Dopamine receptor ligands. Part 18: Modification of the structural skeleton of indolobenzazecine-type dopamine receptor antagonists

Article abstract of DOI:10.1021/jm901291r

On the basis of the D_1/5-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca²⁺ assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f] benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.

Full text of DOI:10.1021/jm901291r

2646 J. Med. Chem. 2010, 53, 2646–2650
DOI: 10.1021/jm901291r
Dopamine Receptor Ligands. Part 18:1 Modification of the Structural Skeleton
of Indolobenzazecine-Type Dopamine Receptor Antagonists
Dina Robaa,† Christoph Enzensperger,† Shams El Din Abul Azm,‡ El Sayeda El Khawass,‡ Ola El Sayed,‡ and
Jochen Lehmann*,†
†Institut fu€r Pharmazie, Lehrstuhl fu€r Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universita€t Jena, Philosophenweg 14, D-07743
Jena, Germany and ‡Department of Medicinal Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
Received August 28, 2009
On the basis of the D1/5-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine
derivative, we changed the annulation pattern of the heterocycles. The target compounds represent
novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef ]benzazecine 2 was inactive, but
the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca2þ assay)
with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the
indolo[2,3-f ]benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.
Introduction
D1 (partial)agonist (-)-4,6,6a,7,8,12b-hexahydro-7-methyl-
indolo[4,3-ab]phenanthridine CY 208-2435,6 (Chart 2). This
benzergoline derivative showed 10-fold selectivity for D5 over
D1 receptor7 and exhibited in vivo antiparkinsonial activity.8
Our second target compound was the indolo-benzazecine 4,
where the 10-membered central alicycle is fused at the 2,3-
positions of the indole ring as opposed to the 3,2-fusion
pattern of 1 (Chart 1).
Dopamine is a major neurotransmitter of the brain
involved in the control of movement, emotion, reward,
and cognition. Dysfunctions of the dopaminergic system
have been associated with several neuropsychiatric dis-
orders including Parkinson’s disease, schizophrenia, and drug
dependence. The azecine-type dopamine receptor antagonist
7-methyl-6,7,8,9,14,15-hexahydro-5H-indolo[3,2-f][3]benza-
zecine (1, LE 300)2-4 represents a novel chemical structure,
possessing high affinities and a unique selectivity profile for
the D1-like receptors. Extensive SAR studies have been
carried out based on 1 (LE 300) as a lead. The objective of
the present study was to rearrange the heterocyclic skeleton
of our lead compound 1 in order to assess how different
annulation patterns would affect the affinities and selecti-
vities for the dopamine receptors. While retaining the basic
structural features of our lead, namely an indole, a benzene
ring, and a central N-methylated azacycloalkane ring, we
mainly wanted to change the annulation of the central
alicycle to the indole ring (Chart 1).
Our first targets were analogues of 1, where the aza-alicycle
is fused not to the 2,3- but to the 3,3a,4-positions of the indole.
As this annulation pattern might impart some rigidity on the
structure, we wanted to synthesize both the indolo-benzaze-
cine 2 and the more flexible indolo-benzazaundecene 3.
Compound 2 resembles the parent compound 1 in containing
a 10-membered central alicycle but differs from it in contain-
ing a methylene rather than an ethylene chain, connecting the
indole ring to the central nitrogen. Conversely, in the ring-
expanded structure of compound 3, the indole ring is con-
nected to the central nitrogen through an ethylene chain.
