Orally Active Isoxazoline Glycoprotein IIb/ IIIa Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2079
2H), 2.43 (m, 1H), 1.79 (d, J ) 12.0 Hz, 2H), 1.49 (m, 2H),
1.46 (s, 9H); MS m/z 229.2 [(M + H)+, 100]; IR (KBr pellet,
cm-1) 3390,1676, 1438, 1240, 1160.
From the coupling of 37b (1.0 g, 3.1 mmol) with 10u (0.9 g,
3.6 mmol), followed by subsequent processing as described in
the preparation of 36a , was obtained 36b as a colorless solid
(0.23 g): 1H NMR (300 MHz, DMSO-d6) δ 8.57 (m, 1H), 8.29
(m, 1H), 8.10 (m, 1H), 7.33 (dd, J ) 4.4, 8.1 Hz, 1H), 4.74 (m,
1H), 4.09 (q, J ) 7.7 Hz, 1H), 3.96 (t, J ) 6.6 Hz, 2H), 3.52
(m, 1H), 3.28 (d, J ) 13.2 Hz, 2H), 3.21 (m, 1H), 3.09 (dd, J )
10.2, 17.2 Hz, 1H), 2.97 (q, J ) 11.7 Hz, 2H), 2.73 (dd, J )
7.3, 17.6 Hz, 1H), 2.47 (dd, J ) 14.6, 8.4 Hz, 1H), 2.32 (d, J )
7.3 Hz, 1H), 2.25 (d, J ) 6.6 Hz, 2H), 1.86 (m, 1H), 1.81 (d, J
) 14.3 Hz, 2H), 1.55 (m, 2H), 1.36 (m, 4H), 0.91 (t, J ) 7.0
Hz, 3H); MS (ESI) m/z 413.4 [(M + H)+, 100]. Anal.
(C19H32N4O6‚1.4CF3CO2H‚0.4H2O) C, H, N.
2-[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]-4-[[[4,5-d i-
h ydr o-3-(4-piper idin ylm eth yl)-5-isoxazolyl]acetyl]am in o]-
bu ta n oic Acid Tr iflu or oa ceta te (36c). N-(tert-Butoxycar-
bonyl)-L-asparagine (5.0 g, 22 mmol) was dissolved in pyridine
(40 mL), and Ac2O (3.1 g, 30.2 mmol) was added. The reaction
was stirred at room temperature overnight, the solvent was
removed in vacuo, and the residue was taken up in EtOAc,
washed with 10% citric acid (100 mL) and saturated NaCl (50
mL), dried (MgSO4), filtered, and concentrated in vacuo to yield
the nitrile as a colorless oil (4.9 g): MS (DCI) m/z 232 [(M +
NH4)+, 100].
To a solution of the nitrile (2.0 g, 9.3 mmol) in CH2Cl2 at 0
°C was added the reagent made from t-BuOH and 1,3-
diisopropylcarbodiimide57 (9.4 g, 46.7 mmol). The reaction was
stirred at room temperature overnight, filtered through a layer
of Celite, washed with citric acid (3 × 50 mL), saturated
NaHCO3 (100 mL), and saturated NaCl (50 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give the tert-
butyl ester as an oil (1.1 g): 1H NMR (300 MHz, CDCl3) δ 5.59
(m, 1H), 4.44 (q, J ) 5.9 Hz, 1H), 4.09 (t, J ) 6.6 Hz, 2H),
2.96 (m, 2H), 1.62 (m, 2H), 1.53 (s, 9H), 1.37 (m, 2H), 0.94 (t,
J ) 7.3 Hz, 3H); MS (DCI) m/z 288.2 [(M + NH4)+, 100].
The tert-butyl ester was hydrogenated at 50 psi in MeOH
(10 mL) and 4 M HCl (15 mL) for 2 h. Filtration through a
layer of Celite and concentration in vacuo afforded the amine
as a colorless solid (1.2 g): 1H NMR (300 MHz, CDCl3) δ 8.27
(m, 2H), 5.78 (m, 1H), 4.28 (m, 1H), 4.06 (m, 2H), 3.2 (m, 2H),
1.63 (m, 2H), 1.48 (s, 9H), 1.38 (m, 4H), 0.93 (t, J ) 6.9 Hz,
3H); MS (ESI) m/z 275 [(M + H)+, 100].
To a solution of the oxime (3.4 g, 14.9 mmol) in CHCl3 (20
mL) was added NCS (1.99 g, 14.9 mmol) followed by 3 drops
of pyridine. The reaction was allowed to stir for 4 h at room
temperature, and the solvent was removed in vacuo. To the
crude chloro oxime in 1:1 THF/water were added n-butyl
vinylacetate (2.70 g, 19 mmol) and NaHCO3 (3.8 g, 44.7 mmol).
The reaction was stirred for 48 h and concentrated in vacuo.
