Structure-activity relationship studies on the 5-ht(1a) receptor affinity of 1-phenyl-4-[ω-(α- or β-tetralinyl)alkyl]piperazines. 4

Article abstract of DOI:10.1021/jm9604538

The synthesis of 1-phenylpiperazines, linked in the α or β position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT(1A), 5-HT2A, D-1, D-2, α₁, and α₂ receptors alo

Full text of DOI:10.1021/jm9604538

4928
J . Med. Chem. 1996, 39, 4928-4934
Str u ctu r e-Activity Rela tion sh ip Stu d ies on th e 5-HT1A Recep tor Affin ity of
1-P h en yl-4-[ω-(r- or â-tetr a lin yl)a lk yl]p ip er a zin es. 41
Roberto Perrone,* Francesco Berardi, Nicola A. Colabufo, Marcello Leopoldo, and Vincenzo Tortorella
Dipartimento Farmaco-chimico, Universita` di Bari, via Orabona, 4, 70126 Bari, Italy
Maria Gioia Fornaretto, Carla Caccia, and Robert A. McArthur
Pharmacia & Upjohn S.p.A., via Giovanni XXIII, 23, 20014 Nerviano (MI), Italy
Received J une 24, 1996X
The synthesis of 1-phenylpiperazines, linked in the R or â position of the tetralin moiety on
the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT1A
,
5-HT2A, D-1, D-2, R1, and R2 receptors along with SAR studies on the 5-HT1A receptor are
reported. Several changes have been carried out on previous structures of type 2, by inserting
the alkyl chain with variable length in the R or â position of the tetralin moiety and by changing
the position of the methoxy group on the aromatic ring of the tetralin nucleus. The highest
affinity (IC50 ) 0.50 nM) and selectivity for the 5-HT1A receptor were showed by 1-phenyl-
piperazine 2a with a three-membered alkyl chain bearing a 5-methoxytetralin-1-yl ring in the
ω position.
The existence of multiple serotonin (5-HT) receptor
subsites in mammalian brain tissue has stimulated
research to identify selective agents as pharmacological
tools in order to evaluate the role of these receptors in
various pathological conditions.2,3 The 5-HT1A serotonin
receptor has been the object of several studies since the
discovery of its involvement in various physiological
functions, such as sleep, appetite, and sexual behavior
or pathological states such as anxiety4,5 and depres-
sion.6,7 The 1-arylpiperazine derivatives constitute one
of the most important classes of the 5-HT1A receptor
ligands. Structure-activity relationship (SAR) studies
focus on the highly active 4-(ω-substitutedalkyl)-1-
arylpiperazine (Ki ranging from 10-8 to 10-10 M) where
an amide or imide function is present in the ω position
of the alkyl chain. Examples include buspirone, NAN-
190, flesinoxan, BMY7378, and ipsapirone.8 The large
number of SAR studies on amide derivatives is justified
by the hypothesis that the terminal amide fragment in
these compounds stabilizes the 5-HT1A receptor-ligand
complex by either π-electron or local dipole-dipole
interactions in a region of bulk tolerance adjoining the
for developing compounds with high affinity and selec-
protonation site.9 However, desamido-1-arylpiperazine
tivity for the 5-HT1A receptor. Among the 1-arylpiper-
derivatives may also show the same 5-HT1A affinity as
azines previously studied with highest affinity for the
corresponding amidic derivatives. This has been re-
5-HT1A receptor, we chose to consider compound 2a as
the reference structure for the present SAR study. This
compound shows the best affinity and selectivity values
ported by some authors.10 On the other hand, the
hypothesis that the amido function does not stabilize
the 5-HT1A receptor-ligand complex has been confirmed
in comparison with compounds 2b,c and their isomers
by us in a recent work1 on alkylamido derivatives of
4-6 (Table 1).1 We now report on the effects of the
1-aryl-4-[(1-tetralinyl)alkyl]piperazines, 1, where the
following structural variations for 5-HT1A receptor af-
corresponding desamido compounds 2a -c showed the
finity and selectivity of compound 2: (a) the insertion
of the alkyl chain in the R or â position of the tetralin
highest affinity for the 5-HT1A receptor.11,12 So it can
be stated that the amide function is not required for
moiety, (b) the changing of the position of the methoxy
binding with the 5-HT1A receptor.
group on the aromatic ring of the tetralin moiety, and
In keeping with this finding, we have carried out
(c) the variation of the length of the methylene spacer
additional work in order to have a better understanding
between the basic nitrogen atom and the tetralin
of this class as part of our continuing research program
nucleus. The synthesis and radioligand binding affini-
ties for 5-HT1A, 5-HT2A, D-1, D-2, R1, and R2 receptors
of compounds with general structure 3 are described.
* To whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, October 15, 1996.
S0022-2623(96)00453-0 CCC: $12.00 © 1996 American Chemical Society

1-Phenylpiperazine SAR on 5-HT1A Receptor Affinity
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4929
Ta ble 1. Physical Properties
Z
compd
R1 or R2
CH3O
R
â
formulaa
mp, °C
recryst solv
2a b
4b
R1
R2
R1
R2
R1
R1
R1
R1
R1
R2
R2
R2
R1
R1
R1
5
8
7
6
5
6
8
5
5
8
7
6
5
6
7
(CH2)3
(CH2)3
(CH2)3
(CH2)3
(CH2)2
(CH2)3
(CH2)3
dCH(CH2)2
(CH2)4
5b
6b
17
18
19
20
21
22
23
24
25
26
27
C23H30N2O‚2HCl‚1/3H2O
C24H32N2O‚2HCl
C24H32N2O‚2HCl
C24H30N2O‚2HCl
C25H34N2O‚2HCl‚H2O
C23H28N2O‚2HCl
C23H28N2O‚2HCl
C23H28N2O‚2HCl
C23H30N2O‚2HCl
C23H30N2O‚2HCl
C23H30N2O‚2HCl
238 dec
212-214
209
194-196
204-206
235
237
217
240
218
MeOH/Et2O
MeOH/Et2O
MeOH/Et2O
MeOH/Et2O
CHCl3/petroleum ether
MeOH/Et2O
MeOH
MeOH/Et2O
MeOH/Et2O
MeOH
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
215
MeOH/Et2O
a
b
Analyses for C,H,N; results were within (0.4% of the theoretical values for the formulas given. Formerly published compounds.11,12
having a two-methylene alkyl chain in the â position,
22-24, were prepared from the respective methoxy-1-
tetralones 7a -c and diethyl chlorophosphate in the
presence of lithium diisopropylamide (LDA).15 Com-
pounds 14a -c underwent condensation with ethylene
oxide in the presence of a base16 to afford the spirocyclic
cyclopropyl ketones 15a -c. The reduction of these
compounds with NaBH4 and the treatment of the crude
intermediates with HBr and glacial acetic acid caused
the dehydration and the opening of the spirocyclo-
propane ring to furnish the key intermediates 16a -c.
