1-Substituted-4-[3-(1,2,3,4-tetrahydro-5- or 7-methoxynaphthalen-1- yl)propyl]piperazines: Influence of the N-1 piperazine substituent on 5- HT(1A) receptor affinity and selectivity versus D2 and α1 receptors. Part 6

Article abstract of DOI:10.1016/S0968-0896(00)00028-6

In the present paper, we report the synthesis and the binding profiles on 5-HT(1A), D₂, and α₁ receptors of 1-substituted-4-[3-(5- or 7-methoxy- 1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine derivatives 19-32 and some related h

Full text of DOI:10.1016/S0968-0896(00)00028-6

Bioorganic & Medicinal Chemistry 8 (2000) 873±881
1-Substituted-4-[3-(1,2,3,4-tetrahydro-5- or
-Methoxynaphthalen-1-yl)propyl]piperazines: In¯uence of the
7
N-1 Piperazine Substituent on 5-HT Receptor Anity and
1
A
y
Selectivity Versus D and ꢀ Receptors. Part 6
2
1
Roberto Perrone,* Francesco Berardi, Nicola A. Colabufo, Marcello Leopoldo
and Vincenzo Tortorella
Dipartimento Farmaco-Chimico, UniversitaÁ degli Studi di Bari, via Orabona, 4, 70126 Bari, Italy
Received 17 September 1999; accepted 26 October 1999
AbstractÐIn the present paper, we report the synthesis and the binding pro®les on 5-HT1A, D , and a receptors of 1-substituted-4-
2
1
[
3
3-(5- or 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine derivatives 19±32 and some related heteroalkyl derivatives
3±35. The results obtained are compared to those previously reported for the 1-phenyl, 1-(2-methoxyphenyl), 1-(2-pyridyl) analo-
gues 2±9. The results pointed out the critical role of the group linked in the N-1 position of the piperazine in terms of 5-HT1A
binding anity. In fact, 1-cyclohexyl, 1-(3-benzisoxazolyl), 1-(benzothiazole-2-carbonyl), 1-(2-benzothiazolyl), 1-(2-quinolyl) sub-
stituted piperazines 21±30 displayed moderate or low 5-HT1A receptor anity; on the contrary, 1-(3-benzisothiazolyl) and 1-(1-
i
naphthalenyl) substituted piperazines 19, 20 and 32 displayed high 5-HT1A receptor anity, the K values being in the sub-
nanomolar range. Furthermore, compounds 19, 20 and 32 demonstrated better selectivity over a receptors than the reference
1
compounds 2±9. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
larly, it a€ects the cholinergic cell groups that innervate
the cortex and hippocampus. This phenomenon
appeared to be especially signi®cant in relation to the
During the last decade, the serotonin 5-HT1A receptor
subtype has been a major target for neurobiological
research because of its involvement in psychiatric dis-
orders such as anxiety and depression.
neuronal substrates underlying the age-related alterations
9,10
2
of cognition such as Alzheimer's disease. For these
reasons it has been suggested that 5-HT1A antagonists
3�5
Furthermore,
some authors suggested that combining dopamine D2
antagonism with 5-HT1A agonism in a single molecule
would give e€ective antipsychotic compounds with a
reduced propensity to induce extrapyramidal side-e€ects
may have a role in the treatment of some of the cogni-
tive symptoms of dementia.1
demonstrated that 5-HT1A receptor agonists show a
neuroprotective potency associated with their ability to
13
inhibit ischemia-induced excessive release of glutamate.
1,12
Moreover, it has been
6�8
(
EPS).
Besides the therapeutic use in anxiety, depres-
sion, and schizophrenia, serotonergic 5-HT1A ligands
have been more recently suggested for other therapeutic
perspectives. It has been shown that the decrement of
5-HT1A receptor binding is remarkably region-selective
in the rat forebrain with increasing age and, particu-
In the light of the therapeutic perspectives mentioned
above, the development of ligands with high anity and
selectivity for the 5-HT1A receptor is still needed. A
large number of arylpiperazine derivatives have been
identi®ed as ligands at the 5-HT1A receptor: the main
shortcoming of this class of compounds is a relatively
high anity at a adrenergic receptors since this may
1
14
cause unwanted cardiovascular e€ects. Our research
group has already studied the anity and selectivity at
*
5
y
Corresponding author. Tel.: +39-080-5442752; fax: +39-080-
442231; e-mail: perrone@farmchim.uniba.it
For part ®ve see Ref. 1.
5-HT1A receptors of some arylpiperazine derivatives of
1,15�17
type 1. These arylpiperazine derivatives display
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00028-6

8
74
R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
the structural requirements for recognition of the 5-HT1A
binding site, i.e., an aromatic ring coupled to a basic
nitrogen atom at a suitable distance; this fundamental
structure is joined by an alkyl chain to a tetralin group.
We studied the e€ect of some structural modi®cations
on the 5-HT1A binding anity and selectivity versus a1
chose either substituents that have already been repor-
ted for long-chain arylpiperazine 5-HT1 receptor
A
18
19�22
26
ligands, such as 3-benzisothiazolyl,
3,24
1-naphthale-
2-benzothiazolyl, 2-quinolyl, as well as sub-
nyl,2
25
stituents not yet studied (cyclohexyl, 3-benzisoxazolyl,
benzothiazole-2-carbonyl).
