ꢀ ꢁ
T. Tomasic et al. / European Journal of Medicinal Chemistry 46 (2011) 3964e3975
3971
d
1.96e2.21 (m, 2H, CHCH2CH2), 2.49 (2H, CHCH2CH2, signal over-
CONHCS) ppm. MS (ESIþ): m/z (%) ¼ 395 ([M þ H]þ, 100). Anal.
lapped with DMSO-d5), 3.59 (s, 3H, CH3), 3.67 (s, 3H, CH3),
4.46e4.54 (m, 1H, CHCH2CH2), 7.63e7.67 (m, 2H, CH]C, AreH-5),
7.77 (d, 1H, J ¼ 7.8 Hz, AreH-4/6), 7.98 (d, 1H, J ¼ 7.8 Hz, AreH-4/6),
8.06 (s, 1H, AreH-2), 8.89 (d, 1H, J ¼ 7.4 Hz, CONH), 13.88 (br s, 1H,
CONHCS) ppm. MS (ESIþ): m/z (%) ¼ 423 ([M þ H]þ, 100). Anal.
(C18H18N2O6S2) C, H, N.
(C16H14N2O6S2) C, H, N.
5.1.11. (R,Z)-Dimethyl 2-(2-fluoro-5-((4-oxo-2-thioxothiazolidin-5-
ylidene)methyl)benzamido)pentanedioate [(R)-17]
Prepared from 2-thioxothiazolidin-4-one (0.038 g, 0.29 mmol)
and (R)-5 (0.094 g, 0.29 mmol) according to general procedure A.
The crude product was purified with flash column chromatography
5.1.7. (R,Z)-2-(3-((2,4-Dioxothiazolidin-5-ylidene)methyl)benzamido)
pentanedioic acid [(R)-15]
using CH2Cl2/MeOH (30:1) as eluent. Yield: 63%; orange needles;
20
m.p. 168e171 ꢀC; [
a
]
þ21.4 (c 0.24, DMF); IR (KBr):
n
¼ 3433,
D
Prepared from [(R)-13] (0.202 g, 0.50 mmol) according to
1750, 1725, 1647, 1546, 1496, 1436, 1230, 1191, 1121, 1064, 808,
general procedure B. Yield: 96%; colourless prisms; m.p.
680 cmꢃ1 1H NMR (CDCl3):
.
d
2.14e2.40 (m, 2H, CHCH2CH2),
20
127e130 ꢀC; [
a
]
D
þ28.5 (c 0.22, DMF); IR (KBr):
n
¼ 3163, 3957,
2.43e2.55 (m, 2H, CHCH2CH2), 3.70 (s, 3H, CH3), 3.83 (s, 3H, CH3),
4.87e4.94 (m, 1H, CHCH2CH2), 7.30 (dd, 1H, FJ ¼ 11.0 Hz, 3J ¼ 8.6 Hz,
1741, 1702, 1535, 1484, 1412, 1322, 1290, 1216, 1162, 1104, 107, 921,
810, 756, 679 cmꢃ1 1H NMR (DMSO-d6):
.
d
1.91e2.18 (m, 2H,
AreH-3), 7.43 (dd, 1H, J ¼ 7.5 Hz, 4J ¼ 2.5 Hz, AreH-6), 7.59e7.64
F
CHCH2CH2), 2.38 (d, 2H, J ¼ 7.5 Hz, CHCH2CH2), 4.40e4.47 (m, 1H,
CHCH2CH2), 7.65 (t, 1H, J ¼ 7.8 Hz, AreH-5), 7.77 (d, 1H, J ¼ 7.8 Hz,
AreH-4/6), 7.84 (s, 1H, CH]C), 7.97 (d, 1H, J ¼ 7.8 Hz, AreH-4/6),
8.09 (s, 1H, AreH-2), 8.73 (d, 1H, J ¼ 7.8 Hz, CONH), 12.41 (br s, 2H,
2ꢂ COOH), 12.66 (br s, 1H, CONHCO) ppm. MS (ESIþ): m/z (%) ¼ 379
([M þ H]þ, 100). Anal. (C16H14N2O7S) C, H, N.
(m, 2H, CH]C, AreH-4), 8.24 (dd, 1H, J1 ¼ 7.4 Hz, J2 ¼ 2.5 Hz,
CONH), 9.62 (br s, 1H, CONHCS) ppm. MS (ESIꢃ): m/z (%) ¼ 439
([MꢃH]ꢃ, 100). HRMS (ESIꢃ): m/z [MꢃH]ꢃ calcd for C18H16FN2O6S2:
439.0434, found: 439.0432. Anal. (C18H17FN2O6S2) C, H, N.
