SAR study of 1-aryl-4-(phenylarylmethyl)piperazines as ligands for both dopamine D2 and serotonin 5-HT1A receptors showing varying degrees of (Ant)agonism. Selection of a potential atypical antipsychotic

Article abstract of DOI:10.1248/cpb.54.1326

The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D₂ and serotonin 5-HT_1A receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in the identification of the drug candidate SLV313 (4e) with equipotent and full D₂ receptor antagonism and 5-HT_1A receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds possessing varying degrees of partial agonism on one or both target receptors.

Full text of DOI:10.1248/cpb.54.1326

1326
Notes
Chem. Pharm. Bull. 54(9) 1326—1330 (2006)
Vol. 54, No. 9
SAR Study of 1-Aryl-4-(phenylarylmethyl)piperazines as Ligands for Both
Dopamine D2 and Serotonin 5-HT1A Receptors Showing Varying Degrees
of (Ant)agonism. Selection of a Potential Atypical Antipsychotic
Roelof Willem FEENSTRA,* Adri van den HOOGENBAND, Cornelis Nicolaas Jozef STROOMER,
Herman Heinrich van STUIVENBERG, Martin Theodorus Maria TULP, Stephen Kenneth LONG,
Johannes Antonius Maria van der HEYDEN, and Cornelis Gerrit KRUSE
Solvay Pharmaceuticals, Research Laboratories; C. J. van Houtenlaan 36, 1381 CP, Weesp, The Netherlands.
Received April 19, 2006; accepted June 13, 2006
The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D2 and
serotonin 5-HT1A receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in
the identification of the drug candidate SLV313 (4e) with equipotent and full D2 receptor antagonism and 5-HT1A
receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds
possessing varying degrees of partial agonism on one or both target receptors.
Key words SLV313; N-phenylpiperazines; biaryl; (partial) dopamine D2 receptor antagonist; (partial) serotonin 5-HT1A recep-
tor agonist; atypical antipsychotic
Schizophrenia1) is a disease of which the etiology is un- velop atypical antipsychotics.4)
known. The disease is characterized by the so-called positive
The rationale behind the combination of a D2 receptor an-
and negative symptoms. Positive symptoms include halluci- tagonist and a 5-HT1A receptor agonist is based on several
nations and paranoia. The most characteristic negative symp- preclinical data, supporting the hypothesis that selective 5-
toms are social withdrawal and flattening of the personality. HT1A receptor agonists are capable of preventing D2 receptor
In addition, both cognitive as well as depressive symptoms antagonist induced EPS in animal models. The 5-HT1A re-
and anxiety may occur.
ceptor agonist 8-hydroxy-2-(di-N-propylamino) tetralin (3)
The most frequently used antipsychotic haloperidol (1) (8-(OH)-DPAT, Fig. 1) is capable of antagonizing haloperidol
(Fig. 1), a dopamine D2 receptor antagonist, only alleviates (1) induced catalepsy in rats and dystonia in non human pri-
the positive symptoms presumably by attenuating the mates,5) and reduces the forelimb retraction time in the paw
dopaminergic neurotransmission system in the mesolimbic test.6) Furthermore, 5-HT1A receptor agonists are active in the
area of the brain, leaving the negative symptoms untreated. forced swimming test (FST), a preclinical model predictive
Therapy with this type of compounds is frequently accompa- of antidepressant activity.7)
nied by extrapyramidal side effects (EPS), resulting from a
This report focusses on compounds of type (4) (Fig. 2)
blockade of dopaminergic activity within the (extrapyrami- which share affinity for dopamine D2 as well as serotonin 5-
dal) motor areas of the brain. This type of compounds is re- HT1A receptors. Compound (4e) of this series possessed the
ferred to as “typical” antipsychotics. There is a strong need desired profile (full dopamine D2 receptor antagonism and
for compounds that will treat all types of symptoms and will full serotonin 5-HT1A receptor agonism) and was selected as
not induce EPS. An example of such an “atypical” antipsy- a clinical candidate.
chotic is clozapine (2) (Fig. 1), a D2 receptor antagonist with
In this paper we like to demonstrate that compounds (4)
modest potency (69 nM, see Fig. 1). Clozapine (2) shows behave quite differently compared to our previously pub-
higher affinity for several other receptors, especially for sero- lished1) series of compounds (5) when examining their func-
tonin receptor subtypes, which may account for the beneficial tional behavior on both dopamine D2 and serotonin 5-HT1A
effect against negative symptoms.2,3) Combining dopaminer- receptors.
gic and serotonergic actitivity may be a valid approach to de-
Chemistry
The synthesis of compounds (4) is depicted in Chart 1.