adrenergic and D dopaminergic receptors. The SAFIR
2
studies showed that the highest values of 5-HT1A bind-
ing anity and selectivity were observed for compounds
(
ring; (b) presenting X=CH , S, NH, N(CH ). More-
a) 5-OCH or 7-OCH substituted on the 1-tetralinyl
3 3
2
3
over, the presence of a heteroatom in the intermediate
chain seems mainly to modulate the selectivity. The
nature of the aryl group on the piperazine ring seemed
to exert a moderate in¯uence, although only three dif-
ferent groups were considered to investigate its e€ect
(
phenyl, 2-OCH -phenyl, 2-pyridyl). Therefore, in this
3
paper we focus our attention on the e€ects of N-1
piperazine substituents on the 5-HT1A receptor anity
and selectivity for this class of 1-arylpiperazines. Our
hypothesis is that speci®c structural requirements are
responsible for 5-HT1A receptor anity and selectivity
for a particular class of long chain arylpiperazines. We
Chemistry
The synthesis of target compounds is depicted in
Scheme 1. Compounds 19±30 were easily obtained by
reacting the appropriate piperazine with bromoalkyl
derivatives 11a,b. Compounds containing a sulfur atom in
Scheme 1. Reagents: (a) 1-substituted piperazines, K
0% aq NaOH, THF; (d) 1-(1-naphthalenyl)piperazine, DCC, CH
LiAlH , THF; (h) methyl chloroformate, 2.4% aq NaOH, CHCl
2
CO
3
, CH
3
CN; (b) ethyl 2-mercaptoacetate or methyl 3-mercaptopropionate, ZnI
2 2 2
, CH Cl ; (c)
1
2
Cl ; (e) LiAlH , Et O; (f) 1-(1-naphthalenyl)piperazine, Et N, toluene; (g)
2
4
2
3
4
3
.

R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
875
the spacer were prepared starting from 5-methoxy-1-
tetralol (12) which was reacted with ethyl 2-mercapto-
acetate or methyl 3-mercaptopropionate in the presence
nergic a receptors by radioligand binding assays. The
1
following speci®c radioligands and tissue sources were
3
used: (a) serotonin 5-HT1A receptorsÐ[ H]-8-OH-
DPAT, rat hippocampal membranes; (b) dopamine D
2
7
of zinc iodide to give esters 13a and 13b, respectively.
The latter compounds were hydrolyzed in alkaline med-
ium and the resulting acids 14a and 14b were condensed,
in the presence of 1,3-dicyclohexylcarbodiimide (DCC),
with 1-(1-naphthalenyl)piperazine to give amides 15a
and 15b, respectively. Reduction of these compounds
with LiAlH4 a€orded target compounds 33 and 34.
Compound 35 was prepared as follows: the bromo
2
3
receptorsÐ[ H]spiroperidol, rat striatal membranes; (c)
3
a adrenergic receptorsÐ[ H]prazosin, rat brain cortex
1
membranes. Concentrations required to inhibit 50% of
radioligand speci®c binding (IC ) were determined by
50
using eight to nine di€erent concentrations of the drug
studied. In all binding assays speci®c binding repre-
sented more than 80% of the total. The results were
analyzed by using the LIGAND program to determine
IC50 values which were used to calculate the inhibition
1
6
derivative 16 was reacted with 1-(1-naphthalenyl)-
piperazine to give amide 17 which was reduced with
LiAlH to give amine 18. N-Methylation was accom-
2
9
constants (K ) using the Cheng±Pruso€ equation.
i
4
28
plished by treating 18 with methyl chloroformate to
yield its carbamate derivative, which was then reduced
with LiAlH to compound 35.
4
Results and Discussion
The results of the in vitro binding studies of the target
compounds 19±35 are summarized in Table 2. Con-
sidering the 5-HT1A receptor anity of compounds
19±32, it can be ®rst noted that there was no great dif-
ference in anity between the 5- and 7-methoxy iso-
Pharmacology
Target compounds (Table 1) were evaluated for in vitro
anity at serotonin 5-HT1A, dopamine D , and adre-
2
Table 1. Physical properties
Formulaa
Recryst. solv.
Mp ( C)
ꢀ
Compound
R
1
R
2
X
R
3
b
2
H
CH
H
3
O
O
O
CH
CH
CH
CH
CH
CH
S
2
2
2
2
2
2
Phenyl
Phenyl
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
222±224
218±220
223±225
196±198
210±212
226±228
220±224
211±213
233±235
229±231
Ð
>260
245±248
235±237
239±240
198±200
240
b
3
CH
3
O
O
O
b
4
H
CH
3
2-CH
2-CH
3
O-phenyl
O-phenyl
b
5
CH
3
H
3
b
6
H
CH
3
2-Pyridyl
2-Pyridyl
b
7
CH
3
H
b
8
H
H
H
CH
CH
CH
3
3
3
O
O
O
2-CH
2-CH
3
O-phenyl
O-phenyl
c
9
N(CH
3
)
3
.
S HCl 1/2H
.
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
S
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3-Benzisothiazolyl
3-Benzisothiazolyl
2-Benzothiazolyl
2-Benzothiazolyl
Benzothiazole-2-carbonyl
Benzothiazole-2-carbonyl
3-Benzisoxazolyl
3-Benzisoxazolyl
2-Quinolyl
C
25
H
C
31
25
31
25
N
H
N
3
O
2
2
O
MeOH/Et
MeOH/Et
2
O
O
.
O S HCl
CH
3
O
O
O
O
O
O
O
H
31
N
3 2
2
.
S 3HCl H
.
2
H
CH
3
O
O
O
O
O
O
C
25
H
3
O
2
O
CH
CH
2
Cl
Cl
2
2
/Et
/Et
2
O
O
.
.
CH
3
H
C
C
C
H
31
31
31
N
3
O
2
S 3HCl
S HCl
.
S HCl
HCl H
2
2
H
CH
CH
3
26
26
31
25
27
33
H
N
3
O
2
MeOH/Et
2
O
CH
3
H
H
N
3
O
2
CH Cl /Et
2
2
2
O
O
O
3
C
2.
O
.
2
MeOH/Et
MeOH/Et
MeOH
MeOH/Et
Ð
2
H
25
H
N
3
O
CH
3
H
C
C
H
31
33
N
3
O
2.
HCl
2
.
O 2HCl
H
CH
CH
3
H
N
3
.
O 2HCl H
Ð
.
CH
3
H
2-Quinolyl
Cyclohexyl
Cyclohexyl
1-Naphthalenyl
1-Naphthalenyl
1-Naphthalenyl
1-Naphthalenyl
1-Naphthalenyl
C
27
H
N
3
2
O
2
2
2
O
O
O
O
d
H
3
.