These target compounds, together with their pentacyclic
precursors 8 and 12, are of additional interest due to their
structural resemblance to ergolines, especially to the selective
Chemistry
To obtain the annulated 10- and 11-membered hetero-
cycles, we had to prepare their ring-closed quinolizine-type
precursors. Previously applied methods for the preparation of
related quinolizines, namely by reacting the respective aralky-
lamines with 1-isochromanone4,9 or with 2(2-chloroethyl)-
benzoyl chloride,10,11 were unsuccessful. So the quinolizine 8
was prepared following a procedure described by Browne for
the preparation of analogous benzo-thieno-quinolizine.12 Re-
acting 4-aminomethylindole (5) with 2-(2-bromoethyl)benz-
aldehyde (6) in dioxane at room temperrature yielded the 3,4-
dihydroisoquinolinium salt 7. This was refluxed in 6N HCl,
and the obtained quinolizinium salt was alkalinized to give the
quinolizine 8. Two different procedures yielded the indolo-
benzazecine 2. First, the quinolizine 8 was quaternized with
methyl iodide and the central C-N bond of the resulting
quaternary salt 9 was subsequently cleaved by treatment with
sodium in liquid ammonia. Second, the quinolizine 8 was
converted with ethylchloroformate/NaCNBH3 to the carba-
mate derivative 10, which upon reduction with lithium alu-
minum hydride also yielded the desired target compound 2.
Spectral dataof the products, obtained by both methods, were
identical. However, the first route proved to be more advan-
tageous with respect to the yield (Scheme 1).
Applying the procedure, previously described for the synth-
esis of the quinolizine 2, failed to produce both the homo-
quinolizine 12 and quinolizine 15. 2-(2-Bromoethyl)benz-
aldehyde (6) did not react with the respective amines 11 and 14
*To whom correspondence should be addressed. Phone: þ49 3641
949803. Fax: þ49 3641 949802. E-mail: j.lehmann@uni-jena.de.
r
pubs.acs.org/jmc
Published on Web 02/24/2010
2010 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6 2647
Chart 1. Rearranging the Indolo[3,2-f]benzazecine Skeleton of 1
to Analogue Indolo[4,3a,3-ef]benzazecine 2, Indolo[4,3a,3-fg]-
benzazaundecene 3 and to Indolo[2,3-f]benzazecine 4
Scheme 1. Total Synthesis of 5-Methyl-4,5,6,7-tetrahydro-
indolo[4,3a,3-ef][3]benzazecine (2)a
Chart 2. Selective D1 (Partial) Agonist (-)-4,6,6a,7,8,12b-Hexa-
hydro-7-methylindolo[4,3-ab]phenanthridine
a Reagents and conditions: (a) dioxane, rt, 3 h; (b) 6 N HCl, reflux, 4 h;
(c) aq NH4OH; (d) MeI, acetone, rt, 24 h; (e) ClCOOEt, dry THF,
-55 °C, 5 h, then NaCNBH3, -55 °C to rt; (f) Na0, liquid NH3, -40 °C,
10 min; (g) LiAlH4, dry THF, reflux, 3 h.
at room temperature. Hence, we modified the reaction condi-
tions. 4-(2-Aminoethyl)indole (11) or 2-(2-aminoethyl)indole
(14) were refluxed with 2-(2-bromoethyl)benzaldehyde (6) in
dioxane in the presence of equimolar amounts of trifluoroacetic
acid. This resulted in the direct formation of the salts of the
homoquinolizine 12 and quinolizine 15, respectively. Alkaliniza-
tion yielded the corresponding bases, which were quaternized
with methyl iodide. Finally the obtained quaternary salts 13 and
16 were cleaved using sodium in liquid ammonia to produce the
target compounds 3 and 4 (Scheme 2).
compounds, together with their pentacyclic precursors, are
derivatives of novel heterocyclic ring systems.
In the radioligand binding experiments, the two homo-
logues, 2 and 3, where the alicycle is fused at the 3,3a,4
positions of the indole ring, were found to possess surprisingly
different affinities: while the indolo[4,3a,3-ef ]benzazecine 2
showed no significant affinities for all dopamine receptor
subtypes (Ki > 10 μM), the ring expanded indolo[4,3a,3-fg]-
benzazacycloundecene 3 displayed nanomolar affinities, com-
parable to those of our lead 1. However, it showed almost
equal affinities for the D1-, D3-, and D5-receptor, showing a
slightly higher affinity for D5 compared to D1. A 10-fold
increase inthe affinityforD2 wasobserved, whencomparedto
our lead1, in additiontoanimprovementinthe affinityfor the
D4-receptor. The indolo[2,3-f ]benzazecine 4 showed a nearly
similar selectivity pattern like that of compound 3 but with
noticeable decrease in the affinities for all D-receptors.
