3636 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Baraldi et al.
(Na2SO4) and evaporated in vacuo, and the residue was
purified by flash chromatography on silica gel using EtOAc
as eluent.
solid; 485 mg (62% yield); mp 220 °C. 1H NMR (DMSO): δ
2.63 (t, 2H, J ) 6.5 Hz), 3.27 (t, 4H, J ) 6.6 Hz), 3.49 (m, 2H),
3.58 (t, 4H, J ) 6.8 Hz), 3.80 (s, 9H), 4.45 (s, 2H), 6.93 (s, 1H),
6.96 (s, 1H), 7.04 (s, 1H), 7.14 (s, 1H), 7.20 (s, 1H), 7.24 (s,
1H), 7.46 (s, 1H), 8.27 (t, 1H), 8.82 (s, 2H), 9.10 (s, 2H), 9.95
(d, 2H), 10.36 (s, 1H), 11.42 (s, 1H). 13C NMR (DMSO): δ 32.39,
35.89, 36.13, 36.22, 36.31, 41.93, 49.79, 54.43, 54.66, 104.10,
104.72, 118.26, 118.53, 121.35, 122.09, 122.23, 122.38, 122.71,
122.89, 141.30, 150.44, 158.4, 161.51, 162.21, 164.13, 169.25.
FAB (EM high resolution) calculated for C31H39N12O6Cl2 [M -
Cl]+: 745.2493. Found: 745.2492. Anal. (C31H39N12O6Cl3): C,
H, Cl, N.
2-[5-Bis(2-ch lor oeth yl)a m in o-2,4-(1H,3H)p yr im id in ed i-
on e]a cetic a cid (22): brown solid; 75 mg (24% yield); mp
1
158 °C. H NMR (CD3OD): δ 3.32 (m, 4H), 3.56 (m 4H), 4.36
(s, 2H), 7.41 (s, 1H). 13C NMR (CD3OD): δ 43.13, 51.22, 56.97,
123.78, 144.11, 152.50, 164.66. FAB (EM high resolution)
calculated for C10H14N3O4Cl2 [M + H]+: 310.0361. Found:
310.0361. FAB (EM high resolution) calculated for C10H12N3O4-
Na2Cl2 [M - H + Na2]+: 354.0000. Found: 354.0002. Anal.
(C10H13N3O4Cl2): C, H, Cl, N.
3-[5-Bis(2-ch lor oet h yl)a m in o-2,4-(1H ,3H )p yr im id in e-
d ion e]p r op ion ic a cid (23): brown gum; 165 mg (51% yield);
mp 200 °C (lit.10 206-300 °C). 1H NMR (CD3OD): δ 2.67 (t,
2H, J ) 6.4 Hz), 3.31 (m, 4H), 3.55 (t, 4H, J ) 6.8 Hz), 3.96 (t,
2H, J ) 6.4 Hz), 7.52 (s, 1H). 13C NMR (CD3OD): δ 34.88,
43.17, 46.64, 56.89, 123.00, 144.20, 152.19, 164.54. FAB (EM
high resolution) calculated for C11H15N3O4NaCl2 [M + Na]+:
346.0337. Found: 346.0338. Anal. (C11H15N3O4Cl2): C, H, Cl,
N.
4-[5-Bis(2-ch lor oet h yl)a m in o-2,4-(1H ,3H )p yr im id in e-
d ion e]bu ta n oic a cid (24): brown solid; 170 mg (50% yield);
mp 129 °C (lit.10 130-130.5 °C). 1H NMR (CD3OD): δ 1.97
(m, 2H), 2.37 (t, 2H, J ) 7 Hz), 3.33 (t, 4H, J ) 6.5 Hz), 3.56
(t, 4H, J ) 6.6 Hz), 3.79 (t, 2H, J ) 6.9 Hz), 7.46 (s, 1H). 13C
NMR (CD3OD): δ 25.22, 31.64, 43.37, 49.05, 56.85, 123.53,
143.60, 152.40, 164.53, 176.49. FAB (EM high resolution)
calculated for C12H17N3O4NaCl2 [M + Na]+: 360.0494. Found:
