Highly Potent HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3475
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N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H-p yr a n -3-yl)-2,2-d im eth ylp r op yl]p h en yl)-5-tr i-
flu or om eth yl-2-p yr id in esu lfon a m id e (37): 1H NMR (CD3-
OD) δ 0.73 (m, 12H), 1.28-1.08 (m, 4H), 1.68-1.40 (m, 2H),
2.5-2.25 (m, 4H), 3.88 (s, 1H), 7.09-6.70 (m, 8H), 7.19 (m,
1H), 7.87-7.7 (m, 1H), 8.07-7.95 (m, 1H), 8.78 (m, 1H); FAB-
HRMS calcd for C33H37N2O5F3S 540.1906, found 540.1938.
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N-(3-[1-(5,6-d ih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H -p yr a n -3-yl)-2,2-d im e t h ylp r op yl]p h e n yl)-5-
a m in o-2-p yr id in esu lfon a m id e (38): 1H NMR δ 7.87 (m,
1H), 7.44 (d, 1H), 7.27 (s, 1H), 7.2-6.7 (m, 8H), 3.99 (s, 1H),
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2.6-2.4 (m, 4H), 1.9-0.8 (m, 9H), 0.88 (s, 9H); EI-MS M+
)
577 found for C32H39N3O5S.
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N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39a ): 1H NMR (CDCl3) δ 0.80
(t, J ) 7.2 Hz, 3H), 0.92 (t, J ) 7.1 Hz, 3H), 1.37 (m, 4H), 1.69
(m, 4H), 1.91 (m, 2H), 2.13 (m, 1H), 2.51 (m, 1H), 2.50 (d, J )
17.2 Hz, 1H), 2.69 (d, J ) 17.2 Hz, 1H), 3.95 (dd, 1H), 6.88 (d,
J ) 7.0 Hz, 1H), 6.97 (m, 1H), 7.25-7.04 (m, 5H), 8.00 (d, J )
8.2 Hz, 1H), 8.17 (d, J ) 8.2 Hz, 1H), 8.91 (s, 1H); FAB-MS
m/z (rel intensity) 603 (MH+, 99), 735 (18), 625 (12), 605 (11),
604 (34), 603 (99), 585 (28), 201 (16), 134 (14), 133 (35), 91
(38); EI-HRMS calcd for C31H33F3N2O5S1 602.2062, found
602.2053. Anal. (C31H33F3N2O5S1) C, H, N, S.
N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39b, P NU-140690): 1H NMR
(CD3OD) δ 0.93-1.03 (m, 6H), 1.36-1.47 (m, 2H), 1.79-2.13
(m, 6H), 2.18-2.30 (m, 1H), 2.63-2.81 (m, 4H), 4.04 (m, 1H),
7.09-7.36 (m, 9H), 8.16 (d, J ) 8.1 Hz, 1H), 8.33 (m, 1H), 9.08
(m, 1H); [R]D +20° (ethanol); HRMS calcd for C31H33N2O5F3S1
+ H1 603.2140, found 603.2153. Anal. (C31H33N2O5F3S1) C,
H, N, S.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39c): mp 93-95 °C; 1H NMR
(CD3OD) δ 8.94 (s, 1H), 8.20 (d, J ) 8.3 Hz, 1H), 8.01 (d, J )
8.2 Hz, 1H), 7.24-6.93 (m, 10H), 3.92 (dd, J ) 7.0, 9.3 Hz,
1H), 2.68-2.51 (m, 4H), 2.22-2.05 (m, 1H), 1.98-1.64 (m, 5H),
1.36-1.28 (m, 2H), 0.90-0.80 (m, 6H); 13C NMR (75 MHz,
CD3OD) δ 168.5, 165.5, 160.1, 146.7, 146.2, 141.4, 136.3, 135.6,
128.8, 128.4, 128.1, 127.8, 125.6, 124.7, 122.7, 121.1, 118.8,
104.7, 80.4, 42.2, 39.4, 39.1, 36.0, 31.4, 29.5, 24.4, 16.5, 13.3,
11.9; [R]D (MeOH, c 0.80) -21°; HRMS calcd for C31H33N2O5F3S1
+ H1 603.2140, found 603.2149. Anal. (C31H33N2O5SF3) C, H,
N.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39d ): mp 156-159 °C; 1H NMR
(CD3OD) δ 8.90 (s, 1H), 8.16 (d, J ) 8.3 Hz, 1H), 8.00 (d, J )
8.2 Hz, 1H), 7.26 (s, 1H), 7.20-6.97 (m, 7H), 6.88 (d, J ) 6.9
Hz, 2H), 3.95 (dd, J ) 6.9, 9.2 Hz, 1H), 2.69-2.40 (m, 4H),
2.20-2.10 (m, 1H), 1.96-1.82 (m, 2H), 1.79-1.61 (m, 3H),
1.40-1.28 (m, 2H), 0.94-0.80 (m, 6H); 13C NMR (75 MHz,
CD3OD) δ 168.2, 165.5, 160.1, 146.6, 146.0, 141.4, 136.3, 135.6,
128.8, 128.4, 128.1, 127.8, 125.5, 124.8, 122.8, 121.0, 118.8,
104.8, 80.4, 41.8, 39.4, 39.0, 36.0, 31.4, 29.4, 24.2, 16.5, 13.3,
11.8; [R]D (MeOH, c 1.5) -31°; HRMS calcd for C31H33N2O5F3S1
+ H1 603.2140, found 603.2154. Anal. (C31H33N2O5SF3) C, H,
N.
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in Complex with VX-478, a Potent and Orally Bioavailable
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1182.
(18) Kaldor, S. W.; Kalish, V. J .; Davies, J . F., II; Shetty, B. V.; Fritz,
J . E.; Appelt, K.; Burgess, J . A.; Campanale, K. M.; Chirgadze,
N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D.
A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A.
K.; Reich, S. H.; Su, K. S.; Tatlock, J . H. Viracept (Nelfinavir
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HIV-1 Protease. J . Med. Chem. 1997, 40, 3979-3985.
(19) Mimoto, T.; Imai, J .; Kisanuki, S.; Enomoto, H.; Hattori, N.;
Akaju, K.; Kiso, Y. Kynostatin KNI-227 and -272, Highly Potent
Anti-HIV Agents: Conformationally Constrained Tripeptide
Inhibitors of HIV Protease Containing Allophenylnorstatine.
Chem. Pharm. Bull. 1992, 40, 2251-2253.
Ack n ow led gm en t. We thank Tom M. J udge for
synthesis of compound 39a and J eanette K. Morris for
synthesis of compounds 39c and 39d .
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