Inhibitors of Human Rhinovirus 3C Protease
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15 2799
CBZ-L-Leu-L-Phe-L-(N-isobutyrylamino-alaninol): IR (KBr)
CBZ-L-Leu -L-P h e-L-(N-ben zoylam in o-alan in al) (7): white
solid, 88%; IR (KBr) 3202, 3057, 2957, 2928, 1709, 1690, 1645,
1535, 1235, 1128, 698 cm-1; 1H NMR (DMSO-d6) δ 0.79 (t, 6H,
J ) 7.4 Hz), 1.31 (m, 2H), 1.49 (m, 1H), 2.86 (dd, 1H, J ) 13.8,
9.0 Hz), 3.02 (dd, 1H, J ) 14.0, 5.5 Hz), 3.60 (m, 2H), 3.99 (m,
1H), 4.31 (m, 1H), 4.55 (m, 1H), 5.00 (s, 2H), 7.19 (m, 5H),
7.33 (m, 5H), 7.38-7.55 (m, 4H), 7.80 (d, 2H, J ) 8.0 Hz), 8.01
(d, 1H, J ) 8.1 Hz), 8.51 (t, 1H, J ) 5.7 Hz), 8.55 (d, 1H, J )
6.6 Hz), 9.33 (s, 1H); HRMS calcd for C33H38N4O6 + Na
609.2689, found 609.2667. Anal. (C33H38N4O6‚1.0H2O) C, H,
N.
3297, 3069, 2963, 1696, 1647, 1541, 1264, 1238, 1047, 698
1
cm-1; H NMR (DMSO-d6) δ 0.79 (t, 6H, J ) 6.3 Hz), 0.92 (d,
6H, J ) 6.6 Hz), 1.28 (m, 2H), 1.49 (m, 1H), 2.25 (sept, 1H, J
) 6.6 Hz), 2.80 (m, 1H), 2.95 (m, 2H), 3.18 (m, 1H), 3.80 (m,
1H), 3.95 (m, 1H), 4.42 (m, 1H), 4.99 (m, 2H), 6.25 (d, J ) 7.0
Hz, hydrate), 6.38 (d, J ) 6.6 Hz, hydrate), 7.16-7.38 (m, 10H),
7.42 (d, 1H, J ) 6.5 Hz), 7.60 (m, 2H), 7.84 (t, 1H, J ) 6.0
Hz), 9.18 (s, 1H); MS calcd for C30H40N4O6 + H 553 found 553.
Anal. (C30H40N4O6‚1.1H2O) C, H, N.
CBZ-L-(N-(tr iflu or oa cetyl)a m in o-a la n in ol). Using the
general procedure, methyl NR-CBZ-L-2,3-diaminopropionate
(2.0 g, 7.94 mmol; generated from the HCl salt by liberation
of the free base with 10% aqueous NaHCO3 and CHCl3
extraction) was reduced with LiBH4. A modified workup using
neutral conditions (pH ) 7.5), CHCl3 (3 × 200 mL) extractions,
drying (Na2SO4), and concentration gave 1.69 g of crude NR-
CBZ-L-2,3-diaminopropanol. The solid was dissolved in 50 mL
of EtOH, and NEt3 (0.77 g, 7.61 mmol) followed by ethyl
trifluoroacetate (6.0 g, 42.2 mmol) was added. The stirred
reaction mixture was heated to 60 °C for 2 h. The mixture
was concentrated under vacuum, and the residue was purified
by column chromatography (5% MeOH/CHCl3) to give a white
solid in 68% (two steps): IR (KBr) 3337, 3304, 3108, 2961,
1690, 1541, 1287, 1182, 1065, 731, 696 cm-1; 1H NMR (DMSO-
d6) δ 3.23 (m, 1H), 3.38 (m, 3H), 3.68 (m, 1H), 4.79 (t, 1H, J )
5.5 Hz), 5.00 (m, 2H), 7.05 (d, 1H, J ) 8.8 Hz), 7.33 (m, 5H),
9.37 (m, 1H). Anal. (C13H15F3N2O4) C, H, N.
