Dopamine/serotonin receptor ligands. 16.1 Expanding dibenz[d,g]azecines to 11- and 12-membered homologues. Interaction with dopamine D1-D5 receptors

Article abstract of DOI:10.1021/jm070388+

Oxygenated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are potent dopamine receptor antagonists, preferentially at D₁/D₅. We synthesized the hydroxylated, methoxylated, and chlorinated 11-membered and 12-membered homologues of

Full text of DOI:10.1021/jm070388+

4528
J. Med. Chem. 2007, 50, 4528-4533
Dopamine/Serotonin Receptor Ligands. 16.1 Expanding Dibenz[d,g]azecines to 11- and
12-Membered Homologues. Interaction with Dopamine D1-D5 Receptors
Christoph Enzensperger, Franziska K. U. Mu¨ller, Ba¨rbel Schmalwasser, Petra Wiecha, Heidi Traber, and Jochen Lehmann*
Lehrstuhl fu¨r Pharmazeutische/Medizinische Chemie, Institut fu¨r Pharmazie, Friedrich-Schiller-UniVersita¨t Jena, Philosophenweg 14,
D-07743 Jena, Germany
ReceiVed April 3, 2007
Oxygenated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are potent dopamine receptor antagonists,
preferentially at D1/D5. We synthesized the hydroxylated, methoxylated, and chlorinated 11-membered and
12-membered homologues of these 10-membered heterocycles. Their affinities for the human cloned D1-
D5 receptors (radioligand binding) and functionalities (calcium assay) were measured. Enlarging the
dibenzazecines to the corresponding dibenzazacycloundecenes and dibenzazacyclododecenes generally
maintains the high antagonistic affinity for D1/D5 but also leads to a compound with a clozapine-like binding
profile due to additional affinity for D4.
Chart 1. Lead Structures 1 (LE 300) and 3-Hydroxy- and
Methoxydibenz[d,g]azecines 2 and 3 and 11-Membered
Homologue 4 with Improved Affinity over 1
Introduction
Dopamine-receptor-mediated neurotransmission plays a key
role in psychiatric, motor, and endocrinologic disorders, and
antagonists at the dopamine receptors are widely used as
antipsychotics. Because of a lack of highly subtype selective
D1 and D5 receptor ligands, knowledge of physiological impacts
of agonism or antagonism at these receptors is very limited.
Discoveries such as the functional interaction between the D1
and the NMDA receptors2 and the direct coupling of the D5
receptor with the GABAa-R γ-subunit3 further increase the
interest in selective D1 and D5 ligands as pharmacological tools
or as potential therapeutic agents. Antagonists at the D1 receptor
family such as ecopipam have been suggested for the treatment
of obsessive compulsive disorder (OCD), obesity, metabolic
disorders, eating disorders such as hyperphagia, and diabetes.4,5
These compounds have also been suggested to be useful in
treating alcohol6 or cocaine7-9 addiction. Many scientists are
convinced nowadays that so-called “dirty drugs” or multiacting
receptor targeted antipsychotics (MARTA) do have advantages
over selective compounds especially for the treatment of
psychosis.10,11
Chart 2. Homologization of Dibenzazecines 2 and 3 to
Corresponding Dibenzazacycloundecenes (5-8) and
Dibenzazacyclododecenes (9 and 10).
With regard to the azecine-type dopamine receptor ligands,
we have performed SAR studies that included variation of the
aromatic parts (benzene replaced by indole, thiophene. and
1-methyl-1H-pyrrole), contraction of the central heterocycle
from 10 to 9,12 or insertion of an oxygen atom.13 Expansion of
the central N-heterocycle has been successfully conducted for
the benzindoloazecine ring system (1 f 4)14 but not for any
dibenzazecine derivatives such as 2 and 3 (Chart 1).
Chart 3. Open-Ring Derivative of Ecopipam
In the present study we performed the homologization of the
hydroxylated and methoxylated hexahydrodibenz[d,g]azecines
2 and 3, and the resulting 11- and 12-membered heterocycles
were investigated with respect to their affinities and selectivity
profiles for the D1-D5 receptors. Retaining the aromatic
substitution pattern unchanged should allow us to exclusively
identify the influence of the ring expansion on affinity and
selectivity. We prepared the 12-membered target compounds
9,10 and both of the possible regioisomers 5,6 and 7,8 of the
nonsymmetric 11-membered ring (Chart 2).
