3010 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 18
Carceller et al.
h at -16 °C, poured onto ice, and extracted with CHCl3. The
8.28 (d, J ) 5.5 Hz, 1H), 7.80 (d, J ) 8.2 Hz, 2H), 7.33 (d, J )
8.2 Hz, 2H), 7.19 (m, 3H), 6.89 (d, J ) 8.3 Hz, 2H), 6.59 (d, J
) 8.3 Hz, 2H), 5.44 (s, 2H), 3.98 (m, 2H), 3.70 (m, 3H), 2.59 (s,
3H), 1.35 (m, 3H), 0.83 (d, J ) 5.7 Hz, 3H), 0.70 (d, J ) 5.7
Hz, 3H). MS m/e 521 (MH+). mp: 249-250 °C. Anal.
(C27H32N6O3S‚1.5H2O) C, H, N, S.
organic phase was dried and concentrated to give 1.8 g (82%)
1
of 28. H NMR (80 MHz, CDCl3) δ (TMS): 9.66 (s, 1H), 8.17
(d, J ) 6.5 Hz, 2H), 7.50 (d, J ) 6.5 Hz, 2H), 6.2 (m, 1H), 5.22
(q, J ) 7.5 Hz, 1H), 4.11 (q, J ) 7.1 Hz, 2H), 2.91 (d, J ) 6.2
Hz, 2H), 1.20 (t, J ) 7.1 Hz, 3H).
1-[[1-[3-(4-Am in op h en yl)-3-[N-(eth oxyca r bon yl)a m in o]-
p r op ion yl]-4-p ip er id yl]m eth yl]-1H-2-m eth ylim id a zo[4,5-
c]p yr id in e (60). The title compound was prepared from 28
following general procedures A and B (33%, 2 steps). 1H NMR
(80 MHz, CDCl3) δ (TMS): 8.94 (s, 1H), 8.35 (d, J ) 5.5 Hz,
1H), 7.21 (d, J ) 5.5 Hz, 1H), 7.07 (d, J ) 9.5 Hz, 2H), 6.63
(m, 3H), 4.95 (m, 1H), 4.60 (m, 1H), 4.06 (q, J ) 7.2 Hz, 2H),
3.88 (m, 3H), 2.59 (s, 3H), 3.6-0.5 (complex signal, 11H), 1.19
(t, J ) 7.2 Hz, 3H). mp: 113-116 °C. Anal. (C25H32N6O3‚
0.5H2O) C, H, N.
N-(4-Nitr oben zoyl)-N-[4-(1H-2-m eth ylim id a zo[4,5-c]p y-
r idylm eth yl)-ph en ylsu lfon yl]-L-leu cin e Eth yl Ester (39a).
To a solution of 38a (2.4 g, 5.4 mmol), obtained as described
in WO 92/03423, in dry THF (80 mL) was added 50% NaH
(0.23 g), and the resulting mixture was heated at 50 °C for
1.5 h and then it was allowed to cool to room temperature;
4-nitrobenzoyl chloride (1.2 g, 6.4 mmol) in THF (20 mL) was
added, and the mixture was stirred for 52 h. The solvent was
removed, and the residue was partitioned between 0.5 N
NaOH and CHCl3. The organic phase was separated, dried,
and concentrated to afford 2.8 g of a crude product, which was
purified by column chromatography (CHCl3:MeOH, 10%) to
afford 39a (1.9 g, 65%). 1H NMR (80 MHz, CDCl3) δ (TMS):
9.02 (s, 1H), 8.40 (d, J ) 5.5 Hz, 1H), 8.11 (d, J ) 8.8 Hz, 2H),
7.87 (d, J ) 8.8 Hz, 2H), 7.53 (d, J ) 8.8 Hz, 2H), 7.11 (d, J )
8.8 Hz, 2H), 7.10 (d, J ) 5.5 Hz, 1H), 5.38 (s, 2H), 4.85 (t, J )
6.7 Hz, 1H), 4.28 (q, J ) 7.1 Hz, 2H), 2.58 (s, 3H), 2.11 (t, J )
6.7 Hz, 2H), 1.78 (quint, J ) 6.7 Hz, 1H), 1.30 (t, J ) 7.1 Hz,
3H), 0.94 (d, J ) 7.3 Hz, 3H), 0.86 (d, J ) 7.3 Hz, 3H). mp:
68-71 °C. Anal. (C29H31N5O7S) C, H, N, S.
1-[[1-[(4-Am in op h en ylm et h yla m in o)ca r b on yl]-4-p ip -
er id yl]m eth yl]-1H-2-m eth ylim id a zo[4,5-c]p yr id in e (56).
