N. Kapuriya et al. / Bioorg. Med. Chem. 19 (2011) 471–485
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4 ꢀ CH2), 6.71 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.29 (2H, d, J = 8.8 Hz,
2 ꢀ ArH), 7.33–7.40 (2H, m, 2 ꢀ ArH), 7.59 (1H, d, J = 7.2 Hz, ArH),
7.91 (1H, s, ArH), 8.30 (1H, t, J = 5.6 Hz, exchangeable, CONH),
8.34 and 8.66 (each 1H, br s, exchangeable, 2 ꢀ NH). Anal. Calcd
for C24H31Cl2N5O3: C, H, N.
3.67–3.71 (8H, m, 4 ꢀ CH2), 6.71 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.29
(2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.49 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.75
(2H, d, J = 8.8 Hz, 2 ꢀ ArH), 8.30–8.31 (1H, m, exchangeable,
CONH), 8.35 and 8.66 (each 1H, br s, exchangeable, 2 ꢀ NH). Anal.
Calcd for C25H33Cl2N5O2: C, H, N.
5.2.10. 1-[4-(Bis(2-chloroethyl)amino)phenyl]-3-[3-(4-(piperi-
din-1-yl)piperidine-1-carbonyl] phenyl)urea hydrochloride
(9af0)
5.2.15. 1-[4-((2-Morpholinoethyl)carbamoyl)phenyl]-3-[4-(bis-
(2-chloroethyl)amino)phenyl]- urea hydrochloride (9be0)
Compound 9be0 was prepared from 7b (0.594 g, 1.5 mmol), DCC
(0.464 g, 2.25 mmol), HOBT (0.304 g, 2.25 mmol), TEA (0.3 mL) and
8e0 (0.195 g, 2.25 mmol). Yield, 538 mg (61%); mp 234–235 °C; 1H
NMR (DMSO-d6) d 2.41–2.47 (6H, m, CH), 3.35–3.39 (2H, m, CH),
3.56–3.57 (4H, m, CH), 3.70–3.71 (8H, m, 4 ꢀ CH2), 6.71 (2H, d,
J = 8.8 Hz, 2 ꢀ ArH), 7.28 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.49 (2H, d,
J = 8.8 Hz, 2 ꢀ ArH), 7.75 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 8.20–8.23
(1H, m, exchangeable, CONH), 8.42 and 8.79 (each 1H, br s,
exchangeable, 2 ꢀ NH). Anal. Calcd for C24H31Cl2N5O3: C, H, N.
Compound 6af0 was prepared from 7a (0.792 g, 2 mmol), DCC
(0.618 g, 3 mmol), HOBT (0.505 g, 3 mmol), TEA (0.4 mL) and 4-
piperidino-piperidine (8f0, 0.504 g, 3 mmol). Yield, 700 mg (60%);
mp 118–119 °C; 1H NMR (DMSO-d6) d 1.37–1.48 (8H, m, CH),
1.68–1.79 (2H, m, CH), 2.47–2.50 (3H, m, CH), 2.73 (1H, br s, CH),
2.98 (1H, br s, CH), 3.37 (4H, br s, CH), 3.66–3.72 (8H, m,
4 ꢀ CH2), 6.71 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 6.90–6.92 (1H, d,
J = 7.2 Hz, ArH) 7.27 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.29–7.32 (1H, m,
ArH), 7.41 (1H, d, J = 8.0 Hz, ArH), 7.51 (1H, s, ArH), 8.42 and 8.71
(each 1H, br s, exchangeable, 2 ꢀ NH). Anal. Calcd for
5.2.16. 1-[4-(Bis(2-chloroethyl)amino)phenyl]-3-[4-(4-(piperi-
din-1-yl)piperidine-1-carbonyl]phenyl)urea hydrochloride
(9bf0)
C28H37Cl2N5O2: C, H, N.