Reaction of these bromo derivatives with 1-phenyl-
piperazine afforded the unsaturated target compounds
22-24. The corresponding saturated compounds 25-
27 were obtained by catalytical hydrogenation.
P h a r m a cology
Ch em istr y
The three pathways described in Scheme 1 were
followed to synthesize compounds 17-27. Condensation
of triethyl phosphonoacetate with 5-methoxy-1-tetralone
(7a ) according to the Wittig-Horner reaction13 yielded
a mixture of the unsaturated isomeric esters 8. The
subsequent steps to obtain the bromo derivative 11 were
carried out as described in the literature14 for 7-methoxy
isomers. The catalytic hydrogenation of 8 afforded the
saturated ester 9 which was reduced with LiAlH4 to the
alcohol 10; the latter was treated with PBr3 to give the
alkyl bromide 11. The target compound 17 was ob-
tained by reaction of 11 with 1-phenylpiperazine. The
homologues 18 and 19 were prepared as reported for
some of their isomers.11,12 Reaction of methoxy-1-
tetralones 7b,d with magnesium cyclopropyl bromide
gave the intermediate cyclopropylcarbinol derivatives.
Following treatment with HBr in acetic acid, the endo-
cyclic unsaturated bromo derivatives 12b,d were ob-
tained. These were hydrogenated in the presence of 5%
Pd-C to compounds 13b,d . Subsequent reaction with
1-phenylpiperazine led to the final compounds 18 and
19.
Final compounds (Table 2) were evaluated for in vitro
affinity for dopamine D-1 and D-2, serotonin 5-HT1A and
5-HT2A, and adrenergic R1 and R2 receptors by radio-
ligand binding assays. All the compounds were used
in the form of hydrochloride salts and were water-
soluble. The following specific radioligands and tissue
sources were used (a) dopamine D-1 receptorss[3H]SCH-
23390, rat striatal membranes; (b) dopamine D-2
receptorss[3H]spiroperidol, rat striatal membranes; (c)
serotonin 5-HT1A receptorss[3H]-8-OH-DPAT, rat hip-
pocampus membranes; (d) serotonin 5-HT2A receptorss
[3H]ketanserin, rat brain prefrontal cortex membranes;
(e) R1 adrenergic receptorss[3H]prazosin, rat brain
cortex membranes; and (e) R2 adrenergic receptorss
[3H]yohimbine, rat brain cortex membranes.
Concentrations required to inhibit 50% of radioligand
specific binding (IC50) were determined using eight to
nine different concentrations of the drug studied. The
specific binding was defined as previously described.1
In all binding assays, it represents more than 80% of
the total binding, except for R2 (>60%). The results
were analyzed by using the program LIGAND to deter-
mine IC50 values.
The â-keto phosphonate derivatives 14a ,c required
for the synthesis of the dihydronaphthalene derivatives

4930 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Perrone et al.
Sch em e 1a
a
Reagents: (A) NaH (60% mineral oil dispersion), triethyl phosphonoacetate; (B) H2, Pd-C (10%); (C) LiAlH4; (D) PBr3; (E)
1-phenylpiperazine; (F) cyclopropyl MgBr; (G) HBr; (H) H2, Pd-C (5%); (I) LDA, diethyl chlorophosphate; (J ) NaH, ethylene oxide; (K)
NaBH4.
Ta ble 2. Binding Affinities and Selectivitiesa,b
IC50, nM
selectivity vs
5-HT1Areceptor, IC50 ratio
5-HT1A
5-HT2A
D-2
R1
R2
compd
[3H]-8-OH-DPAT [3H]ketanserin
[3H]spiroperidol
[3H]prazosin
[3H]yohimbine 5-HT2 D-2
R1
R2
2a
2b
2c
4
5
6
17
18
19
20
21
22
23
24
25
26
27
0.50 ( 0.05c
0.77 ( 0.09c
0.54 ( 0.06c
18.3 ( 5.3d
9.24 ( 0.59e
147 ( 14d
140 ( 15
5.4 ( 0.6
56 ( 6
230 ( 25c
330 ( 29c
250 ( 22c
204 ( 8d
NTe
110 ( 18c
18 ( 2c
43 ( 5c
6.5 ( 0.6c
66 ( 7c
260 ( 35c 460
220
23
259 122
17
3
1
2
17
1
5
7
86
8
520
22
89
17 ( 2c
428
462
11
140 ( 12c
303 ( 39d
28 ( 2e
48 ( 5c
NT
49.0 ( 3.7e
184 ( 15e
173 ( 10e
84 ( 8
3
20
1
0.6
8
2
6
9
1
11
8
NT
NT
22 ( 2
119 ( 5d
12 ( 1
157 ( 13e
210 ( 19
91 ( 9
62 ( 7
100 ( 10
110 ( 9
276 ( 30
170 ( 16
136 ( 14
130 ( 10
120 ( 13
100 ( 12
280 ( 31
5.2 ( 0.6
0.8
0.1
30
11
31
28
1
7
15
3
0.2
31
3
160 ( 17
610 ( 57
580 ( 63
420 ( 38
241 ( 25
56 ( 6
45 ( 5
170 ( 19
140 ( 20
290 ( 35
770 ( 65
357 ( 38
130 ( 14
122 ( 13
600 ( 75
160 ( 18
260 ( 31
130 ( 16
120 ( 13
130 ( 12
194 ( 16
88 ( 9
19 ( 2
15
51
2
16
18
11
43
72
15 ( 2
191 ( 21
8.2 ( 0.9
7.3 ( 0.8
54 ( 6
1
24
22
2
32
28
106 ( 11
160 ( 15
86 ( 9
58 ( 6
100 ( 9
79 ( 8
2
21
22
3.7 ( 0.3
3.6 ( 0.4
30 ( 3
23
64
230 ( 19
80 ( 9
buspirone
8-OH-DPAT
ketanserin
haloperidol
prazosin
>10 000
>10 000
3.4 ( 0.3
>10 000
>10 000
>10 000
2.1 ( 0.2
810 ( 75
4.8 ( 0.5
1.4 ( 0.6
yohimbine
30 ( 3
a
b
NA ) not active; NT ) not tested. Compounds 17-27 showed very high affinity binding values on the D-1 receptor (IC50 > 1000
nM). c See ref 1. See ref 11. e See ref 12.