DPPA (1.6 mL, 7.6 mmol) was added to a solution of 32 (1.9 g,
7.6 mmol) and NEt3 (0.85 mL) in benzene (40 mL) and stirred
for 20 min at room temperature and for 2 h at 90 °C. Then, 7
(1.2 g, 5 mmol) was added, and the resulting mixture was
stirred for 12 h at 90 °C. After cooling, the mixture was
partitioned between 1 N NaOH and AcOEt. The organic phase
was dried and concentrated to a residue which was chromato-
graphed on silica gel (CHCl3:MeOH 9:1) to afford 2.3 g (96%)
1
of 33. H NMR (80 MHz, CDCl3) δ (TMS): 8.96 (s, 1H), 8.36
N-(4-Am in oben zoyl)-N-[4-(1H-2-m eth ylim id a zo[4,5-c]-
p yr id ylm et h yl)-p h en ylsu lfon yl]-L-leu cin e E t h yl E st er
(64a ). A solution of 39a (1.91 g, 0.0032 mol) in MeOH (100
mL) was hydrogenated at atmospheric pressure in the pres-
ence of 10% Pd/C (0.3 g) for 18 h. The catalyst was filtered off,
and the solvent was removed to afford 1.62 g of a crude
product, which was purified by column chormatography (CHCl3:
(d, J ) 5.5 Hz, 1H), 7.28 (m, 5H), 6.90 (s, 1H), 5.05 (m, 1H),
4.31 (d, J ) 5.2 Hz, 2H), 4.03 (m, 2H), 3.96 (d, J ) 7.1 Hz,
2H), 2.62 (m, 2H), 2.60 (s, 3H), 2.1-1.2 (m, 5H), 1.50 (s, 9H).
mp: 125-130 °C. Anal. (C26H34N6O3‚0.5H2O) C, H, N.
A solution of 33 (1 g, 20 mmol) in MeOH (30 mL) was treated
with a solution of HCl (6.2 N in dioxane) (1.4 mL) for 20 h.
After concentration, the residue was taken up in 2 N NaOH
and extracted with CHCl3 to give 0.55 g (70%) of 56 as a white
solid. 1H NMR (80 MHz, CDCl3) δ (TMS): 8.92 (s, 1H), 8.34
(d, J ) 5.5 Hz, 1H), 7.19 (d, J ) 5.5 Hz, 1H), 7.05 (d, J ) 8.2
Hz, 2H), 6.58 (d, J ) 8.2 Hz, 2H), 5.05 (m, 1H), 4.26 (d, J )
5.2 Hz, 2H), 4.08 (m, 2H), 3.96 (d, J ) 7.1 Hz, 2H), 3.40 (m,
2H), 2.60 (m, 2H), 2.59 (s, 3H), 2.1-1.2 (m, 5H);. MS m/e 379
(MH+). mp: 104-109 °C. Anal. (C21H26N6O‚H2O) C, H, N.
1
MeOH:NH3, 60:4:0.2) to yield 0.6 g (33%) of a white solid. H
NMR (80 MHz, CDCl3) δ (TMS): 9.00 (s, 1H), 8.35 (d, J ) 5.5
Hz, 1H), 7.98 (d, J ) 8.8 Hz, 2H), 7.32 (d, J ) 8.8 Hz, 2H),
7.10 (m, 3H), 6.40 (d, J ) 8.8 Hz, 2H), 5.33 (s, 2H), 4.95 (dd,
J ) 8.0 Hz, J ) 4.5 Hz, 1H), 4.20 (q, J ) 7.1 Hz, 2H), 2.54 (s,
3H), 2.0 (m, 5H), 1.32 (t, J ) 7.1 Hz, 3H), 0.86 (d, J ) 7.3 Hz,
3H), 0.74 (d, J ) 7.3 Hz, 3H). MS m/e 564 (MH+). mp: 91-94
°C. Anal. (C29H33N5O5S‚0.25H2O) C, H, N, S.
N-(4-Am in oben zoyl)-N-[(S)-1-isobu tyl-2-eth oxyeth yl]-
4-(1H -2-m et h ylim id a zo[4,5-c]p yr id ylm et h yl)p h en ylsu l-
fon a m id e (64b). Prepared as described for 64a , starting from
38b, 64b was obtained as a white solid (46%). 1H NMR (80
MHz, CDCl3) δ (TMS): 9.03 (s, 1H), 8.38 (d, J ) 5.5 Hz, 1H),
7.92 (d, J ) 8.2 Hz, 2H), 7.48 (d, J ) 8.2 Hz, 2H), 7.07 (m,
3H), 6.48 (d, J ) 8.3 Hz, 2H), 5.36 (s, 2H), 4.40 (m, 1H), 4.00
(m, 2H), 3.50 (m, 4H), 2.57 (s, 3H), 1.56 (m, 3H), 1.08 (t, J )
8.9 Hz, 3H), 0.78 (m, 6H). MS m/e 550 (MH+). mp: 89-92 °C.
Anal. (C29H35N5O4S‚0.5H2O) C, H, N, S.
N-(4-Nitr oben zyl)-N-[4-(1H-2-m eth ylim id a zo[4,5-c]p y-
r idylm eth yl)-ph en ylsu lfon yl]-L-leu cin e Eth yl Ester (40a).