360.0491. Anal. (C12H17N3O4Cl2): C, H, Cl, N.
3-[1-Meth yl-4-[1-m eth yl-4-[1-m eth yl-4-[N1-[5-bis(2-ch lo-
r oeth yl)a m in o-2,4-(1H,3H)p yr im id in ed ion e]p r op a n oyl-
a m in o]p yr r ole-2-ca r boxa m id o]p yr r ole-2-ca r boxa m id o]-
p yr r ole-2-ca r boxa m id o]p r op ion a m id in e h yd r och lor id e
(30): white solid; 630 mg (79% yield); mp 215 °C. 1H NMR
(DMSO): δ 2.63 (m, 4H), 3.19 (t, 4H, J ) 6.7 Hz), 3.48 (t, 4H,
J ) 6.7 Hz), 3.56 (t, 2H, J ) 6.6 Hz), 3.80 (s, 3H), 3.81 (s, 3H),
3.82 (s, 3H), 3.90 (t, 2H, J ) 6.4 Hz), 6.83 (d, 1H), 6.93 (d,
1H), 7.03 (d, 1H), 7.20 (q, 2H), 7.23 (d, 1H), 7.32 (s, 1H), 8.26
(t, 1H, J ) 5.4 Hz), 8.82 (s, 2H), 9.09 (s, 2H), 9.93 (s, 2H),
10.16 (s, 1H), 11.36 (s, 1H). 13C NMR (DMSO): δ 32.39, 34.07,
35.87, 36.04, 36.11, 36.17, 41.95, 44.87, 54.44, 54.67, 103.69,
104.71, 104.78, 118.24, 118.50, 120.52, 121.69, 122.11, 122.23,
122.37, 122.67, 122.75, 141.04, 150.01, 158.4, 161.49, 162.04,
166.85, 169.23. FAB (EM high resolution) calculated for
C
32H41N12O6Cl2 [M - Cl]+: 759.2649. Found: 759.2645. Anal.
(C32H41N12O6Cl3): C, H, Cl, N.
3-[1-Meth yl-4-[1-m eth yl-4-[1-m eth yl-4-[N1-[5-bis(2-ch lo-
r oet h yl)a m in o-2,4-(1H ,3H )p yr im id in ed ion e]b u t a n oyl-
a m in o]p yr r ole-2-ca r boxa m id o]p yr r ole-2-ca r boxa m id o]-
p yr r ole-2-ca r boxa m id o]p r op ion a m id in e h yd r och lor id e
(31): off-white solid; 560 mg (69% yield); mp 198 °C. 1H NMR
(DMSO): δ 1.85 (t, 2H, J ) 7.1 Hz), 2.27 (t, 2H, J ) 7.1 Hz),
2.66 (t, 2H, J ) 6.2 Hz), 3.25 (t, 4H, J ) 6.6 Hz), 3.49 (m, 2H,
J ) 6.1 Hz), 3.57 (t, 4H, J ) 6.6 Hz), 3.67 (t, 2H, J ) 7 Hz),
3.80 (s, 9H), 6.89 (s, 1H), 6.93 (s, 1H), 7.04 (s, 1H), 7.15 (s,
1H), 7.21 (s, 1H), 7.24 (s, 1H), 7.41 (s, 1H), 8.30 (t, 1H, J ) 5.3
Hz), 8.94 (s, 2H), 9.19 (s, 2H), 9.96 (d, 2H), 10.04 (s, 1H), 11.30
(s, 1H). 13C NMR (DMSO): δ 24.71, 32.14, 32.35, 35.82, 36.02,
42.57, 47.13, 54.60, 104.07, 104.84, 118.27, 118.47, 121.20,
121.63, 121.96, 122.11, 122.17, 122.38, 122.69, 140.27, 150.19,
158.47, 161.7, 162.05, 168.68, 169.36. FAB (EM high resolu-
tion) calculated for C33H43N12O6Cl2 [M - Cl]+: 773.2806.
Found: 773.2809. Anal. (C33H43N12O6Cl3): C, H, Cl, N.
5-[5-Bis(2-ch lor oet h yl)a m in o-2,4-(1H ,3H )p yr im id in e-
d ion e]p en ta n oic a cid (25): brown solid; 170 mg (49% yield);
mp 95 °C. H NMR (CDCl3): δ 1.72 (m, 4H), 2.42 (t, 2H, J )
6.1 Hz), 3.35 (t, 4H, J ) 6.1 Hz), 3.50 (t, 4H, J ) 6.2 Hz), 3.75
(t, 2H, J ) 6.3 Hz), 7.29 (s, 1H), 10.26 (s, 1H). 13C NMR
(CDCl3): δ 21.31, 28.20, 33.25, 42.77, 48.52, 55.60, 121.79,
143.13, 150.74, 162.92, 178.24. FAB (EM high resolution)
calculated for C13H19N3O4NaCl2 [M + Na]+: 374.0650. Found:
374.0652. Anal. (C13H19N3O4Cl2): C, H, Cl, N.
1
6-[5-Bis(2-ch lor oet h yl)a m in o-2,4-(1H ,3H )p yr im id in e-
d ion e]h exa n oic a cid (26): dark gum; 175 mg (48% yield);
1
mp 105 °C. H NMR (CD3OD): δ 1.39 (m, 2H), 1.68 (m, 4H),
2.33 (t, 2H), 3.34 (t, 4H), 3.56 (t, 4H, J ) 6.5 Hz), 3.74 (t, 2H,
J ) 7.1 Hz), 7.49 (s, 1H). 13C NMR (CD3OD): δ 25.58, 26.93,
29.62, 34.63, 43.38, 49.42, 56.81, 123.00, 143.78, 152.50,
164.49, 177.00. FAB (EM high resolution) calculated for
C
14H22N3O4Cl2 [M + H]+: 366.0987. Found: 366.0989. Anal.