The compounds (4a—e) were prepared by reacting elto-
Fig. 1. Structures and Affinities (Ki, nM) on Dopamine D2 and Serotonin 5-
Fig. 2. General Structures of Compounds 4 and 5
HT1A Receptors of Haloperidol (1), Clozapine (2) and 8-(OH)-DPAT (3)
∗ To whom correspondence should be addressed. e-mail: rolf.feenstra@solvay.com © 2006 Pharmaceutical Society of Japan

September 2006
1327
Table 1. Structures and Affinities (Ki, nM) of Compounds 4 and 5 on
Dopamine D2 and Serotonin 5-HT1A Receptors, Respectively
Compounds
Ki (nM) D2/5-HT1A
(4a) (2HCl)
(5a) (HOMs)
1.7/1.1
2.2/9.4
(4b) (fb)
26/46
(4c) (2HCl)
(5c) (fb)
5.8/20
2.9/21
(4d) (2HCl)
1.5/1.4
(5d) (2HCl)
0.47/16
Chart 1. Synthesis Scheme of Compounds 4
prazine (6) and a biarylmethyl halide (7) in the presence of
Et(i-Pr)2N and KI in acetonitrile at reflux temperature. Yields
of 4a—e ranged from 38 to 83%. Some of the compounds
(4) were converted into their mono- or di-HCl salts by treat-
ment with HCl/EtOH. The intermediates (7a—e) were syn-
thesized according to the procedures described in the refer-
ences given in the experimental part.
The syntheses of compounds (5) are described in the liter-
ature.1,8) In Table 1 the relevant compounds (4) and (5) are
depicted.
(4e) (HCl)
3.6/3.2
(5e) (fb)
1.6/2.1
Values are based on 3 assays, each using 4 to 6 concentrations in triplicate. fb: free
base.
Table 2. In Vivo Test Results (ED50 Values) in Inhibition of Apomorfine
Induced Climbing Behavior (CB), Suppression of Conditioned Avoidance
Behavior (CAR) and Lowerlip Retraction (LLR) of Compounds 1—5
CB (mg/kg)
CAR (mg/kg)
LLR (mg/kg)
Compounds
Biological Evaluation and Discussion
Mouse p.o.
Rat p.o.
Rat p.o.
The affinities of compounds (1—5) for dopamine D2 and
the serotonin 5-HT1A receptors were measured using [3H]-
spiperone10) and [3H]-8-OH-DPAT respectively.11) Both as-
says make use of rat receptors. In Fig. 1, the Ki values are
given (calculated from at least three independent experi-
ments) for compounds (1), (2) and (3). In Table 1, the affini-
ties of 4 and 5 expressed as Ki values for both receptors are
listed.
1
2
3
4a
4b
4c
4d
0.2
22
0.3
32
ꢀ20
ꢁ10
0.1a)
6
6
ꢀ20a)
16
0.2
0.5
0.1
0.5
2.6
0.6
1.0
1.8
10
4e (SLV313)
5a
Within the series (4), replacement of a carbon atom by a
nitrogen atom in the aromatic ring Ar1 was studied in order
to improve pharmacokinetic properties. This had a dopamine
ED50 values are based on at least 3 dose levels. a) i.p. administration.
