Inhibition of Phospholipase A2 by 2-Oxoamides
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 14 3625
166.0, 148.4, 135.7, 128.6, 128.3, 120.5, 72.2, 66.4, 49.5, 34.9,
34.7, 33.9, 31.9, 29.5, 29.3, 27.7, 25.0, 24.9, 22.6, 22.4, 22.3,
14.1, 13.8.
Com p ou n d s 17a -e were synthesized from compounds
14a -c by procedures H, G, and A.
mp 112-113 °C; [R]D -0.7 (c 0.7, CH3Cl); 1H NMR δ 6.93 (1H,
d, J ) 9 Hz, NH), 4.03 (1H, m, CH), 2.91 (2H, t, J ) 7.8 Hz,
CH2COCO), 2.39 (2H, m, CH2COOH), 1.85 (2H, m, CH2), 1.59
(2H, m, CH2), 1.25 (23H, m, 10 × CH2, CH3), 0.88 (3H, t, J )
6.7 Hz, CH3); 13C NMR δ 199.4, 178.3, 159.7, 45.1, 36.7, 31.9,
31.3, 30.7, 29.6, 29.4, 29.3, 29.0, 23.1, 22.7, 20.7,14.1; MS (FAB)
m/z (%) 356 (100) [M+ + H].
Met h yl (4S)-4-[(2-h yd r oxyp en t a d eca n oyl)a m in o]oc-
1
ta n oa te (17a ): yield 75%; yellow oil; H NMR δ 6.39 (1H, m,
AX012, AX013, AX016, AX017, a n d AX024 were synthe-
sized from compounds 17a -e by procedures B and C.
(4R)-6-Meth yl-4-[(2-oxopen tadecan oyl)am in o]h eptan o-
ic a cid (AX012): yield 67%; white solid; mp 58-59 °C; [R]D
-9.0 (c 1.28 CH3Cl); 1H NMR δ 6.95 (1H, d, J ) 9.2 Hz, NH),
4.00 (1H, m, CH), 2.91 (2H, t, J ) 7.8 Hz, CH2COCO), 2.30
(2H, m, CH2COOH), 1.91 [3H, m, CH2, CH(CH3)2], 1.59 (4H,
m, 2 × CH2), 1.25 (20H, m, 10 × CH2), 0.91 (9H, t, J ) 6.8 Hz,
3 × CH3); 13C NMR δ 199.3, 178.8, 160.0, 47.3, 44.1, 36.8, 31.8,
31.1, 30.4, 29.5, 29.3, 29.2, 28.9, 24.7, 23.0, 22.9, 22.5, 21.9,
13.9; MS (FAB) m/z (%) 398 (100) [M+ + H].
(4R)-6-Met h yl-4-[(2-oxod od eca n oyl)a m in o]h ep t a n oic
a cid (AX013): yield 83%; white solid; mp 55-56 °C; [R]D -9.5
(c 1.3 CH3Cl); 1H NMR δ 6.83 (1H, d, J ) 9 Hz, NH), 4.02
(1H, m, CH), 2.91 (2H, t, J ) 7.8 Hz, CH2COCO), 2.36 (2H, m,
CH2COOH), 1.91 [3H, m, CH2, CH(CH3)2], 1.59 (4H, m, 2 ×
CH2), 1.25 (14H, m, 7 × CH2), 0.91 (9H, t, J ) 6.8 Hz, 3 ×
CH3); 13C NMR δ 199.4, 178.4, 160.1, 47.4, 44.3, 36.8, 31.8,
30.7, 30.4, 29.5, 29.4, 29.3, 29.2, 29.0, 24.9, 23.2, 22.9, 22.6,
22.0, 14.1; MS (FAB) m/z (%) 400 (100) [M+ + 2Na - 1], 378
(46) [M+ + Na].
