Picomolar D5-SelectiVe Dopamine-Receptor Antagonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2115
TLC was performed on silica gel 60 F254 plates (Merck). For some
separations (see respective procedures) a chromatotron, model 8924
by Harrison Research (Palo Alto, CA), was applied using 2 mm
silica gel 60 PF254. MS data were determined by GC/MS, using a
Hewlett-Packard GCD-Plus (G1800C) apparatus (HP-5MS column;
J&W Scientific). IR data were obtained from a Magna-IR FT-IR
spectrometer, system 550 by Nicolet (WI).
water. After drying over MgSO4, the solvent was removed in vacuo,
and the residual oil triturated with a few milliliters of diethyl ether.
After cooling, a white solid (18: beige solid) formed and was
filtered off, washed with ether, and dried in vacuo.
General Procedure 5: Ether Cleavage of Methoxy-dibenzo-
[a,h]quinazolinium Iodides (14, 21, and 30). A solution of 1.2
mmol of the respective methoxy-dibenzo[a,h]quinazolinium iodides
(13, 20, and 29) in 40 mL of 47% hydrogen bromide was refluxed
under stirring for 5 h. After cooling, the solvent was removed in
vacuo, the residue dissolved in 50 mL of methanol, a small amount
of charcoal was added, and the mixture was heated under reflux
for 1 h. The hot suspension was filtered and the solvent removed
under reduced pressure. Purification of the crude product is
described in the Supporting Information.
General Procedure 6: Preparation of 2-(2-Hydroxyethyl)-
N-(2-phenylethyl)benzamides (10, 17, and 27). A mixture of 27
mmol of the respective 2-phenylethylamine (e.g., 9 and 16) and
27 mmol of the respective isochromanone was stirred at 120 °C
for 5h. After cooling, the resulting oil was dissolved in 50 mL of
chloroform and this solution extracted with 2N HCl (2 × 30 mL).
The organic layer was dried over MgSO4 and the solvent removed
in vacuo. The residual oil was heated with 50 mL of 20% aqueous
NaOH at 70 °C for 30 min. After cooling, the solution was extracted
with chloroform (3 × 40 mL), the organic layers dried over MgSO4,
the solvent evaporated, and the crude product purified as described
in the Supporting Information.
Detailed/specified descriptions for the preparation of target
compounds/respective intermediates and their physical/spectral data
(NMR, MS, IR) are reported in the Supporting Information.
General Procedure 1: Synthesis of Dibenzo[d,g]azecines (3).
A solution of the given amounts of dibenzo[a,h]quinazolinium
iodide (13, 14, 20, 21, 29, and 30) in 50 mL of liquid ammonia
was stirred at -40 °C under a nitrogen atmosphere. Small parts of
sodium metal (∼4 mm3) were added portionwise until the mixture
showed a deep-blue color. After 15 min, the reaction was terminated
by adding dropwise a saturated aqueous solution of NH4Cl until
the blue color completely disappeared. The mixture was stirred at
room temperature under nitrogen until the ammonia had completely
evaporated. Then, 50 mL of 2N HCl was added, and the emulsion
was extracted with ether (3 × 20 mL). The combined organic layers
were discarded, the pH adjusted to 7, and the aqueous phase
extracted with methylene chloride (3 × 15 mL) and dried over
MgSO4, and the solvent was removed under reduced pressure to
yield the crude product, which was purified as described in the
Supporting Information for the individual compounds.
General Procedure 2: Synthesis of Dibenzo[a,h]quinazo-
linium Iodides (13, 20, and 29). The given amounts of dibenzo-
[a,h]quinolizine (12, 19, and 28) were dissolved in 30 mL of dried
acetone and then excess methyl iodide was added, and the mixture
was stirred under nitrogen at 65 °C for 18 h. After cooling, the
white solid was filtered off, washed with acetone, and dried in
vacuo.
General Procedure 3: Synthesis of Dibenzo[a,h]quinolizines
from O-Protected Benzamides (12 and 19). A solution of 10 mmol
of the respective benzamides (11 and 18) in 80 mL of acetonitrile
and 8 mL (87 mmol) of phosphoric trichloride (each freshly
distilled) was heated at 95 °C for 18 h. After cooling, the solvent
was removed under reduced pressure, and the dark residue was
dissolved in 50 mL of 2N HCl. This mixture was washed with
chloroform (5 × 20 mL), and after drying over MgSO4, the solvent
of the combined organic layers was removed in vacuo. To the
residual oil, 60 mL of a 20% KOH solution in aqueous ethanol
(70% EtOH, 30% H2O) was added and the mixture stirred for 16
h at r.t.
