V. Pittalà et al. / Bioorg. Med. Chem. 19 (2011) 5260–5276
5273
7.70 (br t, 1H, NHCONHCH2 which exchanges with D2O), 7.52–6.94
(m, 13H, aromatic), 6.51 (d, 4J = 2.4 Hz, 1H, pyrrole), 5.11 (s, 2H,
CH2O), 4.22 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.34–3.25 (m, 2H, NHCH2),
3.10–2.97 (m, 4H, NCH2), 2.65–2.48 (m, 4H + 2H, NCH2 + CON-
HCH2CH2N), 1.28 (t, J = 7.0 Hz, 3H, OCH2CH3). Anal. (C33H36ClN5O4)
C, H, N.
in vacuo. The obtained crude material was purified by column
chromatography (Silica Gel 60, 230–400 mesh, Merck) using cyclo-
hexane/EtOAc (7:3) as eluant, to afford the title compound (14a) as
pure product (0.781 g, 61%): mp 124–126 °C; IR (KBr, selected
lines) cmꢁ1 3140, 1600, 1443, 1348, 1264, 1112, 760, 607; 1H
NMR (DMSO-d6) d 11.36 (br s, 1H, NH which exchanges with
D2O), 9.31 (br s, 1H, NHCONHCH2 which exchanges with D2O),
8.02 (t, J = 5.8 Hz, 1H, NHCONHCH2 which exchanges with D2O),
7.74–7.63 (m, 6H, aromatic), 7.55–7.31 (m, 3H, aromatic), 6.73
(d, 4J = 3.0 Hz, 1H, pyrrole), 4.25 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.72
(t, J = 6.0 Hz, 2H, CH2Cl), 3.54–3.43 (m, 2H, NHCH2), 1.30 (t,
J = 7.0 Hz, 3H, OCH2CH3). Anal. (C22H22ClN3O3) C, H, N.
6.1.43. 2-[[[[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-
amino]carbonyl]amino]-5-[4-(2-phenoxyethoxy)phenyl]-1H-
pyrrole-3-carboxylic acid ethyl ester (15g)
Starting from derivative 14d and 1-(2-methoxyphenyl)pipera-
zine, compound 15g was obtained as crude material. The mixture
was purified by column chromatography (Silica Gel 60, 230–400
mesh, Merck) using EtOAc (100%) as eluant to afford the pure title
compound (65%): mp 240–242 °C; IR (KBr, selected lines) cmꢁ1
2935, 2810, 1639, 1598, 1497, 1451, 1239, 1090, 753, 691; 1H
NMR (DMSO-d6) d 11.27 (br s, 1H, NH which exchanges with D2O),
9.23 (br s, 1H, NHCONHCH2 which exchanges with D2O), 7.70 (br t,
1H, NHCONHCH2 which exchanges with D2O), 7.55–7.24 (m, 4H,
aromatic), 7.09–6.82 (m, 9H, aromatic), 6.51 (s, 1H, pyrrole), 4.31
(s, 2H + 2H, OCH2CH2O), 4.26 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.80 (s,
3H, CH3), 3.39–3.22 (m, 2H, NHCH2), 3.11–2.92 (m, 4H, NCH2),
2.62–2.48 (m, 4H + 2H, NCH2 + CONHCH2CH2N), 1.31 (t, J = 7.0 Hz,
3H, OCH2CH3). Anal. (C35H41N5O6) C, H, N.
Using this procedure the subsequent compounds were
obtained.
6.1.47. 2-[[[(2-Chloroethyl)amino]carbonyl]amino]-5-(4-
phenoxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (14b)
Starting from derivative 13b, the title compound (14b) was ob-
tained as a pure product (0.985 g, 74%): mp 99–101 °C; IR (KBr, se-
lected lines) cmꢁ1 3189, 3270, 1643, 1580, 1485, 1370, 1244, 1099,
839, 693; 1H NMR (DMSO-d6) d 11.28 (br s, 1H, NH which ex-
changes with D2O), 9.26 (br s, 1H, NHCONHCH2 which exchanges
with D2O), 7.99 (t, J = 5.8 Hz, 1H, NHCONHCH2 which exchanges
with D2O), 7.69–7.59 (m, 2H, aromatic), 7.49–7.32 (m, 2H, aro-
matic), 7.21–6.91 (m, 5H, aromatic), 6.60 (d, 4J = 3.0 Hz, 1H, pyr-
role), 4.23 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.70 (t, J = 6.0 Hz, 2H,
CH2Cl), 3.58–3.34 (m, 2H, NHCH2), 1.29 (t, J = 7.0 Hz, 3H, OCH2CH3).
Anal. (C22H22ClN3O4) C, H, N.
6.1.44. 2-[[[[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl]-
amino]carbonyl]amino]-5-[4-(2-phenoxyethoxy)phenyl]-1H-
pyrrole-3-carboxylic acid ethyl ester (15h)
Starting from derivative 14d and 1-(2-chlorophenyl)piperazine
hydrochloride, compound 15h was obtained as crude material.
The mixture was purified by column chromatography (Silica Gel,
60 230–400 mesh, Merck) using EtOAc (100%) as eluant to afford
the pure title compound (63%): mp 245–247 °C; IR (KBr, selected
lines) cmꢁ1 2978, 2957, 1640, 1599, 1484, 1449, 1240, 1081, 757,
691; 1H NMR (DMSO-d6) d 11.26 (br s, 1H, NH which exchanges
with D2O), 9.23 (br s, 1H, NHCONHCH2 which exchanges with
D2O), 7.70 (br t, 1H, NHCONHCH2 which exchanges with D2O),
7.54–6.89 (m, 13H, aromatic), 6.51 (s, 1H, pyrrole), 4.31 (s,
2H + 2H, OCH2CH2O), 4.22 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.36–3.26
(m, 2H, NHCH2), 3.08–2.89 (m, 4H, NCH2), 2.64–2.51 (m, 4H + 2H,
NCH2 + CONHCH2CH2N), 1.28 (t, J = 7.0 Hz, 3H, OCH2CH3). Anal.