5.1.12. (R,Z)-2-(2-Fluoro-5e((4-oxo-2-thioxothiazolidin-5-ylidene)
methyl)benzamido)pentanedioic acid [(R)-18]
5.1.8. (S,Z)-2-(3-((2,4-Dioxothiazolidin-5-ylidene)methyl)benzamido)
pentanedioic acid [(S)-15]
Prepared from (R)-17 (0.070 g, 0.16 mmol) according to general
procedure B. The crude product was purified with flash column
Prepared from [(S)-13] (0.200 g, 0.49 mmol) according to
chromatography using CH2Cl2/MeOH (30:1) as eluent. Yield: 63%;
20
general procedure B. Yield: 69%; colourless prisms; m.p. 92e93 ꢀC;
orange needles; m.p. 108e109 ꢀC; [
a
]
þ17.8 (c 0.31, DMF); IR
D
20
[
a]
ꢃ26.9 (c 0.25, DMF); IR (KBr):
n
¼ 3160, 3057, 2768, 1698,
(KBr):
n
¼ 3423, 3366, 2853,1716,1658,1534,1493,1434,1292,1191,
D
1644, 1578, 1538, 1485, 1416, 1333, 1288, 1215, 1161, 1103, 1018, 916,
1094,1064, 879, 820, 670 cmꢃ1. 1H NMR (DMSO-d6):
d
1.86e2.14 (m,
811, 755, 681 cmꢃ1 1H NMR (DMSO-d6):
.
d
1.91e2.18 (m, 2H,
2H, CHCH2CH2), 2.36e2.40 (m, 2H, CHCH2CH2), 4.40e4.46 (m, 1H,
CHCH2CH2), 7.50 (dd,1H, FJ ¼ 9.7 Hz, 3J ¼ 8.6 Hz, AreH-3), 7.72 (s,1H,
CH]C), 7.78e7.84 (m, 2H, AreH-4, AreH-6), 8.74 (d, 1H, J ¼ 7.1 Hz,
CONH),12.51 (br s, 2H, 2ꢂ COOH),13.90 (br s,1H, CONHCS) ppm. MS
(ESIꢃ): m/z (%) ¼ 411 ([MꢃH]ꢃ, 90), 384 (100), 324 (85). 13C NMR
CHCH2CH2), 2.38 (d, 2H, J ¼ 7.5 Hz, CHCH2CH2), 4.40e4.47 (m, 1H,
CHCH2CH2), 7.65 (t, 1H, J ¼ 7.8 Hz, AreH-5), 7.77 (d, 1H, J ¼ 7.8 Hz,
AreH-4/6), 7.84 (s, 1H, CH]C), 7.97 (d, 1H, J ¼ 7.8 Hz, AreH-4/6),
8.09 (s, 1H, AreH-2), 8.73 (d, 1H, J ¼ 7.8 Hz, CONH), 12.41 (br s, 2H,
2ꢂ COOH), 12.66 (br s, 1H, CONHCO) ppm. MS (ESIþ): m/z (%) ¼ 379
([M þ H]þ, 100). Anal. (C16H14N2O7S ꢂ 0.25H2O) C, H, N.
(CD3OD):
d
27.7, 31.2, 53.8, 118.7 (d, 2J(C,F) ¼ 24 Hz), 125.1 (d,
2J(C,F) ¼ 15 Hz), 128.4, 130.5, 131.6 (d, 3J(C,F) ¼ 3 Hz), 133.9 (d,
4J(C,F) ¼ 2 Hz), 136.0 (d, 3J(C,F) ¼ 9 Hz), 162.0 (d, 1J(C,F) ¼ 257 Hz),
165.8,170.8,174.5,176.4,196.2 ppm. HRMS (ESIꢃ): m/z [MꢃH]ꢃ calcd
for C16H12FN2O6S2: 411.0121, found: 411.0140.
5.1.9. (R,Z)-2-(3-((4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)
benzamido)pentanedioic acid [(R)-16]
Prepared from [(R)-14] (0.147 g, 0.35 mmol) according to
general procedure B. The crude product was purified by flash
5.1.13. (R,Z)-Dimethyl 2-(4-((2-imino-4-oxothiazolidin-5-ylidene)
methyl)benzamido)pentanedioate [(R)-19]
Prepared from 2-iminothiazolidin-4-one (0.135 g, 1.16 mmol)
and (R)-4 (0.356 g, 1.16 mmol) according to general procedure A.
column chromatography using CH2Cl2/MeOH/AcOH (7:1:0.1) as
20
eluent. Yield: 90%; red prisms; m.p. 200e203 ꢀC; [
a
]
þ21.2 (c
D
0.28, DMF); IR (KBr): ¼ 3395, 3032, 1706, 1648, 1598, 1534,
1483, 1441, 1198, 1100, 1065, 1009, 913, 808, 750, 675 cmꢃ1
NMR (DMSO-d6): 1.91e2.18 (m, 2H, CHCH2CH2), 2.39 (d, 2H,
n
.
