Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2123
15 mL of isopropanol was added 4-chloro-8-methoxyquinoline
(17) (0.366 g, 1.89 mmol, 1 equiv). The mixture was refluxed with
stirring for overnight. It was then evaporated, and the concen-
trate was dissolved in CH2Cl2 (50 mL). The solution obtained
was washed with 5% NaHCO3 (3 ꢀ 50 mL), brine (2 ꢀ 50 mL)
and then dried over Na2SO4. The solution was filtered and
evaporated to dryness. The residue was purified through column
chromatography using 20% methanol in ethyl acetate to give
compound as an off-white solid. 1H NMR of HCl salt (400
MHz, DMSO-d6) δ ppm 0.93-0.95 (t, 3H, J = 4 Hz), 1.75 (m,
3H), 2.11-2.21 (m, 2H), 2.69-3.07 (m, 13H), 3.23 (s, 4H), 3.47
(s, 1H), 6.58 (s, 1H), 6.60-6.61 (d, 1H, J = 4 Hz), 6.91-6.93 (d,
1H, J = 8 Hz), 7.35-7.40 (m, 2H), 7.60-7.68 (m, 2H),
8.60-8.62 (d, 1H, J = 8 Hz). Hydrochloride salt, mp
244-246 °C. Anal. (C28H38.8N4O3.4 4HCl) C, H, N.
3
4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)
amino)ethyl)piperazin-1-yl)quinolin-8-ol (19b, Hydrochloride
Salt). This compound was prepared from 18b following proce-
dure J, giving 19b as an off-white solid (31%). 1H NMR of HCl
salt (400 MHz, DMSO-d6) δ ppm 0.92-0.95 (t, 3H, J = 6 Hz),
1.58-1.65 (m, 3H), 2.04-2.14 (m, 2H), 2.73-2.96 (m, 13H),
3.25 (bs, 4H), 3.48 (s, 1H), 6.55-6.57 (d, 1H, J = 8 Hz),
6.62-6.64 (d, 1H, J = 8 Hz), 6.92-6.96 (t, 1H, J = 8 Hz),
7.31-7.33 (d, 1H, J = 8 Hz), 7.39-7.41 (d, 1H, J = 8 Hz),
7.55-7.57 (m, 2H), 8.57-8.59 (d, 1H, J = 8 Hz). Hydrochloride
1
18a as a white wax (0.66 g, 73% yield). H NMR (400 MHz,
CDCl3) δ ppm 0.93-0.95 (t, 3H, 4 Hz), 1.75 (m, 3H), 2.11-2.21
(m, 2H), 2.69-3.07 (m, 13H), 3.23 (s, 4H), 3.47 (s, 1H), 4.02 (s,
3H), 6.60 (s, 1H), 6.66-6.68 (d, 1H, J = 8 Hz), 6.82-6.84 (t, 2H,
J = 4 Hz), 6.98-7.00 (d, 1H, J = 8 Hz), 7.36-7.42 (t, 1H, J =
12 Hz), 7.50-7.52 (d, 1H, J = 8 Hz), 8.67-8.68 (d, 1H, J =
4 Hz).
Preparation of 6-((2-(4-(8-Methoxyquinolin-4-yl)piperazin-1-
yl)ethyl)(propyl) amino)-5,6,7,8-tetrahydronaphthalen-1-ol (18b).
This compound was prepared from 9b (0.668 g, 2.1 mmol) and
17 (0.4 g, 2.1 mmol) following procedure I to get 18b as a white
salt, mp 249-251 °C. Anal. (C28H38.4N4O3.2 4HCl) C, H, N.
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(-)-4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-
(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol ((-)-19b, Hy-
drochloride Salt). This compound was prepared from (-)-18b
(0.480 g, 1.01 mmol) following procedure J to afford (-)-19b as
an off-white solid (0.21 g, 35%). 1H NMR (free base, 400 MHz,
CDCl3) δ ppm 0.95-0.99 (t, 3H, J = 8 Hz), 1.46-1.53 (m, 3H),
2.24-2.50 (m, 2H), 2.84-3.06 (m, 13H), 3.25 (bs, 4H),
3.49-3.67 (m, 1H), 6.52-6.54 (d, 1H, J = 8 Hz), 6.60-6.62
(d, 1H, J = 8 Hz), 6.85-6.86 (d, 1H, J = 4 Hz), 6.95-6.99 (t,
1H, J = 8 Hz), 7.10-7.12 (d, 1H, J = 8 Hz), 7.35-7.39 (t, 1H,
J = 8 Hz), 7.44-7.46 (d, 1H, 8 Hz), 8.57-8.58 (d, 1H, J = 4 Hz).
