N2,N5-Bis[1-isopentyl-5-({[1-methyl-5-({[3-(4-methyl-1-
piperazinyl)propyl]amino}carbonyl)-1H-pyrrol-3-yl]amino}-
carbonyl)-1H–pyrrol-3-yl]-1H-indole-2,5-dicarboxamide (3a)
was dissolved in DMF (1.0 cm3, dry) to which NMM (300 lL,
dry) was added followed by HBTU (723 mg, 1.91 mmol), at
room temperature with stirring. The stirring was continued at
room temperature for 10 min. 3-Aminopropyldimethylamine
(200 lL, 1.96 mmol) was added dropwise, and stirring was
continued at room temperature overnight. The reaction mixture
was diluted with ethyl acetate (50 cm3) and extracted with brine
(50 cm3). The water layer was then extracted with ethyl acetate
(2 × 50 cm3). The combined organic extract was dried (MgSO4),
filtered and the solvent removed under reduced pressure. The
crude product was applied to silica gel column chromatography
using methanol–ethyl acetate–TEA 1:4:0.01 (RF = 0.2). The
product was obtained as a yellow solid after trituration with
The product was obtained as a white solid (17 mg, 13%) with
no distinct melting point. 1H NMR [DMSO-d6]: d 11.95 (1H, s);
10.47 (1H, s); 10.27 (1H, s); 10.01 (1H, s); 9.97 (1H, s); 9.60 (2H,
br, 2 × TFA); 8.39 (1H, s); 8.13 (2H, br); 7.91 (1H, d, J = 8.7 Hz);
7.61 (1H, d, J = 8.7 Hz); 7.49 (1H, s); 7.43 (2H, s); 7.21 (2H, s);
7.14 (2H, s); 6.98 (2H, s); 4.43 (4H, m); 3.88 (6H, s); 3.29 (4H,
m); 3.20–2.73 (20H, m); 1.80 (4H, m); 1.66–1.55 (6H, m); 0.96
(12H, d, J = 6.5 Hz). IR [KBr]: 1676, 1647, 1584, 1533, 1443,
1404, 1200, 1136 cm.−1 HRESMS: Found M + H = 1084.6578,
calculated for C58H82N15O6 M + H = 1084.6567.
1
methanol (296 mg, 95%), m.p. > 230 °C. H NMR (CDCl3):
d 7.68 (1H, d, J = 1.4 Hz); 7.62 (1H, s, exch.); 7.55 (1H, d,
J = 1.4 Hz); 4.09 (3H, s); 4.37–4.44 (1H, m); 3.43 (2H, q, J =
6.9 Hz); 2.31 (6H, s); 2.45 (2H, t, J = 6.9 Hz); 1.79 (2H, quintet,
J = 6.9 Hz); 1.26 (6H, d, J = 6.4 Hz); IR [KBr]: 3131, 2959,
1668, 1551, 1500, 1418, 1310, 1286 cm.−1 HREIMS: Found:
422.17695, calculated for C18H26O4N6S 422.17363.
N2,N5-Bis[1-isopentyl-5-({[1-methyl-5-({[3-(4-morpholinyl)-
propyl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-
pyrrol-3-yl]-1H-indole-2,5-dicarboxamide (3b)
The product was obtained as a pale yellow solid (15 mg, 12%),
1
with no distinct melting point. H NMR [DMSO-d6]: d 11.95
(1H, s); 10.47 (1H, s); 10.28 (1H, s); 10.02 (1H, s); 9.99 (1H, s);
9.66 (2H, br, 2 × TFA); 8.39 (1H, s); 8.24 (2H, t, unresolved);
7.88 (1H, d, J = 8.7 Hz); 7.49 (1H, s); 7.43 (2H, s); 7.23 (2H,
s); 7.14 (2H, s); 7.02 (2H, s); 4.43 (4H, m); 4.06 (4H, m); 3.89
(6H, s); 3.71 (4H, t, J = 4.6 Hz); 3.49 (4H, m); 3.31 (4H, m);
3.19 (8H, m); 1.94 (4H, m); 1.66–1.57 (6H, m); 0.98 (12H, d,
J = 6.5 Hz). IR [KBr]: 1677, 1646, 1533, 1443, 1403, 1198,
1134 cm.−1 HRESMS: Found M + H = 1058.5927, calculated
for C56H76N13O8 M + H = 1058.5934.