CH
3
H
C
C
C
24
28
28
32
28
35
H
38
34
34
N
2
O 2HCl
MeOH/Et
.
H
CH
3
H
N
2
O HCl
EtOH/Et
MeOH/Et
MeOH
MeOH
MeOH/Et
2
.
O 2HCl
CH
3
H
H
N
2
.
OS HCl H
.
H
H
H
CH
CH
CH
3
3
3
O
O
O
C
27
H
N
2
2
O
.
OS 2HCl
SCH
N(CH
2
C
H
34
N
2
2.
O
.
2HCl H
2
2
3
)
C
28
H
N
3
O
O
a
Analyses for C,H,N; results were within ‹0.4% of the theoretical values for the formulas given.
See ref 15.
See ref 16.
b
c
d
See ref 34.

8
76
R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
Table 2. Binding anities
K
i
‹S.E.M., nMa
i
Selectivity (K ratio)
Compound
5-HT1A
D
2
a
1
D
2
/5-HT1A
a
1
/5-HT1A
b
2
0.45
8.32
0.69
1.4
0.48
3.07
0.98
7.9
92
23
15
42.9
117
273
6.53
61
5.2‹0.8
85‹7
36
153
5.4
36
55
218
100
739
80‹9
520‹19
>800
>800
>800
>800
42‹5
112‹8
>800
>800
>800
>800
204
3
80
18
8
26
115
71
102
94
145
433
Ð
Ð
Ð
Ð
Ð
Ð
Ð
b
3
b
4
22
31
244
89
7
b
5
b
6
b
7
b
8
c
9
8
9
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
0.55‹0.02
1.2‹0.3
500‹35
755‹32
827‹80
>900
49‹6
345‹11
80‹6
718‹42
258‹17
718‹64
30‹4
6.4‹0.6
7.3‹0.8
9.1‹0.4
4.6‹0.5
0.89‹0.08
52‹8.1
Ð
71
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
13
28
58
93
185
Ð
Ð
Ð
Ð
>850
>850
>850
>850
>850
308‹21
>850
>850
Ð
Ð
Ð
604‹24
479‹13
385‹18
179‹19
427‹22
>850
>850
320‹21
>800
>800
400‹20
>800
11
125
>100
44
174
Ð
Ð
Ð
Ð
5
-OH-DPAT
Ð
Ð
Ð
Buspirone
Spiroperidol
Prazosin
Ð
0.053‹0.002
Ð
Ð
0.10‹0.08
Ð
aData are the mean of three independent determinations (samples in triplicate).
bSee ref 15.
cSee ref 16.
mers. The best results in terms of 5-HT1A receptor a-
nity were found for the 3-benzisothiazolyl derivatives 19
values ranging between 6.53 and 273 nM, the corre-
sponding compounds 20±35 showed D2 K anity
i
and 20 (K =0.55 and 1.2 nM, respectively) and for the
i
values over 85 nM with the exception of the 3-benz-
isothiazolyl derivative 19 (K =5.2 nM).
1-naphthalenyl derivatives 31 and 32 (K =30 and 6.4
i
i
nM, respectively). All these compounds displayed Ki
anity values at the 5-HT1A receptors in the same range
as our reference compounds 2±7 and as other com-
Furthermore, the a receptor anity values of the new
1
compounds 19±35 are very low as compared with those
of the reference compounds; in particular the most
interesting derivatives of the new series which possess
high anities for the 5-HT1A receptor (compounds 19,
20 and 32) displayed an a /5-HT K ratio higher than
pounds bearing the same kind of aryl substituent.1
9�22
These data point out that no improvement of 5-HT1A
receptor anity was obtained in comparison with the
corresponding compounds 2±7 previously studied having
R =Ph, 2-Py, 2-OCH Ph. On the other hand, the 2-
1
1A
i
100. Compound 31 did not display a satisfactory bind-
ing pro®le, so we decided to carry out a strategy pre-
viously applied to compound 4. In fact, the insertion of
3
3
benzothiazolyl (21 and 22), benzothiazole-2-carbonyl
(
(
23 and 24), 3-benzisoxazolyl (25 and 26), and quinolyl
27 and 28) derivatives displayed moderate or low 5-
an S or N(CH ) group in the alkyl chain of compound 4
3
HT1A binding anity. Furthermore, it is interesting
to note that, when comparing the anities of the
compounds 2 and 3 with those of the corresponding
saturated-ring counterparts 29 and 30, a dramatic loss
in anity was observed. These results point out the
importance of the presence and the nature of an aro-
matic ring in R position for 5-HT receptor anity.
gave compounds 8 and 9 which showed a remarkable
increase in selectivity versus the a receptor (8-fold for
1
compound 4 and about 100-fold for compounds 8 and
9, respectively). The same structural modi®cations have
been e€ected for compound 31. The new compounds 33
and 35 displayed both a remarkable increase in 5-HT1A
receptor anity and decrease in a receptor anity,
3
1A
1
resulting in an increased selectivity for the 5-HT1A over
the a receptor; these data con®rmed the trend pre-
viously observed. We also prepared compound 34 which
When regarding the D2 receptor anity, di€erently
from the reference compounds 2±9, which displayed Ki
1

R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
877
displayed similar properties as compared with the lower
homologous 33.
