Tetraamine Backbone in Macrocyclic Structure
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15 3293
chloroform (3 × 20 mL). Removal of the solvent gave a residue
that was purified by chromatography. Eluting with methylene
chloride/methanol/aqueous 30% ammonia (9:1:0.1) afforded
31: 60% yield; 1H NMR (CDCl3) δ 1.09-1.66 (m, 28 + 2
exchangeable with D2O), 2.32 (s, 6), 2.41-2.48 (m, 8), 2.64 (t,
4), 3.82 (s, 4), 7.33 (s, 4).
1.55 (m, 24), 1.75 (br s, 2, exchangeable with D2O), 2.17-2.23
(m, 4), 2.50-2.57 (m, 4), 2.86 (s, 6), 3.04-3.16 (m, 4), 3.82-
3.83 (m, 4), 7.33-7.38 (m, 4), 7.52-7.57 (m, 4).
7,30-Bis(2-m et h oxyb en zyl)-14,23-d im et h yl-7,14,23,30-
tetr a a za tr icyclo[30.2.2.20,0]octa tr ia con ta -1(35),2(37),3,5-
(38),32(36),33-h exa en e-13,24-d ion e Dih yd r och lor id e (11).
A mixture of 30 (110 mg, 0.19 mmol), 2-methoxybenzyl
chloride16 (119.5 mg, 0.76 mmol), and N,N-diisopropylethy-
lamine (0.13 mL, 0.76 mmol) in MeOH (5 mL) was refluxed
for 24 h and then stirred at room temperature for further 48
h. Removal of the solvent gave a residue that was purified by
chromatography. Eluting with methylene chloride/petroleum
ether/ethanol/aqueous 30% ammonia (4.5:5:0.5:0.05) afforded
11 (41% yield) as the free base that was transformed into the
dihydrochloride: mp 200-205 °C (EtOH/ether); 1H NMR (free
base, CDCl3) δ 1.20-1.56 (m, 24), 2.15-2.27 (m, 4), 2.30-2.45
(m, 4), 2.82-2.86 (m, 6), 3.14-3.29 (m, 4), 3.55-3.57 (m, 4),
3,26-Bis(2-m et h oxyb en zyl)-10,19-d im et h yl-3,10,19,26-
tetr aazabicyclo[26.2.2]dotr iacon ta-1(31),28(32)-tr ien e Tet-
r a h yd r och lor id e (8). A mixture of 31 (130 mg, 0.27 mmol),
NaCNBH3 (34 mg, 0.54 mmol), and CH3COOH (15.4 mL) in
absolute ethanol (10 mL) was stirred for 10 min at room
temperature, and then 2-methoxybenzaldehyde (150 mg, 1.1
mmol) was added and the stirring was continued overnight.
Removal of the solvent gave a residue that was purified by
flash chromatography. Eluting with methylene chloride/etha-
nol/aqueous 30% ammonia (9.5:0.5:0.1) afforded 8 (31% yield)
as the free base that was transformed into the tetrahydro-
chloride salt: mp 74-76 °C (EtOH/Et2O); 1H NMR (free base,
CDCl3) δ 1.28-1.51 (m, 28), 2.22 (s, 6), 2.26-2.47 (m, 12), 3.57
(s, 4), 3.62 (s, 4), 3.81 (s, 6), 6.83-6.99 (m, 4), 7.16-7.32 (m,
6), 7.54-7.57 (m, 2). Anal. (C46H76Cl4N4O2) C, H, N.
3.66-3.68 (m, 4), 3.80 (s, 6), 6.83-7.58 (m, 16). Anal. (C52H74
Cl2N4O4) C, H, N.
-
10,19-Bis-(2-m eth oxyben zyl)-3,10,19,26-tetr aazabicyclo-
[26.2.2]d otr ia con ta -1(31),28(32),29-tr ien e-9,20-d ion e Di-
h yd r och lor id e (13). 13 was obtained from 6 (480 mg, 0.88
mmol) and 28 (118 mg, 0.88 mmol) following the procedure
described for 31 and purified by flash chromatography. Eluting
with methylene chloride/petroleum ether/ethanol/aqueous 30%
ammonia (8:1:1:0.1) gave 13 as the free base that was
converted into the dihydrochloride salt: 38% yield; mp 185-
187 °C (EtOH/Et2O); 1H NMR (free base, CDCl3,) δ 1.23-1.45
(m, 24 + 2 exchangeable D2O), 2.36-2.40 (m, 8), 2.57 (t, 4),
3.55 (t, 4), 3.77 (s, 4), 3.79 (s, 6), 6.81-6.93 (m, 4), 7.16-7.27
(m, 6), 7.39-7.41 (m, 2). MALDI-MS calcd for C44H65N4O4
713.49 (M + H)+, found 713.51. Anal. (C44H66Cl2N4O4) C, H,
N.