Ecopipam represents a rigidified benzazepine-type D1/D5 an-
tagonist that may be useful for treating obesity and has reached
a phase 3 clinical study.5 Furthermore, studies with humans have
been performed to investigate its effects on reducing alcohol
or cocaine dependency.7-9
Finally we aimed for the nor-compound 25, which is not only
important with regard to SAR but also obligatory for developing
an optional 11C-methylated positron emission tomography (PET)
We also wanted to synthesize and screen an open-ring, more
flexible derivative of ecopipam (11 (SCH 39166), Chart 3).
* To whom correspondence should be addressed. Phone: +49 3641/
949803. Fax: +49 3641/949802. E-mail: j.lehmann@uni-jena.de.
10.1021/jm070388+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/04/2007

Expanding Dibenz[d,g]azecines
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18 4529
Scheme 1. Synthesis of the Azacycloundecenes 5-8a
a (a) Methyl iodide, acetonitrile; (b) HBr, glacial acetic acid; (c) Na/NH3
.
liq
Scheme 2. Synthesis of the Azacyclododecenes 9 and 10a
ligand. And we elaborated a new route for the preparation of
N-desalkyl derivatives in this class of compounds by applying
ethyl chloridocarbonate (see Scheme 1).15
Chemistry
In order to obtain the 11-membered dibenzazacycloundecens
5-8, we first synthesized the appropriate tetracyclic precursor
molecules 12 and 15 following a route that has been de-
scribed.16,17 We used 3-methoxyphenylpropylamine and iso-
chromanone to prepare 1216 and 3-methoxyphenethylamine and
the benzoxepinone derivative 19 to get 15.17 19 was synthesized
from tetralone by applying a five-step route described by
Krollpfeiffer and Mu¨ller.18 The homoquinolizine derivatives 12
and 15 were converted to their quaternary salts 13 and 16 with
methyl iodide in acetonitrile. Cleavage of the methoxy ether
was accomplished with hydrobromic acid in glacial acetic acid.
Birch conditions were used for the ring-opening procedure
(Scheme 1).
The corresponding 12-membered congener was prepared
analogously starting from the two three-carbon synthons 18 and
19 (Scheme 2). The resulting hydroxypropylbenzamide deriva-
tive 20 was successfully converted to the benzazepinobenza-
zepine 21 by applying a Bischler-Napieralski cyclization and
NaBH4 reduction sequence that has been performed as well for
the synthesis of 15.17 Methylation and ether cleavage of the
resulting quaternary salt 22 produced the respective phenolic
compound 23. Ring cleavage of 22 and 23 gave the azacy-
cloundecene derivatives 9 and 10.
Chlorinated target compounds including the 11-membered
“opened” ecopipam (Chart 3) could not be synthesized as
described in Scheme 1 because the chlorine atom was com-
pletely removed under Birch conditions. So we looked for other
ring cleavage procedures. Furthermore, we were interested in
having a nonmethylated derivative such as compound 25 for
pharmacological screening. Treatment with ethyl chloridocar-
bonate/NaCNBH319 proved to be a milder method for cleaving
the central C-N bond compared to sodium in liquid ammonia,
and 12 was transferred easily to the urethane derivative 24.
Simultaneous cleavage of the ether moiety and hydrolysis of
the urethane 24 were accomplished with BBr3 as formerly
described by Tanaka et al.15 to yield in the phenolic nor-
compound 25. As outlined in Scheme 3, this route also
represents a further approach to N-methylated azacycloun-
a (a) Toluene, reflux; (b) (1) POCl3/acetonitrile, reflux; (2) NaBH4/MeOH;
liq
(c) methyl iodide, acetonitrile; (d) HBr, glacial acetic acid; (e) Na/NH3
.
decenes by LiAlH4 reduction of the urethane, allowing us to
prepare compound 6 from 13 as well as from 24. Furthermore,
Scheme 3 shows that nor-compounds can be synthesized either
from quinolizine-like derivatives (e.g., 12) or from “opened”
azecine-like compounds by demethylation (e.g., 6).
For the synthesis of the “opened” ecopipam, 2-(4-methoxy-
phenyl)ethylamine was chlorinated to 2620 and reacted with the
benzoxepinone 19 to yield the benzamide 27 (Scheme 4).
