N. Sunduru et al. / European Journal of Medicinal Chemistry 46 (2011) 1232e1244
1239
NMR (200 MHz, CDCl3):
d
(ppm) 14.22 (s, 1H), 8.74 (s, 1H), 7.95 (d,
61.57, 47.73, 24.52, 11.57. Anal. Calc for C21H17F5N2O3: C: 57.24, H:
3.79, N: 6.36. Found: C: 57.29, H: 3.85, N: 6.38.
1H, J ¼ 11.78 Hz), 7.63 (d, 2H, J ¼ 7.80 Hz), 7.25 (m, 2H), 5.66 (s, 2H),
3.35 (m, 4H), 2.62e2.45 (m, 6H), 1.20 (t, 3H, J ¼ 7.30 Hz). 13C
(50 MHz, CDCl3): 176.83, 166.61, 151.58, 150.45, 139.63, 139.37,
132.45, 131.52, 126.76, 126.68, 121.63, 114.51, 109.26, 108.84, 61.75,
53.49, 52.85, 50.91, 12.24. Anal. Calc for C24H22F5N3O3: C: 58.18, H:
4.48, N: 8.48. Found: C: 58.14, H: 4.39, N: 8.51.
6.6.24. 6,8-Difluoro-7-(isopropylamino)-4-oxo-1-(4-
(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid (31)
Yield: 76%; mp 213e215 ꢀC; ESMS: 441 (M þ 1); IR (KBr): 3387,
3056, 2967, 2935, 1722, 1623, 1544, 1465, 1334, 1260, 1167,
1049 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d (ppm) 14.70 (s, 1H), 8.68
6.6.19. 6,8-Difluoro-4-oxo-7-(4-phenylpiperazin-1-yl)-1-(4-
(s, 1H), 7.93 (d, 1H, J ¼ 11.84 Hz), 7.62 (d, 2H, J ¼ 7.76 Hz), 7.26 (m,
2H), 5.65 (s, 2H), 4.02 (m, 1H), 1.17 (d, 6H, J ¼ 5.98 Hz). 13C (50 MHz,
CDCl3): 176.65, 167.72, 151.54, 140.27, 139.43, 132.38, 131.64, 126.71,
126.65, 121.37, 116.82, 109.95, 108.57, 61.64, 47.28, 24.35. Anal. Calc
for C21H17F5N2O3: C: 57.28, H: 3.89, N: 6.36. Found: C: 57.26, H: 3.84,
N: 6.27.
(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid (26)
Yield: 83%; mp 232e234 ꢀC; MS: 544 (M þ 1); IR (KBr): 3428,
3017, 2941, 2766, 1718, 1636, 1570, 1443, 1325, 1242, 1137,
1061 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d (ppm) 14.52 (s, 1H), 7.99
(d,1H, J ¼ 11.68 Hz), 7.64 (d, 2H, J ¼ 7.40 Hz), 7.32e7.26 (m, 6H), 6.98
(m, 1H), 5.68 (s, 2H), 3.30e3.19 (m, 8H). 13C (50 MHz, CDCl3):
176.94, 166.76, 151.31, 150.95, 148.36, 139.54, 138.55, 132.42, 131.64,
129.75, 126.78, 126.62, 126.11, 120.93, 116.72, 115.36, 109.64, 108.78,
61.92, 51.35, 50.46. Anal. Calc for C28H22F5N3O3: C: 61.88, H: 4.08, N:
7.73. Found: C: 61.84, H: 4.05, N: 7.71.
6.6.25. 6,8-Difluoro-7-(2-morpholinoethylamino)-4-oxo-1-(4-
(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid (32)
Yield: 75%; mp 169e171 ꢀC; ESMS: 512 (M þ 1); IR (KBr): 3345,
3049, 2927, 2871, 1717, 1632, 1560, 1485, 1321, 1110, 1079 cmꢁ1; 1H
NMR (200 MHz, CDCl3):
d (ppm) 14.84 (s, 1H), 8.65 (s, 1H), 7.93 (d,
6.6.20. 7-(4-Benzylpiperazin-1-yl)-6,8-difluoro-4-oxo-1-(4-
1H, J ¼ 12.02 Hz), 7.63 (d, 2H, J ¼ 7.52 Hz), 7.26 (m, 2H), 5.64 (s, 2H),
5.25 (bs, 1H), 3.68 (m, 4H), 3.52 (m, 2H), 2.59 (m, 2H), 2.45 (m, 4H).
