Selective Inhibitor of Matrix Metalloproteinase-3
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16 3521
560 (MNH4+). FTIR νmax. (KBr disk) 2980, 2930, 1780, 1725,
ter t-Bu tyl (3R)-3-({[(1S)-2,2-Dim eth yl-1-({[(1S)-2-m eth -
o x y -1-p h e n y le t h y l]a m in o }c a r b o n y l)p r o p y l]a m in o }-
ca r bon yl)-6-(3-m eth yl-4-p h en ylp h en yl)h exa n oa te (17). N-
(Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.50
g, 18.26 mmol) was added to a stirred mixture of 16 (6.78 g,
17.43 mmol), 13 (6.35 g, 16.6 mmol), 1-hydroxy-1,2,3-benzo-
triazole hydrate (2.80 g, 20.75 mmol), and diisopropyleth-
ylamine (5.9 mL, 34.03 mmol) in anhydrous dichloromethane
(82 mL) under nitrogen at 4 °C. After 2 h, the mixture was
allowed to warm to room temperature. After 17 h at room
temperature, the mixture was poured into ethyl acetate (600
mL), washed sequentially with 5% aqueous citric acid (2 ×
250 mL), saturated aqueous sodium bicarbonate (2 × 250 mL),
and brine (200 mL), dried (MgSO4), and concentrated under
reduced pressure. The residue was redissolved in ether and
evaporated to give 17 (10.35 g, 99%), as a colorless foam. Anal.
(C, H, N). Rf 0.16 (hexane:ethyl acetate ) 4:1). δH (400 MHz,
CDCl3) 1.02 (9H, s), 1.40 (9H, s and 1H, m, overlapping), 1.55
(2H, m), 1.68 (1H, m), 2.23 (3H, s), 2.32 (1H, m), 2.55 (4H, m),
3.33 (3H, s), 3.62 (2H, d, J ) 5 Hz), 4.28 (1H, d, J ) 9 Hz),
5.12 (1H, dt, J ) 8 and 5 Hz), 6.35 (1H, br d), 6.44 (1H, br d),
6.96 (1H, d, J ) 8 Hz), 7.00 (1H, s), 7.10 (1H, d, J ) 8 Hz),
7.26 (8H, complex), 7.39 (2H, m). LRMS (thermospray) m/z )
630 (MH+). FTIR νmax. (KBr disk) 3320, 2930, 1729, 1643, 1543,
1370, 1157, and 700 cm-1
1700, 1388, 1350, 1157, 768, 702 cm-1
.
ter t-Bu tyl (3R)-3-(Ca r boxy)-6-(3-m eth yl-4-p h en ylp h en -
yl)h exa n oa te (13). 30% Aqueous hydrogen peroxide (12.75
mL, 114 mmol) was added dropwise to a solution of 12 (10.3
g, 19.0 mmol) in tetrahydrofuran:water (3:1, 400 mL) at 0 °C.
Then lithium hydroxide monohydrate (1.595 g, 38.0 mmol) was
added in one portion. The mixture was stirred for 2 h at 0 °C
and 1 h at 20 °C. The reaction mixture was recooled to 0 °C,
and a solution of sodium sulfite (15.56 g, 123.5 mmol) in water
(80 mL) was added dropwise over 15 min. The mixture was
stirred rapidly at 0 °C for 2.5 h, and then 2 M hydrochloric
acid (ca. 8 mL) was added to adjust the pH to 6. The mixture
was concentrated under reduced pressure to half volume,
acidfied to pH 2 by the addition of 2 M hydrochloric acid, and
extracted with dichloromethane (400 mL and 2 × 200 mL).
