Peptidomimetics as IrreVersible Falcipain-2 Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 993
(s, 3H), 0.19 (s, 3H), 0.99 (s, 9H), 1.62–1.75 (m, 2H), 2.58 (t, J )
8.0 Hz, 2H), 3.73 (t, J ) 6.4 Hz, 1H), 4.21 (d, J ) 15.2 Hz, 1H),
4.25 (m, 1H), 4.38–4.50 (m, 2H), 4.55 (d, J ) 15.2 Hz, 1H),
4.49–5.19 (m, 2H), 5.68 (m, 1H), 7.10–7.70 (m, 14H). 13C NMR:
-5.69, 18.07, 26.02, 31.06, 37.06, 50.87, 54.37, 63.01, 68.43,
115.80, 121.47, 125.01, 126.15, 127.63, 128.72, 128.89, 129.52,
129.54, 131.21, 131.53, 135.28, 138.18, 139.10, 140.87, 170.89,
171.12.
(bt, 1H), 7.16–7.61 (m, 9H). Title compound 12b was purified by
flash chromatography, eluting with petroleum ether/EtOAc (5/5)
(2.33 g, 80%). RP-HPLC-MS: gradient D, retention time 3.60 min.
1
MS (ESI+) m/z 585.0 [M + H]+ (100%). H NMR: 3.76 (t, J )
6.4 Hz, 2H), 3.98 (t, J ) 6.6 Hz, 1H), 4.28 (d, J ) 15.3 Hz, 1 H),
4.58 (d, J ) 15.3 Hz, 1 H), 4.95 (dd, J ) 11.2, 6.3 Hz, 1H),
5.03–5.12 (m, 3H), 5.72 (m, 1H), 6.22 (bt, 1H), 6.91 (s, 1H),
7.23–7.36 (m, 4H), 7.39–7.44 (m, 2H), 4.47 (d, J ) 2.2 Hz, 1H),
7.56 (m, 3H), 7.97 (d, J ) 8.6 Hz, 1H), 8.04 (d, J ) 8.6 Hz, 1H).
13C NMR: 41.75, 54.03, 60.38, 65.86, 114.62, 116.25, 121.75,
121.98, 123.35, 124.58, 125.25, 127.34, 128.97, 129.08, 129.24,
129.46, 130.27, 131.17, 131.32, 132.45, 134.38, 139.04, 140.75,
153.97, 168.67, 171.12, 171.24.
N-Allyl-2-[(3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-
2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetamide
(11b). Compound 11b was obtained from 10 (2.2 g, 5 mmol) and
amine 9b (571 mg, 0.75 mL, 10 mmol) employing the procedure
described for compound 11a. Compound 11b (2.36 g, 99%) was
used without further purification in the following step. RP-HPLC-
MS: gradient D, retention time 4.67 min. MS (ESI+) m/z 478.1
(4-Chloro-2-trifluoromethyl-phenyl)-carbamic Acid 1-[(3-
Methanesulfonyl-(1S)-1-phenethyl-allylcarbamoyl)-methyl]-
(3R)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-
methyl Ester (2a). To a solution of 12a (50 mg, 0.072 mmol)
in dry CH2Cl2 (5 mL) was added methyl vinyl sulfone (13a) (77
mg, 0.72 mmol) followed by Hoveyda-Grubbs second generation
catalyst [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)-
dichloro-(O-isopropoxyphenylmethylene)ruthenium] (4.5 mg, 0.0072
mmol). The resulting mixture was heated under microwave irradia-
tion at 100 °C for 2 h. The solvent was then removed under reduced
pressure, and the residue was purified by preparative RP-HPLC
(Waters 996 system, gradient C) to give the title compound as a
solid (28.9 mg, 47.2%). RP-UPLC-MS: gradient F, retention time
2.29 min. MS (ESI+) m/z 767.0 [M + H]+ (100%). 1H NMR:
1.21–1.39 (m, 2H), 2.56–2.63 (m, 2H), 2.92 (s, 3H), 4.03 (t, J )