3-[1-Meth yl-4-[1-m eth yl-4-[1-m eth yl-4-[N1 [5-bis(2-ch lo-
r oeth yl)a m in o-2,4 (1H,3H)p yr im id in ed ion e]p en ta n oyl-
am in o]pyr r ole-2-car boxam ido]pyr r ole-2-car boxam ido]py-
r r ole-2-car boxam ido]pr opion am idin e h ydr och lor ide (32):
white solid; 420 mg (51% yield); mp 186 °C. 1H NMR
(DMSO): δ 1.56 (m, 4H), 2.26 (m, 2H), 2.63 (t, 2H, J ) 6.5
Hz), 3.26 (t, 4H, J ) 6.7 Hz), 3.52 (m, 2H, J ) 6.5 Hz), 3.57 (t,
4H, J ) 6.7 Hz), 3.65 (t, 2H, J ) 6.3 Hz), 3.81 (m, 9H), 6.88 (s,
1H), 6.94 (s, 1H), 7.04 (s, 1H), 7.16 (s, 1H), 7.19 (s, 1H), 7,23
(s, 1H), 7.43 (s, 1H), 8.26 (t, 1H, J ) 5.7 Hz), 8.75 (s, 2H), 9.05
(s, 2H), 9.92 (m, 3H), 11.31 (s, 1H). 13C NMR (DMSO): δ 22.04,
28.00, 32.40, 34.96, 35.77, 35.99, 42.51, 47.12, 54.48, 103.88,
104.61, 118.02, 118.12, 118.38, 121.07, 121.93, 122.04, 122.14,
122.27, 122.58, 140.16, 150.08, 158.37, 161.39, 161.97, 169.06.
FAB (EM high resolution) calculated for C34H45N12O6Cl2 [M
- Cl]+: 787.2962. Found: 787.2964. Anal. (C34H45N12O6Cl3):
C, H, Cl, N.
(C14H21N3O4Cl2): C, H, Cl, N.
7-[5-Bis(2-ch lor oet h yl)a m in o-2,4-(1H ,3H )p yr im id in e-
d ion e]h ep ta n oic a cid (27): brown solid; 200 mg (52% yield);
mp 82 °C. 1H NMR (CD3OD): δ 1.38 (m, 4H), 1.61 (m, 2H),
1.68 (m, 2H), 2.29 (t, 2H, J ) 7.4 Hz), 3.33 (t, 4H, J ) 6.2 Hz),
3.55 (t, 4H, J ) 6.5 Hz), 3.73 (t, 2H, J ) 7.2 Hz), 7.48 (s, 1H).
13C NMR (CD3OD): δ 25.9, 27.1, 29.7, 34.8, 43.3, 49.3, 56.7,
123.26, 143.84, 152.31, 164.51, 177.71. FAB (EM high resolu-
tion) calculated for C15H23N3O4NaCl2 [M + Na]+: 402,0963.
Found: 402.0972. Anal. (C15H23N3O4Cl2): C, H, Cl, N.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
30-34. To a stirred solution of N-deformyldistamycin
A
dihydrochloride 28 (526 mg, 1 mmol) in anhydrous DMF (5
mL) was added at 0 °C Hunig’s base (192 µL, 1 mmol). After
5 min, 22-27 (1 mmol) and then EDCI (384 mg, 2 mmol) were
added. The resulting mixture was stirred overnight as it
warmed to room temperature, acidified with 20% HCl to pH
2, and then evaporated to dryness in vacum. The residue was
dissolved in a small volume of MeOH, and then ethyl ether
was added to precipitate the crude product as a brown solid.
This procedure was repeated five times. The crude product was
purified by coloumn chromatography (methylene chloride/
methanol, 8:2).
3-[1-Meth yl-4-[1-m eth yl-4-[1-m eth yl-4-[N1-[5-bis(2-ch lo-
r oet h yl)a m in o-2,4-(1H ,3H )p yr im id in ed ion e]h exa n oyl-
a m in o]p yr r ole-2-ca r boxa m id o]p yr r ole-2-ca r boxa m id o]-
p yr r ole-2-ca r boxa m id o]p r op ion a m id in e h yd r och lor id e
1
(33): off-white solid; 545 mg (65% yield); mp 180 °C. H NMR
(DMSO): δ 1.30 (m, 2H), 1.57 (m, 4H), 2.23 (t, 2H, J ) 7.1
Hz), 2.63 (t, 2H, J ) 6.7 Hz), 3.26 (t, 4H, J ) 6.5 Hz), 3.50 (m,
2H), 3.56 (t, 4H, J ) 6.4 Hz), 3.62 (m, 2H), 3.80 (s, 3H), 3.81
(s, 3H), 3.83 (s, 3H), 6.88 (s, 1H), 6.94 (s, 1H), 7.05 (s, 1H),
7.16 (s, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.43 (s, 1H), 8.26 (t, 1H,
3-[1-Meth yl-4-[1-m eth yl-4-[1-m eth yl-4-[N1-[5-bis(2-ch lo-
r oeth yl)am in o-2,4-(1H,3H)pyr im idin edion e]acetylam in o]-
p yr r ole-2-ca r boxa m id o]p yr r ole-2-ca r boxa m id o]p yr r ole-
2-car boxam ido]pr opion am idin e h ydr och lor ide (29): yellow