D2 receptor affinity lowering effect if the nitrogen atom was tonin 5-HT1A receptors in series (4) increases when compar-
introduced on position Y2: affinity drops from 1.7 nM (4a) to ing (5a) to (4a) and (5d) to (4d). Introduction of a nitrogen
26 nM for compound (4b). The affinities for compounds (4c), atom on position Y4 is unfavourable for the serotonin 5-HT1A
(4d) and (4e) in which carbon to nitrogen replacement is on receptor affinity in the case of compound (4c) as well as for
positions Y4, Y6 and Y5 respectively, remain almost unal- compound (5c).
tered. The presence of a fluorine atom in compounds (4c),
The compounds of series (4) were tested in in vivo models
(4d) and (4e) did not seem to play a crucial role for relevant for D2 receptor antagonism—inhibition of the apo-
dopamine D2 receptor affinity. Considering the serotonin 5- morphine-induced climbing behavior (CB) in mice12)—, and
HT1A receptor affinities in series (4), compounds (4b) and for antipsychotic activity—the suppression of the condi-
(4c), in contrast to (4d) and (4e), show a drop in affinity tioned avoidance response (CAR) in rats13)—. To determine
compared to (4a).
the 5-HT1A receptor agonistic component in vivo, the com-
When series (4) are compared to series (5) it can be seen pounds were tested for the occurrence of the so called lower
from Table 1 that series (5) compounds are slightly more po- lip retraction in rats (LLR).14) The results are given in Table
tent on dopamine D2 receptors than series (4) compounds, 2.
with the exception of compound (5a). This effect is most
Considering the in vivo profiles of series (4), compound
pronounced when comparing (4d) to (5d). Affinity for sero- (4b) and (4c) turned out to be not potent enough in the CB

1328
Vol. 54, No. 9
Table 4. Calculated and Measured Properties of Compound (4e)
Table 3. Maximal Partial Agonistic Values (%) of Key Compounds (4a),
(4e), (5a) and (5e) on Dopamine D2 and Serotonin 5-HT1A Receptors, Re-
spectively15—17)
4e SLV313
Criterion
H-Acceptorsa)
H-Donorsa)
5
0
ꢃ10
ꢃ5
ꢃ500
ꢃ5
ꢃ10
ꢃ70
ꢃ1.5
ꢄ20
MWa)
405
3.9
4
35
1.0
33
log Pa),#
Rotable bondsb)
PSA (Å)c)
Compounds
Pgp factord),#
Membrane passage (%)e),#
a) Lipinski’s “Rule of five”,18) log P was measured according to procedure described
in ref. 19. b) Any acyclic single bond connecting non-terminal, non-hydrogen
atoms.20) c) Calculated polar surface area.21) d) P-Glycoprotein transport ratio, ex-
pressed as the ratio of the bottom to top transport and the top to bottom transport.22)
e) Membrane passage expressed as the mean percentage of compound transported.22)
Percentage agonism D2/5-HT1A
#
Experimentally determined values.
(4a)
9/65
(5a)
28/73
development1) shows partial agonism at both sites. Com-
pound (4e) on the other hand displays full antagonism at
dopamine D2 receptors and full agonism at serotonin 5-HT1A
receptors and was therefore studied in more detail. Some cal-
culated and measured physico-chemical properties that may
be of relevance for pharmacokinetic behavior, are depicted in
Table 4.
(4e)
2/96
(5e)
24/96
Favorable absorption may be predicted on the basis of the
low number of H-donor and H-acceptor sites and the rela-
tively low molecular weight, logP18,19) and number of rotat-
able bonds.20) The low polar surface area21) (PSA) and a P-gp
factor22) around 1 indicate a favourable brain penetration.
The measured high membrane passage further substantiates
Values are based on 3 to 6 assays, measured at 1000 nM. When measuring (partial)
agonism at even higher concentrations than 1000 nM, no higher percentages were found,
indicating that the maximum degree of agonism is reached at 1000 nM.
test and were not investigated further. Compounds (4d) and these expectations.
(4e) both show an attractive in vivo profile: they are potent in
Indeed, a favorable bioavailability of 69% (dog)23) and
the CB test and about equipotent with regard to the CAR and brain/plasma ratio of 4 (rat)24) were measured. A more de-
LLR test, which may lead to equal expression of the desired tailed publication describing the pharmacodynamic profile of
D2- and 5-HT1A mediated therapeutic actions at a given dose. SLV313 (4e) is in preparation.