The residue was taken up in CH2Cl2, washed with water and
saturated NaCl, filtered, and dried (MgSO4). The crude
product was purified using column chromatography on silica
gel (hexanes/EtOAc (4:1)) and then recrystallized from CH2-
Cl2/hexanes to afford the ester as colorless crystals (2.5 g,
1
45%): mp 53-54 °C; H NMR (300 MHz, CDCl3) δ 4.96 (m,
1H), 4.12 (m, 4H), 3.16 (dd, J ) 10.2, 17.2 Hz, 1H), 2.84 (m,
4H), 2.56 (m, 1H), 2.53 (dd, J ) 7.7, 15.7 Hz, 1H), 1.84 (d, J )
12.8 Hz, 2H), 1.62 (m, 4H), 1.46 (s, 9H), 1.42 (m, 2H), 0.94 (t,
J ) 7.3 Hz, 3H); MS (NH3-CI) m/z 369.3 [(M + H)+, 100] 386.3
(M + NH4+); IR (KBr pellet, cm-1) 2958, 1732, 1694, 1414,
1238, 1176, 1120. Anal. Calcd for C19H32N2O5: C, 61.93; H,
8.75; N, 7.60. Found: C, 62.03; H, 8.85; N, 7.51.
To the ester (1.0 g, 2.7 mmol) in THF (5 mL) at 0 °C was
added 0.5 M LiOH (7 mL, 3.5 mmol) and the reaction stirred
overnight at room temperature. The solvents were removed
in vacuo, and the residue was taken up in water, acidified with
HOAc, extracted with EtOAc, dried (MgSO4), and filtered.
Concentration of the filtrate in vacuo afforded carboxylic acid
37a as a viscous clear oil (0.95 g): 1H NMR (300 MHz, CDCl3)
δ 4.94 (m, 1H), 4.18 (m, 2H), 3.18 (dd, J ) 10.2, 17.2 Hz, 1H),
2.90 (m, 4H), 1.46 (s, 9H); MS (DCI) m/z 330 [(M + NH4)+,
100]; IR (KBr pellet, cm-1) 3100, 1734, 1690, 1648, 1430, 1276,
1168, 758.
To a solution of 37a (0.35 g, 1.12 mmol) and 10u (0.34 g,
1.3 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethyl-
amine (0.61 mL, 3.50 mmol) followed by 1-ethyl-3-[3-(di-
methylamino)propyl]carbodiimide hydrochloride (0.28 g, 1.45
mmol). The resulting mixture was stirred at room tempera-
ture overnight. The reaction mixture was diluted with CH2-
Cl2, washed successively with 5% citric acid, saturated NaH-
CO3, and saturated NaCl, dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified using
flash chromatography on silica gel with 1% MeOH/CH2Cl2 as
eluent to afford the amide as a colorless foam (0.43 g, 75%):
1H NMR (300 MHz, CDCl3) δ 6.70 (m, 1H), 5.85 (m, 1H), 4.90
(m, 1H), 4.41 (m, 1H), 4.15 (m, 1H), 4.09 (t, J ) 6.6 Hz, 2H),
3.77 (s, 3H), 3.67 (t, J ) 5.5 Hz, 2H), 3.10 (dd, J ) 10.2, 17.2
Hz, 1H), 2.81 (m, 2H), 2.59 (m, 2H), 2.03 (s, 2H), 1.85 (d, J )
10.9 Hz, 2H), 1.62 (m, 4H), 1.46 (s, 9H), 1.41 (m, 3H), 0.95 (t,
J ) 7.3 Hz, 3H); MS (ESI) m/z 513.5 [(M + H)+, 100].
To the amide (0.27 g, 0.53 mmol) was added a mixture of
formic acid (2.25 mL) and concentrated HCl (1.5 mL), and the
reaction was stirred overnight at room temperature. The
solvents were removed in vacuo, and the crude material was
purified via preparative reverse phase HPLC to afford 36a as
a colorless solid (0.171 g, 63%): 1H NMR (300 MHz, DMSO-
d6) δ 8.62 (m, 1H), 8.38 (m, 1H), 8.10 (m, 1H), 7.33 (dd, J )
2.9, 8.4 Hz, 1H), 4.74 (m, 1H), 4.09 (q, J ) 8.1 Hz, 1H), 3.96
(t, J ) 6.6 Hz, 2H), 3.52 (m, 1H), 3.26 (m, 3H), 3.11 (dd, J )
10.2, 17.6 Hz, 1H), 2.97 (q, J ) 10.6 Hz, 2H), 2.76 (dd, J )
7.0, 17.2 Hz, 1H), 2.66 (m, 1H), 2.47 (dd, J ) 14.6, 6.2 Hz,
1H), 2.32 (dd, J ) 7.0, 14.3 Hz, 1H), 1.98 (d, J ) 13.6 Hz, 2
H), 1.70 (m, 2H), 1.55 (q, J ) 7.0 Hz, 2H), 1.39 (m, 2H), 0.91
(t, J ) 7.3 Hz, 3H); MS (ESI) m/z 399.4 [(M + H)+, 100]. Anal.