d
Resu lts a n d Discu ssion
ies,11,12 we found that the 5-HT1A receptor affinity and
selectivity were very high for 1-phenylpiperazine de-
rivatives having the methoxy group on the tetralin in
the 5 position. In fact, compound 2a exhibited higher
affinity (IC50 ) 0.5 nM) and selectivity than the corre-
sponding 7-methoxy derivative 5. For the other posi-
The results of the binding assays are illustrated in
Table 2, and the structure-5-HT1A affinity relationships
are graphically summarized in Figure 1.
P osition of th e Meth oxy Gr ou p on th e Ar om a tic
Rin g of th e Tetr a lin Nu cleu s. In previous stud-

1-Phenylpiperazine SAR on 5-HT1A Receptor Affinity
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4931
F igu r e 1. A-B, CdC (2); A-B, CH-CH (9).
tions on the tetralin ring, the corresponding 6-methoxy
derivative 18 showed a slight decrease in 5-HT1A affinity
(IC50 ) 5.4 nM), whereas the 8-methoxy derivative 19
showed a remarkable lowering (IC50 ) 56 nM) of
affinity. In both cases the selectivity values with respect
to the other receptors were very low. This points out
the importance of the distance between the methoxy
group and the alkyl chain. Indeed, when the alkyl chain
is in the R position of the tetralin nucleus, the ideal
position of the methoxy group is in the 5 position,
whereas, when the alkyl chain is in the â position, the
trend changes. For the latter compounds, the highest
values of affinity for the 5-HT1A receptor were observed
when the methoxy group was in the 6 or 7 position (23,
24, 26, and 27). Instead, when the methoxy group is
in the 5 position (22) or 8 position (25), the affinity
values decreased. In this way the spatial relationships
between the position of the methoxy group and the alkyl
chain on the tetralin nucleus are very evident.
Len gth of th e Ch a in . The alkyl chain functions as
a spacer between the protonation site and the terminal
group in arylpiperazine derivatives. We observed that
a three-methylene-membered chain is required for a
compound to have the highest affinity for the 5-HT1A
receptor (2a , IC50 ) 0.5 nM). This value decreases for
compounds 21 (n ) 4, IC50 ) 15 nM) and 17 (n ) 2,
IC50 ) 140 nM). Thus, when the alkyl chain is in the R
position of the tetralin nucleus, its length has to be three
methylene units. For this reason we inserted a two-
methylene alkyl chain in the â derivatives 22-27 to
obtain a quite similar distance as shown above.
P r esen ce of a n Un sa tu r a ted Bon d on th e Tet-
r a lin Nu cleu s. The saturated compounds 2a , 5, and
25-27 showed higher affinities for the 5-HT1A receptor
as compared to the corresponding unsaturated com-
pounds 4, 6, and 22-24, respectively. A slight differ-
ence in affinity was observed between the exo-unsat-
urated derivative 20 and the corresponding endo-
unsaturated compound 4.
r or â Alk yl Su bstitu tion of th e Tetr a lin Rin g.
The R or â position influences the length of the alkyl
chain which has to be three- or two-methylene-mem-
bered, respectively. Moreover, this also influences the
position of the methoxy group on the tetralin ring.
Therefore the R derivative 2a , with three methylene
units and the methoxy group on the 5 position, showed
a similar affinity value with the â derivatives 26 and
27. These bear two methylene units and the methoxy
group on the 6 and 7 positions, respectively. Concerning
the selectivity for the other receptors tested, R deriva-
tives such as 2a are different from the â derivatives as
the former is more selective.

4932 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Perrone et al.
1-(2-Br om oet h yl)-5-m et h oxy-1,2,3,4-t et r a h yd r on a p h -
th a len e (11). Phosphorus tribromide (4 mL) was added
dropwise to a stirred mixture of the alcohol 10 (3.10 g, 15.0
mmol) and pyridine (0.2 mL) in anhydrous toluene at 0 °C.
The resulting mixture was warmed and stirred at 70 °C for 6
h. The reaction mixture was then poured into ice-water, the
organic layer was separated, and the aqueous layer was
extracted twice with diethyl ether. The combined organic
layers were washed with a NaHCO3-saturated solution fol-
lowed by water and then dried over Na2SO4 and filtered. The
solvent was evaporated in vacuo, and the crude residue was
passed through a short silica gel column (petroleum ether/ethyl
acetate, 4:1, as eluent) to give compound 11 as a colorless oil
(2.02 g, 50% yield): 1H-NMR 1.53-2.36 (m, 6H, 2 endo CH2,
CH2CH2Br), 2.48-3.20 (m, 3H, benzyl CH2, CH), 3.44 (t, 2H,
Con clu sion
The SAR of the 1-phenyl-4-[ω-(R- or â-tetralinyl)alkyl]-
piperazines, described above, indicates the importance
of the distance of the methoxy group on the tetralin ring
from the protonation center of the piperazine ring for
affinity and selectivity toward the 5-HT1A receptor. In
other words, the region of the 5-HT1A sites involved with
N-4 substituents must be capable of actively accom-
modating a chain of three carbon atoms linked to a
position of a 5-methoxy-substituted tetralin.
Exp er im en ta l Section
Ch em istr y. Column chromatography was performed with
1:30 ICN silica gel 60A (63-200 µm) as the stationary phase.