6.0 Hz, 1H), 4.30 (d, J ) 15.3 Hz, 1H), 4.48 (d, J ) 15.3 Hz, 1H),
4.66 (m, 1H), 4.90–5.06 (m, 2H), 6.30 (d, J ) 8.6 Hz, 1H), 6.59
(d, J ) 15.2 Hz, 1H), 6.81 (dd, J ) 15.2, 4.2 Hz, 1H), 7.08–7.66
(m, 15H), 7.75 (d, J ) 9.3 Hz, 1H), 8.2 (d, J ) 9.1 Hz, 1H). 13C
NMR: 30.98, 36.89, 43.25, 48.98, 54.23, 60.45, 65.78, 114.86,
121.67, 121.79, 123.83, 124.85, 125.32, 126.21, 127.43, 128.52,
128.69, 129.70, 129.72, 129.84, 129.95, 130.12, 131.21, 131.33,
132.44, 138.21, 138.30, 139.10, 140.67, 154.19, 168.36, 170.68,
171.02. Anal. (C38H34ClF3N4O6S) C, H, N.
(4-Chloro-2-trifluoromethyl-phenyl)-carbamic Acid 1-[(3-
Ethanesulfonyl-(1S)-1-phenethyl-allylcarbamoyl)-methyl]-(3R)-
2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylmethyl
Ester (2b). Compound 12a(50 mg, 0.072 mmol) was reacted
with ethyl vinyl sulfone (13b) (88 mg, 0.72 mmol) according to
the same procedure described for 2a. The title compound was
obtained after purification by preparative RP-HPLC (Waters
Micromass system, gradient A) as a solid (30.9 mg, 49.5%).
RP-UPLC-MS: gradient F, retention time 2.33 min. MS (ESI+)
m/z 781.0 [M + H]+ (100%). 1H NMR: 1.30 (t, J ) 7.5 Hz,
3H), 1.85–2.04 (m, 2H), 2.58–2.63 (m, 2H), 2.97 (q, J ) 7.5
Hz, 2H), 4.03 (t, J ) 6.7 Hz, 1H), 4.27 (d, J ) 15.0 Hz, 1H),
4.49 (d, J ) 15.0 Hz, 1H), 4.66 (m, 1H), 4.91–5.05 (m, 2H),
6.32 (d, J ) 8.4 Hz, 1H), 6.49 (d, J ) 15.9 Hz, 1H), 6.79 (dd,
J ) 15.9, 4.3 Hz, 1H), 7.08–7.62 (m, 15H), 7.74 (d, J ) 8.0
Hz, 1H), 7.9 (d, J ) 9.1 Hz, 1H). 13C NMR: 5.15, 31.04, 37.01,
45.48, 49.25, 54.26, 60.36, 65.88, 114.67, 121.79, 121.98,
123.35, 124.52, 125.27, 126.18, 127.39, 128.21, 128.92, 129.07,
129.29, 129.46, 129.53, 130.29, 131.14, 131.78, 132.46, 138.08,
138.15, 139.08, 140.73, 153.99, 168.63, 170.89, 171.24. Anal.
(C39H36ClF3N4O6S) C, H, N.
1
[M + H]+ (100%). H NMR: 0.17 (s, 3H), 0.19 (s, 3H), 0.99 (s,
9H), 3.74 (t, J ) 6.6 Hz, 1H), 3.80 (d, J ) 6.4 Hz, 2H), 4.14–4.32
(m, 2H), 4.20 (d, J ) 15.3 Hz, 1H), 4.50 (d, J ) 15.3 Hz, 1H),
4.93–5.02 (m, 2H), 5.67 (m, 1H), 6.30 (bt, 1H), 7.14–7.60 (m, 9H).
13C NMR: -5.75, 18.16, 25.84, 41.76, 54.06, 62.97, 68.19, 116.24,
121.77, 124.59, 127.32, 128.93, 129.25, 129.46, 131.17, 131.34,
134.38, 139.09, 140.74, 171.17, 171.21.
[(3R)-2-Oxo-1-(2-oxo-2-{[(1S)-1-(2-phenylethyl)prop-2-en-1-
yl]amino}ethyl)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-
yl]methyl[4-chloro-2-(trifluoromethyl)phenyl]carbamate (12a).