NH), 4.08 (2H, m, 2 × CH), 3.66 (3H, s, OCH3), 2.95 (1H, br,
OH), 2.34 (2H, m, CH2COO), 1.97-1.42 (6H, m, 3 × CH2),
1.38-1.15 (26H, m, 13 × CH2), 0.98-0.81 (6H, m, 2 × CH3);
13C NMR δ 174.2, 173.8, 72.1, 51.7, 48.7, 35.0, 31.9, 30.8, 30.2,
29.6, 29.5, 29.4, 29.3, 27.9, 25.0, 22.6, 22.5, 14.0, 13.9.
Meth yl (4R)-4-[(2-h yd r oxyocta n oyl)a m in o]-5-p h en yl-
1
p en ta n oa te 17b): yield 80%; white solid; mp 75-77 °C; H
NMR δ 7.23 (5H, m, C6H5), 6.31 (1H, d, J ) 8.4 Hz, NH), 4.20
(1H, m, CH), 4.01 (1H, m, CH), 3.65 (3H, s, OCH3), 2.82-2.64
(3H, m, CH2C6H5, OH), 2.35 (2H, m, CH2COO), 2.02-1.15
(12H, m, 6 × CH2), 0.87 (3H, t, J ) 6.6 Hz, CH3); 13C NMR δ
174.0, 173.6, 137.4, 129.2, 128.6, 126.5, 72.0, 51.7, 49.7, 41.4,
35.0, 31.6, 30.9, 29.0, 24.8, 22.5, 14.0.
Met h yl (4R)-4-[(2-h yd r oxyp en t a d eca n oyl)a m in o]-5-
p h en ylp en ta n oa te (17c): yield 86%; white solid; mp 53-55
°C; 1H NMR δ 7.23 (5H, m, C6H5), 6.47 (1H, m, NH), 4.20 (1H,
m, CH), 4.01 (1H, m, CH), 3.65 (3H, s, OCH3), 2.90 (1H, br,
OH), 2.81 (2H, m, CH2C6H5), 2.35 (2H, m, CH2COO), 2.02-
1.42 (4H, m, 2 × CH2), 1.38-1.12 (22H, m, 11 × CH2), 0.88
(3H, t, J ) 6.6 Hz, CH3); 13C NMR δ 174.0, 173.8, 137.4, 129.3,
128.4, 126.6, 72.1, 51.7, 49.7, 41.3, 34.9, 31.9, 30.9, 29.6, 29.5,
29.4, 29.3, 29.0, 24.9, 22.6, 14.1.
(4R)-4-[(2-Oxopen tadecan oyl)am in o]-5-ph en ylpen tan o-
ic a cid (AX016): yield 82%; white solid; mp 91-92 °C; [R]D
-6.1 (c 0.8, CH3Cl); 1H NMR δ 7.33-7.14 (5H, m, C6H5), 6.97
(1H, d, J ) 9 Hz, NH), 4.20 (1H, m, CH), 2.86 (4H, m, CH2C6H5,
CH2COCO), 2.37 (2H, t, J ) 7.2 Hz, CH2COOH), 1.95 (1H, m,
CHH), 1.81 (1H, m, CHH), 1.56 (2H, m, CH2), 1.26 (20H, m,
10 × CH2), 0.89 (3H, t, J ) 6.8 Hz, CH3); 13C NMR δ 199.2,
178.0, 160.0, 136.9, 129.2, 128.6, 126.8, 50.3, 41.1, 36.7, 31.9,
30.7, 29.6, 29.4, 29.3, 29.0, 28.9, 23.1, 22.7, 14.1; MS (FAB)
m/z (%) 476 (65) [M+ + 2Na - 1], 454 (30) [M+ + Na].
