New Contrast Agents for Cardiac MRI
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2859
added, and the suspension was hydrogenated as described for
10b, dried, and recrystallized from ethanol/chloroform to give
0.45 g (38%) of the crude product 3 as white crystals. 1H NMR
in D2O (ppm): 1.54 (t, 6H, 2 CH3CH2COO), 2.42 (q, 4H, 2
CH3CH2COO), 3.28 (m, 4H, NCH2CH2N), 3.38 (m, 4H, 2
OCOCH2CH2N), 4.06 (2s, 4H, 2 NCH2CON), 4.18 (2s, 8H, 4
NCH2COO), 4.36 (t, 4H, 2 OCOCH2CH2N). IR (cm-1) (KBr):
3434 (vb), 2964 (vb), 2583 (vb), 1735, 1659, 1463, 1381, 1234,
1180, 1049, 973, 880, 842, 755, 640, 597. MS (m/z): 607 (MH+).
Anal. (C24H38N4O14‚0.5H2O) C, H, N.
N-(2-Bu t yr yloxyet h yl)-N′-(2-h yd r oxyet h yl)-N,N-b is-
[N′′,N′′-b is(b en zyloxyca r b on ylm et h yl)a cet a m id o]-1,2-
eth a n ed ia m in e (11). A 15.412-g portion (0.018 mol) of
compound 9 was dissolved in 330 mL of dry THF under
nitrogen atmosphere. Butyryl chloride (1.726 g, 0.0162 mol)
was added dropwise, and the reaction mixture was stirred at
room temperature overnight. 4-(Dimethylamino)pyridine (2.199
g, 0.018 mol) was added, the reaction mixture was stirred at
room temperature for 1 h and filtered, and solvent was
removed on a rotavapor to give the crude product as a mixture
of the starting material, the bis-butyryl, and the desired
monobutyryl analogues. Purification was accomplished using
silica gel column chromatography and elution with hexane:
EtOAc (3:7). The bis-burtyryl analogue was eluted first,
followed by a pure fraction of the desired monobutyryl
analogue 11 as a yellow oil. The column was subsequently
washed with CHCl3:MeOH:NH4OH (900:50:3) to elute the rest
of the product mixed with some of the starting material. This
last fraction was subjected to a second step of chromatography
using silica gel CHCl3:MeOH:NH4OH (900:50:3) which gave a
second, colored, pure fraction of the desired monobutyryl
analogue 11 as a light-orange oil. The total collected amount
N,N′-Bis(2-bu tyr yloxyeth yl)-N,N′-bis[N′′,N′′-bis(ben zyl-
oxycar bon ylm eth yl)acetam ido]-1,2-eth an ediam in e (10d).
A 2.1-g portion (0.0024 mol) of compound 9 was dissolved in
30 mL of dry THF under nitrogen atmosphere and treated with
butyryl chloride (0.523 mL) and 4-(dimethylamino)pyridine
(0.6 g, 0.0049 mol) as explained for 10b. Purification was
accomplished using silica gel column chromatography and
elution with hexane:EtOAc (1:1) yielding the bis-butyryl
1
analogue 10d (1.19 g, 50%) as a yellow oil. H NMR in CDCl3
(ppm): 0.91 (t, 6H, 2 CH3CH2CH2COO), 1.61 (q, 4H, 2 CH3CH2-
CH2COO), 2.23 (t, 4H, 2 CH3CH2CH2COO), 2.62 (m, 4H,
NCH2CH2N), 2.73 (t, 4H, 2 OCOCH2CH2N), 3.41 (s, 4H, 2
NCH2CON), 4.07 (t, 4H, 2 OCOCH2CH2N), 4.04, 4.43 (2s, 4H,
2 NCH2COO), 5.12 (2s, 8H, 4 CH2 benzylic), 7.33 (s, 20H,
aromatic). IR (cm-1) (on NaCl plates): 2963, 2959, 2877, 1741,
1661, 1457, 1383, 1301, 1248, 1179, 991, 742, 699. C54H66N4O14,
MS (m/z): 996 (MH+).
