L. Lintnerová et al. / European Journal of Medicinal Chemistry 72 (2014) 146e159
157
4.2.10. 5-[3,5-Di(pyridin-3-yl)phenyl]-N-[5-(ethylsulfonyl)-2-
methoxyphenyl]oxazol-2-amine (33SYM)
HeC(500)), 7.29 (d, 1H, J(3,4) ¼ 8.6 Hz, HeC(3)), 4.00 (s, 3H, eOCH3),
3.22 (q, 2H,
J
(CH2,CH3)
¼
7.2 Hz, eCH2e), 1.13 (t, 3H,
J
A mixture of 110.0 mg (0.213 mmol, 1.00 mol eq) 5-(3,5-
dibromophenyl)-N-[5-(ethylsulfonyl)-2-methoxyphenyl]oxazol-2-
amine (6), 6.0 mg (0.005 mmol, 0.024 mol eq) tetrakis(-
triphenylphosphine)palladium(0) in 5 ml of 1,2-dimethoxyethane
was stirred at rt within 10 min. Then a solution of 60.0 mg
(0.49 mmol, 2.29 mol eq) 3-pyridinylboronic acid in 2 ml of 1 M
aqueous Na2CO3 was added and the reaction mixture was gently
refluxed within 1 h. The mixture was cooled to rt and 30 ml of
water was added. After separation of organic layer, the water so-
lution was extracted 3 ꢂ 5 ml of CHCl3. The combined organic layer
was extracted with 5 ml of 1 M Na2CO3 aqueous solution, dried by
standing over Na2SO4, filtered and the solvent was removed by RVE
and HV. The crude mixture was separated by FLC (silica, MeOH : EA
(1:3)). The product 63.0 mg (0.123 mmol, 57.8%) 33SYM was ob-
(CH2,CH3) ¼ 7.2 Hz, eCH3). 13C NMR (75 MHz, DMSO-d6):
d
155.5
(C200), 155.2 (C2ox), 150.5 (C2), 149.6 (C600), 144.0 (C5ox), 141.8 (C50),
137.1 (C400),132.4 (C5),131.0 (C1),130.9 (C20),128.6 (C40),126.0 (C60),
123.5 (C30), 123.0 (C500), 122.7 (C4ox), 120.8 (C300), 120.0 (C4), 115.4
(C6), 109.6 (C3), 56.3 (eOCH3), 50.7 (eCH2e), 7.6 (eCH3). Anal.
calcd. for C23H20BrN3O4S (514.39): C, 53.70; H, 3.92; Br, 15.53; N,
8.17; S, 6.23; found: C, 53.52; H, 3.86; Br, 15.57; N, 8.00; S, 6.02.
4.2.12. N-[5-(Ethylsulfonyl)-2-methoxyphenyl]-5-[3-(pyridin-2-yl)-
5-(pyridin-3-yl)phenyl]oxazol-2-amine (23ASYM)
The mixture of 50.0 mg (0.097 mmol, 1.00 mol eq) 5-(3-bromo-
5-(pyridin-2-yl)phenyl)-N-(5-(ethylsulfonyl)-2-methoxyphenyl)
oxazol-2-amine (8), 31.0 mg (0.097 mmol, 1.00 mol eq) tetrabuty-
lammonium bromide, 7.0 mg (0.0061 mmol, 0.062 mol eq) tetra-
kis(triphenylphosphine)palladium(0), 36.0 mg (0.097 mmol,
1.00 mol eq) 3-(tributylstannyl)pyridine in 1 ml of AN was sealed
under Ar and heated by stirring at 100 ꢀC for 48 h. After cooling, the
tube was opened and its content washed out with 25 ml of EA. Then
10 ml of 1 M aqueous KF solution was added to EA suspension and
stirred for 3 h at rt. The organic layer was separated and the water
layer extracted with 3 ꢂ 10 ml of EA. The combined organic layer
was dried by standing over an anhydrous Na2SO4, filtered and
evaporated by RVE and later on by HV to dryness. The crude
mixture was separated by FLC (SiO2; EA:Hex (2:1)). The required
product 31.0 mg (0.060 mmol, 62.3%) 23ASYM was obtained in a
tained as white powder. Mp: 206.0e207.0 ꢀC [FLC]. IR
n (solid,
cmꢁ1): 3426 (m, NH), 2924 (m), 2852 (m), 1613 (s), 1553 (s), 1524
(m), 1430 (m), 1301 (s, S]O), 1264 (s), 1122 (s, S]O), 1022 (s), 706
(m). 1H NMR (300 MHz, DMSO-d6):
d
8.96 (d, 1H, J(200,400) ¼ 2.0 Hz,
HeC(200)), 8.88 (d, 1H, J(4,6) ¼ 2.2 Hz, HeC(6)), 8.62 (dd, 1H,
J(500,600) ¼ 5.0 Hz, J(400,600) ¼ 1.8 Hz, HeC(600)), 8.06 (ddd, 1H,
J(400,500) ¼ 7.9 Hz, J(200,400) ¼ 2.0 Hz, J(400,600) ¼ 1.8 Hz, HeC(400)), 7.81
(d, 2H, J(20,40) ¼ 1.6 Hz, HeC(20)), 7.72 (s, 1H, NH), 7.67 (t, 1H, J
(20,40)
J(4,6)
¼
1.6 Hz, HeC(40)), 7.60 (dd, 1H, J(3,4)
2.2 Hz, HeC(4)), 7.48 (dd, 1H, J(400,500)
¼
¼
8.5 Hz,
7.9 Hz,
¼
J(500,600) ¼ 5.0 Hz, HeC(500)), 7.36 (s, 1H, HeC(4ox)), 7.04 (d, 1H,
J(3,4) ¼ 8.5 Hz, HeC(3)), 4.05 (s, 3H, eOCH3), 3.17 (q, 2H,
J(CH2,CH3) ¼ 7.5 Hz, eCH2e),1.30 (t, 3H, J(CH2,CH3) ¼ 7.5 Hz, eCH3).
