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A. H. Romero et al. / Bioorg. Med. Chem. 23 (2015) 4755–4762
4.1.4.6.
40-Chloro-6-(piperidin-1-ylmethyl)-[1,10-biphenyl]-3-
1H, J = 9.1 Hz, J = 2.2 Hz), 7.65 (d, 1H, J = 8.4 Hz, J = 2.2 Hz), 7.40–
7.54 (m, 6H), 7.10 (d, 1H, J = 6.9 Hz), 4.31 (s, 2H, CH2-N), 2.51 (br
s, 4H, CH2-N), 1.66 (6H, CH2). 13C NMR (60 MHz, d ppm, DMSO-
d6): 155.0, 145.7, 144.6, 139.8, 139.2, 138.5, 133.7, 129.9, 129.5,
128.7, 128.2, 126.9, 126.5, 126.4, 124.5, 120.1, 116.8, 101.6, 56.2
(CH2-N), 52.7 (CH2-N), 22.6 (CH2), 21.45 (CH2). Anal. Calcd (dihy-
drochloride salt) for C27H28Cl3N3: C, 64.74; H, 5.63; N, 8.39.
Found: C, 64.85; H, 5.70; N, 8.29.
amine 10f. Light yellow solid, 70%, mp 145–147 °C. IR (KBr,
m
cmꢀ1): 3422, 3307 (st. N–H). 1H NMR (400 MHz, d ppm, CDCl3):
7.46 (d, 1H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.2 Hz), 7.28 (d, 2H,
J = 8.4 Hz), 6.68 (dd, 1H, J = 8.3 Hz, J = 2.5), 6.52 (d, 1H, J = 2.5 Hz),
3.74 (s, NH2), 3.47 (s, 2H, CH2-N), 2.37 (br s, 4H, CH2), 1.61 (br s,
4H, CH2), 1.39 (2H, CH2). 13C NMR (100 MHz, d ppm, CDCl3):
145.9, 143.0, 139.9, 132.6, 130.9, 128.3, 116.5, 114.6, 59.1 (CH2-
N), 53.5 (CH2-N), 25.0 (CH2), 23.8 (CH2). Anal. Calcd for
C18H21ClN2: C, 71.87; H, 7.04; N, 9.31. Found: C, 71.94; H, 7.08;
4.1.5.3. 7-Chloro-N-(6-(morpholinomethyl)-[1,10-biphenyl]-3-
yl)quinolin-4-amine dihydrochloride 11c. Yellow solid, 79%,
N, 9.27.
mp 232–234 °C. IR (KBr,
m
cmꢀ1): 3528, 3446 (st. N–H). 1H NMR
4.1.4.7.
40-Chloro-6-(morpholinomethyl)-[1,10-biphenyl]-3-
cmꢀ1):
(400 MHz, d ppm, DMSO-d6): 8.79 (d, 1H, J = 9.2 Hz), 8.54 (d, 1H,
H2, J = 7.0 Hz), 8.07 (m, 2H), 7.86 (d, 1H, J = 9.2 Hz), 7.63 (d, 1H,
J = 7.3 Hz) 7.42–7.53 (m, 6H), 7.10 (d, 1H, J = 7.0 Hz), 4.34 (br s,
4H, CH2-O), 3.80 (br s, 2H, CH2-N), 2.49 (br s, 4H, CH2-N). 13C
NMR (100 MHz, d ppm, DMSO-d6): 155.2, 145.7, 144.2, 139.6,
139.3, 139.2, 138.5, 133.9, 129.9, 129.4, 128.7, 128.2, 127.0,
126.7, 126.3, 124.6, 119.9, 116.8, 101.5, 63.5 (CH2-O), 56.6 (CH2-
N), 51.7 (CH2-N). Anal. Calcd (dihydrochloride salt) for
amine 10g. Yellow solid, 79%, mp 105–107 °C. IR (KBr,
m
3314, 3212 (st. N–H). 1H NMR (270 MHz, d ppm, CDCl3): 7.31 (m,
5H), 6.68 (dd, 1H, J = 8.2 Hz, J = 2.5 Hz), 6.54 (d, 1H, J = 2.5 Hz),
3.71 (s, 2H, CH2-O), 3.64 (s, 2H, NH2), 3.45 (s, 2H, CH2-N), 2.42
(br s, 4H, CH2-N). 13C NMR (100 MHz, d ppm, CDCl3): 146.2,
143.2, 139.8, 133.3, 132.6, 130.8, 128.3, 116.5, 114.6, 66.2 (CH2-
O), 59.2 (CH2-N), 52.6 (CH2-N). Anal. Calcd for C17H19ClN2O: C,
67.43; H, 6.32; N, 9.25. Found: C, 67.49; H, 6.37; N, 9.28.
