Calpain Inhibitors
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5287
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viscous oil in 79.2% yield. H NMR (DMSO-d6): δ 7.95 (s, 1H),
7.67 (d, J ) 9.0 Hz, 1H), 7.22 (m, 5H), 4.81 (t, J ) 5.4 Hz, 1H),
4.13 (dd, J ) 3.6, 3.6 Hz, 1H), 3.88 (m, 1H), 3.06 (m, 2H), 2.85
(m, 1H), 2.60 (m, 2H), 2.50 (m, 2H), 1.96 (m, 1H), 1.68 (m, 2H),
1.63 (m, 3H), 1.38 (m, 2H), 0.88 (t, J ) 7.2 Hz, 3H).
1H), 4.13 (m, 1H), 3.68 (m, 2H), 3.48 (m, 1H), 3.36 (m, 1H), 3.13
(m, 1H), 2.96 (m, 2H), 2.12 (m, 1H), 1.64 (m, 3H). ESI MS: m/z
489.6 (M + Na)+.
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(4-iodophenyl-
sulfonyl)pyrrolidine-2-carboxamide (5n). Compound 5n was
obtained as a white crystalline solid in 30.8% yield: mp 178-180
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(isopropyl-
sulfonyl)pyrrolidine-2-carboxamide (5d). Compound 5d was
obtained as viscous oil in 28% yield. H NMR (CDCl3): δ 7.27
(m, 5H), 6.59 (d, J ) 7.8 Hz, 1H), 4.29 (m, 1H), 4.14 (m, 1H),
3.70 (m, 1H), 3.64 (m, 1H), 3.44 (m, 2H), 3.31 (m, 1H), 2.97 (s,
1H), 2.64 (t, J ) 5.7 Hz, 1H), 2.16 (m, 2H), 1.93 (m, 2H), 1.37 (d,
J ) 6.9, 6H).
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°C; H NMR (CDCl3): δ 8.96 (s, br, 1H), 7.90 (m, 2H), 7.61 (m,
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2H), 7.32 (d, J ) 7.50 Hz, 1H), 4.32 (m, 1H), 3.90 (m, 1H), 3.49
(m, 1H), 3.30 (m, 1H), 2.01 (m, 6H). ESI MS: m/z 537.10 (M +
Na)+.
(S)-3-(4-Fluorophenylsulfonyl)-N-((S)-1-hydroxy-3-phenyl-
propan-2-yl)thiazolidine-4-carboxamide (5o). Compound 5o was
obtained as colorless viscous oil in 26.3% yield. 1H NMR (CDCl3,
500 MHz): δ 7.84 (m, 2H), 7.32 (m, 2H), 7.24 (m, 5H), 6.82 (d,
J ) 7.20 Hz, 1H), 4.46 (d, J ) 6.91 Hz, 1H), 4.40 (m, 1H), 4.24
(m, 1H), 4.02 (d, J ) 6.91 Hz, 1H), 3.78 (d, J ) 9.10 Hz, 1H),
3.64 (m, 1H), 3.15 (dd, J ) 5.80, 5.80 Hz, 1H), 3.02 (m, 1H), 2.84
(m, 1H), 2.65 (m, 1H), 2.58 (s, br, 1H). ESI MS: m/z 447.3 (M +
Na)+.
(S)-3-(4-Chlorophenylsulfonyl)-N-((S)-1-hydroxy-3-phenyl-
propan-2-yl)thiazolidine-4-carboxamide (5p). Compound 5p was
obtained as a yellow white solid in 54.3% yield: mp 102-104 °C;
1H NMR (CDCl3): δ 7.78 (m, 2H), 7.56 (m, 2H), 7.28 (m, 5H),
6.82 (d, J ) 8.10 Hz, 1H), 4.48 (d, J ) 10.50 Hz, 1H), 4.40 (m,
1H), 4.24 (m, 1H), 4.04 (d, J ) 10.50 Hz, 1H), 3.80 (m, 1H), 3.65
(m, 1H), 3.18 (dd, J ) 3.60, 3.60 Hz, 1H), 3.02 (m, 1H), 2.81 (m,
1H), 2.65 (m, 1H), 2.58 (s, br, 1H). ESI MS: m/z 463.10 (M +
Na)+.
(S)-3-(4-Bromophenylsulfonyl)-N-((S)-1-hydroxy-3-phenyl-
propan-2-yl)thiazolidine-4-carboxamide (5q). Compound 5q was
obtained as a yellow white solid in 38.7% yield: mp 113-115 °C;
1H NMR (CDCl3, 300 MHz): δ 7.69 (m, 4H), 7.25 (m, 5H), 6.79
(d, J ) 8.1 Hz, 1H), 4.44 (m, 2H), 4.24 (m, 1H), 4.03 (d, J ) 10.5
Hz, 1H), 3.78 (m, 1H), 3.63 (m, 1H), 3.15 (dd, J ) 3.60, 3.60 Hz,
1H), 3.01 (m, 1H), 2.81 (m, 1H), 2.65 (m, 1H). ESI MS: m/z 509.10
(M + Na)+.