8-Methoxy-1-tetralone (7d ) was prepared according to the
literature.17 A 1.5 M solution of LDA in n-hexane was
purchased from Aldrich Chemical Co. Melting points were
determined in open capillaries using a Gallenkamp electro-
thermal apparatus. Elemental analyses were performed by
the Microanalytical Section of our department on solid samples
only; the analytical results (C,H,N) were within (0.4% of the
theoretical values. 1H-NMR spectra were recorded either on
a Varian EM-390 (TMS as internal standard) or on a Bruker
AM 300 WB instrument (where indicated 300 MHz), with
CDCl3 as solvent; all values are reported in ppm (δ). Recording
of mass spectra was done on a HP 5995C gas chromatograph/
mass spectrometer, electron impact 70 eV, equipped with a
HP59970A workstation; only significant m/ z peaks, with their
percent relative intensity indicated in parentheses, are re-
ported herein. All compounds had NMR and mass spectra that
were consistent with their structures.
5-Meth oxy-1,2,3,4-tetr ah ydr o-1-n aph th alen eacetic Acid,
Eth yl Ester (9). Triethyl phosphonoacetate (6.2 mL, 31.3
mmol) was added dropwise to a cooled suspension of NaH (60%
dispersion in mineral oil, 1.25 g, 31.3 mmol) in anhydrous
toluene (20 mL). The mixture was then stirred for 1 h at 50
°C to ensure the reaction was complete. The formed solution
was cooled, and 5-methoxy-1-tetralone (7a ) (3.86 g, 21.9 mmol)
in anhydrous toluene (20 mL) was added dropwise. The
mixture was refluxed for 4 h, cooled, and then washed with
cold water. The separated organic layer was dried over
Na2SO4, and the solvent was evaporated under reduced
pressure. The crude residue was chromatographed (petroleum
ether/ethyl acetate, 9:1, as eluent) to yield a mixture of the
(E/ Z)-naphthylidene isomers 8: GC/MS m/ z 247 (M+ + 1, 5),
246 (M+, 29), 201 (36), 200 (100), 172 (21), 158 (21).
J
) 7 Hz, CH2Br), 3.78 (s, 3H, CH3), 6.56-7.33 (m, 3H,
aromatic); GC/MS m/ z 271 (M+ + 3, 2), 270 (M+ + 2, 12), 269
(M+ + 1, 2), 268 (M+, 12), 162 (24), 161 (100), 115 (21).
The following compounds 12b,d and 13b,d were prepared
and purified according to the procedure already reported.11,12
4-(3-Br om o-n -p r op yl)-1,2-d ih yd r o-7-m eth oxyn a p h th a -
len e (12b): 1H-NMR 1.80-2.45 (m, 4H, CH2CH2CH2Br), 2.45-
3.00 (m, 4H, 2 endo CH2), 3.40 (t, 2H, J ) 7 Hz, CH2Br), 3.80
(s, 3H, CH3), 5.82 (br t, 1H, vinyl CH), 6.57-7.47 (m, 3H,
aromatic); GC/MS m/ z 283 (M+ + 3, 3), 282 (M+ + 2, 21), 281
(M+ + 1, 4), 280 (M+, 22), 174 (100), 159 (83), 144 (30), 115
(37).
4-(3-Br om o-n -p r op yl)-1,2-d ih yd r o-5-m eth oxyn a p h th a -
len e (12d ): 1H-NMR 1.80-2.36 (m, 4H, CH2CH2CH2Br), 2.55-
3.00 (m, 4H, 2 endo CH2), 3.40 (t, 2H, J ) 7 Hz, CH2Br), 3.85
(s, 3H, CH3), 6.02 (br t, 1H, vinyl CH), 6.70-7.37 (m, 3H,
aromatic); GC/MS m/ z 283 (M+ + 3, 4), 282 (M+ + 2, 22), 281
(M+ + 1, 4), 280 (M+, 21), 174 (43), 159 (100), 144 (21), 115
(30).
1-(3-B r o m o -n -p r o p y l)-6-m e t h o x y -1,2,3,4-t e t r a h y -
1
d r on a p h th a len e (13b): H-NMR (300 MHz) 1.56-2.03 (m,
8H, CH2CH2CHCH2CH2), 2.66-2.79 (m, 3H, benzyl CH2, CH),
3.36-3.48 (m, 2H, CH2Br), 3.76 (s, 3H, CH3), 6.59-7.09 (m,
3H, aromatic); GC/MS m/ z 285 (M+ + 3, 1), 284 (M+ + 2, 4),
283 (M+ + 1, 1), 282 (M+, 4), 162 (13), 161 (100), 115 (11).
1-(3-B r o m o -n -p r o p y l)-8-m e t h o x y -1,2,3,4-t e t r a h y -
1
d r on a p h th a len e (13d ): H-NMR (300 MHz) 1.44-2.06 (m,
8H, CH2CH2CHCH2CH2), 2.70-2.80 (m, 2H, benzyl CH2),
2.95-3.02 (m, 1H, CH), 3.37-3.56 (m, 2H, CH2Br), 3.80 (s,
3H, CH3), 6.62-7.09 (m, 3H, aromatic); GC/MS m/ z 285 (M+
+ 3, 1), 284 (M+ + 2, 8), 283 (M+ + 1, 1), 282 (M+, 8), 161
(100), 115 (9).
P r ep a r a tion of Dieth yl â-Keto P h osp h on a tes 14a -c.
Gen er a l P r oced u r e. A solution of a methoxy-1-tetralone,
7a -c (4.93 g, 28.0 mmol), in anhydrous THF (20 mL) was
added dropwise to a stirred mixture of LDA (1.5 M in n-hexane,
20.8 mL, 31.2 mmol) and anhydrous THF (5 mL) at -60 °C.
After 45 min, the resulting mixture was treated with diethyl
chlorophosphate (5.4 mL, 37.4 mmol) and then allowed to
warm to 0 °C over the course of 50 min. After the mixture
was cooled to -60 °C, LDA (1.5 M in n-hexane, 41.6 mL, 62.4
mmol) was added. The resulting solution was allowed to warm
to room temperature and stirred at room temperature for 6 h.
A solution of acetic acid in diethyl ether (1 M, 100 mL) was
added slowly to the cooled reaction mixture; the resulting
suspension was filtered through Celite, and the filtrate was
concentrated under reduced pressure. The crude residue was
chromatographed (CHCl3/ethyl acetate, 3:2, as eluent) to give
compounds 14a -c as brown oils in 60-65% yield.