tetrahydro-naphthalen-1-yl)bromoacetamide (16).16 The
spectral properties of compound 29 have already been
reported.35
2-(1-Piperazinylcarbonyl)benzothiazole (10). A mixture
of anhydrous piperazine (1.25 g, 14.5 mmol) and ethyl
Conclusions
36
In conclusion, for the long-chain arylpiperazines with
structures reported in Table 1, the critical role of the
group linked in the N-1 position of the piperazine ring
seems to be clear: some substituents lead to compounds
2-benzothiazolecarboxylate (1.00 g, 4.8 mmol) was
heated at 160 C for 6 h. Then, the mixture was cooled
ꢀ
and chromatographed (CHCl :MeOH, 19:1, as eluent)
3
to give compound 10 (0.67 g, 56% yield) as a white
ꢀ
1
2
1±30 displaying moderate or low 5-HT1A receptor a-
solid: mp 206±208 C (from CH Cl /Et O); H NMR
2
2
2
nity, while other substituents can give compounds dis-
playing 5-HT1A receptor anity (derivatives 19, 20, 32)
in the subnanomolar range. Furthermore, the modi®ca-
tion herein proposed led to compounds with improved
selectivity in comparison with the reference compounds;
the most suitable N-1 piperazine aromatic substituent
was the 3-benzisothiazole (compounds 19 and 20). The
anity pro®le of these compounds is very interesting
since they show high 5-HT1A receptor anity values
and, in particular, high selectivity versus the a1
adrenergic receptor in comparison with the previously
studied analogues 2±9. An additional increase in selec-
tivity can be achieved by the insertion of an S or
(
(CH ) NCO], 7.45±8.30 (m, 5H, aromatic, NH, 1H D O
90 MHz) 4.05 [br s, 4H, HN(CH ) ], 4.70 [br s, 4H,
2 2
2
2
2
+
exchanged); GC±MS m/z 247 (M , 18), 204 (24), 162
25), 135 (46), 134 (39), 85 (100).
(
1
-Substituted piperazine derivatives 19±32: general pro-
cedure. A stirred suspension of the appropriate alkyl
bromide 11a,b (2.0 mmol), amine (4.0 mmol), and
potassium carbonate (2.0 mmol) in acetonitrile was
re¯uxed overnight. After cooling, the mixture was
evaporated to dryness and water was added to the resi-
due. The aqueous phase was extracted two times with
ethyl acetate. The collected organic layers were dried
over Na SO and evaporated under reduced pressure.
N(CH ) group in the intermediate alkyl chain: in this
3
2
4
way the highly selective compounds 33 and 35 were
developed from the low selective 1-naphthalenyl deriva-
tive 31.
The crude residue was chromatographed, as indicated
below, to yield pure compounds 19±32 as pale yellow
oils.
3-[4-[3-(1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenyl)-
propyl]-1-piperazinyl]-1,2-benzisothiazole (19). Eluted
with CHCl :MeOH, 49:1. H NMR 1.58±1.83 [m, 8H,
3
Experimental
Chemistry
1
CH(CH CH ) ], 2.48±2.76 [m, 9H, benzylic, CH N
2
2
2 2
(
6
4
CH ) ], 3.60 [br s, 4H, (CH ) NAr], 3.79 (s, 3H, CH ),
2 2 2 2 3
.62±7.90 (m, 7H, aromatic); GC±MS m/z 421 (M ,
0), 285 (31), 258 (100), 232 (24).
Column chromatography was performed with 1:30 ICN
silica gel 60A (63±200 mm) as the stationary phase.
Melting points were determined in open capillaries on a
Gallenkamp electrothermal apparatus. Elemental ana-
lyses (C,H,N) were performed on a Carlo Erba model
+
3-[4-[3-(1,2,3,4-Tetrahydro-7-methoxy-1-naphthalenyl)-
propyl]-1-piperazinyl]-1,2-benzisothiazole (20). Eluted
1
106 analyzer; the analytical results were within‹0.4%
1
1
with CH
8
(
6
3
Cl :ethyl acetate, 7:3; H NMR 1.58±1.89 [m,
2 2
of the theoretical values for the formula given. H NMR
spectra were recorded either on a Varian EM-390 where
indicated at 90 MHz (TMS as internal standard) or on a
H, CH(CH CH ) ], 2.48±2.75 [m, 9H, benzylic, CH N
2
2 2
2
CH ) ], 3.59 [br t, 4H, (CH ) NAr], 3.76 (s, 3H, CH ),
2 2 2 2 3
+
.64±7.91 (m, 7H, aromatic); GC±MS m/z 421 (M ,
5), 285 (33), 258 (100), 232 (25).
Bruker AM 300 WB instrument, with CDCl as solvent;
3
all values are reported in ppm (d). Recording of mass
spectra was done on an HP 5995C gas chromatograph/
mass spectrometer, electron impact 70 eV, equipped
with an HP59970A workstation; only signi®cant m/z
peaks, with their % relative intensity in parentheses, are
reported herein. All spectra were in accordance with the
assigned structures. All target compounds were trans-
formed into their hydrochloride or hydrogen oxalate
salts in the usual manner.
2-[4-[3-(1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenyl)-
propyl]-1-piperazinyl]benzothiazole (21). Eluted with
CHCl :MeOH, 49:1; H NMR 1.55±1.83 [m, 8H,
3
CH(CH CH ) ], 2.41 [t, 2H, J=6.3 Hz, CH N(CH ) ],
2
2
1
2 2
2
2 2
.49±2.77 [m, 7H, benzylic, CH N(CH ) ], 3.64 [br t,
2 2 2
4
H, (CH ) NAr], 3.79 (s, 3H, CH ), 6.62±7.59 (m, 7H,
2 2
3
+
aromatic); GC±MS m/z 421 (M , 23), 271 (22), 258
100), 246 (35), 163 (20).
(
The following compounds were synthesized by pub-
lished procedures: 1-(3-bromopropyl)-5-methoxy-1,2,3,4-
2-[4-[3-(1,2,3,4-Tetrahydro-7-methoxy-1-naphthalenyl)-
propyl]-1-piperazinyl]benzothiazole (22). Eluted with
CHCl :MeOH, 49:1; H NMR 1.55±1.88 [m, 8H,
3
1
5
tetrahydronaphthalene (11a),
1-(3-bromopropyl)-7-
1
5
1
methoxy-1,2,3,4-tetrahydronaphthalene (11b),
naphthalenyl)piperazine,
1-(1-
3-(1-piperazinyl)-1,2-benz-
isothiazole, 2-(1-piperazinyl)benzothiazole,
3
piperazinyl)-1,2-benzisoxazole,
30
CH(CH CH ) ], 2.40 [t, 2H, J=6.9 Hz, CH N(CH ) ],
2
2 2
2
2 2
3
1
32
3-(1-
1-(2-quinolinyl)piper-
2.48±2.75 [m, 7H, benzylic, CH N(CH ) ], 3.64 [br t,
2 2 2
2
4H, (CH ) NAr], 3.76 (s, 3H, CH ), 6.64±7.59 (m, 7H,
2 2 3
3
3
+
azine, ethyl 2-[(5-methoxy-1,2,3,4-tetrahydronaphthal-
3
aromatic); GC±MS m/z 421 (M , 23), 419 (25), 271
(23), 258 (100), 246 (37), 163 (23).