Although both compound 2 and our lead 1 contain a benzin-
dolo-azecine moiety, the structure of the former is much more
constrained as a consequence of its annulation. In contrast,
the ring expanded structure of compound 3 shows higher
flexibility, which is accompanied by an extreme increase in
affinities. In accordance with our previous studies,4 only
structures showing a certain degree of flexibility display
relevant affinities for the dopamine receptors.
Pharmacology
All the target compounds 2, 3, and 4 together with their
pentacyclic precursors 8, 12, and 15 were screened for their
affinities for the human cloned dopamine receptor subtypes
D1, D2 L, D3, D4.4, and D5. These receptors were stably
expressed in HEK293 or CHO cells; [3H]SCH 23390 and
[3H]spiperone were used as radioligands at the D1-like and
D2-like receptors, respectively. Ki values are given in nano-
molar units (Table 1). For a detailed protocol, see Supporting
Information (SI). Additionally, the compounds were tested in
an intracellular Ca2þ assay, in order to determine their
functionality at the D1 and D2 receptors. HEK293 cells stably
expressing the respective D-receptor were loaded with a
fluorescent dye, and after preincubation with rising concen-
trations of the test compound, an agonist (SKF 38393 for D1
and quinpirole for D2) was injected and the Ca2þ-induced
fluorescence was measured with a microplate reader. The
ability of the test compound to suppress the agonist-induced
Ca2þ influx is an indication of antagonistic or inverse agonis-
tic properties atthe receptor. For a detailed description, see SI.
The discrepancy in the activities between both homologues
2 and 3 might be attributed to the different distances between
the pharmacophoric groups, which are the central N and both
aromatic rings, but also to the different angles between the
aromatic rings in both structures. Another possibility may be
that analogue 2 is inactive due to the nitrogen’s lone e-pair
being buried in the center of the ring beneath the N-methyl
group. Meanwhile, the flexibility of the additional methylene
Results and Discussion
We synthesized three analogues of the lead compound 1,
possessing a modified annulation pattern. All of these

2648 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6
Robaa et al.
Scheme 2. Total Synthesis of Benzazacycloundecene 3 and Benzazecine 4a
a Reagents and conditions: (a) trifluoroacetic acid, dioxane, reflux, 20 h; (b) 2 N NaOH; (c) MeI, acetone or acetonitrile, rt, 24 h; (d) Na0, liquid NH3,
-40 °C, 10 min.
Table 1. Affinities (Ki, nM) for Human D1-D5 Receptors, Determined by Radioligand Binding Experiments
Ki (nM)
HEK D3
25.9
compd
HEK D1
HEK D2 L
CHO D4.4
HEK D5
1a
2
1.9 ( 0.9
>10000
44.5 ( 15.8
>10000
108 ( 39
>10000
39.1 ( 9.6b
225 ( 50c
>10000
>10000
>10000
7.5 ( 0.3
>10000
>10000
3
4.2 ( 0.5b
28.5 ( 7.2b
>10000
4.0 ( 0.5c
42.9 ( 8.5c
513 ( 217b
>10000
2.5 ( 0.7c
10.3 ( 1.5c
>10000
4
55.1 ( 15.4c
>10000
8
12
15
1836 ( 658b
4458 ( 1192c
>10000
>10000
1525 ( 206c
>10000
2101 ( 703b
1476 ( 28.5c
a Values cited from ref 10, CHO cell lines were used for D2 L, D3, and D4.4; HEK cell lines for D1 and D5. b Ki values are the means of three experiments;
performed in triplicate ( SEM. c Ki values are the means of two; experiments; performed in triplicate ( SEM.
in analogue 3 might permit low-energy conformations to exist
with the N lone e-pair to be directed outward. However,
studies have shown that the receptor binding site contains two
aromatic subsites around a conserved Asp3.32, whose carbox-
ylate group acts as a counterion of the protonated basic N of
the ligand.13 Accordingly, we expect our ligands to interact
with the binding sites in an N-protonated form and not with
the N lone pair of the free base.