Applying the usual treatment with POCl3/NaBH4 unfortunately
resulted in the benzazepine derivative 28, probably via a cyclic
chloroiminium salt. So we protected the hydroxy group16 and
performed a first cyclization of 29 toward the substituted
benzene with POCl3 yielding a dihydroisoquinoline derivative,
which was deprotected by KOH. The hydroxy group of this
intermediate was chlorinated with POCl3, and a subsequent
reduction of the dihydroisoquinolinium derivative with NaBH4
gave way to the second ring closure, yielding the homoquino-
lizine derivative 30 (“one-pot” procedure; intermediates are not
shown in Scheme 4). Reaction with methyl iodide produced
the quaternary salt 31, which yielded the deschloro compound
32 after Birch reduction. The phenolic quaternary salt 33 was

4530 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18
Enzensperger et al.
Scheme 3. Different Approaches for Ring Cleavage and
of these experiments. This may indicate that the aromatic
substituents significantly influence the ability of the quinolozines
and homoquinolizines to undergo ring cleavage. Accordingly,
we had to reintroduce the chlorine after ring cleavage. We
treated 34 with SOCl2 in glacial acetic acid at low temperatures
and detected four different compounds by GC/MS: unreacted
starting material, very low amounts of two monochlorinated
compounds, and one compound bearing two chlorine atoms.
Recrystallization, column chromatography, and preparative TLC
failed to separate and isolate the two monochlorinated com-
pounds. Only starting material 34 and the dichlorinated target
compound 35 could be isolated.
Synthesis of nor-Compoundsa
Pharmacology
Compounds were screened for their affinities for the human
cloned receptor subtypes D1, D2L, D3, D4.4, and D5 in radioligand
displacement experiments. Ki values are given in nanomolar
units (Table 1). For a detailed description, see the Supporting
Information. Additionally, the compounds were tested in an
intracellular Ca2+ assay with regard to their functionality for
the D1, D2L, and D5 receptors. HEK293 cells stably expressing
the respective D receptor were loaded with a fluorescent dye
(Oregon green), and after preincubation with rising concentra-
tions of a test compound, an agonist (SKF 38393) was injected
and fluorescence was measured with a NOVOSTAR microplate
reader. Suppressing the agonist-induced Ca2+ influx with the
test compound indicates antagonistic or inverse agonistic
properties at the receptor. For a detailed description see the
Supporting Information.
a (a) Methyl iodide, acetonitrile; (b) Na/NH3liq; (c) ethyl chloridocarbonate
THF, NaCNBH3, -78 °C to room temp; (d) BBr3 CHCl3; (e) THF, LiAlH4.
obtained from 31 by treatment with HBr/HOAc. Ring cleavage
under Birch conditions gave, as expected, the dechlorinated
phenolic azacycloundecene derivative 34.
To avoid dechlorination, other conditions for cleaving the
C-N bond in compound 30 were selectively investigated,
including C,N-hydrogenolysis with PtO2/H2 or treatment with
ethyl chloridocarbonate/NaCNBH3, but unfortunately none of
them turned out to be successful. In contrast to compound 12
(Scheme 3), unreacted starting material was recovered after all
Results and Discussion
We synthesized 10 dibenzazacycloundecenes or dibenzaza-
cyclododecenes. The benzazepino[1,2-a][2]benzazepine 21 and
the dibenzo[e,h]azacyclododecenes 9 and 10 are derivatives of
Scheme 4. Efforts to Synthesize the Open-Ring Derivative of Ecopipam 11a
a (a) Toluene, reflux; (b) ethyl chloridocarbonate, toluene/pyridine; (c) POCl3/acetonitrile, reflux; (d) (1) KOH EtOH/H2O; (2) POCl3; (e) methyl iodide,
acetonitrile; (f) Na/NH3liq; (g) HBr, glacial acetic acid; (h) SOCl2, glacial acetic acid; (i) (1) ethyl chloridocarbonate THF, NaCNBH3, -78 °C to room temp;
(2) THF, LiAlH4; (j) PtO2/H2.

Expanding Dibenz[d,g]azecines
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18 4531
Table 1. Affinities (Ki values) for Dopamine Receptor Subtypes
Measured by Radioligand Binding Studies
3.2 to 137 for D1, from 4.6 to 95 for D5, from 11 to 1396 for
D2L, from 100 to >10000 for D3, and from 15 to 3751 nM for
D4.4
.