1
of compound 11 was 5.548 g (37%). H NMR in CDCl3 (ppm):
0.91 (t, 3H, CH3CH2CH2COO), 1.59 (q, 2H, CH3CH2CH2COO),
2.24 (t, 2H, CH3CH2CH2COO), 2.62 (m, 4H, NCH2CH2N), 2.66
(t, 2H, HO CH2CH2N), 2.76 (t, 2H, OCOCH2CH2N), 3.39, 3.45
(2s, 4H, 2 NCH2CON), 3.48 (t, 2H, HOCH2CH2N), 4.07 (t, 2H,
OCOCH2CH2N), 4.16, 4.38 (2d, 8H, 4 NCH2COO), 5.11, 5.16
N,N′-Bis(2-b u t yr yloxyet h yl)-N,N′-b is[N′′,N′′-b is(ca r -
boxym eth yl)a ceta m id o]-1,2-eth a n ed ia m in e (BBE-DTTA,
4). A 0.7-g portion (0.0007 mol) of compound 10d was dissolved
in 15 mL of ethanol. Pd/C (0.19 g, 15% w/w) was added, and
the suspension was hydrogenated as described for 10b, dried,
and recrystallized from ethanol/chloroform to give 0.24 g (53%)
of the crude product 4 as white crystals. 1H NMR in D2O
(ppm): 0.88 (t, 6H, 2 CH3CH2CH2COO), 1.62 (q, 4H, 2 CH3CH2-
CH2COO), 2.41 (t, 4H, 2 CH3CH2CH2COO), 3.34 (m, 4H,
NCH2CH2N), 3.42 (m, 4H, 2 OCOCH2CH2N), 4.13, 4.15 (2s,
4H, 2 NCH2CON), 4.24, 4.28 (2s, 8H, 4 NCH2COO), 4.36 (t,
4H, 2 OCOCH2CH2N). IR (cm-1) (KBr): 3434 (vb), 2964 (vb),
2583 (vb), 1735, 1659, 1463, 1381, 1234, 1180, 1049, 973, 880,
(2d, 8H, 4 CH2 benzylic), 7.33 (s, 20H, aromatic). IR (cm-1
)
(on NaCl plates): 3462, 2957, 1742, 1660, 1458, 1386, 1355,
1301, 1182, 1080, 986, 825, 741, 698. C50H60N4O13, MS (m/z):
925 (MH+). Note: The following additional peak splittings
[3.39, 3.45 (2s, 4H, 2 NCH2CON), 4.16-4.18 (d, 4H, 2 NCH2-
COO), 4.35-4.38 (d, 4H, 2 NCH2COO), 5.110, 5.115 (d, 2H,
CH2 benzylic), 5.16 (d, 2H, CH2 benzylic)] do not exist in the
dihydroxy intermediate (9). These remarkable splittings are
due, most likely, to a slowed rotation around the N-R bond
induced by the acyl substitutions. This slow rotation causes
the two methylene protons in all methylene groups to become
magnetically unequivalent.
842, 755, 640, 597. MS (m/z): 635 (MH+). Anal. (C26H42N4O14
1.9H2O) C, H, N.
‚
N-(2-Bu t yr yloxyet h yl)-N′-(2-et h yloxyet h yl)-N,N-b is-
[N′′,N′′-b is(b en zyloxyca r b on ylm et h yl)a cet a m id o]-1,2-
eth a n ed ia m in e (12). A 5.548-g portion (0.006 mol) of com-
pound 11 was dissolved in 50 mL of dry THF under nitrogen
atmosphere. Acetyl chloride (0.8 g, 0.0101 mol) and 4-(dim-
ethylamino)pyridine (0.879 g, 0.00719 mol) were added drop-
wise, the reaction mixture was stirred at room temperature
for 5 h and filtered, and the solvent was removed on a
rotavapor to give the crude product 12 as a dark-yellow oil.
Purification was accomplished using silica gel column chro-
matography and elution with CHCl3:MeOH:NH4OH (900:50:
3) to give pure 12 (4.92 g, 85%) as a bright-yellow oil. 1H NMR
in CDCl3 (ppm): 0.91 (t, 3H, 2 CH3CH2CH2COO), 1.61 (q, 2H,
CH3CH2CH2COO), 1.98 (s, 3H, CH3COO), 2.23 (t, 2H, CH3-
CH2CH2COO), 2.62 (m, 4H, NCH2CH2N), 2.73 (t, 4H, 2
OCOCH2CH2N), 3.41 (s, 4H, 2 NCH2CON), 4.07 (t, 4H, 2
OCOCH2CH2N), 4.04, 4.43 (2s, 8H, 4 NCH2COO), 5.12, 5.15
(2s, 8H, 4 CH2 benzylic), 7.33 (s, 20H, aromatic). IR (cm-1) (on
NaCl plates): 2959, 1741, 1661, 1457, 1383, 1240, 1180, 988,
737, 699. C52H62N4O14, MS (m/z): 968 (MH+).