General Procedure 7: Chlorination of 2-Phenylethylamines
(2-(3-Chloro-4-methoxyphenyl)ethylamine (9) Hydrochloride
and 2-(2-Chloro-5-methoxyphenyl)ethylamine (16) Hydrochlo-
ride). To a solution of 10 g (66.1 mmol) of 2-(4-methoxyphenyl)-
ethylamine (8) or 2-(3-methoxyphenyl)ethylamine (15) in 130 mL
of glacial acetic acid, 13.4 g (99.2 mmol) of sulfonyl chloride was
added under stirring and cooling over ice so that the temperature
did not exceed 25 °C. A solid formed but dissolved again later.
After 3 h, 200 mL of diethyl ether was added, and the stirring was
continued for 1h. The precipitate formed was filtered off and was
recrystallized from MeOH/diethyl ether.
Pharmacology. Experimental details of both the radioligand-
binding studies7 and the calcium assay1,18 have been described in
detail in recent publications.
Acknowledgment. M.D. gratefully acknowledges the finan-
cial support by the Fonds der Chemischen Industrie (FCI). We
thank Ba¨rbel Schmalwasser, Petra Wiecha, and Heidi Traber
for skillful technical assistance.
After removal of the solvent in vacuo, the solution was acidified
with concentrated HCl and extracted with chloroform (6 × 20 mL),
and after drying over MgSO4, the solvent of the combined organic
layers was removed under reduced pressure. The residue was
dissolved in 15 mL of phosphoric trichloride and heated for 15
min under stirring at 60 °C. After cooling, 50 mL of petrol ether
(60/40) was added, and the mixture was intensively extracted three
times so that a dark oil could separate. Finally, the dark residue
was dissolved in 50 mL of methanol, to which 3 g (78 mmol) of
sodium borohydride was added under stirring and cooling over ice
for 30 min. The mixture was stirred for another 30 min at r.t. and
concentrated to dryness in vacuo. The residue was resuspended in
50 mL of water and extracted with diethyl ether (3 × 40 mL). The
combined organic layers were dried over MgSO4, and the solvent
was removed under reduced pressure to yield the crude product,
which was purified as described in the Supporting Information.
General Procedure 4: Protection of the Hydroxy Groups of
2-(2-Hydroxyethyl)-N-(2-phenylethyl)benzamides (11 and 18).
To a solution of 2.4 mmol of the respective 2-(2-hydroxyethyl)-
N-(2-phenylethyl)benzamides (10 and 17) in 45 mL of pyridine/
chloroform (2/1) were added under stirring 2 g (18.9 mmol) of
ethyl chloroformiate (ethyl chloridocarbonate) in 15 mL of chlo-
roform over 30 min. The stirring was continued for 1 h at room
temperature, after which the solvent was removed in vacuo and
the residue dissolved in 60 mL of methylene chloride. The solution
was washed twice with 2N HCl, once each with 2N NaOH and
Supporting Information Available: Synthetic procedures and
spectral characterization for compounds 3-31. This material is
References
(1) Ho¨fgen, B.; Decker, M.; Mohr, P.; Schramm, A. M.; Rostom, S. A.
F.; El-Subbagh, H.; Schweikert, P. M.; Rudolf, D. R.; Kassack, M.
U.; Lehmann J. Dopamine/serotonin receptor ligands. 10: SAR
studies on azecine-type dopamine receptor ligands by functional
screening at human cloned D1, D2L, and D5 receptors with a
microplate reader based calcium assay lead to a novel potent D1/D5
selective antagonist. J. Med. Chem. 2006, 49, 760-769.
(2) Kebabian, J.; Tarazi, F.; Kula, N.; Baldessarini, R. Compounds
selective for dopamine receptor subtypes. Drug DiscoVery Today
1997, 2, 333-340.
(3) Liu, F.; Wan, Q.; Pristupa, Z. B.; Yu, X.-M.; Wang, Y. T.; Niznik,
H. B. Direct protein-protein coupling enables cross-talk between
dopamine D5 and γ-aminobutyric acid A receptors. Nature 2000, 403,
274-280.
(4) Elliot, E. E.; Sibley, D. R.; Katz, J. L. Locomotor and discriminative-
stimulus effects of cocaine in dopamine D5 receptor knockout mice.
Psychopharmacology 2003, 169, 161-168.
(5) Decker, M.; Schleifer, K.-J.; Nieger, M.; Lehmann J. Dopamine/
serotonin receptor ligands. 8: The dopamine receptor antagonist
LE300 - modelled and X-ray structure plus further pharmacological
characterization, including serotonin receptor binding, biogenic amine
transporter testing and in vivo testings. Eur. J. Med. Chem. 2004,
39, 481-489.
Mohr, Patrick