(S)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-3-(4-iodophenyl-
sulfonyl)thiazolidine-4-carboxamide (5r). Compound 5r was
obtained as a yellow white solid in 40.3% yield: mp 100-102 °C;
1H NMR (CDCl3, 300 MHz): δ 7.94 (m, 2H), 7.54 (m, 2H), 7.27
(m, 5H), 6.79 (d, J ) 7.8 Hz, 1H), 4.47 (d, J ) 10.5 Hz, 1H), 4.39
(m, 1H), 4.23 (m, 1H), 4.04 (d, J ) 10.5 Hz, 1H), 3.78 (m, 1H),
3.66 (m, 1H), 3.18 (dd, J ) 3.60, 3.60 Hz, 1H), 3.02 (m, 1H), 2.82
(m, 1H), 2.65 (m, 1H), 2.53 (m, 1H). ESI MS: m/z 559.10 (M +
Na)+.
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(naphthalen-1-
ylsulfonyl)pyrrolidine-2-carboxamide (5e). Compound 5e was
obtained as a white crystalline solid in 68.4% yield: mp 120-122
°C; 1H NMR (CDCl3): δ 8.42 (s, 1H), 7.96 (m, 3H), 7.84 (m, 1H),
7.67 (m, 2H), 7.34 (m, 5H), 7.13 (d, J ) 7.2 Hz, 1H), 4.16 (m,
1H), 3.70 (m, 2H), 3.53 (m, 1H), 3.23 (m, 1H), 2.96 (m, 3H), 2.10
(m, 1H), 1.65 (m, 3H). ESI MS: m/z 461 (M + Na)+.
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(phenylsulfonyl)-
pyrrolidine-2-carboxamide (5f). Compound 5f was obtained as a
white solid in 84.6% yield: mp 98-100 °C; 1H NMR (CDCl3): δ
7.85 (m, 2H), 7.60 (m, 3H), 7.30 (m, 5H), 7.10 (d, J ) 7.2 Hz,
1H), 4.07 (m, 2H), 3.67 (m, 2H), 3.50 (m, 1H), 3.17 (m, 1H), 3.03
(m, 2H), 2.78 (m, 1H), 2.11 (m, 1H), 1.59 (m, 2H).
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(4-methoxy-
phenylsulfonyl)pyrrolidine-2-carboxamide (5g). Compound 5g
was obtained as a white solid in 73.8% yield: mp 146-148 °C;
1H NMR (CDCl3): δ 7.78 (m, 2H), 7.32 (m, 5H), 7.13 (d, J ) 7.5
Hz, 1H), 7.02 (m, 2H), 4.11 (m, 1H), 4.00 (m, 1H), 3.90 (s, 3H),
3.72 (m, 2H), 3.49 (m, 1H), 3.14 (m, 1H), 2.97 (m, 2H), 2.71 (m,
1H), 2.10 (m, 1H), 1.60 (m, 2H).
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(2-nitrophenyl-
sulfonyl)pyrrolidine-2-carboxamide (5h). Compound 5h was
obtained as colorless oil in 49% yield. 1H NMR (CDCl3, 300
MHz): δ 8.08 (m, 1H), 7.72 (m, 3H), 7.26 (m, 5H), 6.79 (d, J )
8.1 Hz, 1H), 4.43 (dd, J ) 4.0, 4.0 Hz, 5H), 4.09 (m, 1H), 3.66
(m, 1H), 3.54 (m, 3H), 2.74 (dd, J ) 2.7, 2.7 Hz, 2H), 2.14 (m,
1H), 1.86 (m, 3H).
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(3-nitrophenyl-
sulfonyl)pyrrolidine-2-carboxamide (5i). Compound 5i was ob-
tained as a white solid in 76% yield: mp 119-121 °C; H NMR
(CDCl3): δ 8.70 (m, 1H), 8.50 (m, 1H), 8.19 (m, 1H), 7.80 (t, J )
4.8 Hz, 1H), 7.24 (m, 5H), 6.89 (d, J ) 6.3 Hz, 1H), 4.23 (m, 2H),
3.58 (m, 2H), 3.52 (m, 1H), 3.25 (m, 1H), 2.98 (m, 2H), 1.54 (m,
4H).
(R)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-1-(4-nitrophenyl-
sulfonyl)pyrrolidine-2-carboxamide (5j). Compound 5j was
obtained as a white solid in 73% yield: mp 184-186 °C; 1H NMR
(CDCl3): δ 8.42 (d, J ) 9.0 Hz, 2H), 8.06 (d, J ) 9.0 Hz, 2H),
7.33 (m, 5H), 6.83 (d, J ) 9.0 Hz, 1H), 4.17 (m, 1H), 4.08 (m,
2H), 3.68 (m, 2H), 3.53 (m, 1H), 3.19 (m, 1H), 2.97 (m, 2H), 2.43
(m, 1H), 2.14 (m, 1H), 1.73 (m, 2H).