form of a white powder. Mp: 195.0e197.0 ꢀC [FLC]. IR
n (solid,
cmꢁ1): 3398 (w, NH), 2939 (w), 1610 (s), 1575 (s), 1526 (m), 1488
13C NMR (75 MHz, DMSO-d6):
d
155.5 (C2ox), 150.5 (C2), 148.9 (C200),
(w), 1429 (m), 1301 (m, S]O), 1265 (s), 1142 (s), 1123 (s), 1083 (m),
148.0 (C600), 144.8 (C5ox), 139.5 (C30), 135.9 (C400), 134.9 (C300), 131.0
(C1), 129.7 (C5), 128.7 (C10), 124.9 (C40), 123.9 (C20), 123.2 (C4ox),
122.8 (C4), 121.4 (C500), 115.4 (C6), 109.5 (C3), 56.4 (-OCH3), 50.7 (e
CH2e), 7.6 (eCH3). Anal. calcd. for C28H24N4O4S (512.58): C, 65.61;
H, 4.72; N, 10.93; S, 6.26; found: C, 65.23; H, 4.58; N, 10.79; S, 6.16.
1020 (w). 1H NMR (300 MHz, DMSO-d6):
d 8.98 (d, 1H,
J(2000,4000) ¼ 1.7 Hz, HeC(2000)), 8.89 (d, 1H, J(4,6) ¼ 2.1 Hz, HeC(6)),
8.76 (ddd, 1H, J(500,600) ¼ 4.9 Hz, J(400,600) ¼ 1.8 Hz, J(300,600) ¼ 0.9 Hz,
HeC(600)), 8.67 (dd, 1H, J(5000,6000) ¼ 4.9 Hz, J(4000,6000) ¼ 1.5 Hz, He
C(60’’)), 8.25 (dd, 1H, J(20,40) ¼ 1.7 Hz, J(20,60) ¼ 1.5 Hz, HeC(20)), 8.12
(dd, 1H, J(40,60) ¼ 1.7 Hz, J(20,60) ¼ 1.5 Hz, HeC(60)), 8.05 (ddd, 1H,
J(4000,5000) ¼ 7.7 Hz, J(2000,4000) ¼ 1.7 Hz, J(4000,600) ¼ 1.5 Hz, HeC(4000)),
7.91 (ddd, 1H, J(300,400) ¼ 7.9 Hz, J(300,500) ¼ 1.4 Hz, J(300,600) ¼ 0.9 Hz,
HeC(300)), 7.85 (ddd, 1H, J(300,400) ¼ 7.9 Hz, J(400,500) ¼ 7.4 Hz,
J(400,600) ¼ 1.8 Hz, HeC(400)), 7.82 (dd, 1H, J(20,40) ¼ J(40,60) ¼ 1.7 Hz,
HeC(40)), 7.72 (s br, 1H, NH), 7.59 (dd, 1H, J(3,4) ¼ 8.7 Hz,
J(4,6) ¼ 2.1 Hz, HeC(4)), 7.44 (dd, 1H, J(4000,5000) ¼ 7.7 Hz,
J(5000,6000) ¼ 4.9 Hz, HeC(5000)), 7.37 (s, 1H, HeC(4ox)), 7.32 (ddd, 1H,
J(400,500) ¼ 7.4 Hz, J(500,600) ¼ 4.9 Hz, J(300,500) ¼ 1.4 Hz, HeC(500)), 7.03
(d, 1H, J(3,4) ¼ 8.7 Hz, HeC(3)), 4.05 (s, 3H, eOCH3), 3.17 (q, 2H,
J(CH2,CH3) ¼ 7.3 Hz, eCH2e), 1.30 (t, 2H, J(CH2,CH3) ¼ 7.3 Hz, eCH3).