(C34H38ClN5O5) C, H, N.
6.1.48. 2-[[[(2-Chloroethyl)amino]carbonyl]amino]-5-[4-
(phenylmethoxy)phenyl]-1H-pyrrole-3-carboxylic acid ethyl
ester (14c)
Starting from derivative 13c, the title compound (14c) was ob-
tained as a pure product (1.180 g, 86%): mp 152–154 °C; IR (KBr,
selected lines) cmꢁ1 3027, 2362, 1639, 1558, 1265, 1096, 776; 1H
NMR (DMSO-d6) d 11.21 (br s, 1H, NH which exchanges with
D2O), 9.25 (br s, 1H, NHCONHCH2 which exchanges with D2O),
7.97 (t, J = 5.8 Hz, 1H, NHCONHCH2 which exchanges with D2O),
7.69–7.59 (m, 2H, aromatic), 7.53–7.29 (m, 2H, aromatic), 7.05–
6.95 (m, 5H, aromatic), 6.52 (d, 4J = 2.8 Hz, 1H, pyrrole), 5.11 (s,
2H, CH2O), 4.22 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.70 (t, J = 6.0 Hz,
2H, CH2Cl), 3.54–3.43 (m, 2H, NHCH2), 1.28 (t, J = 7.0 Hz, 3H,
OCH2CH3). Anal. (C23H24ClN3O4) C, H, N.
6.1.45. 2-[[[[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl]-
amino]carbonyl]amino]-5-phenyl-1-(phenylmethyl)-1H-
pyrrole-3-carboxylic acid ethyl ester (15i)
6.1.49. 2-[[[(2-Chloroethyl)amino]carbonyl]amino]-5-[4-(2-
phenoxyethoxy)phenyl]-1H-pyrrole-3-carboxylic acid ethyl
ester (14d)
Starting from derivative 14f and 1-(2-chlorophenyl)piperazine
hydrochloride, compound 15i was obtained as crude material.
The mixture was purified by column chromatography (Silica Gel
60, 230–400 mesh, Merck) using EtOAc (100%) as eluant to afford
the pure title compound (79%): mp 162–164 °C; IR (KBr, selected
lines) cmꢁ1 3858, 3377, 2817, 1692, 1631, 1519, 1480, 1281,
1236, 933, 787; 1H NMR (DMSO-d6) d 11.91 (br s, 1H, NH which ex-
changes with D2O), 7.70–7.59 (m, 2H, aromatic), 7.40–6.80 (m,
12H + 1H, aromatic + pyrrole), 5.80 (br t, 1H, NCONH), 4.79 (s,
2H, CH2Ar), 4.07 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.22–3.10 (m, 2H,
NHCH2), 2.85–2.69 (m, 4H, NCH2), 2.50–2.35 (m, 4H + 2H,
NCH2 + CONHCH2CH2N), 1.20 (t, J = 7.0 Hz, 3H, OCH2CH3). Anal.
(C33H36ClN5O3) C, H, N.
Starting from derivative 13d, the title compound (14d) was ob-
tained as a pure product (0.873 g, 60%): mp 140–142 °C; IR (KBr,
selected lines) cmꢁ1 2935, 1632, 1556, 1495, 1370, 1235, 1172,
1065, 940, 777; 1H NMR (DMSO-d6) d 11.20 (br s, 1H, NH which ex-
changes with D2O), 9.24 (br s, 1H, NHCONHCH2 which exchanges
with D2O), 7.97 (t, J = 5.8 Hz, 1H, NHCONHCH2 which exchanges
with D2O), 7.55–7.21 (m, 4H, aromatic), 7.03–6.88 (m, 5H, aro-
matic), 6.52 (d, 4J = 3.0 Hz, 1H, pyrrole), 4.31 (s, 2H + 2H, OCH2-
CH2O), 4.23 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.70 (t, J = 6.0 Hz, 2H,
CH2Cl), 3.54–3.42 (m, 2H, NHCH2), 1.29 (t, J = 7.0 Hz, 3H, OCH2CH3).
Anal. (C24H26ClN3O5) C, H, N.
6.1.50. 2-[[[(2-Chloroethyl)amino]carbonyl]amino]-4,5-
diphenyl-1H-pyrrole-3-carboxylic acid ethyl ester (14e)
Starting from derivative 13e,28 the title compound was ob-
tained as a pure product (0.794 g, 62%): mp 134–136 °C; IR (KBr,
selected lines) cmꢁ1 2984, 1611, 1445, 1290, 1230, 1138, 1096,
762, 699; 1H NMR (DMSO-d6) d 11.28 (br s, 1H, NH which ex-
changes with D2O), 9.42 (br s, 1H, NHCONHCH2 which exchanges
6.1.46. 5-[4-(1,1’-Biphenyl)]-2-[[[(2-chloroethyl)amino]-
carbonyl]amino]-1H-pyrrole-3-carboxylic acid ethyl ester (14a)
A suspension of 2-amino-5-[4-(1,1’-biphenyl)]-1H-pyrrole-3-
carboxylic acid ethyl ester (13a) (3.10 mmol, 0.950 g) and 2-chlo-
roethyl isocyanate (4.65 mmol, 0.397 mL) in 7 mL of toluene was
stirred for 6 h at reflux. The reaction mixture was then evaporated