IR (Nujol)
1
mp >250 °C; IR (Nujol) νmax 3325, 1657, 1609 cm-1; H NMR
(DMSO-d6) δ 11.75 (bs, 1H), 9.94 (s, 1H), 8.57 (d, 1H), 7.66 (d,
2H), 7.39 (d, 1H), 7.20 (d, 1H), 7.10 (d, 2H), 7.09 (d, 1H), 5.88
(bt, 1H), 5.41 (bs, 2H), 3.14 (m, 2H), 2.60 (m, 2H); MS m/e 483.
Anal. (C21H17Cl2N4O4Na‚1.5H2O) C, H, N.
ν
max 3206, 1696, 1653, 1609 cm-1; 1H NMR (DMSO-d6) δ 13.73
(bs, 1H), 12.51 (s, 1H), 10.17 (s, 1H), 8.73 (s, 1H), 8.52 (d, 1H),
8.26 (d, 1H, 15.6 Hz), 8.10 (dd, 1H), 7.89 (ddd, 1H), 7.66 (d,
2H), 7.47 (d, 1H), 7.29 (d, 1H), 7.24 (d, 2H), 6.79 (d, 1H, 15.6
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylu r eid oeth yl)p h en yl]-
ca r ba m oyl]vin yl}-1H-in d ole-2-ca r boxylic Acid Sod iu m
Sa lt (9). Prepared starting from the commercially available
ethyl isocyanate according to the general procedures A, B, and
Hz), 6.73 (t, 1H), 4.25 (d, 2H); MS m/e 524. Anal. (C25H19
Cl2N5O4‚H2O) C, H, N.
-
D: mp 220 °C; IR (Nujol) νmax 3315, 1599 cm-1
;
1H NMR
(E)-4,6-Dich lor o-3-{2-[[4-(R)-(1-u r eidoeth yl)ph en yl]car -
ba m oyl]vin yl}-1H-in d ole-2-ca r boxylic Acid Sod iu m Sa lt
(17). Prepared starting from (R)-1-(4-aminophenyl)ethylurea
according to the general procedures C and D: mp >250 °C;
[R]D ) +23.8 (c ) 0.30 in DMSO); IR (Nujol) νmax 3369, 3184,
(DMSO-d6) δ 11.77 (bs, 1H), 9.97 (bs, 1H), 8.58 (d, 1H), 7.67
(m, 2H), 7.39 (d, 1H), 7.19 (d, 1H), 7.14 (d, 2H), 7.09 (d, 1H),
6.21 (t, 1H), 5.83 (t, 1H), 4.12 (d, 2H), 3.02 (m, 2H), 0.98 (t,
3H); MS m/e 497. Anal. (C22H19Cl2N4O4Na) C, H, N.
1
1657, 1599 cm-1; H NMR (DMSO-d6) δ 11.84 (bs, 1H), 9.99
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylth iou r eid oeth yl)p h e-
n yl]ca r ba m oyl]vin yl}-1H-in d ole-2-ca r boxylic Acid (10).
Prepared starting from the commercially available ethyl
isothiocyanate according to the general procedures A, B, and
(bs, 1H), 8.61 (d, 1H), 7.70 (d, 2H), 7.43 (d, 1H), 7.22 (d, 1H),
7.21 (d, 2H), 7.11 (d, 1H), 6.35 (d, 1H), 5.41 (s, 2H), 4.67 (m,
1H), 1.31 (d, 3H); MS m/e 483. Anal. (C21H17Cl2N4O4Na) C, H,
N.
D: mp >250 °C; IR (Nujol) νmax 3290, 3196, 1712, 1664 cm-1
;
1H NMR (DMSO-d6) δ 13.37 (bs, 1H), 12.54 (bs, 1H), 10.18
(bs, 1H), 8.26 (d, 1H, 15.8 Hz), 7.65 (d, 2H), 7.48 (d, 1H), 7.31
(d, 1H), 7.23 (d, 2H), 7.78-7.4 (m, 2H), 6.77 (d, 1H, 15.8 Hz),
4.58 (m, 2H), 3.32 (m, 2H), 1.06 (t, 3H); MS m/e 491. Anal.
(C22H20Cl2N4O3S‚H2O) C, H, N.
(E)-4,6-Dich lor o-3-{2-[[4-(S)-(1-u r eid oeth yl)p h en yl]ca r -
ba m oyl]vin yl}-1H-in d ole-2-ca r boxylic Acid Sod iu m Sa lt
(18). Prepared starting from (S)-1-(4-aminophenyl)ethylurea
according to the general procedures C and D: mp >250 °C;
[R]D ) -25.6 (c ) 0.38 in DMSO); IR (Nujol) νmax 3323, 1657,
1609 cm-1; 1H NMR (DMSO-d6) δ 11.83 (bs, 1H), 9.99 (bs, 1H),
8.62 (d, 1H), 7.70 (d, 2H), 7.43 (d, 1H), 7.22 (d, 1H), 7.21 (d,
2H), 7.11 (d, 1H), 6.35 (d, 1H), 5.40 (bs, 2H), 4.67 (m, 1H),
1.31 (d, 3H); MS m/e 483. Anal. (C21H17Cl2N4O4Na) C, H, N.
(E)-4,6-Dich lor o-[3-(2-p yr id in -3-ylca r b a m oyl)vin yl]-
1H-in d ole-2-ca r boxylic Acid Sod iu m Sa lt (19). Prepared
reacting 3-aminopyridine with intermediate 4 following the
general procedure previously described:10b mp >250 °C; IR
(Nujol) νmax 3229, 1624 cm-1; 1H NMR (DMSO-d6) δ 12.03 (bs,
1H), 10.33 (bs, 1H), 8.89 (d, 1H), 8.66 (d, 1H), 8.19 (m, 2H),
(E)-4,6-Dich lor o-3-{2-[[4-(m eth ylu r eidom eth ylcar boxyl)-
p h en yl]ca r b a m oyl]vin yl}-1H -in d ole-2-ca r b oxylic Acid
(11). Prepared starting from the commercially available ethyl
isocyanoacetate according to the general procedures A, B, and
D: mp 190 °C; IR (Nujol) νmax 3400-2500, 1661, 1610 cm-1
;
1H NMR (DMSO-d6) δ 13.8 (b, 2H), 12.54 (bs, 1H), 10.18 (bs,
1H), 8.25 (d, 1H), 7.64 (d, 2H), 7.48 (d, 1H), 7.30 (d, 1H), 7.18
(m, 2H), 6.77 (d, 1H), 6.59 (bs, 1H), 6.16 (bs, 1H), 4.15 (s, 2H),
3.71 (s, 2H); MS m/e 505. Anal. (C22H18Cl2N4O6‚1.5H2O) C, H,
N.