The more constrained tetracyclic homoquinolizine derivatives
12, 15, 21, and 30 did not display any significant affinity for
any of the dopamine receptor subtypes, whereas for all of the
11- and 12-membered “open” target compounds, which include
phenylethyl- and phenylpropylamine moieties in a very mod-
erately constrained way, reasonable to high affinities were found.
Interestingly, the affinities of the two possible types of the 11-
membered derivatives for the dopamine receptors are signifi-
cantly different. The position of the nitrogen in relation to the
substituted benzene ring is crucial. Compounds with the nitrogen
closer to the substituted benzene ring (7, 8) are more active
than the other regioisomers, where the distance between the
nitrogen and the substituted benzene is greater (5, 6). This
finding is completely in line with our previous investigation of
the respective 11-membered benzindoloazacycloundecene de-
rivatives.14
The hydroxylated dibenzazacycloundecenes 5, 7, and 34
exhibit higher affinities for the D1 receptor than do their
methoxylated analogues 6, 8, and 32. Affinities of 7 and 34 are
twice as high as those of 8 and 32, and the phenolic 5 is nearly
6 times more potent than the methoxy derivative 6. Basically,
these results resemble the affinity profiles we have found for
the 10-membered counterparts, but there the OH compound 2
is even 70 times more active than the MeO compound 3.20
Interestingly, the affinity of the N-methyl derivative 6 for all
receptor subtypes decreases dramatically when the N-methyl is
replaced by NH (25). The functional assay showed that 25
maintained the antagonistic activity and did not switch into an
agonist, as do some benzazepine-type ligands with a free NH
(e.g., SKF 38393). With regard to the compounds’ affinity for
dopamine receptors, that of the 11-membered compound with
two MeO substituents 36 is low and that of the benzazepine 28
is nonexistent. Expanding the size of the central N-heterocycle
from 11 to 12 proved to be less favorable. The affinities of 9
and 10 for D1 and D5 are comparatively low, and in contrast to
the affinities of all of the 11-membered compounds (see Table
1) and the previously investigated 10-membered compounds,
the affinities of the methoxy derivative (10) are higher than those
of phenolic 9 (Table 1).
The chlorination of 34, yielding 35, did not improve the
affinity for the D1 and D5 receptor but revealed a new subtype
selectivity profile. Surprisingly, the affinities for D2L and D4.4
(11 and 15 nM) are higher than for D1 and D5 (124 and 89
nM). We found 35 to be the first “dibenzazecine-type” dopamine
receptor antagonist without selectivity toward the D1 receptor
family. The additional high affinity for the D4.4 receptor subtype
characterizes 35 as a compound with a binding profile that
resembles the profile of the well-established atypical antipsy-
chotic clozapine (Table).
The radioligand binding data of the ring-enlarged compounds
were used among other data to investigate the molecular
mechanism of the interaction of antagonistic compounds with
the dopamine D1 receptor. For this purpose, the novel xMaP-
4D-QSAR technique was applied. A companion paper on this
is in preparation (Josef Scheiber, Christoph Enzensperger,
Jochen Lehmann, and Knut Baumann).
a Values from ref 12. b Values from the PDSP database.21
novel heterocyclic ring systems. We have recently published
the synthesis of the dibenzazacycloundecene derivative 36.13
Furthermore, the 11- and 12-membered heterocycles can be
considered ring-enlarged homologues of the previously de-
scribed highly potent dibenzazecine-type dopamine receptor
antagonists.12,20 Using radioligand displacement experiments,
we screened these target compounds and some of the intermedi-
ates for their affinity for all human cloned dopamine receptors.
As radioligands, we used [3H]SCH 23390 for the D1 receptor
family and [3H]spiperone for the D2 family. The functionality
of the compounds was determined using a fluorescent calcium
assay (see Supporting Information). All of the active compounds
in Table 1 proved to be antagonists or inverse agonists,
preferentially for the D1/D5 family. The Ki values of the novel
monooxygenated N-methylated target compounds range from
Experimental Section
Most of the protocols for the preparation of the target compounds
and intermediates together with their physical and spectral data
(NMR, GC/MS) are given in the Supporting Information.

4532 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18
Enzensperger et al.