(R)-1-(4-Fluorophenylsulfonyl)-N-((S)-1-hydroxy-3-phenyl-
propan-2-yl)pyrrolidine-2-carboxamide (5k). Compound 5k was
obtained as a white crystalline solid in 81.1% yield: mp 150-152
°C; 1H NMR (CDCl3): δ 7.86 (m, 2H), 7.28 (m, 7H), 7.03 (d, J )
7.20 Hz 1H), 4.13 (m, 1H), 4.01 (m, 1H), 3.68 (m, 2H), 3.48 (m,
1H), 3.06 (m, 3H), 2.63 (m, 1H), 2.12 (m, 1H), 1.64 (m, 3H). ESI
MS: m/z 429 (M + Na)+.
(R)-1-(4-Chlorophenylsulfonyl)-N-((S)-1-hydroxy-3-phenyl-
propan-2-yl)pyrrolidine-2-carboxamide (5l). Compound 5l was
obtained as a white crystalline solid in 52% yield: mp 100-102
°C; 1H NMR (CDCl3): δ 7.71 (m, 3H), 7.28 (m, 6H), 7.03 (d, J )
7.20 Hz, 1H), 4.13 (m, 1H), 4.01 (m, 1H), 3.68 (m, 2H), 3.48 (m,
1H), 3.06 (m, 3H), 2.63 (m, 1H), 2.12 (m, 1H), 1.64 (m, 2H). ESI
MS: m/z 445.5 (M + Na)+.
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Synthesis of Compounds 1a-r. The synthesis of compounds
1a and 1b have been previously reported.25 Compounds 1c-m were
synthesized using oxidation Method A while 1n-r were synthesized
using oxidation Method B.
(R)-1-(Butylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-yl)-
pyrrolidine-2-carboxamide (1c). Compound 1c was obtained as
colorless oil in 32% yield. 1
H NMR (CDCl3): δ 9.62 (s, 1H), 7.27
(m, 6H), 4.69 (m, 1H), 4.30 (m, 1H), 3.40 (m, 2H), 3.19 (m, 2H),
2.95 (m, 2H), 2.15 (m, 2H), 1.93 (m, 2H), 1.79 (m, 2H), 1.43 (m,
2H), 0.97 (t, J ) 7.2 Hz, 3H). Anal. (C18H26N2O4S), C, H, N. ESI
MS: m/z 421 (M + Na + CH3OH)+.
(R)-1-(Isopropylsulfonyl)-N-((R,S)-1-oxo-3-phenylpropan-2-
yl)pyrrolidine-2-carboxamide (1d). Compound 1d was obtained
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as colorless oil in 68% yield. H NMR (CDCl3): δ 9.62 (s, 1H),
7.23 (m, 5H), 7.01 (m, 1H), 4.68 (q, J ) 6.9, 6.9 Hz, 2H), 4.39
(m, 1H), 3.49 (m, 1H), 3.37 (m, 1H), 3.16 (m, 3H), 2.13 (m, 2H),
1.90 (m, 2H), 1.31 (m, 6H). Anal. (C17H24N2O4S ‚ 0.6H2O), C, H,
N. ESI MS: m/z 407 (M + Na + CH3OH)+.
(R)-1-(Naphthalen-1-ylsulfonyl)-N-((R,S)-1-oxo-3-phenylpro-
pan-2-yl)pyrrolidine-2-carboxamide (1e). Compound 1e was
obtained as a white foamy solid in 75.8% yield: mp 60-62 °C;
1H NMR (CDCl3, 300 MHz): δ 9.65 (s, 1H), 8.42 (s, 1H), 7.98
(m, 3H), 7.82 (m, 1H), 7.67 (m, 2H), 7.31 (m, 6H), 4.71 (q, J )
7.5, 7.5 Hz, 1H), 4.25 (m, 1H), 3.56 (m, 1H), 3.22 (m, 3H), 2.11
(m, 1H), 1.74 (m, 1H), 1.58 (m, 2H). Anal. (C24H24N2O4S‚
0.16H2O), C, H, N. ESI MS: m/z 491 (M + Na + CH3OH)+.
(R)-1-(4-Bromophenylsulfonyl)-N-((S)-1-hydroxy-3-phenyl-
propan-2-yl)pyrrolidine-2-carboxamide (5m). Compound 5m was
obtained as a white crystalline solid in 50.4% yield. 1H NMR
(CDCl3): δ 7.48 (m, 4H), 7.29 (m, 5H), 7.03 (d, J ) 7.50 Hz,