4
en-1-yl)-thio]acetate (13a),
N-(5-methoxy-1,2,3,4-

8
78
R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
2-[4-[3-(1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenyl)-
propyl]-1-piperazinylcarbonyl]benzothiazole (23). Eluted
4H, (CH ) NAr], 3.80 (s, 3H, CH ), 6.63±8.20 (m, 10H,
2 2 3
aromatic); GC±MS m/z 414 (M , 75), 225 (100), 212
(33).
+
1
with CHCl3;
(
H
CH CH ) ], 2.40 [t, 2H, J=6.7 Hz, CH N(CH ) ],
NMR 1.53±1.83 [m, 8H, CH
2
2 2
2
2 2
2.46±2.77 [m, 7H, benzylic, CH N(CH ) ], 3.76 (s, 3H,
CH ), 3.85 and 4.43 [2 br t, 4H, (CH ) NCO], 6.62±8.08
1-(1-Naphthalenyl)-4-[3-(1,2,3,4-tetrahydro-7-methoxy-
1-naphthalenyl)propyl]piperazine (32). Eluted with
CHCl :MeOH, 19:1; H NMR 1.62±1.90 [m, 8H,
3
2
2 2
3
2 2
+
1
(
m, 7H, aromatic); GC±MS m/z 449 (M , 21), 260 (41),
258 (100).
CH(CH CH ) ], 2.49±2.82 [m, 9H, benzylic, CH N
2
2 2
2
(
6.65±8.21 (m, 10H, aromatic); GC±MS m/z 414 (M ,
96), 225 (100), 212 (32).
CH ) ], 3.15 [br s, 4H, (CH ) NAr], 3.77 (s, 3H, CH ),
2 2 2 2 3
+
2
-[4-[3-(1,2,3,4-Tetrahydro-7-methoxy-1-naphthalenyl)-
propyl]-1-piperazinylcarbonyl]benzothiazole (24). Eluted
1
with CHCl :MeOH, 49:1; H NMR 1.56±1.88 [m, 8H,
3
CH(CH CH ) ], 2.41 [t, 2H, J=6.8 Hz, CH N(CH ) ],
2
Methyl 3-[(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)-
thio]propanoate (13b). Anhydrous ZnI2 (4.44 g, 13.9
mmol) was added to a solution of 5-methoxy-1-tetralol
(12) (4.96 g, 27.8 mmol) in CH Cl . Then was added
2 2
2
2 2
2.51±2.74 [m, 7H, benzylic, CH N(CH ) ], 3.76 (s, 3H,
CH ), 3.86 and 4.44 [2 br t, 4H, (CH ) NCO], 6.64±8.08
2 2 2
3
2 2
+
(
m, 7H, aromatic); GC±MS m/z 449 (M , 35), 260 (40),
2
2
2
59 (21), 258 (100), 162 (20).
methyl 3-mercaptopropionate (3.8 mL, 33.4 mmol) and
the mixture was stirred at room temperature for 40 min.
Then the reaction was quenched with H O (30 mL). The
3-[4-[3-(1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenyl)-
propyl]-1-piperazinyl]-1,2-benzisoxazole (25). Eluted
with CH Cl :MeOH, 49:1; H NMR 1.55±1.84 [m, 8H,
2
2
organic phase was separated, dried over Na SO and
2
4
1
concentrated under reduced pressure. The crude residue
was chromatographed (CH Cl as eluent) to give 7.12 g
2
CH(CH CH ) ], 2.41±2.77 [m, 9H, benzylic, CH N
2
2 2
2
2
2
1
(
CH ) ], 3.59 [br s, 4H, (CH ) NAr], 3.79 (s, 3H, CH ),
2
of compound 13b as a pale yellow oil (91% yield). H
NMR (90 MHz) 1.75±2.20 (m, 4H, endo CH CH ),
2
2 2
3
6.62±7.68 (m, 7H, aromatic); GC±MS m/z 288 (65), 246
2
2
(
36), 99 (100).
2.50- 3.00 (m, 6H, CH CH CO, benzylic CH ), 3.70 and
2 2 2
3
(m, 3H, aromatic); GC±MS m/z 280 (M , 0.3), 161
(100), 160 (63), 115 (21).
.80 (2 s, 6H, 2 CH ), 4.13 (br t, 1H, CHS), 6.63±7.33
3
+
3-[4-[3-(1,2,3,4-Tetrahydro-7-methoxy-1-naphthalenyl)-
propyl]-1-piperazinyl]-1,2-benzisoxazole (26). Eluted
1
with CH Cl :ethyl acetate, 1:1; H NMR 1.57±1.86 [m,
2
2
8
H, CH(CH CH ) ], 2.47±2.74 [m, 9H, benzylic, CH N
2 2
2-[(1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenyl)thio]-
ethanoic acid (14a). Ethyl 2-[(1,2,3,4-tetrahydro-5-meth-
oxy-1-naphthalenyl)thio]ethanoate (13a) (3.57 g, 12.7
mmol) was re¯uxed overnight in THF in the presence of
2
2
(
CH ) ], 3.59 [br s, 4H, (CH ) NAr], 3.76 (s, 3H, CH ),
2 2 2 2 3
6.64±7.68 (m, 7H, aromatic); GC±MS m/z 288 (79), 246
(
39), 99 (100).
1
0% aqueous NaOH (20 mL). Then the mixture was
1
-(2-Quinolinyl)-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-
naphthalenyl)propyl]piperazine (27). Eluted with
CH Cl :ethyl acetate, 1:1; H NMR 1.58±1.81 [m, 8H,
concentrated under reduced pressure and acidi®ed with
3 N HCl. The aqueous phase was extracted with CH Cl
and the separated organic layer was dried over Na SO .
