Effect of Quinoline Derivatives on Tumor Cell MDR
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2051
Ta ble 5. Distance and Basicity of Nitrogen (Nb)
Meth od B To Obta in N-Acyl Der iva tives: 5-[3-{4-(2,2-
Dip h en yla cetyl)p ip er a zin -1-yl}-2-h yd r oxyp r op oxy]qu in -
olin e 1.5F u m a r a te (16, MS-209). (i) N-(2,2-Dip h en y-
la cetyl)p ip er a zin e (30b). 2,2-Diphenylacetyl chloride (125
g, 0.542 mol) in dry CHCl3 (350 mL) was slowly added to a
solution of N-formylpiperazine (64.8 g, 0.568 mol) and triethy-
lamine (66 g, 0.65 mol) in dry CHCl3 (350 mL) immersed in
an ice bath. The reaction mixture was stirred for 30 min at
room temperature. Then the resultant solution of 29b was
washed with 0.1 N HCl solution (500 mL), 0.1 N NaOH
solution (500 mL), and saturated NaCl solution (500 mL). To
the CHCl3 solution of 29b was added 10% HCl/methanol
solution (1000 mL), and the mixture was allowed to stand at
room temperature overnight. About 775 mL of NaOH solution
was added to adjust the pH of the final solution to the range
of 8-9. The organic layer was separated and washed with
saturated NaCl aqueous solution, then dried, and evaporated
to give 30b (136.6 g, 90%): mp 83-84 °C; 1H-NMR (CDCl3) δ
2.5-2.6 (m, 2H), 2.8-2.9 (m, 2H), 3.4-3.5 (m, 2H), 5.19 (s,
1H), 7.2-7.4 (m, 10H); IR (KBr) 2833, 1634, 1434, 1218, 1040,
a
See corresponding footnote in Table 1.
is the requirement that the distance between the basic
nitrogen atoms and hydrophobic moieties is at least
about 5 Å.
782, 746, 700 cm-1
.
(ii) 5-[3-{4-(2,2-Dip h en yla cet yl)p ip er a zin -1-yl}-2-h y-
d r oxyp r op oxy]qu in olin e. Compounds 27a (4.4 g, 21.9
mmol) and 30b (6.50 g, 23.2 mmol) were dissolved in 85 mL
of IPA and heated under reflux for 4 h. Then the solvent was
distilled off, and the residue was purified by short silica gel
column chromatography to give the free form of 16 (7.37 g,
Exp er im en ta l Section
Ch em istr y. Melting points were obtained on a Buchi
capillary melting point apparatus. 1H-NMR spectra were
obtained using a J EOL EX-270 instrument, and infrared
spectra were recorded with a J ASCO IRA-2 spectrometer using
KBr pellets. Elemental analyses were within 0.4% of the
theoretical values, and structural assignments were consistent
with NMR and IR spectra.
1
70%): mp 161-162 °C; H-NMR (CDCl3) δ 2.2-2.8 (m, 6 H),
3.5-3.6 (m, 2H), 3.7-3.9 (m, 2H), 4.1-4.3 (m, 3H), 5.20 (s,
1H), 6.86 (d, 1H, J ) 7.3 Hz), 7.2-7.4 (m, 11H), 7.59 (t, 1H, J
) 8.1 Hz), 7.71 (d, 1H, J ) 8.1 Hz), 8.54 (d, 1H, J ) 7.3 Hz),
8.91 (dd, 1H, J ) 2, 4 Hz); IR (KBr) 2954, 1630, 1587, 1268,
1091, 802, 748, 703 cm-1
.
Meth od A To Obta in N-Alk yl Der iva tives: 5-[3-{4-(10,-
11-Dih yd r o-5H-d iben zo[a ,d ]cycloh ep ta n -5-yl)p ip er a zin -
1-yl}-2-h yd r oxyp r op oxy]qu in olin e (4, MS-073). (i) N-(10,-
1 1 -D i h y d r o -5 H -d i b e n z o [ a ,d ] c y c l o h e p t a n -5 -y l ) -
p ip er a zin e (28a ). 5-Chlorodibenzosuberane (5.0 g, 21.9
mmol) was added to anhydrous piperazine (11.3 g, 131 mmol)
in 80 mL of dioxane and heated under reflux for 7 h. After it
cooled to room temperature, insoluble salts were removed by
filtration, and the solvent was distilled off. A small amount
of petroleum ether was added for crystallization, and crystal-
line 28a was collected (5.1 g, 84%): mp 110-111.5 °C; 1H-
NMR (CDCl3) δ 2.1-2.4 (brs, 4H), 2.7-2.9 (m, 6H), 3.9-4.1
(m, 2H), 3.95 (s, 1H), 3.9-4.1 (m, 2H), 7.0-7.3 (m, 8H); IR
(KBr) 3420, 3250, 2920, 2800, 1630, 1490, 1450, 1330, 1140
(iii) 5-[3-{4-(2,2-Dip h en yla cetyl)p ip er a zin -1-yl}-2-h y-
d r oxyp r op oxy]qu in olin e 1.5F u m a r a te (16, MS-209). The
free form of 16 (1.22 g, 2.54 mmol) was added to a solution of
fumaric acid (0.89 g, 7.67 mmol) in MeOH (15 mL) and allowed
to stand at room temperature for 6 h. Crystals were collected
by filtration and washed with MeOH. Then the crystals were
recrystallized from MeOH (26 mL) to give 16 (1.0 g, 60%): mp
1
210 °C dec; H-NMR (DMSO-d6) δ 2.2-2.6 (m, 6H), 3.4-3.6
(m, 4H), 4.0-4.2 (m, 3H), 5.53 (s, 1H), 6.63 (s, 3H), 7.03 (d,
1H, J ) 8.1 Hz), 7.2-7.4 (m, 10H), 7.5-7.7 (m, 3H), 8.61 (d,
1H, J ) 8.1 Hz), 8.89 (dd, 1H, J ) 1.5, 4.4 Hz); IR (KBr) 3424,
1644, 1592, 1277, 1180, 1110, 799 cm-1
.