C26H26Cl3N3O: C, 62.10; H, 5.21; N, 8.36. Found: C, 62.18; H,
5.17; N, 8.42.
4.1.4.8. 40-Chloro-6-(pyrrolidin-1-ylmethyl)-[1,10-biphenyl]-3-
amine 10h. Yellow solid, 71%, mp 99–101 °C. IR (KBr,
m
cmꢀ1):
4.1.5.4. 7-Chloro-N-(6-(pyrrolidin-1-ylmethyl)-[1,10-biphenyl]-
3-yl)quinolin-4-amine dihydrochloride 11d. Yellow solid, 87%,
mp 228–230 °C. IR (KBr,
3430, 3280 (est. N–H). 1H NMR (270 MHz, d ppm, CDCl3): 7.29–
7.33 (m, 4H), 6.67 (d, 1H, J = 8.2 Hz, J = 2.5 Hz), 6.53 (d, 1H,
J = 3.0 Hz), 3.67 (s, 2H, CH2-N), 2.41 (br s, 4H, CH2-N), 1.70 (br s,
4H, CH2). 13C NMR (60 MHz, d ppm, CDCl3): 145.3, 142.0, 140.2,
132.9, 131.6, 130.9, 128.1, 116.4, 114.6, 56.5 (CH2-N), 53.6 (CH2-
N), 23.4 (CH2). Anal. Calcd for C17H19ClN2: C, 71.19; H, 6.68; N,
9.77. Found: C, 71.24; H, 6.64; N, 9.80.
m
cmꢀ1): 3525, 3400 (st. N–H). 1H NMR
(400 MHz, d ppm, DMSO-d6): 8.72 (d, 1H, J = 9.5 Hz), 8.52 (d, 1H,
J = 7.4 Hz), 8.05 (d, 1H, J = 2.2 Hz), 7.94 (d, 1H, J = 8.1 Hz), 7.85 (d,
1H, J = 9.5 Hz), 7.62 (dd, 1H, J = 7.0 Hz, J = 2.2 Hz), 7.40–7.55 (m,
6H), 7.07 (d, 1H, J = 7.0 Hz), 4.38 (s, 2H, CH2-N), 2.49 (br s, 4H,
CH2-N), 1.80 (br s, 4H, CH2). 13C NMR (60 MHz, d ppm, DMSO-
d6): 155.0, 145.0, 144.6, 139.9, 139.2, 139.0, 138.7, 132.9, 129.8,
129.5, 128.8, 128.2, 127.9, 126.9, 126.4, 124.6, 120.2, 116.8,
101.5, 54.1 (CH2-N), 53.8 (CH2-N), 22.6 (CH2). Anal. Calcd (dihy-
drochloride salt) for C26H26Cl3N3: C, 64.14; H, 5.38; N, 8.63.
Found: C, 64.23; H, 5.44; N, 8.57.
4.1.5. General procedure for the preparation of 4-amino-
quinolines 11a–h
To a solution of 4,7-dichloroquinoline (1 mmol) in ethanol
(20 mL) was added concentrated hydrochloric acid (1 equiv), fol-
lowed by the corresponding aniline (10a–h) (1 mmol) previously
dissolved in ethanol (10 mL). The reaction mixture was heated
under reflux with continuous stirring for 6 h. The mixture was then
cooled at room temperature and the precipitated solid was fil-
trated, washed with ethanol and dried under vacuo to yield the
desired quinolines 11a–h as their practically pure dihydrochloride
salts.
4.1.5.5.
methyl)-[1,10-biphenyl]-3-yl)quinolin-4-amine dihydrochloride
11e. Orange solid, 38%, mp 238–240 °C. IR (KBr,
cmꢀ1): 3448
7-Chloro-N-(40-chloro-6-((4-methylpiperazin-1-yl)
m
(est. N–H). 1H NMR (400 MHz, d ppm, DMSO-d6): 11.27 (s, 1H),
8.90 (d, 1H, J = 6.4 Hz), 8.56 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H,
J = 1.8 Hz), 7.90 (dd, 1H, J = 1.8 Hz, J = 9.5 Hz), 7.51–760 (m, 6H),
7.42 (d, 1H, J = 1.5 Hz), 7.02 (d, 1H, J = 7.4 Hz), 3.51 (s, 2H, CH2-
N), 2.75 (m, 8H, CH2-N), 2.09 (s, 3H, N-CH3). 13C NMR (100 MHz,
d ppm, DMSO-d6): 155.3, 144.1, 143.5, 139.5, 139.2, 138.6, 137.3,
133.3, 132.9, 131.8, 129.2, 129.0, 128.2, 126.9, 126.6, 124.7,
119.8, 116.7, 101.3, 52.2 (CH2-N), 49.0 (CH2-N), 42.6 (CH2-N),
31.2 (N-CH3). Anal. Calcd (dihydrochloride salt) for C27H28Cl4N4:
C, 58.93; H, 5.13; N, 10.18. Found: C, 58.99; H, 5.09; N, 10.25.