The pentacyclic precursor compounds 8, 12, and 15 had
generally weak to no affinities. The quinolizine 8 displayed no
affinities (Ki > 10 μM) for all dopamine receptors, whereas its
homologue 12 showed micromolar ones for the D1, D2, and
D5 subtypes. Similarly, the quinolizine 15 showed micromolar
affinities for theD1 and D2 subtypes. With the exception of the
quinolizine 2, removal of the C-N bond of the quinolizines
and the consequent impartment of a moderate flexibility to
the central ring results in a dramatic increase in affinities. This
is in accordance with some previous observations.4
We conclude that modifying the annulation pattern of the
parent compound 1 does not result in significant changes in
the affinities for the different dopamine receptors; equally
active (compound 3) or slightly less active (compound 4)
dopamine antagonists have been obtained. It seems, however,
that decreasing the flexibility of the structure together with
decreasing the distances between the alicyclic nitrogen and the
aromatic moieties both have a negative effect on the affinities
and can lead to a complete loss of activity.
Experimental Section
General Methods. Melting points are uncorrected and were
measured in open capillary tubes using a Gallenkamp melting
point apparatus. 1H and 13C NMR spectral data were obtained
from a Bruker Advance 250 spectrometer (250 MHz) and
Advance 400 spectrometer (400 MHz). TLC was performed
on silica gel F254 plates (Merck). MS data were determined by
GC/MS using a Hewlett-Packard GCD-Plus (G1800C) appa-
ratus (HP-5MS column; J&W Scientific). Purities of the com-
pounds were determined by elemental analysis, performed on a
Hereaus Vario EL apparatus. All values for C, H, and N were
found to be within (0.4. All compounds showed >95% purity.
All tested compounds, displaying affinities in the radioli-
gand binding assay, were found to possess antagonistic
activities at the D1 and D2 receptors in the calcium assay.

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6 2649
2,8,9,13b-Tetrahydro-6H-isoquino[2,1-b]pyrrolo[4,3,2-de]-
isoquinoline (8). To a stirred solution of 4-aminomethylindole14
(1.16 g, 8 mmol) in 30 mL dioxane was added dropwise a
solution of 2-(2-bromoethyl)benzaldehyde15 (3.4 g, 16 mmol)
in 10 mL dioxane. Stirring was continued for 3 h, whereupon the
intermediate isoquinolinium salt separated as a brownish sticky
substance. The mixture was then allowed to settle, the super-
natant was decanted, the sediment washed twice with dioxane
and then twice with diethyl ether, and finally dried under
vacuum. The obtained isoquinolinium salt 7 was subsequently,
without further purification, dissolved in 30 mL 6 N HCl and the
solution was refluxed for 4 h. The formed quinolizinium salt,
which separated as white solid, was filtered off, washed several
times with cold water, and dried. It was then alkalinized with
aqueous ammonia and the formed quinolizine base 8 was
extracted with a mixture of dichloromethane/isopropanol
(3:1). Finally, the extract was dried over Na2SO4 and the
solvents removed under reduced pressure to give 0.86 g
(41.1%) of a white solid. This was recrystallized from chloro-
form/ethanol giving cream-white crystals; mp: 185-188 °C. 1H
NMR: 250 MHz (DMSO-d6): δ 2.64-3.01 (m, 4H, 8, 9),
3.93-3.99 (d, J = 15.85, 1H, 6), 4.31-4.37 (d, J = 15.85, 1H,
6), 5.33 (s, 1H, 13b), 6.73-6.76 (m, 2H, Ar-H), 6.98-7.04 (t, 1H,
J = 7.4, Ar-H) 7.16-7.27 (m, 4H, Ar-H), 7.41-7.44 (d, J = 7.1,
1H, 5), 10.66 (s, 1H, indole-NH). 13C NMR: 250 MHz (DMSO-
d6): δ 29.43 (9), 46.48 (8), 55.34 (6), 57.8 (13b), 109.48 (3), 113.53
(13c), 113.92 (1), 120.19 (5), 122.51 (11), 124.83 (5b), 126.03 (12),
126.54 (4), 127.24 (13), 128.13 (5a), 129.35 (10), 133.93 (9a),
saturated ammonium chloride solution were added to terminate
the reaction, and the mixture was stirred under nitrogen until the
liquid ammonia completely evaporated. To the residue was
added 10 mL water, and the mixture was then extracted with
30 mL diethyl ether. The organic phase was dried over Na2SO4,
and the solvent was removed under reduced pressure to yield the
crude products, which (except for compound 2) were sufficiently
pure and did not require further purification.