Meth od C To Obta in P ip er id in e Der iva tives: 5-[3-{4-
(10,11-Dih yd r o-5H-d iben zo[a ,d ]cycloh ep ten -5-yl)p ip er i-
d in -1-yl}-2-h yd r oxyp r op oxy]qu in olin e (20). (i) 4-(10,11-
Dih yd r o-5H -d ib e n zo[a ,d ]cycloh e p t e n -5-yl)-N-m e t h yl-
p ip er id in e (31c). 4-Chloro-1-methylpiperidine (7.5 g, 56
mmol) in dry THF (10 mL) was added to a suspension of Mg
(1.34 g) in dry THF (18 mL), and the mixture was refluxed for
1 h. The reaction mixture was cooled to 0 °C, dibenzosuberone
(9.4 g, 45 mmol) in toluene (10 mL) was added, and the solution
was warmed to 40 °C. The reaction mixture was poured into
dilute HCl solution and washed with Et2O (150 mL). Then
the aqueous layer was neutralized with saturated NaHCO3
solution and extracted with CH2Cl2 (three times, 500 mL). The
organic layer was dried and concentrated, and the resulting
residue was crystallized by the addition of Et2O. The crystals
were collected by filtration, washed with Et2O, and then
dissolved in CF3COOH (15 mL) and allowed to stand overnight
at room temperature. The solution was added to cold dilute
NaOH solution, and the resulting basic solution was extracted
with CH2Cl2 three times. Then the solution was dried and
evaporated to give 31c (4.9 g, 36%): 1H-NMR (CDCl3) δ 2.0-
2.2 (m, 2H), 2.3 (s, 3H), 2.4-2.5 (m, 4H), 2.6-2.7 (m, 2H),
2.75-2.9 (m, 2H), 7.0-7.1 (m, 8H).
cm-1
.
(ii) 5-(2,3-Ep oxyp r op oxy)qu in olin e (27a ). 5-Hydrox-
yquinoline (1 g, 6.9 mmol) was added to a solution of potassium
tert-butoxide (0.93 g, 8.3 mmol) in dry DMF (20 mL), and the
resulting solution was heated at 50 °C for 30 min. After the
solution was allowed to cool to room temperature, epichloro-
hydrin (1.92 g, 20.75 mmol) was added, and the mixture was
heated at 90 °C for 3 h. The solvent was distilled off under
reduced pressure at a temperature below 50 °C. Ice-water
was added to the residue and then extracted with ethyl acetate
three times. Then the organic layer was dried and evaporated,
to give 27a as a reddish oil (0.88 g, 53%, unstable): 1H-NMR
(CDCl3) δ 2.85 (dd, 1H, J ) 2.9, 5.2 Hz), 2.97 (dd, 1H, J ) 5.2,
9.5 Hz), 3.45-3.5 (m, 1H), 4.11 (dd, 1H, J ) 5.9, 11 Hz), 4.45
(dd, 1H, J ) 2.9, 11 Hz), 6.87 (d, 1H, J ) 8.1 Hz), 7.72 (d, 1H,
J ) 8.1 Hz), 8.64 (d, 1H, J ) 8 Hz), 8.91 (dd, 1H, J ) 1.5, 4.4
Hz).
(iii) 5-[3-{4-(10,11-Dih yd r o-5H-d iben zo[a ,d ]cycloh ep -
ta n -5-yl)p ip er a zin -1-yl}-2-h yd r oxyp r op oxy]qu in olin e (4,
MS-073). Compounds 27a (0.88 g, 4.4 mmol) and 28a (1.2 g,
4.3 mmol) were dissolved in 20 mL of ethanol and were under
reflux for 3 h. Then the solvent was distilled off, and the
residue was purified by silica gel column chromatography
(CHCl3/MeOH ) 50/1) and recrystallized from EtOH, to give
(ii) 4-(10,11-Dih yd r o-5H -d ib en zo[a ,d ]cycloh ep t en -5-
yl)p ip er id in e (32c). A solution of 31c (1.45 g, 5 mmol) and
2,2,2-trichloroethyl chloroformate20 (2.1 g, 10 mmol) was
stirred under reflux with potassium carbonate (1.03 g, 7.5
mmol) in 1,1,2-trichloroethane (80 mL) for 11 h; then MeOH
(1 mL) was added and the solution concentrated. The residue
was dissolved in a solution of 1 M NH4Cl (4 mL) and THF (20
mL), and then zinc powder (4 g) was added. The solution was
1
compound 4 (1.4 g, 66%): mp 126-128 °C; H-NMR (CDCl3)
δ 2.2-2.9 (m, 12H), 3.1-3.6 (brs, 1H), 3.9-4.3 (m, 6H), 6.86
(d, 1H, J ) 8.0 Hz), 7.0-7.2 (m, 8H), 7.36 (dd, 1H, J ) 4.4, 8.1
Hz), 7.59 (t, 1H, J ) 8.0 Hz), 7.69 (d, 1H, J ) 8.1 Hz), 8.57 (d,
1H, J ) 8.0 Hz), 8.90 (dd, 1H, J ) 1.5, 4.4 Hz); IR (KBr) 2900,
2800, 1620, 1590, 1570, 1450, 1260, 1140, 1100 cm-1
.