A methanolic solution of the above intermediates was
hydrogenated in the presence of 10% palladium on charcoal
(100 mg) at 30 kg/cm2 pressure of H2 for 18 h at room
temperature. The reaction mixture was filtered over Celite
and the filtrate evaporated to dryness in vacuo to give
compound 9 as a pale yellow oil (4.70 g, 86% overall yield):
1H-NMR 1.25 (t, 3H, J ) 7 Hz, CH3CH2), 1.77 (br s, 4H, 2
endo CH2), 2.37-2.93 (m, 4H, CH2CO, benzyl CH2), 3.13-3.53
(m, 1H, CH), 3.77 (s, 3H, OCH3), 4.15 (q, 2H, J ) 7 Hz,
CH3CH2), 6.57-7.36 (m, 3H, aromatic); GC/MS m/ z 249 (M+
+ 1, 7), 248 (M+, 43), 174 (100), 161 (86), 160 (94), 159 (77),
158 (47).
5-Met h oxy-1,2,3,4-t et r a h yd r o-1-n a p h t h a len eet h a n ol
(10). A solution of compound 9 (4.40 g, 17.7 mmol) in
anhydrous THF (20 mL) was added dropwise to a cooled
suspension of LiAlH4 (0.68 g, 17.9 mmol) in the same solvent
(40 mL). After the mixture stirred overnight at room tem-
perature, the excess of the hydride was destroyed with some
drops of water. The mixture was filtered and the filtrate
concentrated to dryness. The residue was taken up with
CH2Cl2. The solution was washed with water, dried over
Na2SO4, and concentrated under reduced pressure. The crude
residue was eluted with CH2Cl2 to give the alcohol 10 as a
colorless oil (3.28 g, 90% yield): 1H-NMR 1.53-2.17 (m, 7H, 2
endo CH2, CH2CH2OH, 1H D2O exchanged), 2.53-3.10 (m, 3H,
benzyl CH2, CH), 3.57-3.98 (s + m, 5H, CH3, CH2O), 6.60-
7.33 (m, 3H, aromatic); GC/MS m/ z 207 (M+ + 1, 5), 206 (M+,
32), 162 (100), 161 (56), 131 (23).
2-(Diet h oxyp h osp h in yl)-5-m et h oxy-1-oxo-1,2,3,4-t et -
1
r a h yd r on a p h th a len e (14a ): H-NMR 1.10-1.47 (m, 6H, 2
CH2CH3), 2.13-3.50 (m, 5H, endo), 3.86 (s, 3H, OCH3), 3.95-
4.40 (m, 4H, 2 CH2CH3), 6.93-7.86 (m, 3H, aromatic); GC/
MS m/ z 313 (M+ + 1, 6), 312 (M+, 33), 175 (32), 174 (100),
115 (12).
2-(Diet h oxyp h osp h in yl)-6-m et h oxy-1-oxo-1,2,3,4-t et -
1
r a h yd r on a p h th a len e (14b): H-NMR 1.10-1.46 (m, 6H, 2
CH2CH3), 2.13-3.50 (m, 5H, endo), 3.83 (s, 3H, OCH3), 3.95-
4.40 (m, 4H, 2 CH2CH3), 6.60-8.15 (m, 3H, aromatic); GC/
MS m/ z 313 (M+ + 1, 7), 312 (M+, 43), 175 (42), 174 (100).

1-Phenylpiperazine SAR on 5-HT1A Receptor Affinity
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4933
2-(Diet h oxyp h osp h in yl)-7-m et h oxy-1-oxo-1,2,3,4-t et -
r a h yd r on a p h th a len e (14c): 1H-NMR 1.10-1.50 (m, 6H, 2
CH2CH3), 2.16-3.50 (m, 5H, endo), 3.85 (s, 3H, OCH3), 3.96-
4.43 (m, 4H, 2 CH2CH3), 6.98-7.70 (m, 3H, aromatic); GC/
MS m/ z 313 (M+ + 1, 6), 312 (M+, 32), 175 (35), 174 (100).
MS m/ z 269 (M+ + 3, 10), 268 (M+ + 2, 71), 267 (M+ + 1, 13),
266 (M+, 75), 173 (67), 159 (100), 144 (30), 128 (34), 115 (46).
4-Su bstitu ted 1-P h en ylp ip er a zin e Der iva tives 17-24.
Gen er a l P r oced u r e. A stirred suspension of the appropriate
alkyl halide (2.0 mmol), 1-phenylpiperazine (4.0 mmol), and
potassium carbonate (2.0 mmol) in DMF (compounds 20, 22-
24) or acetonitrile (compounds 17-19, 21) was refluxed
overnight. After cooling, the mixture was evaporated to
dryness, and water was added to the residue. The aqueous
phase was extracted twice with CH2Cl2. The collected organic
layers were dried over Na2SO4 and evaporated under reduced
pressure. The crude residue was chromatographed, as indi-
cated below, to yield pure compounds 17-24 as pale yellow
oils.
4-[2-(5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
eth yl]-1-p h en ylp ip er a zin e (17): eluted with CH2Cl2/ethyl
acetate, 3:1, 52% yield; 1H-NMR (300 MHz) 1.64-1.98 (m, 6H,
CH2CH2CHCH2), 2.47-2.80 [m, 8H, CH2N(CH2)2, benzyl CH2],
2.81-2.87 (m, 1H, CH), 3.21 [br t, 4H, (CH2)2NAr], 3.80 (s,
3H, CH3), 6.63-7.28 (m, 8H, aromatic); GC/MS m/ z 351 (M+
+ 1, 10), 350 (M+, 40), 189 (19), 175 (100), 162 (29).
4-[3-(6-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
p r op yl]-1-p h en ylp ip er a zin e (18): eluted with CH2Cl2/ethyl
acetate, 7:3, 75% yield; 1H-NMR (300 MHz) 1.50-1.88 (m, 8H,
CH2CH2CHCH2CH2), 2.38-2.42 [m, 2H, CH2N(CH2)2], 2.52-
2.72 [m, 7H, benzyl CH2, CH, CH2N(CH2)2], 3.20 [br t, 4H,
(CH2)2NAr], 3.75 (s, 3H, CH3), 6.57-7.28 (m, 8H, aromatic);
GC/MS m/ z 365 (M+ + 1, 26), 364 (M+, 94), 175 (100), 162
(46), 120 (25).