5-Methyl-4,5,6,7-tetrahydroindolo[4,3a,3-ef][3]benzazecine (2).
Evaporation of the solvent yielded a cream-colored solid, which
was crystallized from chloroform; yield 24%; mp: 257-260 °C.
1H NMR: 250 MHz (CDCl3): δ 1.55 (mc, 2H, 6), 2.12 (s, 3H,
N-Me), 2.78 (mc, 2H, 7), 3.15 (mc, 2H, 4), 4.58 (s, br, 2H, 12),
6.73-6.76 (d, J = 7.1, 1H, Ar-H), 6.97-7.26 (m, 7H, Ar-H), 8.00
(s, 1H, indole-NH). HRMS 276.1621 (calcd for C19H20N2:
276.1626). Anal. (C19H20N2): C, H, N.
6-Methyl-5,6,7,8,13,15-hexahydro-4H-indolo[4,3a,3-fg][3]benz-
azacycloundecene (3). Evaporation of the solvent yielded a yellowish
solid; yield 62%; mp: 157-159 °C. 1H NMR: 250 MHz (CDCl3): δ
2.49 (s, 3H, N-Me), 2.88 (mc, 4H, 4, 8), 3.07 (mc, 4H, 5, 7), 4.42 (s,
2H, 13), 6.79-6.82 (d, J = 7.1, 1H, Ar-H), 7.02-7.27 (m, 7H,
Ar-H), 8.39 (s, 1H, indole-NH). 13C NMR: (CDCl3): δ 28.96 (4),
29.03 (8), 44,64 (N-Me), 56.72 (7), 57.66 (5), 109.63 (1), 115.15 (13),
121.24 (3), 124.68 (2), 124.68 (10), 125.61 (3b), 126.04 (14), 126.14
(12), 129.33 (11), 130.34 (9), 133.39 (3a), 137.58 (8a), 140.11 (14a)
140.89 (12a). Anal. (C20H22N2 0.67H2O): C, H, N.
3
7-Methyl-6,7,8,9,10,15-hexahydroindolo[2,3-f ][3]benzazecine (4).
Evaporation of the solvent yielded a beige solid; yield 65%; mp:
139-141 °C (analytical data see SI).
134.03 (2a), 137.77 (13a). Anal. (C18H16N2 0.25EtOH): C, H, N.
3
Ethyl 4,5,6,7-Tetrahydroindolo[4,3a,3-ef ][3]benzazecine-5-car-
boxylate (10). A stirred solution of the quinolizine 8 (0.56 g,
2.2 mmol) in 200 mL of dry THF was cooled in methanol/dry ice
at -55 °C. While keeping the reaction mixture under nitrogen,
ethyl chloroformate (1.26 g, 11.6 mmol) was added and stirring
was continued for 5 h. Then a solution of sodium cyanoboro-
hydride (0.46 g; 7.3 mmol) in 10 mL dry THF was added at
-55 °C and the reaction mixture was stirred overnight while
allowing it to reach room temperature. It was subsequently
treated with 120 mL of 2 N NaOH, the THF layer was separated,
washed with brine, and finally the organic layer was evaporated
under reduced pressure (analytical data, see SI).
General Procedure for the Preparation of Homoquinolizine 12
and Quinolizine 15. A solution of 4-(2-aminoethyl)-16 or 2-(2-
aminoethyl)indole17 (7.5 mmol), 2-(2-bromoethyl) benzalde-
hyde (9.4 mmol), and trifluoroacetic acid (7.5 mmol) in dioxane
was refluxed under nitrogen for 20 h, whereupon a solid formed.
The precipitated salts were filtered off, washed with dioxane and
then with diethyl ether, and subsequently dissolved in hot water,
filtered, and the filtrate rendered alkaline with 1 N NaOH.
Finally, the formed bases were extracted with chloroform and
the extracts dried over Na2SO4.