2
2
1
2
2
2
4
CH(CH CH ) ], 2.44±2.77 [m, 9H, benzylic, CH N
2
The solvent was evaporated in vacuo to give a crude
residue which was chromatographed (CHCl as eluent)
2 2
2
(
9
CH ) ], 3.78 [br s, 7H, CH , (CH ) NAr], 6.62±7.89 (m,
2 2
H, aromatic); GC±MS m/z 415 (M , 10), 413 (23), 271
2
2
3
3
+
yielding acid 14a as a pale yellow semisolid (2.2 g, 69%
yield). 1H NMR (90 MHz) 1.75±2.25 (m, 4H, endo
CH CH ), 2.43±2.85 (m, 2H, benzylic CH ), 3.25±3.35
(
47), 258 (34), 157 (100), 128 (29).
2
2
2
1
-(2-Quinolinyl)-4-[3-(1,2,3,4-tetrahydro-7-methoxy-1-
naphthalenyl)propyl]piperazine (28). Eluted with
CH Cl :ethyl acetate, 1:1; H NMR 1.54±1.85 [m, 8H,
(m, 2H, SCH ), 3.76 (s, 3H, CH ), 4.33 (br t, 1H, CHS),
2 3
6.30±7.30 (m, 3H, aromatic), 10.70 (br s, 1H, OH, D O
2
1
+
exchanged); GC±MS m/z 252 (M , 4), 161 (100), 160
(76), 159 (21), 115 (34).
2
2
CH(CH CH ) ], 2.44±2.75 [m, 9H, benzylic, CH N
2
2 2
2
(
7
CH ) ], 3.76±3.78 [m+s, 7H, CH , (CH ) NAr], 6.63±
2 2 3 2 2
.89 (m, 9H, aromatic); GC±MS m/z 415 (M , 11), 413
+
3-[(1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenyl)thio]-
propanoic acid (14b). As above, starting from ester
(
21), 271 (41), 258 (34), 157 (100), 128 (27).
1
as a pale yellow semisolid (4.05 g, 60% yield).
3b (7.12 g, 25 mmol) the title compound was obtained
1
1-Cyclohexyl-4-[3-(1,2,3,4-tetrahydro-7-methoxy-1-naph-
thalenyl)propyl]piperazine (30). Eluted with CHCl :
H
NMR (90 MHz) 1.70±2.20 (m, 4H, endo CH CH ),
3
2
2
1
MeOH, 19:1; H NMR 1.05±1.28 (m, 6H, cyclohexyl),
1.51±1.89 [m, 12H, cyclohexyl NCH(CH ) , CH
2.55±2.95 (m, 6H, SCH CH , benzylic CH ), 3.80 (s,
2 2 2
3H, CH ), 4.20 (br t, 1H, CHS), 6.66±7.20 (m, 3H,
3
2
2
(
CH CH N, benzylic), 3.75 (s, 3H, CH ), 6.62±7.24 (m,
CH CH ) ], 2.22±2.71 (m, 14H, piperazine, NCH, CH
aromatic), 9.15 (br s, 1H, OH, D O exchanged); GC±
2
MS m/z 266 (M , 0.3), 161 (100), 160 (61), 115 (20), 90
(19).
2
2 2
2
+
2
2
3
+
3H, aromatic); GC±MS m/z 370 (M , 67), 327 (26), 260
(
32), 181 (100).
1
-(1-Naphthalenyl)-4-[[1,2,3,4-tetrahydro-5-methoxy-1-
1
1
-(1-Naphthalenyl)-4-[3-(1,2,3,4-tetrahydro-5-methoxy-
-naphthalenyl)propyl]piperazine (31). Eluted with
naphthalenyl)thio]acetyl]piperazine (15a). A solution of
1-(1-naphthalenyl)piperazine (0.62 g, 2.9 mmol), in
CH Cl , was added dropwise to a stirred solution of
1
CH Cl ; H NMR 1.60±1.90 [m, 8H, CH(CH CH ) ],
2
2
2
2 2
2
2
2
.50±2.78 [m, 9H, benzylic, CH N(CH ) ], 3.17 [br s,
2
acid 14a (0.60 g, 2.4 mmol) and DCC (0.64 g, 3.1 mmol)
2 2

R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
879
in the same solvent. The reaction mixture was stirred
overnight at room temperature, then a few milliliters of
glacial acetic acid were added to decompose the excess
reagent. The insoluble urea was removed by ®ltration;
the ®ltrate was washed with 2 N NaOH, the organic
layer was separated and dried over Na SO . Evapora-
(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)bromo-
acetamide (16) (1.31 g, 4.4 mmol), and triethylamine
(2 mL) in toluene (40 mL) was re¯uxed overnight.
Then the solution was cooled and washed with 20%
aqueous Na CO . The separated organic layer was dried
2
3
(Na SO ) and concentrated under reduced pressure.
2
2
4
4
tion of the solvent in vacuo provided the crude amide
which was chromatographed (petroleum ether:ethyl
acetate, 19:1, as eluent) to give the expected amide 15a
The crude residue was chromatographed (CHCl :ethyl
3
acetate, 3:2, as eluent) to give compound 17 (1.61 g,
1
84% yield). H NMR (90 MHz) 1.55±2.10 (m, 4H, endo
CH CH ), 2.50±3.10 (m, 11H, piperazine, benzylic CH ,
1
as a pale yellow semisolid (0.90 g, 83% yield): H NMR
2
2
2
1
2
3
4
.65±1.89 (m, 2H, endo CH ), 2.00±2.20, 2.44±2.55 and
2
NH, 1H D O exchanged), 3.20 (s, 2H, COCH ), 3.76 (s,
2 2
.76±2.85 (m, 12H, piperazine, CHCH , benzylic CH ),
2
3H, CH ), 5.05±5.20 (m, 1H, CHNH), 6.65±8.25 (m,
3
2
+
.45 (d, 2H, J=3.1 Hz, SCH ), 3.79 (s, 3H, CH ), 4.09±
2
10H, aromatic); GC±MS m/z 429 (M , 26), 225 (100),
70 (35).