Step 1. To a solution of 11a (2.61 g, 4.5 mmol) in dry THF (45
mL) was added tetrabutylammonium fluoride (TBAF) (1 M
solution in THF, 6.75 mL, 6.75 mmol) dropwise. The mixture
was stirred at room temperature until disappearance of the
starting material (TLC monitoring), and then it was diluted with
EtOAc (100 mL) and washed with water (2 × 100 mL). The
organic layer was separated, dried (Na2SO4), filtered, and
concentrated under reduced pressure to give the deprotected
compound (2.05 g, 99%) as a yellow oil, which was used in the
next step without further purification. RP-HPLC-MS: gradient
D, retention time 2.66 min. MS (ESI+) m/z 468.0 [M + H]+
(100%). 1H NMR: 1.71–1.76 (m, 2H), 2.55 (t, J ) 7.9 Hz, 2H),
3.87 (t, J ) 6.3 Hz, 1H), 4.21 (m, 1H), 4.27 (d, J ) 15.3 Hz,
1H), 4.36–4.48 (m, 2H), 4.57 (d, J ) 15.3 Hz, 1H), 5.07–5.15
(m, 2H), 5.71 (m, 1H), 6.20 (d, J ) 8.2 Hz, 1H), 7.07–7.72 (m,
14H). Step 2. To a solution of 2-[(3R)-3-(hydroxymethyl)-2-
oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]-N-[(1S)-
1-(2-phenylethyl)prop-2-en-1-yl]acetamide (2.05 g, 4.4 mmol)
in dry CH2Cl2 (45 mL) was added 4-Cl,2-CF3C6H3NCO (1.94
g, 1.32 mL, 8.8 mmol), and the resulting mixture was stirred
for 12 h at room temperature. After this time, PS-Trisamine (5
equiv) was added and the mixture was stirred for a further 1 h,
then filtered, and washed with water (2 × 50 mL). The residue
was purified by flash chromatography, eluting with petroleum
ether/EtOAc (7/3), to afford compound 12a (2.27 g, 75%). RP-
HPLC-MS: gradient D, retention time 4.70 min. MS (ESI+) m/z
1
689.1 [M + H]+ (100%). H NMR: 1.63–1.75 (m, 2H), 2.49 (t,
J ) 8.0 Hz, 2H), 3.79 (t, J ) 6.4 Hz, 1H), 4.11 (m, 1H), 4.15
(d, J ) 15.2 Hz, 1H), 4.29–4.44 (m, 2H), 4.48 (d, J ) 15.2 Hz,
1H), 4.49–5.12 (m, 2H), 5.66 (m, 1H), 6.10 (d, J ) 8.2 Hz,
1H), 7.01–7.69 (m, 17H). 13C NMR: 31.05, 37.03, 50.86, 54.38,
60.35, 65.88, 114.65, 115.83, 121.71, 121.94, 123.35, 124.56,
125.28, 126.19, 127.32, 128.21, 128.94, 129.06, 129.27, 129.45,
130.27, 131.18, 131.35, 132.48, 135.29, 138.14, 139.07, 140.73,
153.92, 168.67, 170.88, 171.29.
(4-Chloro-2-trifluoromethyl-phenyl)-carbamic Acid 1-{[3-
Benzenesulfonyl-(1S)-1-phenethyl-allylcarbamoyl]-methyl}-(3R)-
2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-
methyl Ester (2c). Compound 12a (50 mg, 0.072 mmol) was
reacted with vinyl phenyl sulfone (13c) (121 mg, 0.72 mmol)
according to the same procedure described for 2a. The title
compound was obtained after purification by preparative RP-HPLC
(Waters Micromass system, gradient A) as a solid (32 mg, 48.2%).
RP-UPLC-MS: gradient F, retention time 2.10 min. MS (ESI+)
{(3R)-1-[2-(Allylamino)-2-oxoethyl]-2-oxo-5-phenyl-2,3-dihy-
dro-1H-1,4-benzodiazepin-3-yl}methyl [4-Chloro-2-(trifluoro-
methyl)phenyl]carbamate (12b). Compound 12b was obtained
from 11b (2.36 g, 4.9 mmol) by employing the same procedure
described for compound 12a. Intermediate N-allyl-2-[(3R)-3-
(hydroxymethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-
1-yl]acetamide was obtained in 99% yield (1.74 g). RP-HPLC-
MS: gradient D, retention time 1.76 min. MS (ESI+) m/z 364.1
1
m/z 829.0 [M + H]+ (100%). H NMR: 1.68–1.80 (m, 2H), 2.54
1
[M + H]+ (100%). H NMR: 3.75 (t, J ) 6.6 Hz, 1H), 3.81 (d, J
(t, J ) 8.0 Hz, 2H), 4.06 (t, J ) 6.4 Hz, 1H), 4.30 (d, J ) 15.2 Hz,
1H), 4.46 (m, 1H), 4.60 (d, J ) 15.2 Hz, 1H), 4.89–5.01 (m, 2H),
6.52 (d, J ) 15.3 Hz, 1H), 6.82 (dd, J ) 15.3, 4.4 Hz, 1H),
) 6.4 Hz, 2H), 4.16–4.34 (m, 2H), 4.25 (d, J ) 15.3 Hz, 1H),
4.54 (d, J ) 15.3 Hz, 1H), 4.94–5.03 (m, 2H), 5.69 (m, 1H), 6.32