Compound (4a) does show activity (p.o.) in the CB, CAR
Further clinical studies with (4e) may reveal if these pre-
and LLR tests, but less potently than (4d) and (4e). After fur- clinical properties also translate into a favorable therapeutic
ther preclinical profiling of the compounds (4d) and (4e), the profile.
latter was selected for further investigation.
In order to establish the desired full dopamine D2 receptor
Experimental
1H- and 13C-NMR spectra were recorded on a Varian UN400 instrument
antagonism and full serotonin 5-HT1A receptor agonism,
some related compounds of series (4) and (5) were tested for
their (ant)agonistic properties in vitro. This was accom-
plished by using CHO cells transfected with either the
human dopamine D2 receptor15,16) or the human serotonin 5-
HT1A receptor.17) In this type of experiments receptor ago-
nists decrease forskolin induced levels of the tritium labeled
second messenger [3H]-cAMP, giving the value of the intrin-
sic efficacy (e) of the compound studied. A ligand not de-
creasing the cAMP level, is an antagonist (eꢂ0%), a com-
pound bringing cAMP levels down to zero is a full agonist
(eꢂ100%). Partial agonists have e values between 0 and
100%. As can be seen from Table 3, it turned out that inde-
pendent of the arylpiperazine chosen, the 3-(4-fluorophenyl)-
pyridyl-5-yl-methyl moiety induces full 5-HT1A agonism
((4e) eꢂ96% and (5e) eꢂ96%). Furthermore, the benzodi-
(400 MHz for 1H-NMR, 100 MHz for 13C-NMR), using DMSO-d6 or CDCl3
with (CH3)4Si as an internal standard, as solvents. Chemical shifts are given
in ppm (d scale). Thin-layer chromatography was performed on Merck pre-
coated 60 F254 plates, and spots were visualised with UV light. Column
chromatography was performed using silica gel 60 (0.040—0.063 mm,
Merck). Melting points were recorded on a Büchi B-545 melting point appa-
ratus and are uncorrected. Mass spectra were recorded with a Micromass
GCT or Kratos Concept 1S instrument.
1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazine Hydrochloride (6)
This compound was synthesized according to the procedure described in
patent EP 0189612.25)
1-Biphenyl-3-yl-methyl-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piper-
azine (4a) Under a nitrogen atmosphere 4.9 g (19.0 mmol) of 1-(2,3-
dihydro-benzo[1,4]dioxin-5-yl)-piperazine (6) hydrochloride and 4.8 g
(19.5 mmol) of 1-bromomethyl-3-phenyl benzene (7a) were suspended in
250 ml of dry acetonitrile. While stirring 10.5 ml (60 mmol) of diisopropyl-
ethylamine were added and the mixture was brought to reflux temperature
for 16 h. After cooling to room temperature the reaction mixture was con-
centrated in vacuo, the residue was purified by flash column chromatography
oxanyl piperazine moiety induces full D2 antagonism, ((4a) (SiO2, eluent CH2Cl2/MeOH 99/1). The product containing fraction was
concentrated in vacuo, the residue taken up in methanol to which 2 eq of
eꢂ9% and (4e) eꢂ2%), independently of the biarylmethyl
part of the molecule. These structural tools enable to design
all four possible combinations of D2 antagonism/partial ago-
nism and 5HT1A full agonism/partial agonism.
HCl (1 N HCl/MeOH) were added. Concentration in vacuo yielded 7.0 g
(80%) of (4a) as the dihydrogenchloride salt. mp 223—225 °C. 1H-NMR
(CDCl3) d: 3.10 (pseudo t, 2H), 3.62—3.40 (cluster, 6H), 4.18—4.28 (clus-
ter, 4H), 4.32 (s, 2H), 6.51 (dd, Jꢂ8, 2 Hz, 1H), 6.63 (dd, Jꢂ8, 2 Hz, 1H),
6.76 (t, Jꢂ8 Hz, 1H), 7.37 (mp, 1H), 7.47 (m, 2H), 7.53 (t, Jꢂ8 Hz, 1H),
Compound (5a) that was previously selected for clinical

September 2006
1329
7.62—7.72 (cluster, 4H), 7.88 (pseudo s, 1H), 12.9 (s broad, NHꢅ, 1H).