[R]25D -36° (c 0.5, CH3OH). Hydrochloride salt, mp 237-240 °C.
1
wax (yield 0.76 g, 75%). H NMR (400 MHz, CDCl3) δ ppm
0.92-0.95 (t, 3H, J = 6 Hz), 1.58-1.65 (m, 3H), 2.04-2.14 (m,
2H), 2.73-2.96 (m, 13H), 3.25 (bs, 4H), 3.48 (s, 1H), 4.04 (s, 3H),
6.57-6.59 (d, 1H, J = 8 Hz), 6.66-6.68 (d, 1H, J = 8 Hz),
6.86-6.87(d, 1H, J = 4 Hz), 6.92-6.96 (t, 1H, J = 8 Hz),
6.99-7.01 (d, 1H, J = 8 Hz), 7.37-7.41 (t, 1H, J = 8 Hz),
7.54-7.56 (d, 1H, J = 8 Hz), 8.72-8.73 (d, 1H, J = 4 Hz) .
Preparation of (-)-6-((2-(4-(8-Methoxyquinolin-4-yl)piper-
azin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol,
(-)-18b. This compound was prepared from (-)-9b (0.50 g, 1.6
mmol) and 17 (0.305 g, 1.6 mmol) following procedure I to
1
afford (-)-18b as a white wax (0.419 g, 56%). H NMR (400
Anal. (C28H37N4O2.5 4HCl) C, H, N.
3
MHz, CDCl3) δ ppm 0.98-1.00 (t, 3H, J = 4 Hz), 1.58-1.65 (m,
3H), 2.04-2.14 (m, 2H), 2.85-3.12 (m, 13H), 3.25 (bs, 4H), 3.48
(s, 1H), 4.06 (s, 3H), 6.57-6.59 (d, 1H, J = 8 Hz), 6.87-6.88 (d,
1H, J = 4 Hz), 6.92-6.97 (m, 2H), 7.01-7.03 (d, 1H, J = 8 Hz),
7.39-7.43 (t, 1H, J = 8 Hz), 7.54-7.57 (t, 1H, J = 6 Hz),
8.73-8.74 (d, 1H, J = 4 Hz).
(þ)-4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-
(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol ((þ)-19b, Hy-
drochloride Salt). This compound was prepared from (þ)-18b
(0.520 g, 1.10 mmol) following procedure J to make (þ)-19b as
an off-white solid (0.26 g, 39%). 1H NMR (free base, 400 MHz,
CDCl3) δ ppm 0.96-0.99 (t, 3H, J = 6 Hz), 1.47-1.52 (m, 3H),
2.24-2.50 (m, 2H), 2.85-3.05 (m, 13H), 3.25 (bs, 4H),
3.49-3.67 (m, 1H), 6.53-6.55 (d, 1H, J = 8 Hz), 6.61-6.63
(d, 1H, J = 8 Hz), 6.86-6.88 (d, 1H, J = 8 Hz), 6.95-6.99 (t,
1H, J = 8 Hz), 7.10-7.12 (d, 1H, J = 8 Hz), 7.34-7.38 (t, 1H,
J = 8 Hz), 7.46-7.48 (d, 1H, 8 Hz), 8.56-8.57 (d, 1H, J = 4 Hz).
[R]25D þ33.6° (c0.5, CH3OH). Hydrochloride salt, mp 230-232 °C.
(þ)-6-((2-(4-(8-Methoxyquinolin-4-yl)piperazin-1-yl)ethyl)-
(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol, (þ)-18b. This
compound was prepared from (þ)-9b (0.62 g, 1.95 mmol) and
17 (0.378 g, 1.95 mmol) following procedure I to make (þ)-18b as a
1
white wax (0.565 g, 61%). H NMR (400 MHz, CDCl3) δ ppm
0.97-0.99 (t, 3H, J = 4 Hz), 1.57-1.64 (m, 3H), 2.04-2.14 (m,
2H), 2.85-3.12 (m, 13H), 3.25 (bs, 4H), 3.48 (s, 1H), 4.06 (s, 3H),
6.57-6.59 (d, 1H, J = 8 Hz), 6.87-6.88 (d, 1H, J = 4 Hz),
6.93-6.97(m, 2H), 7.01-7.03 (d, 1H, J = 8 Hz), 7.38-7.42 (t, 1H,
J = 8 Hz), 7.53-7.56 (t, 1H, J = 6 Hz), 8.72-8.73 (d, 1H, 4 Hz).