5.2.11. 1-[4-((2-(Dimethylamino)ethyl)carbamoyl)phenyl]-3-[4-
(bis(2-chloroethyl)amino)-phenyl]urea hydrochloride (9ba0)
Compound 9ba0 was prepared from 7b (0.396 g, 1 mmol), DCC
(0.309 g, 1.5 mmol), HOBT (0.202 g, 1.5 mmol), TEA (0.2 mL) and
8a0, (0.132 g, 1.5 mmol). Yield, 340 mg (72%); mp 189–190 °C; 1H
NMR (DMSO-d6) d 2.17 (6H, s, 2 ꢀ NMe), 2.38 (2H, br s, CH2),
3.28 (2H, br s, CH2), 3.69 (8H, br s, 4 ꢀ CH2), 6.71 (2H, d,
J = 8.8 Hz, 2 ꢀ ArH), 7.29 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.49 (2H, d,
J = 8.8 Hz, 2 ꢀ ArH), 7.76 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 8.18, 8.47
and 8.83 (each 1H, br s, exchangeable, 3 ꢀ NH). Anal. Calcd for
Compound 9bf0 was prepared from 7b (0.594 g, 1.5 mmol), DCC
(0.464 g, 2.25 mmol), HOBT (0.304 g, 2.25 mmol), TEA (0.3 mL) and
8f0 (0.378 g, 2.25 mmol). Yield, 638 mg (73%); mp 222–224 °C; 1H
NMR (DMSO-d6) d 1.38–1.50 (9H, m, CH), 1.75 (2H, br s, CH),
2.51 (2H, br s, CH), 2.84 (2H, br s, CH), 3.32–3.40 (4H, m, CH),
3.68–3.72 (8H, m, 4 ꢀ CH2), 6.71 (2H, d, J = 8.8 Hz, 2 ꢀ ArH),
7.27–7.31 (4H, m, 4 ꢀ ArH), 7.48 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 8.46
and 8.81 (each 1H, br s, exchangeable, 2 ꢀ NH). Anal. Calcd for
C
28H37Cl2N5O2ꢂ0.8H2O: C, H, N.
C22H29Cl2N5O2: C, H, N.
5.3. Alternative method for preparing 9aa0, 9ad0, and 9bd0
hydrochloride
5.2.12. 1-[4-((3-(Dimethylamino)propyl)carbamoyl)phenyl]-3-
[4-(bis(2-chloroethyl)amino)-phenyl]urea (9bb0)
5.3.1. N-(2-(Dimethylamino)ethyl)-3-nitrobenzamide (12aa0)
A solution of N,N-dimethylethylene diamine (8a0, 13.2 mL) in
dry THF was added to a solution of 3-nitrobenzoyl chloride (11a,
18.5 g, 100 mmol) in dry THF at 0 °C. After being stirred at room
temperature for 3 h, the solvent was evaporated to dryness. The
oily residue was dissolved in minimum amount of water and then
evaporated to dryness. The solid separated was recrystallized from
water and washed with hexane to give 12aa0, 21 g, (89%); mp 89–
90 °C; MS (ESI) m/z: 238 [M+H]+. 1H NMR (DMSO-d6) d 2.19 (6H, s,
2 ꢀ NMe), 2.43 (2H, t, J = 6.8 Hz, CH2), 3.40 (2H, q, J = 12.6 and
6.4 Hz, CH2), 7.78 (1H, t, J = 7.9 Hz, ArH), 8.29 (1H, d, J = 7.8 Hz,
ArH), 8.37–8.39 (1H, m, ArH), 8.68 (1H, s, ArH), 8.79–8.82 (1H, m,
exchangeable, NH).
Compound 9bb0 was prepared from 7b (0.594 g, 1.5 mmol), DCC
(0.464 g, 2.25 mmol), HOBT (0.304 g, 2.25 mmol), TEA (0.3 mL) and
8b0 (0.229 g, 2.25 mmol). Yield, 534 mg (69%); mp 203–205 °C; 1H
NMR (DMSO-d6) d 1.62–1.67 (2H, m, CH2), 2.13 (6H, s, 2 ꢀ NMe),
2.25 (2H, t, J = 6.8 Hz, CH2), 3.24 (2H, q, J = 6.8 Hz, CH2), 3.69–
3.72 (8H, m, 4 ꢀ CH2), 6.71 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.29 (2H,
d, J = 8.8 Hz, 2 ꢀ ArH), 7.49 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.75 (2H,
d, J = 8.8 Hz, 2 ꢀ ArH), 8.39 (1H, t, J = 5.2 Hz, exchangeable, CONH),
8.49 and 8.86 (each 1H, br s, exchangeable, 2 ꢀ NH). Anal. Calcd for
C23H31Cl2N5O2ꢂ2H2O: C, H, N.