CBZ-L-[N-(Me)Ac-a m in o-Ala ]-OMe. By applying the pro-
cedure of Grieco,18 methyl NR-CBZ-L-2,3-diaminopropionate
hydrochloride (2.5 g, 8.67 mmol) was dissolved in 100 mL of
H2O, followed by 3.6 mL of 37% aqueous formaldehyde and
freshly prepared cyclopentadiene (2.87 g, 43.4 mmol). The
reaction mixture was stirred at room temperature for 12 h and
then extracted with 300 mL of EtOAc. The organic phase was
washed with 10% aqueous NaHCO3, dried over MgSO4,
concentrated, and purified by column chromatography (5%
MeOH/CHCl3) to give a 3:2 diastereomeric mixture of the
azanorbornene intermediate 21 in 74% yield. 1H NMR (DMSO-
d6) δ 1.25 (m, 1H), 1.37 (m, 2H), 2.23 (m, 1H), 2.69, 2.80 (2 dd,
1H, J ) 12.3, 9.0 Hz, J ) 12.1, 6.6 Hz), 2.87 (bs, 1H), 3.05 (m,
1H), 3.60 (s, 3H), 3.76 (bs, 1H), 4.06 (m, 1H), 5.02 (s, 2H), 6.00
(m, 1H), 6.30 (m, 1H), 7.35 (m, 5H), 7.55, 7.60 (2 d, 1H, J )
8.5 Hz, J ) 7.4 Hz).
Intermediate 21 (1.5 g, 4.55 mmol) was dissolved in 100 mL
of 1:1 TFA:CHCl3. To this stirred solution was added Et3SiH
(1.59 g, 13.7 mmol). After 2 h of stirring at room temperature,
the solution was concentrated under vacuum and the residue
was taken up in 200 mL of CHCl3 and washed with 100 mL of
10% aqueous NaHCO3. The organic layer was dried over
NaSO4, filtered, and concentrated to give 1.09 g (95%) of the
crude CBZ-L-[N-Me-amino-Ala]-OMe which was used im-
mediately. The amine was dissolved in 30 mL of 1:1 pyridine:
AcOAc and stirred at room temperature for 12 h. At this time
the mixture was pour into 100 mL of 1 N HCl and then
extracted with 200 mL of EtOAc. The organic phase was
washed with 100 mL of 10% aqueous NaHCO3 and 100 mL of
H2O and dried over Na2SO4. Filtration, concentration, and
purification of the residue by column chromatography (3%
MeOH/CHCl3) afforded the product as a white solid in 89%
yield: 1H NMR (DMSO-d6) δ 1.92 (s, 3H), 2.75, 2.93 (2s, 3H,
rotomers), 3.26 (dd, 1H, J ) 13.4, 8.3 Hz), 3.61, 3.65 (2s, 3H,
rotomers), 3.81 (dd, 1H, J ) 13.4, 6.4 Hz), 4.33 (m, 1H), 5.03
(m, 2H), 7.34 (m, 5H), 7.73, 7.92 (2 d, 1H, rotomers, J ) 8.1
Hz, J ) 8.5 Hz). Anal. (C15H20N2O5‚0.3H2O) C, H, N.
CBZ-L-[N-(Me)Ac-a m in o-a la n in ol]: white solid, 78%; (5%
MeOH/CHCl3); 1H NMR (DMSO-d6) δ 1.91, 1.97 (2s, 3H,
rotomers), 2.76, 2.93 (2s, 3H, rotomers), 3.19-3.48 (m, 4H),
3.69 (m, 1H), 4.68, 4.85 (2t, 1H, rotomers, J ) 5.7 Hz, J ) 5.5
Hz), 4.99 (m, 2H), 6.94, 7.20 (2d, 1H, rotomers, J ) 8.5 Hz, J
) 9.2 Hz), 7.33 (m, 5H). Anal. (C14H20N2O4‚0.5H2O) C, H, N.