Ring Opening. General Procedure. A 100 mL three-neck flask
equipped with a balloon as an overflow tank was cooled in a liquid
nitrogen bath. Ammonia was condensed into this flask until the
flask was 3/4 filled. The cooling bath was removed, and the ammonia
was allowed to liquefy. The quaternary salts (e.g., 13, 14, 16, 17,
22, 23, 31, 33) were added. Rice-grain-sized pieces of sodium were
added to the stirred mixture until the developing blue color remained
for 10-15 min. The mixture was quenched by adding 1-2 drops
of saturated aqueous NH4Cl. The ammonia was evaporated under
nitrogen, and 5 mL of water and then 15 mL of diethyl ether were
added to the residue. The mixture was stirred until two phases
formed. The aqueous phase was extracted with diethyl ether (3 ×
15 mL). For the phenolic compounds the pH was adjusted to 8.
The ethereal phase was dried over MgSO4 and evaporated to yield
the open-ring compounds, usually with sufficient purity. If neces-
sary, the product was purified as described in the Supporting
Information.
diethyl ether was added to the resulting oil; storage in the
refrigerator induced crystallization. The crystals were removed by
filtration, washed with small amounts of diethyl ether, and dried.
Chlorination of Azacycloundecene (34 f 35). A solution of
0.56 g (2 mmol) of 34 in 4 mL of glacial acetic acid was stirred
and cooled carefully to prevent glacial acetic acid from solidifying.
A solution of 200 µL (2.5 mmol) of sulfuryl chloride in 200 µL of
glacial acetic acid was added slowly and dropwise. The mixture
was allowed to return to room temperature overnight. An amount
of 10 mL of diethyl ether was added, and the precipitated
hydrochloride salts were dissolved in methanol. GC/MS of the free
bases showed four peaks: starting material, two monochlorinated
compounds, and a double-chlorinated compound. The double-
chlorinated compound could be separated by column chromatog-
raphy, but no monochlorinated compound could be separated by
column chromatography, preparative TLC, or recrystallization.
Ring Cleavage (12 f 24) or Demethylation (6 f 24) with
Ethyl Chloridocarbonate and NaCNBH3. General Procedure.
A solution of 3.5 mmol of the respective quinolizine derivative/or
N-methylazacycloundecene in 75 mL of dry THF was cooled under
nitrogen to -75 °C in a methanol/dry ice bath. With a syringe, an
amount of 20 mmol (1.9 mL) of ethyl chloridocarbonate was added
through a septum in several small portions. The mixture was stirred
for 4 h, and the temperature was allowed to come up to -40 °C.
The mixture was cooled again to -75 °C, and a total of 12.3 mmol
(770 mg) of NaCNBH3 in 6 mL of dry THF was added dropwise
during a period of 10 min. The reaction mixture was stirred in an
ice bath overnight and allowed to return to room temperature
overnight again. A total of 175 mL of 2 N NaOH was added to the
resulting emulsion and stirred for 10 min. The THF layer was
separated and evaporated in vacuo, and the aqueous layer was
extracted with dichloromethane (2 × 50 mL) and added to the
evaporated THF layer. The combined organic phases were dried
over Na2SO4 and evaporated. The oily residue contained the crude
carbamate, which was used for either LiAlH4 reduction or hydrolysis
with BBr3. The yield for the ring opening was approximately
quantitative, and the yield for the demethylation was about 80%.
Simultaneous Ether Cleavage and Carbamate Hydrolysis
with BBr3. General Procedure Exemplified for Compound 25.
According to ref 15, a solution of 1 mmol of the respective
methoxylated carbamate in 10 mL of dry toluene and then 5 mmol
(473 µL) of boron tribromide were added under nitrogen by
injecting it through a septum. The mixture was refluxed for 2.5 h,
allowed to return to room temperature, and quenched with 30 mL
of ice-water. The aqueous layer was washed two times with toluene
(unreacted carbamate could then be recovered from the toluene).
The pH value of the water layer was adjusted to 8-9 with ammonia,
and the aqueous layer was extracted with chloroform (5 × 30 mL).
The pooled extracts were dried (Na2SO4) and evaporated. The oily
residue was dissolved in 5 mL of diethyl ether, and the hydrochlo-
ride salt was formed by adding ethereal HCl. Recrystallization was
performed from diethyl ether and isopropanol.
LiAlH4 Reduction of the Phenolic Carbamate 24 to 6. A
suspension of 20 mmol (150 mg) LiAlH4 in 20 mL of dry THF
was stirred and cooled to 0 °C. Under nitrogen, a solution of 1.47
mmol (520 mg) of 24 in 8 mL of THF was added in small portions
by injecting it through a septum. The mixture was refluxed for 4 h
and stirred overnight. The excess LiAlH4 was decomposed by the
dropwise addition of 5 mL of 50% aqueous THF. The solids were
removed by filtration, and THF was evaporated from the liquid.