(C18H30N4O6‚1.2CF3CO2H‚0.5H2O) C, H, N.
The coupling of the amine with 37b using the procedure
reported for the synthesis of 25b afforded the amide: 1H NMR
(300 MHz, CDCl3) δ 6.7 (m, 1H), 5.4 (m, 1H), 4.9 (m, 1H), 4.2
(m, 1H), 4.05 (t, J ) 6.6 Hz, 4H), 3.1 (m, 1H), 3.0 (m, 1H),
2.8-2.4 (m, 5H), 2.25 (d, J ) 7.0 Hz, 2H), 1.72-1.58 (m, 6H),
1.47 (s, 9H), 1.45 (s, 9H), 1.43 (m, 3H), 1.2 (m, 3H), 0.96 (t, J
) 7.3 Hz, 3H); MS (ESI) m/z 583 [(M + H)+, 100].
The preceding amide (360 mg, 0.06 mmol) was stirred in
CH2Cl2 (3 mL) and TFA (1 mL) overnight. The volatiles were
removed in vacuo, and the crude material was purified via
preparative reverse phase HPLC to afford 36c as a colorless
solid (226 mg): 1H NMR (300 MHz, DMSO-d6) δ 8.5 (m, 1H),
8.2 (m, 1H), 8.0 (m, 1H), 7.46 (d, J ) 8.4 Hz, 1H), 4.74 (m,
1H), 3.94 (m, 3H), 3.60 (m, 1H), 3.28 (m, 2H), 3.10 (m, 3H),
2.88 (m, 2H), 2.71 (m, 1H), 2.44 (m, 2H), 2.26 (m, 3H), 1.78
(m, 2H), 1.70 (m, 1H), 1.55 (m, 2H), 1.34 (m, 4H), 0.89 (t, J )
7.3 Hz, 3H); MS (ESI) m/z 427 [(M + H)
(C20H34N4O6‚1.4CF3CO2H) C, H, N.
+, 100]. Anal.
N-[(1,1-Dim et h ylet h oxy)ca r b on yl]-3-[[[4,5-d ih yd r o-3-
[2-(4-p ip er id in yl)eth yl]-5-isoxa zolyl]a cetyl]a m in o]-L-a la -
n in e Tr iflu or oa ceta te (36d ). The compound was synthe-
sized using the general procedure reported for 25b: 1H NMR
(300 MHz, DMSO-d6) δ 4.85 (m, 1H), 4.28 (m, 1H), 4.02 (t, J
) 6.6 Hz, 2H), 3.62 (m, 1H), 3.38 (m, 3H), 3.12 (dd, J ) 17.7,
10.1 Hz, 1H), 2.95 (dt, J ) 12.8, 2.6 Hz, 2H), 2.80 (dd, J )
17.2, 7.2 Hz, 1H), 2.55 (ddd, J ) 16.8, 4.0, 2.6 Hz, 1H), 2.40
(m, 3H), 1.96 (bd, J ) 14.3 Hz, 2H), 1.57 (m, 5H), 1.37 (m,
4H), 0.92 (t, J ) 7.3 Hz, 3H); MS (ESI) m/z 427 [(M + H)+,
100]. Anal. (C20H34N4O6‚1.5CF3CO2H) C, H, N.
N-(Bu toxysu lfon yl)-3-[[[4,5-dih ydr o-3-[2-(4-piper idin yl)-
eth yl]-5-isoxa zolyl]a cetyl]a m in o]-L-a la n in e Tr iflu or oa c-
eta te (36e). The compound was synthesized using the general
procedure reported for 25b: 1H NMR (300 MHz, DMSO-d6) δ
8.5 (m, 1H), 8.12 (m, 2H), 7.55 (m, 1H), 4.71 (m, 1H), 3.96 (m,
N-(Bu toxyca r bon yl)-3-[[[4,5-d ih yd r o-3-(4-p ip er id in yl-
m eth yl)-5-isoxa zolyl]a cetyl]a m in o]-L-a la n in e Tr iflu or o-
a ceta te (36b). Following the general procedure for 36a ,
starting with 4-N-(tert-butoxycarbonyl)piperidinylmethane-
carboxaldehyde,56 acid 37b was obtained as a colorless foam
(0.38 g, 67%): 1H NMR (300 MHz, CDCl3) δ 4.95 (m,1H), 4.10
(m, 2H), 3.15 (dd, J ) 10.2, 17.2 Hz, 1H), 2.85 (m, 4H), 2.30
(d, J ) 7.0 Hz, 1H), 2.05 (m, 2H), 1. 80 (m, 1H), 1.75 (d, J )
14.6 Hz, 2H), 1.46 (s, 9H), 1.22 (m, 2H); MS (ESI) m/z 327.3
[(M + H)+, 100].