N,N′-Bis(2-h exa n oyloxyeth yl)-N,N′-bis[N′′,N′′-bis(ben -
zyloxyca r b on ylm et h yl)a cet a m id o]-1,2-et h a n ed ia m in e
(10e). A 3.04-g portion (0.00355 mol) of compound 9 was
dissolved in 15 mL of dry THF under nitrogen atmosphere and
treated with hexanoyl chloride (1.052 g, 0.007117 mol) and
4-(dimethylamino)pyridine (2.199 g, 0.018 mol) as explained
for 10b. Purification was accomplished using silica gel column
chromatography and elution with hexane:EtOAc (1:1) yielding
1
the bis-hexanoyl analogue 10e (1.6 g, 42%) as a yellow oil. H
NMR in CDCl3 (ppm): 0.91 (t, 6H, 2 CH3CH2CH2CH2CH2-
COO), 1.61 (q, 12H, 2 CH3CH2CH2CH2CH2COO), 2.23 (t, 4H,
2 CH3CH2CH2CH2CH2COO), 2.62 (m, 4H, NCH2CH2N), 2.73
(t, 4H, 2 OCOCH2CH2N), 3.41 (s, 4H, 2 NCH2CON), 4.07 (t,
4H, 2 OCOCH2CH2N), 4.04, 4.43 (2s, 8H, 4 NCH2COO), 5.12,
5.15 (2s, 8H, 4 CH2 benzylic), 7.33 (s, 20H, aromatic). IR (cm-1
)
(on NaCl plates): 2959, 2864, 1741, 1661, 1457, 1383, 1240,
1180, 986, 742, 698. C58H74N4O14, MS (m/z): 1052 (MH+).
N,N′-Bis(2-h exa n oyloxyeth yl)-N,N′-bis[N′′,N′′-bis(ca r -
boxym eth yl)a ceta m id o]-1,2-eth a n ed ia m in e (BHE-DTTA,
5). A 1.6-g portion (0.00152 mol) of compound 10b was
dissolved in 15 mL of ethanol. Pd/C (0.19 g, 15% w/w) was
added, and the suspension was hydrogenated as described for
10b, dried, and recrystallized from ethanol/chloroform to give
0.76 g (72%) of the crude product 5 as white crystals. 1H NMR
in D2O (ppm): 0.93 (t, 6H, 2 CH3CH2CH2CH2CH2COO), 1.31
(q, 12H, 2 CH3CH2CH2CH2CH2COO), 2.41 (t, 4H, 2 CH3CH2-
CH2CH2CH2COO), 3.34 (m, 4H, NCH2CH2N), 3.42 (m, 4H, 2
OCOCH2CH2N), 4.13, 4.15 (2s, 4H, 2 NCH2CON), 4.35 (2s, 8H,
4 NCH2COO), 4.36 (t, 4H, 2 OCOCH2CH2N). IR (cm-1) (KBr):
3434 (vb), 2964 (vb), 2583 (vb), 1735, 1659, 1463, 1381, 1234,
1180, 1049, 973, 880, 842, 755, 640, 597. MS (m/z): 690 (MH+).
Anal. (C30H50N4O14‚1H2O) C, H, N.
N-(2-Bu t yr yloxyet h yl)-N′-(2-et h yloxyet h yl)-N,N′-b is-
[N ′′,N ′′-b is(ca r b oxym e t h yl)a ce t a m id o]-1,2-e t h a n e d i-
a m in e (ABE-DTTA, 6). A 1.85-g portion (0.00191 mol) of
compound 12 was dissolved in 20 mL of methanol. Pd/C (0.277
g, 15% w/w) was added, and the suspension was hydrogenated
as described for 10b, dried, and recrystallized from ethanol/
chloroform to yield 0.87 g (75%) of pure product as white
crystals. 1H NMR in D2O (ppm): 0.93 (t, 3H, CH3CH2CH2-
COO), 1.62 (q, 2H, CH3CH2CH2COO), 2.14 (s, 3H, CH3COO),
2.41 (t, 2H, CH3CH2CH2COO), 3.34 (m, 4H, NCH2CH2N), 3.42
(m, 4H, 2 OCOCH2CH2N), 4.13, 4.15 (2s, 4H, 2 NCH2CON),
4.24, 4.28 (2s, 8H, 4 NCH2COO), 4.36 (t, 4H, 2 OCOCH2CH2N).
IR (cm-1) (KBr): 3434 (vb), 2964 (vb), 2583 (vb), 1735, 1659,