1248 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 7
Strekowski et al.
8 or 34 (AcOEt/MeOH, 4:1) and 14 or 37 (AcOEt/MeOH/Et3N,
3:1:1). Compound 53 (from XX) was eluted with AcOEt/EtOH/
Et3N (15:3:1). Salts were obtained by using a general proce-
dure23 and crystallized from EtOH/AcOEt. Compound, yield,
mp: 8‚3HCl‚2.5H2O, 10%, 278-281 °C; 14‚5HCl‚3.5H2O, 50%,
242-245 °C; 34‚3HBr‚2H2O, 40%, 225-228 °C; 37‚3HBr‚
5H2O, 38%, 233-236 °C; 53‚9HCl‚3H2O, 45%, 256-259 °C.
2-(4-P ip er id in op h en yl)qu in olin -4-a m in es 15-17 a n d
2-[4-(4-Meth ylp ip er a zin o)p h en yl]qu in olin -4-a m in es 42-
51. A solution of a lithium amide reagent prepared by stirring
piperidine (0.50 mL, 5 mmol) or N-methylpiperazine (0.54 mL,
5 mmol) and n-BuLi (2 M in cyclohexane, 2.5 mL, 5 mmol) in
anhydrous THF (10 mL) under a nitrogen atmosphere at -10
°C for 30 min was treated with a solution of a 2-(4-fluorophen-
yl)quinolin-4-amine (0.5 mmol) in anhydrous THF (2 mL).
After the sample was stirred at 23 °C for 20 h, the mixture
was quenched with water (0.2 mL), and the organic layer was
concentrated under a reduced pressure. Compounds were
purified by silica gel chromatography eluting with AcOEt/Et3N
(25:1) followed by crystallization of solid samples from AcOEt/
hexanes. Oily products were transformed into salts,23 and the
salts were crystallized from 95% EtOH. Compound, yield,
mp: 15‚3H2O, 72%, 112-114 °C; 16, 85%, 134-135 °C; 17‚
2HBr‚2H2O, 40%, 175-176 °C; 42‚2H2O, 75%, 144-145 °C;
43‚3HBr‚H2O, 65%, 269-272 °C; 44‚3HBr‚2.5H2O, 88%, 239-
241 °C; 45, 40%, 172-173 °C; 46‚4HBr‚4.5H2O, 50%, 280-
283 °C; 47‚3HBr‚2H2O, 61%, 313-315 °C; 48‚3HBr‚1.5H2O,
68%, 260-261 °C; 49‚3HBr‚3H2O, 81%, 210-212 °C; 50,19 76%,
132-133 °C; 51‚7HCl‚2H2O, 40%, 250-252 °C.
Bis-qu in olin es 54-56 a n d Qu in olin e 57. A solution of
tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3, 4.5 mg,
0.005 mmol] and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
(BINAP, 12.2 mg, 0.02 mmol) in dioxane (20 mL) under a
nitrogen atmosphere was stirred at 23 °C for 5 min before the
addition of a 2-(4-bromophenyl)quinolin-4-amine XXI (0.35 g,
0.94 mmol) and piperazine, 4,4′-ethylenedipiperidine or 4,4′-
trimethylenedipiperidine (0.4 mmol). After the sample was
stirred for 5 min, the resultant yellow solution was treated
with t-BuOK (0.27 g, 2.8 mmol). The deep-red mixture was
stirred and heated to 80 °C for 40 h, then cooled, and treated
with AcOEt (50 mL) and filtered. The solution was washed
with brine, dried (Na2SO4), and concentrated. The product was
purified by silica gel chromatography eluting with AcOEt/Et3N/
EtOH (30:3:1) and then crystallized from EtOH/hexanes. The
hydrobromide of 57 was crystallized from 95% EtOH. Com-
pound, yield, mp: 54, 37%, 257-259 °C; 55, 32%, 240-243
°C; 56, 34%, 198-200 °C; 57‚3HBr‚4H2O, 10%, 217-220 °C.
Biologica l Eva lu a tion . The ability of test compounds to
reverse the action of CpG-ODN on WEHI 231 murine B-cell
lymphoma cells was assessed in vitro as described previously.8-11
Briefly, these cells are killed by anti-surface IgM, an effect
that is reversed by CpG-ODN. Test compounds were added in
triplicate at 3-fold dilutions together with 6 µg/mL CpG-ODN
1760 with or without 10 µg/mL anti-surface-IgM to WEHI 231
cells at 2 × 105 per mL. The cells were incubated 16 h at 37
°C before the addition of 0.5 µCi 3H thymidine for an additional
4 h. The concentration test compound that reduces the effect
of CpG-ODN by half was estimated graphically from log dose-
response plots. Each assay included quinacrine as an internal
control, which established that the assay was both highly
reproducible and did not change with time.
the Veterans Administration (D.E.M. and L.M.) is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Characterization of
all new compounds (1H NMR, 13C NMR, 19F NMR, and
elemental analysis) and experimental and calculated log(1/
EC50) values of quinolines 1-51 are available free of charge
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Ack n ow led gm en t. Financial support of this study
by the National Institutes of Health (L.S.), the Petro-
leum Research Fund, administered by the American
Chemical Society (L.S.), and a Merit Review grant from