HR-EI-MS m/z: 387.2073 (Calcd for C25H26N2O2: 387.2072). Anal.
(C25H26N2O2·2HCl): Calcd (%): C: 65.4, H: 6.1, N: 6.1, Found (%): C: 65.3,
H: 6.0, N: 6.0.
149.5, 149.9, 162.9, 165.4. HR-EI-MS m/z: 406.1948 (Calcd for
C24H24FN3O2: 406.1931). Anal. (C24H24FN3O2·0.3H2O·2HCl): Calcd (%):
C: 59.6, H: 5.5, N: 8.7, Found (%): C: 59.3, H: 5.5, N: 8.5.
1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-
3-yl-methyl]-piperazine (4e) To
a
suspension of 1-(2,3-dihydro-
1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-4-(6-phenyl-pyridin-2-yl-
methyl)-piperazine (4b) 0.95 g (4.0 mmol) of (7b) and 1.08 g (4.2 mmol)
of (6) hydrochloride were suspended in 30 ml of acetonitrile after which
4.2 ml (25 mmol) of diisopropylethylamine were added and the mixture was
brought to reflux temperature for 2 h. After cooling to room temperature the
reaction mixture was concentrated in vacuo, to the residue water was added,
after which extraction took place with CH2Cl2. The combined organic frac-
tions were dried on Na2SO4. After removal of the drying agent by filtration
and solvent by concentration in vacuo, the obtained residue was subjected to
flash column chromatography (SiO2, eluent CH2Cl2/MeOH 97/3). The prod-
uct containing fraction was concentrated in vacuo, the residue suspended in
petroleum ether to which some diethyl ether was added. Stirring yielded
0.73 g (45%) of a white solid containing the free base of (4b), mp 125—
126 °C.
benzo[1,4]dioxin-5-yl)-piperazine (6) hydrochloride (1.10 g, 4.3 mmol) in
CH3CN (40 ml) was added 3-chloromethyl-5-(4-fluoro-phenyl)-pyridinium
chloride (7e) (1.0 g, 3.4 mmol) and diisopropylethylamine (2.45 g,
19.0 mmol). The mixture was stirred at reflux for 3 h. After cooling and
evaporation of the solvent in vacuo, the residue was taken up in CH2Cl2,
washed with 5% NaHCO3 solution, saturated NaCl, dried (Na2SO4), filtered,
and evaporated in vacuo. The resulting dark oil was purified by flash chro-
matography on silica gel (CH2Cl2/MeOH/NH4OH (25%), 97.25/2.5/0.25
v/v/v) to give the free base of (4e) (0.91 g, 52%) as an oil. The product was
converted to its monohydrochloride salt: the residue was dissolved in Et2O
and treated with 1 eq of ethanolic HCl. The product precipitated as a white
solid. The solid hydrochloride of (4e) was collected by filtration and dried:
mp 233—235 °C, dec. 1H-NMR (400 MHz, DMSO-d6/CDCl3, 4/1) d (ppm):
3.17 (m, 2H), 3.29 (m, 2H), 3.40—3.58 (cluster, 4H), 4.24 (cluster, 4H),
4.51 (s broad, 2H), 6.49 (dd, Jꢂ8, 2 Hz, 1H), 6.55 (dd, Jꢂ8, 2 Hz, 1H), 6.73
(t, Jꢂ9 Hz, 1H), 7.34 (cluster, 2H), 7.86 (cluster, 2H), 8.56 (broad, 1H), 8.77
(m, 1H), 8.95 (d, Jꢂ2 Hz, 1H), 11.7 (s broad, 1H, NHꢅ). 13C-NMR (DMSO-
d6/CDCl3 4/1) d: 46.8, 51.0, 56.1, 63.7, 63.9, 110.4, 111.9, 115.9, 120.3,
125.5, 129.1, 132.8, 134.4, 136.1, 137.6, 139.7, 143.9, 148.2, 150.5, 162.5.
HR-EI-MS m/z: 406.1942 (Calcd for C24H24FN3O2: 406.1931). Anal.