5.2.13. 1-[4-((2-(Pyrrolidin-1-yl)ethyl)carbamoyl)phenyl]-3-[4-
(bis(2-chloroethyl)amino) phenyl]urea hydrochloride (9bc0)
Compound 9bc0 was prepared from 7b (0.594 g, 1.5 mmol), DCC
(0.464 g, 2.25 mmol), HOBT (0.304 g, 2.25 mmol), TEA (0.3 mL) and
8c0 (0.256 g, 2.25 mmol). Yield, 419 mg (53%); mp 183–185 °C; 1H
NMR (DMSO-d6) d 1.05–2.00 (4H, m, CH), 3.02–3.04 (2H, m, CH),
3.30–3.33 (2H, m, CH), 3.42–3.45 (4H, m, CH), 3.70 (8H, s,
4 ꢀ CH2), 6.72 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.29 (2H, d, J = 8.8 Hz,
2 ꢀ ArH), 7.52 (2H, d, J = 8.8 Hz, 2 ꢀ ArH), 7.85 (2H, d, J = 8.8 Hz,
2 ꢀ ArH), 8.67–8.69 (1H, m, exchangeable, CONH), 9.01 and 9.48
(each 1H, br s, exchangeable, 2 ꢀ NH). Anal. Calcd for
By following the same procedure as described for 12aa0, the fol-
lowing compounds were synthesized.
5.3.2. 3-Nitro-N-(2-(piperidin-1-yl)ethyl)benzamide (12ad0)
Compound 12ad0 was synthesized from 1-(2-aminoethyl)piper-
idine (8d0, 3.31 g, 22.0 mmol) and 3-nitrobenzoyl chloride (11ad0,
4.0 g, 21.5 mmol). Yield, 5.5 g, (92%); mp 203–204 °C; MS (ESI) m/
z: 278 [M+H]+. 1H NMR (DMSO-d6) d 1.67–1.69 (6H, m, 3 ꢀ CH2),
2.91–2.92 (2H, m, CH2), 3.22–3.32 (2H, m, CH2), 3.50–3.70 (2H,
m, CH2), 3.72–3.74 (2H, m, CH2), 7.76–7.80 (1H, m, ArH), 8.37–
8.43 (2H, m, 2 ꢀ ArH), 8.72–8.73 (1H, m, ArH), 9.38 (1H, t,
J = 5.4 Hz, exchangeable, NH).
C24H31Cl2N5O2ꢂ2H2O: C, H, N.
5.2.14. 1-[4-((2-(Piperidin-1-yl)ethyl)carbamoyl)phenyl]-3-(4-
(bis(2-chloroethyl)amino)-phenyl)urea hydrochloride (9bd0)
Compound 9bd0 was prepared from 7b (0.594 g, 1.5 mmol), DCC
(0.464 g, 2.25 mmol), HOBT (0.304 g, 2.25 mmol), TEA (0.3 mL) and
8d0 (0.288 g, 2.25 mmol). Yield, 400 mg (49%); mp 198–200 °C; 1H
NMR (DMSO-d6) d 1.37–1.39 (1H, m, CH), 1.67–1.79 (5H, m, CH),
2.98 (2H, s, CH), 3.43–3.50 (4H, m, CH), 3.60–3.63 (2H, m, CH2),
5.3.3. 4-Nitro-N-(2-(piperidin-1-yl)ethyl)benzamide (12bd0)
Compound 12bd0 was synthesized from 2-(piperidin-1-yl)eth-
anamine (8d0, 4.23 g, 33 mmol) and 3-nitrobenzoyl chloride (11b,
5.56 g, 30 mmol). Yield, 7.2 g, (86%); mp 165–167 °C (lit.27 97–
99 °C). MS (ESI) m/z: 278 [M+H]+. 1H NMR (DMSO-d6) d 1.54–
1.57 (2H, m, CH), 1.81–1.82 (4H, m, CH), 3.09–3.22 (4H, m, CH),