2,6,7,9,10,14b-Hexahydroindolo[30,40:3,4,5]azepino[2,1-a]-
isoquinoline (12). Evaporation of the solvent yielded a brown
solid that was crystallized from isopropanol/ether and then
recrystallized from chloroform to give cream colored crystals;
crude yield 89%; mp: 188-190 °C. 1H NMR for the base:
250 MHz (CDCl3): δ 2.75-3.63 (m, 8H, 6, 7, 9, 10), 5.42 (s,
1H, 14b), 6.55 (s, 1H, 1), 6.91-6.94 (d, J = 6.9, 1H, 11),
7.09-7.27 (m, 6H, 3, 4, 5, 12, 13, 14), 8.04 (s, 1H, indole-NH).
13C NMR for HCl salt: 400 MHz (MeOD-d4): δ 25.60 (10), 28.09
(6), 57.82 (7), 59.39 (9), 66.74 (14b), 109.54 (14c), 110.02 (3),
118.57 (1), 122.64 (4), 125.36 (5b), 126.36 (5), 126.67 (12), 128.16
(14), 128.56 (13), 128.89 (11), 130.58 (5a), 131.19 (14a), 131.94
Reduction of the Carbamate. A solution of compound 10
(200 mg, 0.6 mmol) in 10 mL of THF was slowly added to an
ice-cooled, stirred suspension of lithium aluminum hydride
(100 mg, 2.6 mmol) in 15 mL of dry THF while keeping the
reaction under nitrogen. After the addition was completed, the
reaction mixture was heated under reflux for 3 h. It was then
cooled in an ice bath, and the excess of unreacted lithium
aluminum hydride was quenched by careful addition of satu-
rated potassium sodium tartarate solution until no H2 evolved.
The resulting suspension was then filtered off and the filtrate
evaporated under reduced pressure to yield compound 2, which
was crystallized from chloroform yielding white crystals; yield
(10a), 136. (2a). Anal. (C19H18N2 0.5CHCl3): C, H, N.
03
5,6,8,9,10,14c-Hexahydroindolo[3 ,20:3,4,]pyrido[2,1-a]isoquinoline
(15). Evaporation of the solvent yielded an orange-brown solid,
which was purified by column chromatography (EtOAc-MeOH,
15:1); yield 21%; mp: 197-200 °C (analytical data see SI).
1
40%; mp: 257-260 °C. H NMR: 250 MHz (CDCl3): δ 1.56
(mc, 2H, 7), 2.13 (s, 3H, N-Me), 2.79 (mc, 2H, 6), (mc, 2H, 4), (s,
br, 2H, 12), 6.73-6.76 (d, J = 7, 1H, Ar-H), 7.00-7.26 (m, 7H,
Ar-H), 8.00 (s, 1H, NH).
General Procedure for the Preparation of the Quaternary
Salts. To a stirred solution of the respective quinolizine or
homoquinolizine in acetone (or acetonitrile for compound 15)
was added a 10-fold molar excess of methyl iodide. Stirring was
continued for a period ranging from 24 to 48 h, and the formed
quaternary salts were isolated (analytical data, see SI).
€
Acknowledgment. We thank Barbel Schmalwasser, Petra
Wiecha, and Heidi Traber for skillful technical assistance in
performing the pharmacological assays. We thank the Egyp-
tian Cultural Affairs and Mission Section for their financial
support. Furthermore, we thank the DFG for the financial
support of the project (EN 875/1-1).
General Procedure for the Ring-Opening. Ammonia was con-
densed in a three-necked 100 mL flask, which was equipped with
a balloon and a stopper and cooled in a liquid nitrogen bath.
3
After filling
/ of the flask’s volume, the cooling bath was
4
removed and ammonia was allowed to liquefy. The respective
quaternary salts were then added to the stirred liquid ammonia.
This was followed by gradual addition of small pieces of sodium
metal until the blue color remained for 10 min. A few drops of
Supporting Information Available: Detailed synthetic proce-
dures as well as physical and spectral data for some target and
intermediary compounds; table of elemental analysis for key
compounds; a detailed protocol for the pharmacological assays.

2650 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 6
Robaa et al.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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