(C24H24FN3O2·0.5H2O·HCl): Calcd (%): C: 63.9, H: 5.8, N: 9.3, Found
(%): C: 64.3, H: 5.6, N: 9.2.
1H-NMR (CDCl3) d: 2.79 (t, 4H) 3.14 (t, 4H), 3.85 (s, 2H), 4.20—4.35
(cluster, 4H), 6.55 (dd, Jꢂ8, 2 Hz 1H), 6.59 (dd, Jꢂ8, 2 Hz, 1H), 6.77 (t,
Jꢂ8 Hz, 1H), 7.36 (cluster, 4H), 7.59 (d, Jꢂ8 Hz, 1H), 7.72 (t, Jꢂ8 Hz, 1H),
8.00 (m, 2H). 13C-NMR (DMSO-d6) d: 50.9, 53.4, 63.9, 64.3, 64.7, 110.7,
111.8, 118.7, 120.6, 121.3, 127.0, 128.7, 128.8, 136.5, 137.0, 139.6, 141.9,
144.1, 156.8, 158.6. HR-EI-MS m/z: 388.2044 (Calcd for C24H25N3O2:
388.2025). Anal. (C24H25N3O2·0.4H2O): Calcd (%): C: 73.0, H: 6.6, N: 10.6,
Found (%): C: 73.0, H: 6.3, N: 10.4.
1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-4-[2-(4-fluoro-phenyl)-pyridin-
4-yl-methyl]-piperazine (4c) 0.63 g (2.37 mmol) of bromide (7c) and
0.61 g (2.38 mmol) of the hydrochloride of (6) together with 1.0 ml
(5.7 mmol) of diisopropylethylamine were suspended/dissolved in 20 ml of
dry acetonitrile. A little potassium iodide was added and the reaction mix-
ture was stirred and brought to 80 °C, under a nitrogen atmosphere. After
16 h the reaction mixture was cooled to room temperature and concentrated
in vacuo. The residue was purified by column chromatography (SiO2, eluent:
CH2Cl2/MeOH/NH4OH (25%) 92/7.5/0.5 v/v/v), yielding 0.48 g of a brown
siruppy oil. To the latter 20 ml of tert-butyl methyl ether was added upon
which some precipitate formed which was removed by filtration. The filtrate
was treated with 5 ml 1 N HCl/EtOH and the precipitate which formed was
collected by filtration yielding 1.3 g of a light brown solid, which was again
purified by column chromatography (SiO2, eluent: CH2Cl2/MeOH/NH4OH
(25%) 92/7.5/0.5 v/v/v), yielding a brown oil. The latter oil was dissolved in
tert-butyl methyl ether and HCl (g) was led through the solution. The precip-
itate which formed was filtered, the residue washed with tert-butyl methyl
ether and dried, yielding 0.36 g (32%) of the dihydrochloride of (4c). mp ca.
162 °C with decomposition.
Intermediates 1-Bromomethyl-3-phenylbenzene (7a): The synthesis of
(7a) has been described in ref. 8.
2-Chloromethyl-6-phenylpyridine (7b): The synthesis of (7b) and precur-
sors has been described in refs. 26, 27 and 29.
4-Bromomethyl-2-(4-fluoro-phenyl)pyridine (7c): The synthesis of (7c)
and precursors has been described in refs. 26 and 30.
2-Chloromethyl-4-(4-fluoro-phenyl)pyridine (7d): The synthesis of (7d)
and precursors has been described in refs. 26 and 31.
3-Chloromethyl-5-(4-fluoro-phenyl)pyridine (7e): The synthesis of (7e)
and precursors has been described in refs. 26, 28, 32 and 33.
Acknowledgement We would like to thank Alice Borst and Karel
Stegman for preparing and interpreting the NMR and mass spectra.
References and Notes
1) For a more extensive introduction see: Feenstra R. W., de Moes J.,
Hofma J. J., Kling H., Kuipers W., Long S. K., Tulp M. Th. M., van der
Heyden J. A. M., Kruse C. G., Bioorg. Med. Chem. Lett., 11, 2345—
2349 (2001).
2) King D. J., Eur. Neuropsychopharmacol., 8, 33—42 (1998).