CBZ-L-Leu -L-P h e-[N-(Me)Ac-a m in o-a la n in ol]: white
solid, 48%; (5% MeOH/CHCl3); 1H NMR (DMSO-d6) δ 0.79 (d,
3H, J ) 6.6 Hz), 0.82 (d, 3H, J ) 6.6 Hz), 1.28 (m, 2H), 1.46
(m, 1H), 1.90, 1.97 (2s, 3H, rotomers), 2.75, 2.90 (2s, 3H,
rotomers), 2.80-2.98 (m, 2H), 3.20 (m, 4H), 3.44 (dd, 1H, J )
13.2, 5.5 Hz), 3.94 (m, 2H), 4.44 (m, 1H), 4.65, 4.88 (2t, 1H,
rotomers, J ) 5.5 Hz, J ) 5.0 Hz), 5.01 (s, 2H), 7.19 (m, 5H),
7.34 (m, 5H), 7.41 (d, 1H, J ) 8.5 Hz), 7.74, 7.97 (2d, 1H,
rotomers, J ) 8.8 Hz, J ) 8.1 Hz), 7.86 (m, 1H). Anal.
(C29H40N4O6‚0.5 H2O) C, H, N.
C B Z -L -L e u -L -P h e -( N -( t r i f l u o r o a c e t y l ) a m i n o -
a la n in ol): white solid, 82%; (5% MeOH/CHCl3); IR (KBr)
3291, 3067, 2957, 1707, 1647, 1541, 1454, 1215, 1046, 698
cm-1; 1H NMR (DMSO-d6) δ 0.78 (d, 3H, J ) 6.6 Hz), 0.82 (d,
3H, J ) 6.6 Hz), 1.31 (m, 2H), 1.48 (m, 1H), 2.80 (d, 1H, J )
14.0, 8.5 Hz), 2.97 (d, 1H, J ) 13.6, 5.5 Hz), 3.20 (m, 1H), 3.31
(m, 3H), 3.91 (m, 2H), 4.45 (m, 1H), 4.80 (t, 1H, J ) 5.5 Hz),
4.97 (d, 1H, J ) 12.9 Hz), 5.03 (d, 1H, J ) 12.5 Hz), 7.18 (m,
5H), 7.34 (m, 5H), 7.44 (d, 1H, J ) 8.5 Hz), 7.80 (d, 1H, J )
8.5 Hz), 7.86 (d, 1H, J ) 8.1 Hz), 9.26 (t, 1H, J ) 6.3 Hz).
Anal. (C28H35F3N4O6) C, H, N.
CBZ-L-Leu -L-P h e-(N-tr iflu or oacetyl)am in o-alan in al) (6):
white solid, 69%; 1H NMR (DMSO-d6) δ 0.80 (m, 6H), 1.29 (m,
2H), 1.47 (m, 1H), 2.81 (m, 1H), 2.99 (m, 1H), 3.42 (m, 2H),
3.98 (m, 2H), 4.56 (m, 1H), 5.00 (m, 2H), 7.21 (m, 5H), 7.34
(m, 5H), 7.98 (m, 2H), 8.66 (d, 1H, J ) 7.4 Hz), 9.35 (s, 1H),
9.41 (m, 1H). HRMS calcd for C28H33F3N4O6 + Cs 711.1407,
found 711.1375. Anal. (C28H33F3N4O6) C, H, N.
CBZ-L-(N-ben zoyla m in o-Ala )-OMe: white solid, 88%; IR
(KBr) 3286, 3061, 2946, 1748, 1696, 1640, 1536, 1267, 1026,
698 cm-1 1H NMR (DMSO-d6) δ 3.55 (m, 2H), 3.61 (s, 3H),
;
4.32 (m, 1H), 5.00 (d, 1H, J ) 12.5 Hz), 5.05 (d, 1H, J ) 12.5
Hz), 7.33 (m, 5H), 7.49 (m, 3H), 7.79 (d, 2H, J ) 7.0 Hz), 8.55
(t, 1H, J ) 5.7 Hz). Anal. (C19H20N2O5) C, H, N.