4.2.11. 5-[3-Bromo-5-(pyridin-2-yl)phenyl]-N-[5-(ethylsulfonyl)-2-
methoxyphenyl]oxazol-2-amine (8)
A mixture of 50.0 mg (0.097 mmol, 1.00 mol eq) 5-(3,5-
dibromophenyl)-N-[5-(ethylsulfonyl)-2-methoxyphenyl]oxazol-2-
amine (6), 31.0 mg (0.096 mmol, 1.00 mol eq) tetrabutylammonium
bromide, 7.0 mg (0.0061 mmol, 0.063 mol eq) tetrakis(-
triphenylphosphine)palladium(0), 36.0 mg (0.097 mmol, 1.00 mol
eq) 2-(tributylstannyl)pyridine in 1 ml of AN was sealed in a dry
glass Pasteur tube under Ar. The reaction mixture was stirred and
heated at 100 ꢀC for 48 h. Then the tube was opened and the
mixture poured into 25 ml of EA and 10 ml of 1 M aqueous solution
of KF. The mixture was stirred for 3 h at rt. The organic layer was
separated and the water layer extracted 3 ꢂ 10 ml of EA. The
combined organic layers were dried by standing over Na2SO4,
filtered and evaporated to dryness by RVE and HV. An obtained
solid material was separated by FLC (SiO2, EA:Hex (2:1)). The
product 26.0 mg (0.051 mmol, 52.0%) 8 was a white powder. Mp:
13C NMR (75 MHz, DMSO-d6) : 156.3 (C200), 156.1 (C2ox), 150.5 (C2),
d
149.8 (C600), 148.9 (C2000), 148.3 (C6000), 143.7 (C5ox), 140.9 (C30), 139.2
(C50), 137.1 (C400), 136.1 (C4000), 134.8 (C3000), 131.0 (C1), 129.4 (C5),
128.8 (C10), 124.8 (C40), 123.7 (C60), 122.9 (C20), 122.8 (C500), 122.7
(C4ox), 121.2 (C5000), 120.9 (C300), 120.1 (C4), 115.3 (C6), 109.6 (C3),
56.3 (eOCH3), 50.7 (eCH2e), 7.6 (eCH3). Anal. calcd. for
C28H24N4O4S (512.58): C, 65.61; H, 4.72; N, 10.93; S, 6.26; found: C,
183.0e186.0 ꢀC [EA]. IR
n
(solid, cmꢁ1): 3342 (w, NH), 3102 (m),
65.19; H, 4.61; N, 10.88; S, 6.13.
2923 (m), 1602 (m), 1575 (s), 1425 (m), 1306 (m, S]O), 1263 (m),
1122 (s, S]O), 1083 (m), 1020 (w), 734 (m), 717 (m). 1H NMR
4.3. Biological evaluation
(300 MHz, DMSO-d6):
d
9.92 (s, 1H, NH), 8.80 (d, 1H, J(4,6) ¼ 2.3 Hz,
HeC(6)), 8.72 (ddd, 1H, J(500,600) ¼ 4.8 Hz, J(400,600) ¼ 1.8 Hz,
J(300,600) ¼ 0.9 Hz, HeC(600)), 8.36 (dd, 1H, J(20,40) ¼ J(20,60) ¼ 1.5 Hz,
HeC(60)), 8.15 (dd,1H, J(20,40) ¼ J(40,60) ¼ 1.5 Hz, HeC(40)), 8.11 (ddd,
1H, J(300,400) ¼ 8.0 Hz, J(300,500) ¼ J(300,600) ¼ 0.9 Hz, HeC(300)), 7.96
(ddd, 1H, J(300,400) ¼ 8.0 Hz, J(400,500) ¼ 7.8 Hz, J(400,600) ¼ 1.8 Hz, He
C(400)), 7.92 (dd, 1H, J(20,40) ¼ J(20,60) ¼ 1.5 Hz, HeC(20)), 7.80 (s, 1H,
HeC(4ox)), 7.52 (dd, 1H, J(3,4) ¼ 8.6 Hz, J(4,6) ¼ 2.3 Hz, HeC(4)),
7.45 (ddd, 1H, J(400,500) ¼ 7.8 Hz, J(500,600) ¼ 4.8 Hz, J(300,500) ¼ 0.9 Hz,
4.3.1. Materials
Bovine aortic endothelial cells (BAEC) were obtained by colla-
genase digestion and maintained in Dulbecco’s modified Eagle’s
medium (DMEM) containing glucose (1 g/L), glutamine (2 mM),
penicillin (50 IU/mL), streptomycin (50
mg/mL) and amphoterycin
(1.25 g/mL) supplemented with 10% FBS. All the cancer cell lines
m
used in this study were obtained from the American Type Culture
Collection (ATCC). Human fibrosarcoma HT1080 cells were