To a solution of 38a (3 g, 6.7 mmol) in dry THF (30 mL), cooled
in an ice bath, was added 50% NaH (0.28 g), and the resulting
mixture was stirred at 0 °C for 0.5 h. Next, a solution of
4-nitrobenzyl mesylate (2.3 g, 9.9 mmol) in THF (20 mL) was
added, and the reaction mixture was stirred at room temper-
ature for 18 h. The solvent was removed, and the residue was
partitioned between 0.5 N NaOH and CHCl3. The organic
phase was separated, dried, and concentrated to afford 6 g of
a crude product. This was purified by column chromatography
(CHCl3:MeOH:NH3, 60:2:0.2) to give 2.12 g (55%) of a yellow
solid. 1H NMR (80 MHz, CDCl3) δ (TMS): 9.03 (s, 1H), 8.48
(d, J ) 5.5 Hz, 1H), 8.15 (d, J ) 8.7 Hz, 2H), 7.75 (d, J ) 8.7
Hz, 2H), 7.57 (d, J ) 8.7 Hz, 2H), 7.17 (m, 3H), 5.40 (s, 2H),
4.80 (d, J ) 17 Hz, 1H), 4.51 (d, J ) 17 Hz, 1H), 4.50 (m, 1H),
3.79 (m, 2H), 2.60 (s, 3H), 1.43 (m, 3H), 1.00 (t, J ) 7.1 Hz,
3H), 0.87 (d, J ) 5.6 Hz, 3H), 0.58 (d, J ) 5.6 Hz, 3H). mp:
60-65 °C. Anal. (C29H33N5O6S‚0.5H2O).
(S)-1-[[1-[[N-[2-(4-Am in oph en yl)-1-eth oxycar bon yleth yl]-
a m in o]ca r b on yl]-4-p ip er id yl]m et h yl]-1H -2-m et h ylim i-
d a zo[4,5-c]p yr id in e (57) A solution of 34 (0.84 g, 2.4 mmol)
and 7 (0.6 g, 2.4 mmol) in pyridine was heated to reflux for 18
h. After concentration, the residue was partitioned between
0.5 N NaOH and CHCl3. The organic phase was dried and
concentrated to a residue which was purified by chromatog-
raphy on silica gel (CHCl3:MeOH, 5%) to afford 35 as a white
solid (64%). This was hydrogenated following procedure B to
give 57. 1H NMR (80 MHz, CDCl3) δ (TMS): 8.96 (s, 1H), 8.36
(d, J ) 5.5 Hz, 1H), 7.20 (d, J ) 5.5 Hz, 1H), 6.88 (d, J ) 9.2
Hz, 2H), 6.57 (d, J ) 9.2 Hz, 2H), 4.97 (d, J ) 8.1 Hz, 1H),
4.65 (q, J ) 8.12 Hz, 1H), 4.18 (q, J ) 6.5 Hz, 2H), 4.00 (m,
1H), 3.98 (d, J ) 7.3 Hz, 2H), 2.98 (d, J ) 5.8 Hz, 2H), 2.80
(m, 5H), 2.61 (s, 3H), 2.1-1.4 (complex signal, 5H), 1.25 (t, J
) 6.5 Hz, 3H). MS m/e 465 (MH+). mp: 87-96 °C. Anal.
(C25H32N6O3‚H2O) C, H, N.
N-[(S)-1-[(3-Am in oben zyl)a m in oca r bon yl]-3-m eth ylbu -
tyl]-N-m eth yl-4-(1H-2-m eth ylim id a zo[4,5-c]p yr id ylm eth -
yl)p h en ylsu lfon a m id e (62). Starting from 42a and 3-ni-
trobenzylamine and following general procedure A and B gave
1
62 (42%) H NMR (80 MHz, CD3OD) δ (TMS): 8.83 (s, 1H),
8.28 (d, J ) 5.5 Hz, 1H), 7.72 (d, J ) 8.2 Hz, 2H), 7.46 (d, J )
5.5 Hz, 1H), 7.20 (d, J ) 8.2 Hz, 2H), 6.93 (m, 1H), 6.48 (m,
3H), 5.59 (s, 2H), 4.75 (s, 3H), 4.47 (m, 1H), 3.94 (m, 2H), 2.90
(s, 3H), 2.60 (s, 3H), 1.35 (m, 3H), 0.88 (d, J ) 5.7 Hz, 6H).
MS m/e 535 (MH+). mp: 100-104 °C. Anal. (C28H34N6O3S‚
0.25H2O) C, H, N, S.
N-[(S)-1-[(4-Am in oben zyl)a m in oca r bon yl]-3-m eth ylbu -
tyl]-4-(1H-2-m eth ylim id a zo[4,5-c]p yr id ylm eth yl)p h en yl-
su lfon a m id e (63). Preparation from 42b and 4-nitrobenzy-
lamine following general procedure A and B gave 63 (44%).
1H NMR (80 MHz, CDCl3 + CD3OD) δ (TMS): 8.92 (s, 1H),
N-(4-Am in oben zyl)-N-[4-(1H-2-m eth ylim id a zo[4,5-c]p y-
r id ylm eth yl)-ph en ylsu lfon yl]-L-leu cin e Eth yl Ester (65a).
Prepared as described for 64a using 40a , 65a was obtained
as a white solid (48%). 1H NMR (80 MHz, CDCl3) δ (TMS):