N1,N3-Bis(2-{[5-({[4-({[3-(dimethylamino)propyl]amino}-
carbonyl)-5-isopropyl-1,3-thiazol-2-yl]amino}carbonyl)-1-
methyl-1H-pyrrol-3-yl]amino}-2-oxoethyl)isophthalamide (9)
N-[3-(Dimethylamino)propyl]-5-isopropyl-2-{[(1-methyl-4-
nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carbox-
amide 18 (100 mg, 0.236 mmol) was dissolved in methanol
(25 cm3). The solution was cooled to 0 °C under N2 then Pd/C
10% (86 mg) was added. The reaction mixture was hydroge-
nated at room temperature and atmospheric pressure for 5 h.
The catalyst was removed over kieselguhr and the solvent was
then removed under reduced pressure at 50 °C. The amine
so formed was dissolved in DMF (2 cm3, dry), to which [(3-
{[(carboxymethyl)amino]carbonyl}benzoyl)amino]acetic acid7
(33 mg, 0.12 mmol) was added followed by HBTU (270 mg,
0.710 mmol) and NMM (300 lL, dry). An additional amount of
DMF (2 cm3, dry) was added with stirring at room temperature
and the stirring was continued for 72 h. The reaction mixture
was diluted with ethyl acetate containing 5% methanol (50 cm3)
and extracted with brine. The organic layers were collected,
dried over (MgSO4) and the solvents were then removed under
reduced pressure. The product was purified by HPLC and the
fractions containing the desired material were freeze-dried. The
product was obtained as a white solid (25 mg, 16%) with no
N2,N5-Bis[5-({[5-({[3-(dimethylamino)propyl]amino}carbonyl)-1-
methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-isopentyl-1H-pyrrol-
3-yl]-1H-indole-2,5-dicarboxamide (3c)
The product was obtained as a pale yellow solid (36 mg, 30%)
1
with no distinct melting point. H NMR [DMSO-d6]: d 11.95
(1H, s); 10.47 (1H, s); 10.28 (1H, s); 10.02 (1H, s); 9.99 (1H, s);
9.39 (2H, br, 2 × TFA); 8.39 (1H, s); 8.22 (2H, t, unresolved,
2 × CONH); 7.91 (1H, d, J = 8.7 Hz); 7.61 (1H, d, J = 8.7 Hz);
7.49 (1H, s); 7.43 (2H, s); 7.23 (2H, s); 7.13 (2H, s); 7.01 (2H,
s); 4.43 (4H, m); 3.89 (6H, s); 3.31 (4H, m); 3.14 (4H, m); 2.86
(12H, d, J = 3.8 Hz); 1.91 (4H, m); 1.66–1.55 (6H, m); 0.98
(12H, d, J = 6.5 Hz). IR [KBr]: 1677, 1647, 1583, 1533, 1443,
1404, 1199, 1135 cm.−1 HRESMS: Found M + H = 974.5719,
calculated for C52H72N13O6 M + H = 974.5723.