The combined extracts were dried (MgSO4) and concentrated
under reduced pressure, and the residue was purified by flash
chromatography (gradient elution with pentane:ether ) 15:1
to 1:4) to give 13 (7.05 g, 97%) as a colorless oil. [R]D ) +12.9°
(c ) 0.716, methanol, 25 °C). Anal. (C, H). Rf 0.5 (pentane:
ether:acetic acid ) 30:70:1). δH (300 MHz, CDCl3) 1.45 (9H,
s), 1.63 (1H, m), 1.77 (4H, m), 2.26 (3H, m), 2.42 (dd, J ) 5
and 17 Hz), 2.65 (3H, m), 2.87 (1H, m), 7.06 (2H, m), 7.15 (1H,
d, J ) 8 Hz), 7.34 (5H, m). LRMS (thermospray) m/z ) 400
(MNH4+). FTIR νmax.(film) 2980, 2930, 1730, 1705, 1485, 1368,
(3R )-3-({[(1S )-2,2-D im e t h y l-1-({[(1S )-2-m e t h o x y -1-
p h en yleth yl]a m in o}ca r bon yl)-p r op yl]a m in o}ca r bon yl)-
6-(3-m eth yl-4-p h en ylp h en yl)h exa n oic Acid (7). A solution
of 17 (535 mg, 0.85 mmol) in anhydrous dichloromethane (5
mL) was treated with trifluoroacetic acid (5 mL) at room
temperature for 2 h. The solvents were removed under reduced
pressures, and the residue was dissolved in toluene and
concentrated under reduced pressure (twice). The residue was
recrystallized from ethyl acetate to give a colorless solid (387
mg, 80%). mp 178-180 °C (from ethyl acetate). Anal. (C, H,
N). Rf 0.47 (hexane/ether/acetic acid ) 50:50:1). δH (400 MHz,
CD3OD)(exchangeable hydrogens only partially exchanged)
1.03 (9H, s), 1.51 (4H, m), 2.15 (3H, s), 2.36 (1H, dd, J ) 5
and 17 Hz), 2.46 (2H, m), 2.60 (1H, dd, J ) 10 and 17 Hz),
2.82 (1H, m), 3.32 (3H, s), 3.57 (2H, d, J ) 7 Hz), 4.42 (1H, d,
J ) 10 Hz), 5.10 (1H, q, J ) 7 Hz), 6.87 (1H, d, J ) 8 Hz), 6.98
(2H, s and d, J ) 8 Hz, overlapping), 7.22 (8H, complex), 7.39
(2H, t, J ) 7 Hz), 7.74 (1H, br d), 8.48 (1H, br d). LRMS
(thermospray) m/z ) 573 (MH+). FTIR νmax. (KBr disk) 3300,
1157, 764, 702 cm-1
.
(2S)-ter t-(Bu toxyca r bon yl)a m in o-3,3-d im eth yl-N-[(1S)-
2-m eth oxy-1-p h en yleth yl]bu ta n a m id e. N-(Dimethylami-
nopropyl)-N′-ethylcarbodiimide hydrochloride (25.35 g, 132.3
mmol) was added to a stirred mixture of tert-butyl N-[(1S)-
2,2-dimethyl-1-carboxypropyl]carbamate (27.79 g, 120.3 mmol),
(1S)-2-methoxy-1-phenylethylamine (14) (19.12 g, 126.6 mmol),
N-methylmorpholine (14.4 mL, 132.3 mmol), and 1-hydroxy-
1,2,3-benzotriazole hydrate (20.24 g, mmol) in anhydrous
dichloromethane (600 mL) under nitrogen at 2 °C. The mixture
became homogeneous after 10 min. The mixture was stirred
for 1 h and then allowed to warm to room temperature. After
2.5 h at room temperature, the mixture was concentrated
under reduced pressure, and the residue was diluted with ethyl
acetate (1400 mL), washed sequentially with 5% aqueous citric
acid (2 × 500 mL), saturated aqueous sodium bicarbonate (2
× 250 mL), and brine (250 mL), dried (MgSO4), and concen-
trated under reduced pressure. The residue was recrystallized
from hot ethyl acetate/hexane (1:2, 300 mL) to give the title
compound (20.02 g, 46%), as a colorless solid, mp 135-137 °C.
Anal. (C, H, N). δH (400 MHz, CDCl3) 1.03 (9H, s), 1.44 (9H,
s), 3.35 (3H, s), 3.63 (2H, d, J 7 Hz), 3.85 (1H, d, J 10 Hz),
5.13 (1H, q, J 7 Hz), 5.20 (1H, br d, J 10 Hz), 6.34 (1H, br d,
J 10 Hz), 7.30 (5H, m). LRMS (thermospray) m/z ) 365 (MH+),
FTIR νmax. (KBr disk) 3290, 2973, 1721, 1685, 1633, 1173, 702
cm-1. The mother liquors were concentrated under reduced
pressure, and the residue was triturated with ether to afford
an additional 15.44 g (35%) of product.