4.1.5.1. 7-Chloro-N-(6-((diethylamino)methyl)-[1,10-biphenyl]-
3-yl)quinolin-4-amine monohydrochloride 11a. In this case,
concentrated HCl was added as a catalyst (1 drop). Beige solid,
82%, mp 198–200 °C. IR (KBr,
m
cmꢀ1): 3342 (st. N–H). 1H NMR
(400 MHz, d ppm, DMSO-d6): 9.11 (s, 1H, N–H), 8.44 (d, 1H, H2,
J = 5.5 Hz), 8.38 (d, 1H, H6, J = 9.2 Hz), 7.88 (d, 1H, H8, J = 2.2 Hz),
7.58 (d, 1H, H5, J = 8.4 Hz), 7.53 (dd, 1H, J = 8.8 Hz, J = 2.2 Hz),
7.34–7.43 (m, 6H), 7.15 (d, 1H, J = 2.2 Hz), 7.01 (d, 1H, J = 5.5 Hz),
3.43 (s, 2H, CH2-N), 2.34 (q, 4H, CH2-N), 0.82 (t, 6H, CH3). 13C
NMR (100 MHz, d ppm, DMSO-d6): 151.5, 149.8, 148.7, 143.4,
141.0, 138.7, 134.7, 133.5, 131.4, 129.7, 128.7, 127.8, 127.7,
125.7, 124.9, 124.0, 121.7, 118.8, 102.3, 54.2 (CH2-N), 46.6 (CH2-
N), 11.9 (CH3). Anal. Calcd (monohydrochloride salt) for
4.1.5.6.
biphenyl]-3-yl)quinolin-4-amine dihydrochloride 11f. Yellow
solid, 84%, mp 260 °C decomp. IR (KBr,
cmꢀ1): 3441 (st. N–H).
7-Chloro-N-(40-chloro-6-(piperidin-1-ylmethyl)-[1,10-
m
1H NMR (270 MHz, d ppm, DMSO-d6): 8.42 (d, 1H, J = 8.8 Hz),
8.30 (d, 1H, J = 7.0 Hz), 7.91 (s, 1H), 7.74 (d, 1H, J = 8.2 Hz), 7.70
(d, 1H, J = 9.2 Hz), 7.54 (dd, 1H, J = 1.8 Hz, J = 8.2 Hz), 7.48 (d, 2H,
J = 7.7 Hz), 7.33 (m, 3H), 7.03 (d, 1H, J = 7.0 Hz), 4.27 (s, 2H, CH2-
N), 2.66 (m, 4H, CH2-N), 1.82 (br s, 4H, CH2), 1.66 (br s, 2H, CH2).
13C NMR (100 MHz, d ppm, DMSO-d6): 155.2, 144.7, 143.7, 139.9,
139.2, 138.4, 137.5, 133.9, 133.6, 131.5, 129.4, 128.5, 126.8,
126.1, 125.4, 124.9, 119.8, 101.3, 55.4 (CH2-N), 52.9 (CH2-N), 22.5
(CH2), 21.2 (CH2). Anal. Calcd (dihydrochloride salt) for
C26H28Cl3N3: C, 69.03; H, 6.02; N, 9.29. Found: C, 69.12; H, 6.09;
N, 9.35.
4.1.5.2. 7-Chloro-N-(6-(piperidin-1-ylmethyl)-[1,10-biphenyl]-3-
yl)quinolin-4-amine dihydrochloride 11b. Yellow solid, 90%,
mp 252–254 °C. IR (KBr,
m
cmꢀ1): 3524, 3446 (st. N–H). 1H NMR
(400 MHz, d ppm, DMSO-d6): 8.77 (d, 1H, J = 8.8 Hz), 8.54 (d, 1H,
C27H27Cl4N3: C, 60.58; H, 5.08; N, 7.85. Found: C, 60.49; H, 5.03;
J = 6.8 Hz), 8.10 (d, 1H, J = 1.8 Hz), 8.06 (d, 1H, J = 8.4 Hz), 7.85 (d,
N, 7.91.