4-[3-(8-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
p r op yl]-1-p h en ylp ip er a zin e (19): eluted with CH2Cl2/ethyl
acetate, 7:3, 91% yield; 1H-NMR (300 MHz) 1.35-1.92 (m, 8H,
CH2CH2CHCH2CH2), 2.32-2.81 [m, 8H, CH2N(CH2)2, benzyl
CH2], 2.96-3.01 (m, 1H, CH), 3.21 [br t, 4H, (CH2)2NAr], 3.79
(s, 3H, CH3), 6.63-7.29 (m, 8H, aromatic); GC/MS m/ z 365
(M+ + 1, 12), 364 (M+, 44), 175 (100), 162 (17), 132 (16).
4-[1-(5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
1(E)-3-p r op ylid en e]-1-p h en ylp ip er a zin e (20). The title
compound was prepared starting from (E)-1-(3-chloro-n-pro-
pylidene)-5-methoxy-1,2,3,4-tetrahydronaphthalene12 following
the procedure described above. Column chromatography was
performed with CHCl3 as eluent (49% yield): 1H-NMR (300
MHz) 1.18-1.87 (m, 2H, endo CH2), 2.41-2.60 (m, 6H,
CH2CdCHCH2CH2N), 2.62-2.74 [m, 6H, benzyl CH2, CH2N-
(CH2)2], 3.23 [br s, 4H, (CH2)2NAr], 3.81 (s, 3H, CH3), 6.00 (br
t, 1H, vinyl CH), 6.68-7.29 (m, 8H, aromatic); GC/MS m/ z
363 (M+ + 1, 2), 362 (M+, 8), 176 (13), 175 (100), 173 (14), 132
(18).
4-[4-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-n -
bu tyl]-1-p h en ylp ip er a zin e (21). The title compound was
prepared and purified as for compound 20, starting from 1-(4-
chloro-n-butyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene,18 in
73% yield: 1H-NMR (300 MHz) 1.35-1.83 [m, 10H, CH2CH2-
CH(CH2)3], 2.41 [t, 2H, J ) 7.6 Hz, CH2N(CH2)2], 2.50-2.79
[m, 7H, benzyl CH2, CH, CH2N(CH2)2], 3.21 [br t, 4H, (CH2)2-
NAr], 3.79 (s, 3H, CH3), 6.62-7.28 (m, 8H, aromatic); GC/MS
m/ z 379 (M+ + 1, 17), 378 (M+, 63), 376 (13), 217 (15), 176
(13), 175 (100).
P r ep a r a tion of Sp ir ocyclic Cyclop r op yl Keton es 15a-
c. Gen er a l P r oced u r e. A 100 mL screw-top Pyrex vial was
charged with oil free NaH (0.40 g, 16.7 mmol) and anhydrous
toluene (20 mL). A phosphonate, 14a -c (4.40 g, 14.1 mmol),
in anhydrous toluene (20 mL) was added dropwise under
cooling. The reaction mixture was stirred at room temperature
for 1 h and then cooled to -10 °C. Ethylene oxide (4.5 mL, 90
mmol) was then added. The vial was fitted with a Teflon screw
cap, and the mixture was heated at 130 °C for 6 h. The
reaction mixture was cooled, the reaction quenched with water,
and the mixture extracted with diethyl ether (three times).
The collected organic layers were dried over Na2SO4, and the
solvent was removed in vacuo. The crude residue was eluted
with CHCl3 to furnish derivatives 15a -c as colorless oils in
50-59% yield.
3,4-Dih yd r o-5-m eth oxy-1-oxon a p h th a len e-2(1H)-sp ir o-
cyclop r op a n e (15a ): 1H-NMR 0.73-0.94 (m, 2H) and 1.25-
1.50 (m, 2H) (spirocyclic), 1.95 (br t, 2H, ArCH2CH2), 2.96 (br
t, 2H, ArCH2CH2), 3.86 (s, 3H, CH3), 6.94-7.83 (m, 3H,
aromatic); GC/MS m/ z 203 (M+ + 1, 13), 202 (M+, 100), 201
(60), 174 (23), 159 (25), 115 (35).
3,4-Dih yd r o-6-m eth oxy-1-oxon a p h th a len e-2(1H)-sp ir o-
cyclop r op a n e (15b): 1H-NMR 0.65-0.96 (m, 2H) and 1.30-
1.52 (m, 2H) (spirocyclic), 1.98 (br t, 2H, ArCH2CH2), 2.98 (br
t, 2H, ArCH2CH2), 3.87 (s, 3H, CH3), 6.70-8.17 (m, 3H,
aromatic); GC/MS m/ z 203 (M+ + 1, 14), 202 (M+, 100), 201
(85), 174 (23), 148 (34).
3,4-Dih yd r o-7-m eth oxy-1-oxon a p h th a len e-2(1H)-sp ir o-
cyclop r op a n e (15c): 1H-NMR 0.65-0.96 (m, 2H) and 1.30-
1.53 (m, 2H) (spirocyclic), 1.97 (br t, 2H, ArCH2CH2), 2.95 (br
t, 2H, ArCH2CH2), 3.85 (s, 3H, CH3), 6.95-7.83 (m, 3H,
aromatic); GC/MS m/ z 203 (M+ + 1, 14), 202 (M+, 100), 201
(57), 174 (26), 159 (25), 120 (37).
3-(2-Br om oet h yl)-1,2-d ih yd r om et h oxyn a p h t h a len es
16a -c. Gen er a l P r oced u r e. To a solution of 15a -c (2.62
g, 13.0 mmol) in methanol (40 mL) at 0 °C was added NaBH4
(1.17 g, 30.9 mmol) in several portions. After being stirred at
room temperature overnight, the mixture was cooled to 0 °C,
and water (25 mL) was carefully added. This was followed by
HCl (1 M, 5 mL). The solution was concentrated in vacuo,
and CH2Cl2 (30 mL) was added. After the resulting layers
were separated, the aqueous phase was extracted twice with
CH2Cl2, and the combined organic extracts were dried over
Na2SO4. Concentration in vacuo afforded the crude intermedi-
ate which was used directly in the following step.
The crude residue was solubilized in acetic acid (9 mL) and
stirred with 20% aqueous HBr (14 mL) for 22 h at room
temperature. The mixture was cooled, diluted with water, and
alkalized with K2CO3. The aqueous layer was extracted three
times with CH2Cl2. The collected organic layers were dried
over Na2SO4. Evaporation of the solvent in vacuo afforded a
residual oil that was chromatographed (petroleum ether/
CH2Cl2, 1:1, as eluent) to obtain the pure products 16a -c as
colorless oils (92-95% overall yield).