3
.33 (m, 1H, CH), 6.66±8.23 (m, 10H, aromatic); GC±
+
MS m/z 446 (M , 31), 255 (26), 254 (100), 182 (63), 160
95).
(
4-(1-Naphthalenyl)-N-(1,2,3,4-tetrahydro-5-methoxy-1-
naphthalenyl)-1-piperazineethanamine (18). Amide 17
(1.02 g, 2.4 mmol), in anhydrous THF, was added to a
1
-(1-Naphthalenyl)-4-[3-[1,2,3,4-tetrahydro-5-methoxy-1-
naphthalenyl)thio]propanoyl]piperazine (15b). As above,
the title compound was obtained in 80% yield starting
from acid 14b (0.96 g, 3.6 mmol) and 1-(1-naphthale-
stirred suspension of LiAlH (0.18 g, 4.8 mmol) in the
4
same solvent (20 mL). The reaction mixture was
re¯uxed for 2 h. After cooling, a few drops of water
were added, the suspension was ®ltered, and the ®ltrate
was concentrated under reduced pressure. The residue
was diluted with water and extracted twice with
CH Cl . The separated organic layers were dried over
1
nyl)piperazine (0.91 g, 4.3 mmol). H NMR (90 MHz)
1.65±2.00 (m, 2H, endo CH ), 2.40±3.20 (m, 12H,
piperazine, CHCH , benzylic CH ), 3.55±3.85 (m+s,
2
2
2
7
H, SCH CH , CH ), 4.05±4.25 (m, 1H, CH), 6.60±8.30
2 2 3
2
2
+
(m, 10H, aromatic); GC±MS m/z 460 (M , 23), 300
(28), 299 (100), 239 (35), 182 (39), 169 (39), 161 (49), 160
(47), 154 (27).
Na SO and concentrated under reduced pressure to
2 4
give a crude residue which was chromatographed
(CH Cl :MeOH, 19:1, as eluent). Pure 18 was a pale
2
2
1
yellow oil (0.45 g, 46% yield). H NMR 1.71±2.03 (m,
4H, endo CH CH ), 2.51±2.93 [m, 11H, CH CH N
1
1
-(1-Naphthalenyl)-4-[2-[(1,2,3,4-tetrahydro-5-methoxy-
-naphthalenyl)thio]ethyl]piperazine (33). Amide 15a
2
2
2
2
(CH ) , benzylic CH , NH, 1H D O exchanged], 3.12
2 2 2 2
(
placed in a two-necked round bottom ¯ask which was
0.9 g, 2.0 mmol) and LiAlH (0.15 g. 4.0 mmol) were
(br s, 4H, CH NAr), 3.79 (s, 3H, CH ), 3.84±3.87 (m,
2 3
4
1H, NHCH), 6.67±8.20 (m, 10H, aromatic); GC±MS
+
ꢀ
Et O was slowly added and the resulting suspension was
¯
ushed with N and cooled at 0 C. Then anhydrous
2
m/z 415 (M , 9), 226 (46), 225 (100), 197 (20), 195 (33),
182 (30), 161 (60), 154 (27).
2
stirred overnight at rt. Then the mixture was cooled and
a few drops of H O were added to destroy the excess of
N-Methyl-4-(1-naphthalenyl)-N-(1,2,3,4-tetrahydro-5-
methoxy-1-naphthalenyl)-1-piperazineethanamine (35).
2.4% aqueous NaOH (8.7 mL, 5.2 mmol) was added to
2
hydride. The mixture was ®ltered and the ®ltrate was
dried over Na SO . Evaporation of the solvent under
2
4
reduced pressure gave a crude residue which was chro-
matographed (CH Cl :ethyl acetate, 19:1, as eluent)
yielding pure 33 as a pale yellow oil (0.57 g, 65% yield).
a solution of amine 18 (0.92 g, 2.2 mmol) in CHCl (50
3
mL). Then methyl chloroformate (0.4 mL, 5.2 mmol) in
CHCl (5 mL) was added dropwise to the ice-cooled
2
2
3
1
H NMR 1.78±1.86 and 2.00±2.17 (m, 4H, endo
CH CH ), 2.46±2.57 and 2.74±2.83 [m, 10H, CH N
mixture, under vigorous stirring. The cold mixture was
stirred for 1 h, then acidi®ed with 6 N HCl, and stirred
2
2
2
ꢀ
extracted with CHCl . The combined organic layers
(
NAr], 3.79 (s, 3H, CH ), 4.18 (br t, 1H, CHS), 6.66±8.17
CH ) , benzylic CH , SCH ], 3.20 [br s, 4H, (CH )
2 2
for 0.5 h at 25 C. The separated aqueous phase was
2
2
2
2
3
3
+
(
(
m, 10H, aromatic); GC±MS m/z 432 (M , 26), 225
100).
were washed ®rst with aqueous NaHCO , then with
3
water, dried over Na SO4 and concentrated under
2
reduced pressure to yield the oily carbamate derivative.
To a stirred suspension of LiAlH (0.17 g, 4.4 mmol) in
1
1
-(1-Naphthalenyl)-4-[3-[(1,2,3,4-tetrahydro-5-methoxy-
-naphthalenyl)thio]propyl]piperazine (34). As described
4
anhydrous THF was added a solution of the carbamate
derivative in the same solvent. The mixture was re¯uxed
for 24 h, then it was cooled, and the excess of reagent
was decomposed with a few drops of water. The mixture
was ®ltered and the ®ltrate was concentrated under
reduced pressure. The residue was diluted with CHCl3
and washed with water. The separated organic layer was
dried over Na SO and evaporated in vacuo to a€ord
for 33, starting from amide 15b (1.20 g, 2.6 mmol),
compound 34 was obtained after elution with petroleum
ether:ethyl acetate, 1:1 (0.57 g, 50% yield). H NMR
1.70±2.21 (m, 6H, endo CH CH , SCH CH ), 2.46±2.84
1
2 2 2 2
[
m, 10H, CH N(CH ) , benzylic CH , SCH ], 3.18 (br s,
2 2 2 2 2
4
6
2
H, CH NAr), 3.79 (s, 3H, CH ), 4.12 (br t, 1H, CHS),
2 3
.66±8.21 (m, 10H, aromatic); GC±MS m/z 446 (M ,
), 286 (21), 285 (100), 225 (24).