14,23-Dim eth yl-7,14,23,30-tetr a a za tr icyclo[30.2.2.20,0]-
octa tr ia con ta -1(35),2,4,32(36),33,37-h exa en e Tetr a h yd r o-
ch lor id e (12). 12 was obtained from 2715 (130 mg, 0.34 mmol)
and 2913 (71.5 mg, 0.34 mmol) following the procedure de-
scribed for 31 and purified by flash chromatography. Eluting
with methylene chloride/ethanol/aqueous 30% ammonia (9:1:
0.1) gave 12 as the free base that was converted into the
tetrahydrochloride salt: 64% yield; mp 212-215 °C (EtOH/
1
Et2O); H NMR (free base, CDCl3) δ 1.28-1.50 (m, 28), 1.91
(br s, 2, exchangeable with D2O), 2.21-2.33 (m, 14), 2.58 (t,
4), 3.87 (s, 4), 7.39 (d, 4), 7.60 (d, 4). Anal. (C36H64Cl4N4) C, H,
N.
7,30-Bis(2-m et h oxyb en zyl)-14,23-d im et h yl-7,14,23,30-
tetr a a za tr icyclo[30.2.2.20,0]octa tr ia con ta -1(35),2,4,32(36),-
33,37-h exa en e Tetr a oxa la te (9). 9 was obtained from 12 (90
mg, 0.16 mmol) and 2-methoxybenzaldehyde (98 mg, 0.72
mmol) following the procedure described for 8 and purified by
flash chromatography. Eluting with methylene chloride/etha-
nol/aqueous 30% ammonia (9:1:0.1) gave 9 as the free base
that was converted into the tetraoxalate salt: 48% yield; mp
105 °C; 1H NMR (free base, CDCl3) δ 1.16-1.50 (m, 28), 2.16-
2.33 (m, 14), 2.43 (t, 4), 3.55 (s, 4), 3.68 (s, 4), 3.82 (s, 6), 6.83-
6.87 (m. 2), 6.96 (t, 2), 7.21 (t, 2), 7.40-7.59 (m, 10). Anal.
(C60H84N4O18) C, H, N.
14,23-Bis(2-m eth oxyben zyl)-7,14,23,30-tetr aazatr icyclo-
[30.2.2.20,0]oct a t r ia con t a -1(35),2,4,32(36),33,37-h exa en e-
13,24-d ion e Dih yd r och lor id e (14). 14 was obtained from 6
(210 mg, 0.34 mmol) and 2913 (71.5 mg, 0.34 mmol) following
the procedure described for 31 and purified by flash chroma-
tography. Eluting with methylene chloride/petroleum ether/
ethanol/aqueous 30% ammonia (8:1:1:0.1) gave 14 as the free
base that was converted into the dihydrochloride salt: 56%
yield; mp 280-285 °C (EtOH/Et2O); 1H NMR (free base, CDCl3)
δ 1.04-1.57 (m, 24 + 2 exchangeable D2O), 2.24-2.31 (m, 4),
2.39-2.69 (m, 4), 3.22-3.30 (m, 4), 3.79-3.84 (m, 10), 4.43-
4.57 (m, 4), 6.83-7.56 (m, 16). MALDI-MS calcd for C50H69N4O4
789.52 (M + H)+, found 789.62. Anal. (C50H70Cl2N4O4) C, H,
N.