3-(2-B r om oe t h y l)-1,2-d ih yd r o-8-m e t h o xy n a p h t h a -
len e (16a ): 1H-NMR 2.20 (br t, 2H, CH2CH2Br), 2.56-3.05 (m,
4H, 2 endo CH2), 3.50 (t, 2H, J ) 7 Hz, CH2Br), 3.80 (s, 3H,
CH3), 6.25 (br s, 1H, vinyl), 6.77-7.30 (m, 3H, aromatic); GC/
MS m/ z 269 (M+ + 3, 5), 268 (M+ + 2, 36), 267 (M+ + 1, 5),
266 (M+, 36), 173 (46), 159 (100), 128 (28), 115 (45).
4-[2-(1,2-Dih yd r o-8-m eth oxy-3-n a p h th a len yl)eth yl]-1-
p h en ylp ip er a zin e (22): eluted with CH2Cl2/ethyl acetate, 1:1,
89% yield; 1H-NMR (300 MHz) 2.25 [t, 2H, J ) 8.3 Hz,
CH2CH2N(CH2)2], 2.42-2.54 (m, 2H, endo CH2), 2.60-2.69 [m,
6H, benzyl CH2, CH2N(CH2)2], 2.80 [t, 2H, J ) 8.3 Hz,
CH2N(CH2)2], 3.23 [br t, 4H, (CH2)2NAr], 3.81 (s, 3H, CH3),
6.22 (s, 1H, vinyl CH), 6.62-7.28 (m, 8H, aromatic); GC/MS
m/ z 349 (M+ + 1, 2), 348 (M+, 7), 175 (100), 173 (14), 132 (18).
4-[2-(1,2-Dih yd r o-7-m eth oxy-3-n a p h th a len yl)eth yl]-1-
p h en ylp ip er a zin e (23): eluted with CH2Cl2/ethyl acetate, 1:1,
80% yield; 1H-NMR (300 MHz) 2.24 [t, 2H, J ) 8.0 Hz,
CH2CH2N(CH2)2], 2.42-2.48 (m, 2H, endo CH2), 2.61-2.80 [m,
8H, benzyl CH2, CH2N(CH2)2], 3.26 [br t, 4H, (CH2)2NAr], 3.77
(s, 3H, CH3), 6.20 (s, 1H, vinyl CH), 6.34-7.29 (m, 8H,
aromatic); GC/MS m/ z 349 (M+ + 1, 2), 348 (M+, 8), 175 (100),
173 (19), 132 (18).
3-(2-B r om oe t h y l)-1,2-d ih y d r o -7-m e t h o x y n a p h t h a -
len e (16b): 1H-NMR 2.23 (br t, 2H, CH2CH2Br), 2.65-2.97
(m, 4H, 2 endo CH2), 3.50 (t, 2H, J ) 7 Hz, CH2Br), 3.80 (s,
3H, CH3), 6.25 (br s, 1H, vinyl), 6.57-7.20 (m, 3H, aromatic);
GC/MS m/ z 269 (M+ + 3, 4), 268 (M+ + 2, 30), 267 (M+ + 1,
4), 266 (M+, 30), 173 (100), 159 (21), 115 (29).
3-(2-B r om oe t h y l)-1,2-d ih y d r o -6-m e t h o x y n a p h t h a -
len e (16c): 1H-NMR 2.22 (br t, 2H, CH2CH2Br), 2.70 (br t,
4H, 2 endo CH2), 3.50 (t, 2H, J ) 7 Hz, CH2Br), 3.75 (s, 3H,
CH3), 6.25 (br s, 1H, vinyl), 6.50-7.17 (m, 3H, aromatic); GC/
4-[2-(1,2-Dih yd r o-6-m eth oxy-3-n a p h th a len yl)eth yl]-1-
p h en ylp ip er a zin e (24): eluted with CH2Cl2/ethyl acetate, 1:1,

4934 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Perrone et al.
87% yield; 1H-NMR (300 MHz) 2.26 [t, 2H, J ) 8.1 Hz,
CH2CH2N(CH2)2], 2.51-2.60 (m, 2H, endo CH2), 2.70-2.90 [m,
8H, benzyl CH2, CH2N(CH2)2], 3.37 [br t, 4H, (CH2)2NAr], 3.76
(s, 3H, CH3), 6.23 (s, 1H, vinyl CH), 6.54-7.32 (m, 8H,
aromatic); GC/MS m/ z 349 (M+ + 1, 1), 348 (M+, 5), 176 (13),
175 (100), 132 (19).
(3) Peroutka, S. J . 5-Hydroxytriptamine receptors. J . Neurochem.
1993, 60, 408-416.
(4) Barrett, J . E.; Vanover, K. E. 5-HT Receptors as target for the
development of novel anxiolytic drugs: models, mechanisms, and
future directions. Psychopharmacology 1993, 112, 1-12.
(5) Handley, S. L.; McBlane, J . W. 5-HT drugs and animal models
of anxiety. Psychopharmacology 1993, 112, 13-49.
4-[2-(Meth oxy-1,2,3,4-tetr ah ydr on aph th alen -2-yl)eth yl]-
1-ph en ylpiper azin es 25-27. Gen er al P r ocedu r e. A meth-
anolic solution of compounds 22-26 (0.70 g, 2.0 mmol) was
hydrogenated at normal pressure and room temperature in
the presence of 5% palladium on charcoal (0.1 g), until the
uptake ceased. The catalyst was removed by filtration through
Celite and the solvent evaporated in vacuo. Compounds 25-
27 were obtained as pale yellow semisolids (quantitative yield).
4-[2-(5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -2-yl)-
eth yl]-1-p h en ylp ip er a zin e (25): 1H-NMR (300 MHz) 1.35-
2.00 (m, 5H, CH2CHCH2), 2.40-2.89 [m, 10H, CH2N(CH2)2, 2
benzyl CH2], 3.22 [br t, 4H, (CH2)2NAr], 3.79 (s, 3H, CH3),
6.62-7.28 (m, 8H, aromatic); GC/MS m/ z 351 (M+ + 1, 18),
350 (M+, 72), 176 (13), 175 (100), 162 (15).