1H
The crude product was recrystallized from methanol. Yield: 23%;
20
d
orange needles; m.p. 221e224 ꢀC; [
a
]
þ5.2 (c 0.27, DMF); IR
D
J ¼ 7.5 Hz, CHCH2CH2), 4.40e4.48 (m, 1H, CHCH2CH2), 7.63e7.68
(m, 2H, CH]C, AreH-5), 7.77 (d, 1H, J ¼ 7.8 Hz, AreH-4/6), 7.99
(d, 1H, J ¼ 7.8 Hz, AreH-4/6), 8.08 (s, 1H, AreH-2), 8.75 (d, 1H,
J ¼ 7.5 Hz, CONH), 12.47 (br s, 2H, 2ꢂ COOH), 13.88 (br s, 1H,
(KBr):
n
¼ 3199, 3010, 1737, 1644, 1534, 1438, 1371, 1268, 1006, 897,
841, 771, 696 cmꢃ1
.
1H NMR (DMSO-d6):
d
1.96e2.20 (m, 2H,
CHCH2CH2), 2.47 (d, 2H, J ¼ 7.5 Hz, CHCH2CH2), 3.59 (s, 3H, CH3),
3.66 (s, 3H, CH3), 4.45e4.52 (m, 1H, CHCH2CH2), 7.64e7.69 (m, 3H,
CH]C, AreH-2,6/3,5), 7.99 (d, 2H, J ¼ 8.4 Hz, AreH-2,6/3,5), 8.85 (d,
1H, J ¼ 7.4 Hz, CONH), 9.37 (br s, 2H, 2ꢂ NH) ppm. MS (ESIþ): m/z
(%) ¼ 428 ([M þ Na]þ, 100), 406 ([M þ H]þ, 55). 13C NMR (CD3OD):
CONHCS) ppm. 13C NMR (CD3OD):
d 27.7, 31.6, 54.0, 128.8, 130.2,
130.7, 130.9, 131.6, 134.0, 135.2, 136.6, 169.4, 170.9, 175.2, 176.7,
196.5 ppm. MS (ESIþ): m/z (%) ¼ 395 ([M þ H]þ, 100). Anal.
(C16H14N2O6S2) C, H, N.
d
27.4, 31.3, 52.5, 53.0, 53.7, 129.1, 129.4, 129.6, 130.7, 135.5, 139.1,
169.1, 173.6, 174.7, 178.2, 182.9 ppm. HRMS (ESIþ): m/z [M þ H]þ
5.1.10. (S,Z)-2-(3-((4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)
benzamido)pentanedioic acid [(S)-16]
calcd for C18H20N3O6S: 406.1073, found: 406.1072.
Prepared from [(S)-14] (0.197 g, 0.47 mmol) according to general
5.1.14. (R,Z)-2-(4-((2-Imino-4-oxothiazolidin-5-ylidene)methyl)
benzamido)pentanedioic acid [(R)-20]
procedure B. Yield: 98%; orange prisms; m.p. 252e255 ꢀC;
20
[
a]
ꢃ19.9 (c 0.26, DMF); IR (KBr):
n
¼ 3414, 3061, 2852, 1709,
Prepared from (R)-19 (0.083 g, 0.21 mmol) according to general
D
1638, 1591, 1483, 1444, 1401, 1311, 1289, 1197, 1068, 1013, 805, 754,
procedure B. Yield: 87%; yellow prisms; m.p. >300 ꢀC; [
a
]
D
20 ꢃ5.7
675 cmꢃ1. 1H NMR (DMSO-d6):
d
1.91e2.18 (m, 2H, CHCH2CH2), 2.39
(c 0.28, DMF); IR (KBr):
n
¼ 3240, 3036, 1724, 1640, 1534, 1501, 1367,
(d, 2H, J ¼ 7.5 Hz, CHCH2CH2), 4.40e4.48 (m, 1H, CHCH2CH2),
7.63e7.68 (m, 2H, CH]C, AreH-5), 7.77 (d, 1H, J ¼ 7.8 Hz, AreH-4/
6), 7.99 (d, 1H, J ¼ 7.8 Hz, AreH-4/6), 8.08 (s, 1H, AreH-2), 8.75 (d,
1H, J ¼ 7.5 Hz, CONH), 12.47 (br s, 2H, 2ꢂ COOH), 13.88 (br s, 1H,
1284, 1206, 1135, 905, 841, 768 cmꢃ1 1H NMR (DMSO-d6):
.
d
1.91e2.17 (m, 2H, CHCH2CH2), 2.37 (d, 2H, J ¼ 7.4 Hz, CHCH2CH2),
4.38e4.46 (m, 1H, CHCH2CH2), 7.64 (s, 1H, CH]C), 7.67 (d, 2H,
J ¼ 8.4 Hz, AreH-2,6/3,5), 8.00 (d, 2H, J ¼ 8.4 Hz, AreH-2,6/3,5), 8.72