3) Galletly C. A., Clark C. R., McFarlane A. C., Weber D. L., Psychiatry
Res., 72, 161—166 (1997).
4) Wadenberg M.-L., Neurosci. Behav. Rev., 20, 325—339 (1996).
5) Liebman J. M., Gerhardt S. C., Gerber R., Psychopharmacology, 97,
456—461 (1989).
6) Ellenbroek B. A., Prinssen E. P. M., Cools A. R., Eur. J. Neurosci., 6,
1—8 (1994).
1H-NMR (DMSO-d6/CDCl3 4/1) d: 3.22—3.58 (m, 8H), 4.20—4.28 (m,
4H), 4.63 (s, 2H), 6.50 (dd, Jꢂ8, 2 Hz, 1H), 6.55 (dd, Jꢂ8, 2 Hz, 1H), 6.74
(t, Jꢂ8 Hz, 1H), 7.37 (t, JHFꢂ8 Hz, 2H), 8.26 (dd, JHFꢂ8 Hz, 2H), 7.93 (d
broad, Jꢂ5 Hz, 1H), 8.70 (s broad, 1H), 8.80 (d, Jꢂ5 Hz, 1H), 12.0—12.4
(broad band, NHꢅ, 1H). 13C-NMR (DMSO-d6/CDCl3 4/1) d: 46.7, 51.3,
57.3, 63.7, 63.9, 110.4, 112.1, 116.0, 120.3, 125.7, 129.8, 131.7, 136.1,
139.5, 143.9, 147.0, 153.8, 163.8. HR-EI-MS m/z: 406.1932 (Calcd for
C24H24FN3O2: 406.1931). Anal. (C24H24FN3O2·2H2O·2HCl): Calcd (%): C:
56.0, H: 5.9, N: 8.2, Found (%): C 55.8, H: 5.5, N: 7.9.
7) Porsolt R. D., Anton G., Blaver N., Jaffre M., Eur. J. Pharmacol., 47,
379—391 (1978).
1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-4-[4-(4-fluoro-phenyl)-pyridin-
2-yl-methyl]-piperazine (4d) To 50 ml of dry acetonitrile were added:
0.50 g (1.95 mmol) of the hydrochloride of (6), 0.50 g (1.94 mmol) of the hy-
drochloride of (7d), 0.80 ml (5.9 mmol) of triethylamine and 0.29 g
(1.93 mmol) of sodium iodide. The resulting mixture was brought to reflux
temperature for 3 h after which stirring was continued for 48 h at room tem-
perature. To the reaction mixture some silicagel was added after which the
mixture was concentrated in vacuo. The resulting powder was put on top of
a flash chromatography column (SiO2, eluent: CH2Cl2/MeOH/NH4OH(25%)
92/7.5/0.5 v/v/v), and elution was started. The collected product containing
fractions were concentrated in vacuo yielding 0.72 g of a brown sirup. The
latter was dissolved in some diethyl ether and 2 eq of 1 N HCl/EtOH were
added. The formed precipitate was isolated by filtration and dried, giving
0.77 g (83%) of the dihydrochloride of (4d). mp 233 °C with decomposition.
1H-NMR (DMSO-d6) d: 3.36 (broad signal, 4H), 3.45 (broad signal, 4H),
4.23 (m, 4H), 4.72 (s, 2H), 5.1—5.7 (broad signal, H2O, 2NHꢅ) 6.51 (dd,
Jꢂ8, 2 Hz, 1H), 6.57 (dd, Jꢂ8, 2 Hz, 1H), 6.74 (t, Jꢂ8 Hz, 1H), 7.38 (t,
2H), 8.0—8.1 (cluster, 3H), 8.52 (d, Jꢂ2 Hz, 1H), 8.81 (d, Jꢂ8 Hz, 1H).
13C-NMR (DMSO-d6) d: 47.4, 52.2, 58.7, 64.5, 64.7, 111.2, 112.8, 116.9,
117.2, 121.1, 122.9, 125.6, 130.4, 130.5, 133.0, 136.8, 140.6, 144.6, 148.5,
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Vol. 54, No. 9
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