13C (50 MHz, CDCl3): 176.75, 166.92, 151.54, 150.94, 139.57, 132.43,
131.58, 126.75, 126.52, 126.27, 121.76, 116.51, 108.56, 108.18, 67.34,
61.73, 57.39, 53.46, 41.25. Anal. Calc for C24H22F5N3O4: C: 56.36, H:
4.34, N: 8.22. Found: C: 56.32, H: 4.29, N: 8.26.
(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid (27)
Yield: 78%; mp >250 ꢀC; ESMS: 558 (M þ 1); IR (KBr): 3425, 3045,
2926, 2817, 1722, 1624, 1526, 1467, 1332, 1298, 1126, 1058. cmꢁ1; 1H
NMR (200 MHz, CDCl3): d (ppm) 14.53 (s,1H), 8.73 (s,1H), 7.96 (d,1H,
J ¼ 11.58 Hz), 7.62 (d, 2H, J ¼ 7.36 Hz), 7.35e7.26 (m, 5H), 7.19 (m, 2H),
5.64 (s, 2H), 3.56 (m, 2H), 3.34 (m, 4H), 2.63 (m, 4H). 13C (50 MHz,
CDCl3): 176.78, 167.27, 151.43, 150.95, 147.46, 139.51, 135.62, 132.67,
131.26, 129.75, 129.52, 128.84, 126.71, 126.59, 121.72, 116.75, 109.81,
108.96, 63.44, 61.78, 53.74, 51.19. Anal. Calc for C29H24F5N3O3: C:
62.48, H: 4.34, N: 7.54. Found: C: 62.41, H: 4.36, N: 7.48.
6.6.26. 6,8-Difluoro-7-(3-morpholinopropylamino)-4-oxo-1-(4-
(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid (33)
Yield: 71%; mp 188e190 ꢀC; ESMS: 526 (M þ 1); IR (KBr): 3356,
3052, 2925, 2855, 1720, 1629, 1561, 1481, 1327, 1119, 1065 cmꢁ1; 1H
NMR (200 MHz, CDCl3):
d (ppm) 14.86 (s, 1H), 8.64 (s, 1H), 7.89 (d,
6.6.21. 7-(Butylamino)-6,8-difluoro-4-oxo-1-(4-(trifluoromethyl)
benzyl)-1,4-dihydroquinoline-3-carboxylic acid (28)
1H, J ¼ 12.3 Hz), 7.62 (d, 2H, J ¼ 7.72 Hz), 7.26 (m, 3H), 5.63 (s, 2H),
3.66 (m, 6H), 2.56 (m, 6H),1.65 (m, 2H). 13C (50 MHz, CDCl3): 176.75,
167.17, 150.82, 147.45, 139.63, 132.65, 131.72, 126.68, 126.54, 126.47,
121.85, 115.39, 108.61, 108.26, 66.84, 61.62, 61.36, 54.06, 30.12,
24.65. Anal. Calc for C25H24F5N3O4: C: 57.14, H: 4.60, N: 8.00, Found:
C: 57.06, H: 4.57, N: 8.04.
Yield: 72%; mp 208e210 ꢀC; MS: 455 (M þ 1); IR (KBr): 3372,
3018, 2927, 1724, 1622, 1549, 1436, 1335, 1217, 1136, 1064 cmꢁ1; 1H
NMR (200 MHz, CDCl3):
d (ppm) 15.16 (s, 1H), 9.05 (s, 1H),
7.81e7.67 (m, 3H), 7.32 (d, 2H, J ¼ 8.12 Hz), 6.57 (bs, 1H), 5.91 (d,
2H, J ¼ 3.24 Hz), 3.24e3.21 (m, 2H), 1.25e1.06 (m, 4H), 0.73 (t, 3H,
J ¼ 7.02 Hz). 13C (50 MHz, CDCl3): 176.56, 166.52, 151.67, 140.18,
139.41, 132.53, 131.87, 126.65, 126.49, 121.32, 116.85, 109.94,
108.59, 61.78, 45.82, 33.23, 20.61, 14.25. Anal. Calc for
C22H19F5N2O3: C: 58.15, H: 4.21, N: 6.17. Found: C: 58.11, H: 4.16, N:
6.15.