(4R)-4-[(2-Oxooctan oyl)am in o]-5-ph en ylpen tan oic acid
(AX017): yield 75%; pale-yellow solid; mp 94-96 °C; [R]D -8.7
(c 0.24, CH3Cl); 1H NMR δ 7.38-7.14 (5H, m, C6H5), 6.95 (1H,
d, J ) 9 Hz, NH), 4.20 (1H, m, CH), 2.86 (4H, m, CH2C6H5,
CH2COCO), 2.37 (2H, t, J ) 7.4 Hz, CH2COO), 1.97 (1H, m,
CHH), 1.78 (1H, m, CHH), 1.57 (2H, m, CH2), 1.26 (6H, m, 3
× CH2), 0.87 (3H, t, J ) 6.8 Hz, CH3); 13C NMR δ 199.2, 177.6,
160.0, 136.9, 128.7, 128.1, 127.0, 50.3, 41.1, 36.7, 31.5, 28.7,
26.3, 22.4, 14.0; MS (FAB) m/z (%) 334 (57) [M+ + H].
(4S)-4-[(2-Oxop en t a n od eca n oyl)a m in o]oct a n oic a cid
(AX024): yield 56%; white solid; mp 74-75 °C; [R]D -1.6 (c
0.6, CH3Cl); 1H NMR δ 6.85 (1H, d, J ) 9.8 Hz, NH), 3.93
(1H, m, CH), 2.92 (2H, t, J ) 7.4 Hz, CH2COCO), 2.37 (2H, t,
J ) 7.1 Hz, CH2COO), 2.03-1.44 (6H, m, 3 × CH2), 1.42-
1.17 (24H, m, 12 × CH2), 0.91-0.83 (6H, t, J ) 6.3 Hz, 2 ×
CH3); 13C NMR δ 199.4, 178.1, 160.1, 49.3, 36.8, 34.7, 31.9,
30.8, 30.0, 29.6, 29.4, 29.3, 29.0, 28.0, 23.2, 22.7, 22.4, 14.1,
13.9; MS (FAB) m/z (%) 398 (100) [M+ + H].
Meth yl (4R)-4-[(2-Hyd r oxyd od eca n oyl)a m in o]-6-m eth -
ylh ep ta n oa te (17d ): yield 65%; yellow oil; 1H NMR δ 6.35
(1H, m, NH), 4.04 (2H, m, 2 × CH), 3.65 (3H, s, OCH3), 3.22
(1H, br, OH), 2.34 (2H, t, J ) 7.6 Hz, CH2COO), 1.47-1.95
(5H, m, 2 × CH2, CH), 1.40-1.18 (18H, m, 9 × CH2), 0.95-
0.78 (9H, m, 3 × CH3); 13C NMR δ 174.1, 173.8, 72.0, 51.6,
46.8, 46.6, 44.7, 44.5, 34.9, 31.9, 30.8, 30.6, 29.6, 29.5, 29.4,
25.1, 24.9, 23.0, 22.6, 22.0, 14.0.
Met h yl (4R)-4-[(2-h yd r oxyp en t a d eca n oyl)a m in o]-6-
1
m eth ylh ep ta n oa te (17e): yield 63%; yellow oil; H NMR δ
6.37 (1H, m, NH), 4.04 (2H, m, 2 × CH), 3.65 (3H, s, OCH3),
3.15 (1H, br, OH), 2.34 (2H, t, J ) 7.8 Hz, CH2COO), 1.95-
1.47 (5H, m, 2 × CH2, CH), 1.40-1.18 (24H, m, 12 × CH2),
0.95-0.81 (9H, m, 3 × CH3); 13C NMR δ 174.0, 173.8, 72.1,
51.6, 46.8, 46.6, 44.7, 44.5, 34.9, 31.9, 30.8, 30.6, 29.6, 29.5,
29.4, 29.3, 25.0, 24.9, 23.0, 22.6, 22.1, 14.0.