CBZ-L-(N-ben zoyla m in o-a la n in ol): white solid, 97%; IR
(KBr) 3290, 3074, 3028, 2957, 2930, 1688, 1640, 1541, 1329,
1256, 1062, 1040, 696 cm-1; 1H NMR (DMSO-d6) δ 3.27-3.44
(m, 4H), 3.73 (m, 2H), 4.96 (d, 1H, J ) 12.9 Hz), 5.02 (d, 1H,
J ) 12.9 Hz), 7.03 (d, 1H, J ) 8.5 Hz), 7.30 (m, 5H), 7.39-
7.54 (m, 3H), 7.81 (d, 2H, J ) 7.0 Hz), 8.43 (t, 1H, J ) 5.3
Hz). Anal. (C18H20N2O4) C, H, N.
L-(N-Ben zoyla m in o-a la n in ol): white solid, 98%; IR (KBr)
3355, 3297, 3178, 3088, 3028, 2926, 2845, 1632, 1543, 1487,
1318, 1065, 966, 698, 677 cm-1 1H NMR (DMSO-d6/D2O) δ
;
2.82 (quin, 1H, J ) 5.9 Hz), 3.12 (dd, 1H, J ) 13.1, 6.8 Hz),
3.24 (dd, 1H, J ) 10.7, 5.9 Hz), 3.31 (m, 2H), 7.41-7.56 (m,
3H), 7.82 (d, 2H, J ) 7.0 Hz). Anal. (C10H14N2O2) C, H, N.
CBZ-L-Leu -L-P h e-L-(N-ben zoyla m in o-a la n in ol): white
solid, 60%; IR (KBr) 3277, 3171, 3065, 2955, 1690, 1640, 1539,
1231, 1036, 746, 698 cm-1; 1H NMR (DMSO-d6) δ 0.78 (t, 6H,
J ) 7.2 Hz), 1.31 (m, 2H), 1.48 (m, 1H), 2.85 (dd, 1H, J ) 13.2,
4.8 Hz), 2.98 (dd, 1H, J ) 13.6, 5.2 Hz), 3.21-3.38 (m, 4H),
3.46 (m, 1H), 3.94 (m, 2H), 4.24 (m, 1H), 4.97 (d, 1H, J ) 12.9
Hz), 5.03 (d, 1H, J ) 12.9 Hz), 7.18 (m, 5H), 7.33 (m, 5H),
7.48 (m, 4H), 7.79 (m, 3H), 7.93 (d, 1H, J ) 8.1 Hz), 8.32 (t,
1H, J ) 6.3 Hz). Anal. (C33H40N4O6) C, H, N.
CBZ-L-Leu -L-P h e-[N-(Me)Ac-a m in o-a la n in a l] (8): white
solid, 29%; (5% MeOH/EtOAc); 1H NMR (DMSO-d6) δ 0.80 (m,
6H), 1.27 (m, 2H), 1.57 (m, 1H), 1.91, 1.97 (2bs, 3H, rotomers),
2.73, 2.98 (2bs, 3H, rotomers), 2.85 (m, 2H), 3.75 (m, 1H), 3.94
(m, 2H), 4.54, 4.81 (2m, 1H, rotomers), 5.00 (s, 2H), 5.94 (m,
hydrate), 7.20 (m, 5H), 7.34 (m, 6H), 7.80-8.15 (m, 2H,
rotomers), 8.48 (d, 1H, J ) 7.4 Hz), 9.25 (bs, 1H). HRMS calcd
for
C29H38N4O6 + H 539.2870, found 539.2891. Anal.
(C29H38N4O6‚0.5H2O) C, H, N.