15,24-Dim eth yl-8,15,24,31-tetr a a za tr icyclo[31.2.2.20,0]-
n on a tr ia con ta -1(36),3,5,33(37),34,38-h exa en e (32). 32 was
obtained from 2715 (130 mg, 0.34 mmol) and 3014(76.3 mg, 0.34
mmol) following the procedure described for 31 and purified
by flash chromatography. Eluting with methylene chloride/
methanol/aqueous 30% ammonia (9:1:0.1) gave 32 as the free
15,24-Bis(2-m eth oxyben zyl)-8,15,24,31-tetr aazatr icyclo-
[31.2.2.20,0]n on a tr ia con ta -1(36),3,5,33(37),34,38-h exa en e-
14,25-d ion e Dih yd r och lor id e (15). 15 was obtained from 6
(230 mg, 0.375 mmol) and 3014 (84 mg, 0.375 mmol) following
the procedure described for 31 and purified by flash chroma-
tography. Eluting with methylene chloride/petroleum ether/
ethanol/aqueous 30% ammonia (8:1:1:0.08) gave 15 as the free
base that was converted into the dihydrochloride salt: 49%
1
base: 57% yield; H NMR (CDCl3) δ 1.24-1.47 (m, 28), 2.01
(br s, 2, exchangeable with D2O), 2.23 (s, 6), 2.32-2.38 (m, 8),
2.59 (t, 4), 3.75 (s, 4), 3.93 (s, 2), 7.11-7.14 (m, 4), 7.22-7.25
(m, 4).
8,31-Bis(2-m et h oxyb en zyl)-15,24-d im et h yl-8,15,24,31-
t et r a a za t r icyclo[31.2.2.20,0]n on a t r ia con t a -1(36),3,5,33-
(37),34,38-h exa en e Tetr a oxa la te (10). 10 was obtained from
32 (110 mg, 0.20 mmol) and 2-methoxybenzaldehyde (106 mg,
0.78 mmol) following the procedure described for 8 and purified
by flash chromatography. Eluting with methylene chloride/
ethanol/aqueous 30% ammonia (9.4:0.6:0.05) gave 10 as the
free base that was converted into the tetraoxalate salt: 50%
1
yield; mp 121 °C (EtOH/Et2O); H NMR (free base, CDCl3) δ
1.23-1.58 (m, 24), 2.10 (br s, 2, exchangeable with D2O), 2.22-
2.40 (m, 4), 2.55-2.68 (m, 4), 3.21 (t, 2), 3.32 (t, 2), 3.76-3.82
(m, 10), 3.95 (s, 2), 4.45 (s, 2), 4.59 (s, 2), 6.84-7.27 (m, 16).
MALDI-MS calcd for C51H71N4O4 803.54 (M + H)+, found
803.59. Anal. (C51H72Cl2N4O4) C, H, N.
18,27-Di(2-m etossifen il)-11,18,27,34-tetr a a za tetr a cyclo-
[34.2.2.22,5.26,9]t et r a t et r a con t a -1(38),2,4,6,8,36,39,41,43-
n on a en e-17,28-d ion e Dih yd r och lor id e (16). 16 was ob-
tained from 6 (171 mg, 0.28 mmol) and 3417 (80 mg, 0.28 mmol)
following the procedure described for 31 and purified by flash
chromatography. In this case, the aldehyde was dissolved in
150 mL of CHCl3. Eluting with methylene chloride/petroleum
ether/ethanol/aqueous 30% ammonia (8:1:1:0.05) gave 16 as
the free base that was converted into the dihydrochloride
salt: 22% yield; mp 185-187 °C (EtOH/Et2O); 1H NMR
(CDCl3, free base) δ 1.26-1.46 (m, 24), 2.01 (br s, 2, exchange-
able with D2O), 2.29-2.33 (m, 4), 2.49-2.63 (m, 4), 3.08-3.31
1
yield; mp 110 °C (EtOH/Et2O); H NMR (free base, CDCl3) δ
1.29-1.93 (m, 28), 2.23 (s, 6), 2.26-2.47 (m, 12), 3.59 (s, 4),
3.63 (s, 4), 3.82 (s, 6), 3.96 (s, 2), 6.84-7.00 (m, 4), 7.12-7.33
(m, 10), 7.53-7.57 (m, 2). Anal. (C61H86N4O18) C, H, N.
14,23-Dim et h yl-7,14,23,30-t et r a za t r icyclo[30.2.2.20,0]-
oct a t r ia con t a -1(35),2,4,32(36),33,37-h e xa e n e -13,24-d i-
on e (33). 33 was obtained from 2615 (140 mg, 0.35 mmol) and
2913 (72 mg, 0.34 mmol) following the procedure described for
31 and purified by flash chromatography. Eluting with me-
thylene chloride/petroleum ether/ethanol/aqueous 30% am-
monia (8:1:1:0.1) gave 33: 55% yield; 1H NMR (CDCl3) δ 1.20-