+
2
4
1
the N-methylated derivative 35 (0.40 g, 42% yield). H
NMR 1.59±1.68 and 1.98±2.10 (m, 4H, endo CH CH ),
2
2
4
-(1-Naphthalenyl)-N-(1,2,3,4-tetrahydro-5-methoxy-1-
2.37 (s, 3H, NCH ), 2.45±3.00 [m, 10H, CH CH N
3 2 2
naphthalenyl)-1-piperazineacetamide (17). A solution of
-(1-naphthalenyl)piperazine (2.6 g, 12.2 mmol), N-
(CH ) , benzylic CH ], 3.22 (br s, 4H, CH Ar), 3.79 (s,
2 2 2 2
3H, OCH ), 4.03 (br s, 1H, CHNH), 6.68±8.16 (m, 10H,
3
1

8
80
R. Perrone et al. / Bioorg. Med. Chem. 8 (2000) 873±881
+
aromatic); GC±MS m/z 429 (M , 2), 204, (38), 161
100).
4. Kostowski, W.; Dyr, W.; Krzascik, P.; Jarbe, T.; Archer, T.
Pharmacol. Toxicol. 1992, 71, 24.
(
5
6
. File, S. E. Pharmacol. Biochem. Behav. 1996, 54, 3.
. Wadenberg, M. L.; Ahlenius, S. J. Neural Transm. Gen.
Pharmacological methods
-HT1A serotonergic binding assay. Binding experiments
Sect. 1991, 83, 43.
. Neal-Beliveau, B. S.; Joyce, J. N.; Lucki, I. J. Pharmacol.
Exp. Ther. 1993, 265, 207.
. Wadenberg, M. L.; Cortizo, L.; Ahlenius, S. Pharmacol.
Biochem. Behav. 1994, 47, 509.
. Nyakas, C.; Oosterink, B. J.; Keijser, J.; Felszeghy, K.; de
7
5
37
were performed according to Borsini et al. with minor
modi®cations. Each tube received in a ®nal volume of 1
8
.
mL of 50 mM Tris HCl (pH 7.6) hippocampus mem-
3
9
branes suspension and 1 nM [ H]-8-OH-DPAT. For
Jong, G. I.; Korf, J.; Luiten, P. G. J. Chem. Neuroanat. 1997,
13, 53.
10. Keck, B. J.; Lakoski, J. M. Brain Res. Brain Res. Protoc.
competitive inhibition experiments various concentra-
tions of drugs studied were incubated. Nonspeci®c
binding was de®ned using 1 mM 8-OH-DPAT. Samples
1
997, 1, 364.
11. Harder, J. A.; Maclean, C. J.; Alder, J. T.; Francis, P. T.;
ꢀ
were incubated at 37 C for 20 min and then ®ltered on
Ridley, R. M. Psychopharmacology 1996, 127, 245.
Whatman GF/B glass micro®ber ®lters. The K value
d
determined for 8-OH-DPAT was 8.8 nM.
1
1
1
2. Francis, P. T. Neurodegeneration 1996, 5, 461.
3. Semkova, I.; Wolz, P.; Krieglstein, J. Eur. J. Pharmacol.
998, 359, 251.
D2 dopaminergic binding assay. Binding experiments
were performed according to Creese and co-workers38
with minor modi®cations. Each tube received in a ®nal
14. Carruthers, S. G. Drug Safety 1994, 11, 12.
5. Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.;
1
Tortorella, V.; Fiorentini, F.; Olgiati, V.; Ghiglieri, A.;
Govoni, S. J. Med. Chem. 1995, 38, 942.
16. Perrone, R.; Berardi, F.; Leopoldo, M.; Tortorella, V.;
Fornaretto, M. G.; Caccia, C.; McArthur, R. J. Med. Chem.
1996, 39, 3195.
.
volume of 3 mL of 50 mM Tris HCl containing 120 mM
NaCl, 5 mM KCl, 2 mM CaCl , 1 mM MgCl and
2
2
5
.7 mM ascorbic acid (pH 7.4), rat striatal membranes
3
suspension, and 0.2 nM [ H]spiroperidol. For competi-
tive inhibition experiments various concentrations of
drugs studied were incubated. Non-speci®c binding was
de®ned using 1 mM haloperidol. Samples were incu-
17. Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.;
Tortorella, V.; Fornaretto, M. G.; Caccia, C.; McArthur, R.
A. J. Med. Chem. 1996, 39, 4928.
1
8. Hibert, M. H.; Gittos, M. W.; Middlemiss, D. N.; Mir, A.
ꢀ
bated at 37 C for 20 min and then ®ltered on Whatman
K.; Fozard, J. R. J. Med. Chem. 1988, 31, 1087.
19. Hrib, N. J.; Jurcak, J. G.; Burgher, K. L.; Conway, P. G.;
Hartman, H. B.; Kerman, L. L.; Roehr, J. E.; Woods, A. T. J.
Med. Chem. 1994, 37, 2308.
GF/B glass micro®ber ®lters. The K value determined
d
for spiroperidol was 0.05 nM.
ꢀ1
performed according to Glossman and Hornung with
minor modi®cations. Each tube received in a ®nal
Adrenergic binding assay. Binding experiments were
3
20. Norman, M. H.; Rigdon, G. C.; Navas, F., III; Cooper, B.
R. J. Med. Chem. 1994, 37, 2552.
9
2
1. Norman, M. H.; Rigdon, G. C.; Hall, W. R.; Navas, F.,
III J. Med. Chem. 1996, 39, 1172.
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volume of 1 mL of 50 mM Tris HCl (pH 7.4) rat cere-
2
3
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ꢀ
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.
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2
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This study was supported by research grant no.
9
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MURST (Italy) for the scienti®c program in CO7X
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