1
distinct melting point. H NMR [DMSO-d6]: d 12.03 (2H, s);
N2,N5-Bis[5-({[4-({[3-(dimethylamino)propyl]amino}carbonyl)-5-
isopropyl-1,3-thiazol-2-yl]amino}carbonyl)-1-methyl-1H-pyrrol-
3-yl]-1H-indole-2,5-dicarboxamide (4)
10.08 (2H, s); 9.24 (2H, br, 2 × TFA); 8.93 (2H, t, J = 5.8 Hz);
8.05 (2H, d, J = 1.5 Hz); 7.94 (2H, t, J = 6.0 Hz); 7.61 (1H, t, J =
7.8 Hz); 7.39 (2H, d, J = 1.6 Hz); 7.25 (2H, d, J = 1.6 Hz); 4.21
(2H, quintet, J = 6.9 Hz); 4.06 (2H, d, J = 5.7 Hz); 3.87 (6H, s);
3.30 (4H, m); 3.07 (4H, m); 2.79 (6H, d, J = 4.5 Hz); 1.86 (4H,
quintet, J = 7.9 Hz); 1.28 (12H, d, J = 6.9 Hz). IR [KBr]: 1655,
1548, 1467, 1403, 1288, 1202, 1132 cm.−1 HRLCMS: Found:
[M + 2]/2 = 515.2313, calculated for C48H66N14O8S2 [M + 2]/2 =
515.2309.
The product was obtained as a pale yellow solid (32 mg, 23%)
1
with no distinct melting point. H NMR [DMSO-d6]: d 12.15
(1H, s), 12.09 (1H, s); 11.95 (1H, s); 10.52 (1H, s); 10.32 (1H,
s); 9.37 (2H, br, 2 × TFA, exch); 8.35 (1H, s); 7.99 (2H, m); 7.85
(1H, m); 7.54 (2H, m); 7.46 (2H, m); 3.93 (6H, s); 3.23 (4H, m);
3.07 (4H, m); 2.81 (6H, s); 2.80 (6H, s); 2.08 (1H, m); 1.85–1.92
(4H, m); 1.3 (12H, s, isopropylMe2); IR [KBr]: 3415, 2960, 2362,
1654, 1549, 1467, 1398, 1287, 1200, 1134 cm.−1 HRESMS:
found M + H = 954.4200, calculated for C46H60N13O6S2 M +
H = 954.4230.
The following compounds were prepared similarly:
N2,N7-Bis[5-({[4-({[3-(dimethylamino)propyl]amino}carbonyl)-5-
isopropyl-1,3-thiazol-2-yl]amino}carbonyl)-1-methyl-1H-pyrrol-
3-yl]-9,10-dihydro-2,7-phenanthrenedicarboxamide (7)
N2,N5-Bis[5-({[5-({[3-(dimethylamino)propyl]amino}carbonyl)-1-
methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-
yl]-1H-indole-2,5-dicarboxamide (5)
The product was obtained as a pale yellow solid with no
1
distinct melting point (46 mg, 19%). H NMR [DMSO-d6]:
d 12.11 (2H, s); 10.46 (2H, s); 9.26 (2H, br, 2 × TFA); 8.07–
7.91 (6H, m); 7.53 (2H, s); 7.46 (2H, s); 4.20 (2H, quintet,
J = 6.9 Hz); 3.92 (6H, s); 3.33 (4H, m); 3.07 (4H, m); 2.97 (2H,
s); 2.96 (2H, s); 2.80 (12H, d, J = 4.1 Hz); 1.87 (4H, quintet,
J = 7.7 Hz); 1.27 (12H, d, J = 6.9 Hz). IR [KBr]: 1660, 1548,
1468, 1284, 1199, 1132, 832, 800, 721 cm.−1 HRESMS: Found:
[M + 2]/2 = 509.2331, calculated for C52H66N12O6S2 [M + 2]/
2 = 509.2329.
The product was obtained as a pale yellow solid with no
distinct melting point (58 mg, 42%). 1H NMR [DMSO-d6]:
d 10.41 (1H, s); 11.91 (1H, s); 10.21 (1H, s); 9.96 (1H, s); 9.93
(1H, s); 9.26 (2H, br, 2 × TFA, exch); 8.33 (1H, s); 8.15 (2H, t,
unresolved); 7.82 (1H, s); 7.53 (1H, m); 7.43 (1H, s); 7.33 (2H,
m); 7.18 (2H, s); 7.12 (2H, s); 7.10 (2H, s); 6.97 (2H, s); 3.90
(3H, s); 3.88 (3H, s); 3.83 (6H, s); 3.24 (4H, m); 3.07 (4H, m);
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 1 9 – 3 1 2 7
3 1 2 5