ter t-Bu tyl (4S)-4-[(2-Hyd r oxyp en ta d eca n oyl)a m in o]-
p en ta n oa te (18). Compound 18 was synthesized from com-
pound 15 by procedure H (using EtOH instead of MeOH)
followed by procedure A (using 2.2 mmol of Et3N instead of
1
4.4 mmol of Et3N). Yield 92%; wax; H NMR δ 6.48 (1H, m,
NH), 4.12-3.90 (2H, m, 2 × CH), 3.05 (1H, br, OH), 2.27 (2H,
t, J ) 7.8 Hz, CH2CO2), 1.98-1.52 (4H, m, 2 × CH2), 1.44 [9H,
s, C(CH3)3], 1.40-1.21 (22H, m, 11 × CH2), 1.16 (3H, d, J )
6.6 Hz, CH3), 0.88 (3H, t, J ) 6.6 Hz, CH3); 13C NMR δ 173.5,
173.0, 80.6, 72.0, 44.8, 35.0, 32.3, 31.9, 31.6, 29.6, 29.5, 29.4,
29.3, 28.0, 24.9, 22.6, 21.0, 14.1.
AX018 a n d AX019 were synthesized from Boc-L-prolinol by
procedures E-H and A-C.
(4S)-4-[(2-Oxododecan oyl)am in o]octan oic Acid (AX007).
AX007 was synthesized from compound 16 by procedure H
(using EtOH instead MeOH) followed by procedure C. Yield
(S)-3-[1-(2-Oxop en t a d eca n oyl)p yr r olid in -2-yl]p r op i-
on ic a cid (AX018): Pale-yellow solid; mp 55-56 °C; [R]D -42.7
(c 1.0, CH3Cl); 1H NMR δ 4.21 (1H, m, CH), 3.54 (2H, m, CH2-
NH), 2.84 (2H, m, CH2COCO), 2.35 (2H, m, CH2COOH), 2.01-
1.41 (8H, m, 4 × CH2), 1.25 (20H, m, 10 × CH2), 0.86 (3H, t,
J ) 6.6 Hz, CH3); 13C NMR δ 201.0, 177.9, 163.6, 57.1, 47.2,
39.2, 31.8, 31.1, 29.6, 29.4, 29.3, 29.1, 29.0, 28.4, 24.2, 22.9,
22.6, 14.1; MS (FAB) m/z (%) 426 (100) [M+ + 2Na - 1], 404
(27) [M+ + Na].
1
57%; white solid; mp 50-52 °C; [R]D -1.8 (c 0.5, CH3Cl); H
NMR δ 6.86 (1H, d, J ) 9.4 Hz, NH), 3.90 (1H, m, CHNH),
2.90 (2H, t, J ) 7.8 Hz, CH2COCO), 2.35 (2H, t, J ) 6.3 Hz,
CH2COO), 2.01-1.05 (24H, m, 12 × CH2), 0.87 (3H, t, J ) 6.0
Hz, CH3); 13C NMR δ 199.4, 178.5, 160.1, 49.3, 36.8, 34.7, 31.8,
30.7, 29.8, 29.5, 29.3, 29.2, 29.0, 27.9, 23.1, 22.6, 22.4, 14.1,
13.9; MS (FAB) m/z (%) 378 (35) [M+ + Na], 356 (45) [M+
H].
+
(S)-3-[1-(2-Oxod od eca n oyl)p yr r olid in -2-yl]p r op ion ic
1
AX008 was synthesized in a similar way to AX007. The
spectroscopic data were identical to those obtained for the (S)-
enantiomer. [R]D -1.6 (c 0.5, CH3Cl).
(4S)-4-[(2-Oxop en t a d eca n oyl)a m in o]p en t a n oic Acid
(AX014). AX014 was synthesized from compound 18 by
procedure D followed by procedure I. Yield 63%; white solid;
a cid (AX019): yellow oil; [R]D -37.7 (c 0.5, CH3Cl); H NMR
δ 4.21 (1H, m, CH), 3.54 (2H, m, CH2NH), 2.84 (2H, m, CH2-
COCO), 2.35 (2H, m, CH2COOH), 2.01-1.41 (8H, m, 4 × CH2),
1.25 (14H, m, 7 × CH2), 0.86 (3H, t, J ) 7 Hz, CH3); 13C NMR
δ 201.0, 177.6, 164.1, 57.1, 47.2, 39.3, 31.9, 31.2, 29.5, 29.4,
29.3, 29.1, 28.6, 24.2, 22.9, 22.6, 14.1.