4-[2-(6-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -2-yl)-
eth yl]-1-p h en ylp ip er a zin e (26): 1H-NMR (300 MHz) 1.35-
1.95 (m, 5H, CH2CHCH2), 2.31-2.84 [m, 10H, CH2N(CH2)2, 2
benzyl CH2], 3.21 [br t, 4H, (CH2)2NAr], 3.76 (s, 3H, CH3),
6.60-7.29 (m, 8H, aromatic); GC/MS m/ z 351 (M+ + 1, 19),
350 (M+, 75), 175 (100), 162 (21), 120 (16).
(6) Robertson, D. W.; Fuller, R. W. Progress in antidepressant drugs.
Annu. Rep. Med. Chem. 1991, 26, 23-32.
(7) Romero, A. G.; McCall, R. B. Advances in central serotoninergics.
Annu. Rep. Med. Chem. 1992, 27, 21-30.
(8) Glennon, R. A. Concepts for design of 5-HT1A serotonin agonists
and antagonists. Drug Dev. Res. 1992, 26, 251-274.
(9) Misztal, S.; Bojarski, A.; Mackowiak, M.; Boksa, J .; Bielecka,
Z.; Mokrosz, J . L. Structure-activity relationship studies of CNS
agents. 6. Effect of terminal amide fragment on 5-HT1A and
5-HT2 receptor affinity for N-[3-(4-aryl-1-piperazinyl)propyl]
derivatives of 3,4-dihydroquinolin-2-(1H)-one and its isomeric
isoquinolinones. Med. Chem. Res. 1992, 2, 82-87.
(10) El-Bermawy, M.; Raghupathi, R.; Ingher, S. P.; Teitler, M.;
Maayani, S.; Glennon, R. A. 4-[4-(1-Noradamantane-car-
boxamido)butyl]-1-(2-methoxyphenyl)piperazine: a high-affinity
5-HT1A-selective agent. Med. Chem. Res. 1992, 2, 88-95.
(11) Perrone, R.; Berardi, F.; Colabufo, N. A.; Tortorella, V.; Fioren-
tini, F.; Olgiati, V.; Vanotti, E.; Govoni, S. Mixed 5-HT1A/D-2
activity of a new model of arylpiperazine: 1-aryl-4-[3-(1,2-
dihydronaphthalen-4-yl)-n-propyl]piperazines. 1. Synthesis and
structure-activity relationships. J . Med. Chem. 1994, 37, 99-
104.
4-[2-(7-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -2-yl)-
eth yl]-1-p h en ylp ip er a zin e (27): 1H-NMR (300 MHz) 1.34-
1.97 (m, 5H, CH2CHCH2), 2.43-2.87 [m, 10H, CH2N(CH2)2, 2
benzyl CH2], 3.21 [br t, 4H, (CH2)2NAr], 3.75 (s, 3H, CH3),
6.59-7.29 (m, 8H, aromatic); GC/MS m/ z 351 (M+ + 1, 18),
350 (M+, 78), 175 (100), 162 (15), 132 (13).
Hyd r och lor id e Sa lts. Gen er a l P r oced u r e. The hydro-
chloride salts were prepared by adding an HCl ethereal
solution to a methanolic solution of amine. Recrystallization
solvents, crystallization formulas, and melting points are listed
in Table 1. They were obtained as white to sand yellow
crystals or crystalline powders.
(12) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella,
V.; Fiorentini, F.; Olgiati, V.; Ghiglieri, A.; Govoni, S. High
affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[(1-
tetralin)alkyl]-piperazines. 2. J . Med. Chem. 1995, 38, 942-949.
(13) Wadsworth, W. S., J r.; Emmons, W. D. Ethyl cyclohexylidene-
acetate. Organic Syntheses; Wiley: New York, 1965; Collect. Vol.
XLV, pp 44-47.
(14) Nova´k, L.; Roha´ly, J .; Poppe, L.; Hornya´nszsky, G.; Kolonits,
P.; Zelei, I.; Fehe´r, I.; Fekete, J .; Szabo´, E.; Za´horszky, U.; J a´vor,
A.; Sza´ntay, C. Synthesis of novel HGM-CoA reductase inhibi-
tors, I: naphthalene analogs of mevinolin. Liebigs Ann. Chem.
1992, 145-157.
(15) Calogeropoulou, T.; Hammond, G. B.; Wiemer, D. F. Synthesis
of â-keto phosphonates from vinyl phosphates via
a 1,3-
P h a r m a cologica l Meth od s. All the procedures used to
perform the binding assays have been recently reported.1
phosphorus migration. J . Org. Chem. 1987, 52, 4185-4190.
(16) J acks, T. E.; Nibbe, H.; Wiemer, D. F. Preparation of spirocyclic
cyclopropyl ketones through condensation of epoxides with â-keto
phosphonates. J . Org. Chem. 1993, 58, 4584-4588.
Ack n ow led gm en t. The financial support from CNR
is gratefully acknowledged.
(17) Chatterjee, A.; Hazra, B. G. Total synthesis of ring-C aromatic
18-nor steroid. Tetrahedron 1980, 36, 2513-2519.
Refer en ces
(18) This compound was prepared by catalytic hydrogenation of the
corresponding dihydronaphthalene derivative.12 1H-NMR (300
MHz) 1.39-1.98 (m, 10H, CH2CH2CHCH2CH2CH2CH2Cl), 2.63-
2.86 (m, 3H, CH, benzyl CH2), 3.62 (t, 2H, J ) 6.7 Hz, CH2Cl),
3.88 (s, 3H, CH3), 6.71-7.24 (m, 3H, aromatic); GC/MS m/ z 254
(M+ + 2, 5), 253 (M+ + 1, 2), 252 (M+, 13), 162 (27), 161 (100),
115 (11).
(1) Perrone, R.; Berardi, F.; Leopoldo, M.; Tortorella, V.; Fornaretto,
M. G.; Caccia, C.; McArthur, R. 1-Aryl-4-[(1-tetralinyl)alkyl]-
piperazines: alkylamido and alkylamino derivatives. Synthesis,
5-HT1A receptor affinity, and selectivity. 3. J . Med. Chem. 1996,
39, 3195-3202.
(2) Glennon, R. A.; Westkaemper, R. B.; Bartyzer, P. In Serotonin
receptor subtypes; Peroutka, S. J ., Ed.; Wiley-Liss: New York,
1991; pp 19-64.
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