6.7. General procedure for the synthesis of targeted compounds
34e51
To the solution of cyanuric chloride (2,4,6-trichloro-1,3,5-
triazine) in dry THF, Compound 10 (1 equiv.) was added in portion
during 30 min. After stirring for 1 h at room temperature, respec-
tive amines (2.2 equiv.) (Table 2) were added to the reaction
mixture and refluxed for 7 more hours. When the reaction was
completed, the reaction mixture was evaporated to dryness under
vacuum. The solid residue obtained was purified with flash column
chromatography using chloroform to methanol gradient elution to
obtain the final compounds 34e42. The same procedure was
carried out to synthesize targeted compounds 43e51 from the
compound 23.
6.6.22. 7-(Tert-butylamino)-6,8-difluoro-4-oxo-1-(4-
(trifluoromethyl)benzyl)-1,4-dihydroquinoline-3-carboxylic acid (29)
Yield: 76%; mp 155e157 ꢀC; ESMS: 455 (M þ 1); IR (KBr): 3343,
3017, 2942, 1729, 1618, 1560, 1456, 1324, 1215, 1173, 1102 cmꢁ1; 1H
NMR (200 MHz, CDCl3):
d (ppm) 14.72 (s, 1H), 8.86 (s, 1H), 7.97 (d,
1H, J ¼ 10.86 Hz), 7.62 (d, 2H, J ¼ 7.52 Hz), 7.26 (m, 2H), 5.67 (s, 2H),
1.24 (s, 9H). 13C (50 MHz, CDCl3): 176.54, 167.47, 150.93, 141.27,
139.54, 132.51, 131.95, 126.62, 126.17, 121.35, 116.86, 109.97, 108.51,
61.6, 51.16, 29.85. Anal. Calc for C22H19F5N2O3: C: 58.09, H: 4.21, N:
6.17. Found: C: 58.16, H: 4.24, N: 6.13.
6.7.1. 7-(4-(4,6-Dimorpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-1-
ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(34)
6.6.23. 6,8-Difluoro-4-oxo-7-(propylamino)-1-(4-(trifluoromethyl)
benzyl)-1,4-dihydroquinoline-3-carboxylic acid (30)
Yield: 64%; mp >250 ꢀC; ESMS: 587 (M þ 1); IR (KBr): 3058,
Yield: 75%; mp 203e205 ꢀC; ESMS: 441 (M þ 1); IR (KBr): 3347,
2927, 2853, 1727, 1563, 1458, 1267, 1122 cmꢁ1 1H NMR (CDCl3,
;
3071, 2975, 2880, 1717, 1632, 1565, 1421, 1323, 1268, 1111,
200 MHz):
d (ppm) 14.59 (bs, 1H), 8.63 (s, 1H), 7.99 (d, 1H,
1055 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
(ppm) 14.71 (s, 1H), 8.68
J ¼ 11.48 Hz), 4.48 (m, 2H), 4.02e3.79 (m, 12H), 3.61 (m, 8H), 3.31
(m, 4H), 1.58 (t, 3H, J ¼ 6.83 Hz). 13C (CDCl3, 50 MHz): 176.93, 167.41,
166.57, 150.13, 138.84, 115.24, 108.72, 67.27, 55.17, 51.54, 45.18, 16.11.
Anal. Calc for C27H32F2N8O5: C: 55.28, H: 5.50, N: 19.10. Found: C:
55.27, H: 5.42, N: 19.07.
(s, 1H), 7.93 (d, 1H, J ¼ 11.60 Hz), 7.62 (d, 2H, J ¼ 6.78 Hz), 7.26 (m,
2H), 5.64 (s, 2H), 3.39 (m, 2H), 1.59e1.52 (m, 2H), 0.92 (t, 3H,
J ¼ 6.90 Hz). 13C (50 MHz, CDCl3): 176.63, 167.87, 151.65, 141.39,
139.54, 132.32, 131.58, 126.72, 126.49, 121.36, 117.75, 109.81, 108.54,