(þ)-7-((2-(4-(8-Methoxyquinolin-4-yl)piperazin-1-yl)ethyl)-
(propyl)amino)-5,6,7,8-tetrahydronaphthalen-2-ol, (þ)-18a. This
compound was prepared from (þ)-9a (0.39 g, 1.22 mmol) and
17 (0.214 g, 1.11 mmol) following procedure I to get (þ)-18a as a
white wax (0.110 g, 19%). 1H NMR (400 MHz, CDCl3) δ ppm
0.93-0.95 (t, 3H, 4 Hz), 1.75 (m, 3H), 2.11-2.21 (m, 2H),
2.69-3.07 (m, 13H), 3.23 (s, 4H), 3.47 (s, 1H), 4.02 (s, 3H),
6.60 (s, 1H), 6.66-6.68 (d, 1H, J = 8 Hz), 6.82-6.84 (t, 2H, J =
4 Hz), 6.98-7.00 (d, 1H, J = 8 Hz), 7.36-7.42 (t, 1H, J = 12
Hz), 7.50-7.52 (d, 1H, J = 8 Hz), 8.67-8.68 (d, 1H, J = 4 Hz).
Procedure J. Preparation of 4-(4-(2-((7-Hydroxy-1,2,3,4-tet-
rahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazine-1-yl)-
quinolin-8-ol (19a, Hydrochloride Salt). Compound 18a (0.5 g,
1.05 mmol) and 48% aqueous HBr (10 mL) were refluxed for
overnight. It was then cooled and concentrated under vacuum,
and 50 mL of water was added to the crude residue and made
freebase with NaHCO3 powder which was then extracted with
CH2Cl2, dried over Na2SO4, filtered, and evaporated. The
greenish solid crude product was dissolved in a minimum
amount of ethanol, at which time ethereal HCl was added,
and the crude salt was filtered and dried over vacuum oven. The
crude salt was then purified by recrystallization in ethanol. The
HCl salt was filtered and dried to yield 0.329 g (26%) of the final
Anal. (C28H41N4O4.5 4HCl) C, H, N.
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(þ)-4-(4-(2-((7-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-
(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol ((þ)-19a, Hy-
drochloride Salt). This compound was prepared from (þ)-18a
(0.110 g, 0.232 mmol) following procedure J that yielded (þ)-19a
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as an off-white solid (0.05 g, 43%). H NMR of HCl salt (400
MHz, DMSO-d6) δ ppm 0.89-0.91 (t, 3H, J = 4 Hz), 1.71 (m,
3H), 2.09-2.19 (m, 2H), 2.67-3.06 (m, 13H), 3.20 (s, 4H), 3.47
(s, 1H), 6.56 (s, 1H), 6.59-6.60 (d, 1H, J = 4 Hz), 6.91-6.92 (d,
1H, J = 4 Hz), 7.32-7.36 (m, 2H), 7.64-7.68 (m, 2H),
8.59-8.61 (d, 1H, J = 8 Hz). [R]25 þ32.4° (c 0.5, CH3OH).
D
Hydrochloride salt, mp 239-241 °C. Anal. (C28H37.4N4O2.7
4HCl) C, H, N.
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Complexation of 19b with Iron(III) Chloride. Compound 19b
(4HCl salt) was dissolved in water to make a 600 μM solution,
and the pH of the solution was found to be 3.66. The UV
scanned spectra of the solution was taken from 200 to 760 nm.
FeCl3 6H2O was next dissolved in water to make a 600 μM
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colorless solution. The two solutions were mixed together in
equal volume, which gave a green solution at pH 3.76. The
solution was subjected to UV scan as before. Then the pH of the
solution was increased to 4.0 by adding base diisopropylethyla-
mine (DIPEA) (diluted with H2O) which produced a deep-green
color which was followed by UV spectra scan. The pH of the
solution was next increased to 7.4 by adding an additional
amount of DIPEA which produced a light-brown solution
followed by UV scanning from 390 to 770 nm.