The aqueous residue was portioned between 20 mL of diethyl ether
and 20 mL of 2 N HCl. The phases were separated, and the aqueous
layer was washed with diethyl ether (2 × 20 mL). The water phase
was adjusted to pH 8-9 and again extracted with dichloromethane
(3 × 50 mL) to yield a white foam of 6 after drying (Na2SO4) and
evaporation. The yield was 316 mg, 73%.
Synthesis of the Quaternary Salts (e.g., 13, 14, 16, 17, 22, 23,
31, 33). General Procedure. A 10-fold molar excess of methyl
iodide was added to a stirred solution of the respective homoqui-
nolozine in acetonitrile. Under nitrogen, the mixture was stirred
for 48h at ∼40 °C. The precipitated solids were isolated by filtration
and dried in vacuo (yield, ∼90%).
Synthesis of Homoquinolizines. General Procedure Exempli-
fied for Compound 30. According to ref 16, a solution of 4.4 g
(10,4 mmol) of the protected benzamide 29 in 150 mL of a 2:1
mixture of acetonitrile and POCl3 was refluxed for 4 days under
nitrogen. The solvents were removed in vacuo, the residue was
portioned between 170 mL of 2 N HCl and 30 mL of ethyl acetate,
and the aqueous layer was washed with 20 mL of ethyl acetate.
The dihydroisoquinolinium salt was extracted as an ion pair from
the acidic aqueous layer with chloroform (5 × 40 mL). The
combined chloroform layers were evaporated, and the residue (2.44
g) was stirred into 70 mL of a 20% KOH solution in aqueous
ethanol (70% EtOH, 30% H2O) at room temperature for 12 h. The
solvents were concentrated in vacuo to about 10 mL, maintaining
the temperature below 40 °C. An amount of 160 mL of 2 N HCl
was added to this residue and extracted with chloroform (5 × 30
mL). After the mixture was dried (Na2SO4) and evaporated, the
remaining oil was dissolved in 17 mL of POCl3 and stirred for 15
min at 60 °C. The mixture was cooled to room temperature, and
an amount of 100 mL of petroleum ether (40-60) was added under
vigorous stirring. The oil was allowed to deposit, and the upper
layer, containing POCl3 and petroleum ether, was decanted and
discarded. This procedure was repeated until no more POCl3 was
detected by smell. An amount of 3 g of NaBH4 was added under
cooling to the residue, dissolved in 85 mL of methanol. After the
reaction subsided, the solution was refluxed for 1 h, evaporated to
dryness, and redissolved with 150 mL of water. Extraction with
diethyl ether (5 × 40 mL), drying (Na2SO4), and evaporating yielded
1.3 g of the crude 30 as a free base. The HCl salt was obtained by
dissolving the base in 10 mL of diethyl ether and adding ethereal
HCl. The precipitated HCl salt was recrystallized from isopropanol.
The total yield of 30 (based on 29) was 1.2 g (39%).
Ether Cleavage of Methoxylated Quaternary Salts (13, 16,
22, 31). General Procedure. The quaternary salt of the respective
methoxy compound was dissolved in a mixture of 20 mL of glacial
acetic acid and 20 mL of aqueous HBr (48%) and refluxed under
nitrogen for 5 h. The solvents were removed in vacuo, and the
residue was crystallized from methanol/diethyl ether.
Preparation of 2-(2-Hydroxyalkyl)-N-(2-phenylalkyl)benza-
mides (20, 27). General Procedure. A solution of 40 mmol of
the respective phenylalkylamine and 40 mmol of the lactone in 40
mL of toluene was refluxed for 24 h. The mixture was washed
with 2 N HCl (5 × 30 mL), and the organic layer was evaporated
to dryness. An amount of 50 mL of 20% NaOH was added to the
residue and stirred vigorously at 70 °C. A total of 100 mL of
chloroform was added to the residue, after which the organic layer
was separated, dried (Na2SO4), and evaporated to dryness. Some
Pharmacology. Experimental details of the radioligand binding
studies and the calcium assay are described in the Supporting
Information.

Expanding Dibenz[d,g]azecines
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18 4533
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Acknowledgment. Appreciation is expressed to Josef Scheiber
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Supporting Information Available: Synthetic procedures and
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