2960, 2930, 1711, 1639, 1543, 700 cm-1
.
(2R )-N 1-[(1S )-2,2-D im e t h y l-1-({[(1S )-2-m e t h o x y -1-
p h en ylet h yl]a m in o}ca r b on yl)p r op yl]-2-{3-(3-m et h yl-4-
p h en ylp h en yl)p r op yl}-(N4-h yd r oxy)bu ta n ed ia m id e (6).
(a) O-Allylhydroxylamine hydrochloride (81 mg, 0.73 mmol)
was added to a stirred solution of (7) (347 mg, 0.61 mmol) and
diisopropylethylamine (375 µL, 2.19 mmol) in anhydrous di-
chloromethane (5 mL) under nitrogen at 0 °C. PyAOP (379
mg, 0.73 mmol) was added in one portion, and the mixture
was stirred at 0 °C for 2 h and then allowed to warm to room
temperature. After an additional 1 h, the mixture was poured
into ethyl acetate (50 mL) and washed sequentially with 5%
aqueous citric acid (2 × 20 mL) and saturated aqueous sodium
bicarbonate (2 × 20 mL). The organic solution was dried
(Na2SO4) and concentrated under reduced pressure. Purifica-
tion of the crude product by flash chromatography (eluting
with hexane:ethyl acetate ) 2:1) followed by trituration with
ether and ethyl acetate gave (2R)-N1-[(1S)-2,2-dimethyl-1-
({[(1S)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]-2-{3-
[(3-methyl-4-phenylphenyl)propyl}-(N4-3-propenyloxy)butane-
diamide (306 mg, 80%) as a white solid, mp 117-120 °C, Rf
0.28 (hexane:ethyl acetate ) 1:2), δH (400 MHz, CDCl3) 1.02
(9H, s), 1.40-1.70 (4H, complex), 2.20 (3H, s, and 1H, m
overlapping), 2.34-2.60 (3H, complex), 2.76 (1H, m), 3.36 (3H,
s), 3.63 (2H, d, J ) 5 Hz), 4.28 (1H, d, J ) 9.5 Hz), 4.34 (2H,
d, J ) 6 Hz), 5.12 (1H, dt, J ) 7.5 and 5 Hz), 5.30 (2H, m),
5.90 (1H, m), 6.44 (1H, d, J ) 7.5 Hz and 1H, br s overlapping),
6.94 (1H, m), 6.98 (1H, s), 7.08 (1H, d, J ) 7 HZ), 7.18-7.38
(8H, complex), 7.40 (2H, m), 8.50 (1H, br s), LRMS (thermo-
spray) m/z ) 628 (MH+).
(2S)-Am in o-3,3-d im eth yl-N-[(1S)-2-m eth oxy-1-p h en yl-
eth yl]bu ta n a m id e Hyd r och lor id e (16). (2S)-tert-(Butoxy-
carbonyl)amino-3,3-dimethyl-N-[(1S)-2-methoxy-1-phenylethyl]-
butanamide (34.99 g, 96.0 mmol) was dissolved in a mixture
of anhydrous dichloromethane (250 mL) and dioxane (250 mL)
and cooled to 2 °C. Hydrogen chloride gas was bubbled through
the solution with stirring until a saturated solution had formed
(about 1 h). After being stirred for 40 min at 4 °C, the solution
was warmed to room temperature and stirred for an additional
40 min. The solution was concentrated under reduced pressure.
The residue was slurried with anhydrous ether (200 mL) and
evaporated (three times), and the solid was placed in a vacuum
desiccator overnight to give 16 (hydrochloride salt) (36.27 g,
97%), as a colorless hygroscopic solid, mp 197-199 °C, Anal.
(C, H, N). δH (400 MHz, DMSO-d6) 1.02 (9H, s), 3.24 (3H, s),
3.52 (2H, m), 3.61 (1H, d, J 10 Hz), 5.09 (1H, m), 7.25 (1H, t,
J 7 Hz), 7.33 (2H, t, J 7 Hz), 7.39 (2H, d, J 7 Hz), 8.05 (3H, bs
s), 8.83 (1H, d, J 10 Hz), (LRMS (thermospray) m/z ) 265
(MH+), FTIR νmax. (KBr disk) 1682, 1559, 1507, 1125, 870, 705
cm-1
.