New benzocycloalkylpiperazines, potent and selective 5-HT(1A) receptor ligands

Article abstract of DOI:10.1021/jm950759z

A series of 1-(benzocycloalkyl)-4-(benzamidoalkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT(1A) receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'- (benzamidoethyl)piperazines (32-37) were bound to 5-HT(1A) receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotatory ones for 5-HT(1A) sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.

Full text of DOI:10.1021/jm950759z

952
J . Med. Chem. 1997, 40, 952-960
New Ben zocycloa lk ylp ip er a zin es, P oten t a n d Selective 5-HT1A Recep tor Liga n d s
Youssef El Ahmad,† Elisabeth Laurent,† Philippe Maillet,† Akram Talab,† J ean Franc¸ois Teste,†
Raymond Dokhan,‡ Gilles Tran,† and Roland Ollivier*,†
Centre de Recherche, Cooperation Pharmaceutique Franc¸aise, 13-15, rue Benjamin Franklin, 77000 La Rochette, France, and
Laboratoire LDK France, Les Algorythmes, Batiment Aristote, Saint Aubin, 91194, Gif sur Yvette, France
Received October 12, 1995X
A series of 1-(benzocycloalkyl)-4-(benzamidoalkyl)piperazine derivatives was prepared in order
to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications
of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored.
Most of N-(1,2,3,4-tetrahydronaphthyl)-N′-(benzamidoethyl)piperazines (32-37) were bound
to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After
resolution, levorotatory enantiomers showed affinity and selectivity higher than those of
dextrorotatory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also
confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin
and, in vivo, on the induction of the lower lip retraction in rats.
In tr od u ction
alcoholism.27-30 Today buspirone (Buspar) is the only
compound commercialized for the treatment of anxiety
Serotonin is a neuromediator well-known for its
implication in mood regulation, anxiety, depression, and
insomnia.1-3 It was proved that the increase in its
bioavailability, as seen with specific reuptake inhibi-
tors,4 such as fluoxetine (Chart 1), made it possible to
treat depressive symptoms. The discovery of several
classes of receptors for serotonin and the search for their
implications in the mechanisms of mood and anxiety
have been widely studied. Today four types of receptors
have been identified, 5-HT1, 5-HT2, 5-HT3, and 5-HT4,
In the past, we studied a new piperazinotetralyl
derivative, MB 35,31 which possessed, in vivo, the same
pharmacological profile as that of buspirone. Binding
studies showed that this compound had a good affinity
for adrenergic R1 (Ki ) 18 nM) and serotoninergic
5-HT1A (Ki ) 17 nM) receptors, an intermediate affinity
for histaminergic H1 (Ki ) 42 nM), serotoninergic 5-HT2
(Ki ) 66 nM), and dopaminergic D2 (Ki ) 109 nM)
receptors, and a low affinity for serotoninergic 5-HT3,
dopaminergic D1, â-adrenergic, muscarinic M1, M2,
benzodiazepinic, and GABA receptors. MB 35 was a
nonselective 5-HT1A ligand. We postulated that D2 and
5-HT2 affinities were carried by the (4-fluorophenyl)-
butyrophenone moiety which is also present in halo-
peridol, a D2 receptor antagonist. We replaced the
butyrophenone group by a benzamidoalkyl group to try
to obtain selective 5-HT1A agonists. In this work we
studied the affinity and the selectivity of new (benzo-
cycloalkyl)piperazines (I) for 5-HT1A receptor in relation
to the structural modifications such as the benzocy-
cloalkyl size (m), the length of the aliphatic chain (n),
the nature of the substituents on the benzamide moiety
(R1, R2, R3), and the stereochemistry of the benzocy-
cloalkyl moiety.
and in the 5-HT1 group, four subtypes, 5-HT1A, 5-HT1B
,
5-HT1C, and 5-HT1D have been found.5,6 One of these
receptor subtypes, the 5-HT1A one, is found in high
concentrations in the limbic system in which it is
thought to play a role in emotional processes.7 The
activation of the 5-HT1A receptor leads to a number of
physiological changes that can be easily quantified. For
example, the administration of 5-HT1A agonists can
result in a temperature decrease,8 an increase in serum
corticosterone,9 an inhibition of firing of 5-HT-containing
neurons,10 and a characteristic set of motor changes
collectively known as the serotonin motor syndrome.11
The synthesis of a specific 5-HT1A receptor ligand, the
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT),12
and the study of its pharmacological properties showed
that agonists inhibited 5-HT function and release, which
is a potentially important event for the treatment of
anxiety states. Several structurally different com-
pounds possessed high affinity and selectivity for 5-HT1A
receptors.13 Among these some piperazine compounds
such as buspirone,14 gepirone,15 tandospirone16 or ipsa-
pirone17 showed selective agonist or partial agonist
activity for 5-HT1A receptors and have proved to be
effective for the treatment of anxiety states or depres-
sion. The search for new selective 5-HT1A receptor
agonists has yielded active compounds (Chart 1). Dur-
ing the recent years, serotoninergic 5-HT1A ligands have
been suggested to be useful as therapies for anxiety,18,19
depression,20 nausea and vomiting,21,22 Alzheimer’s
disease,23 prostate cancer,24 hypertension, pain,25,26 or
Ch em istr y
(Benzocycloalkyl)piperazines I (19-51) were prepared
by the condensation of substituted benzoyl chlorides (10)
with 1-(aminoalkyl)-4-(benzocycloalkyl)piperazine (9a -
f) as specified in Scheme 1 (process A).
The reduction of ketones 1a -c with sodium borohy-
dride and subsequent treatment of the corresponding
alcohols 2a -c with thionyl chloride gave 1-chloroben-
zocycloalkanes (3a -c). The condensation of ethyl pip-
erazine-1-carboxylate (4) with 1-chlorobenzocycloal-
kanes (3a -c), followed by saponification and decar-
boxylation, provided N-(benzocycloalkyl)piperazines (6a-
c) via carbamates 5a -c. The treatment of compounds
6a -c with (bromoalkyl)phthalimides (7) gave 1-[ω-(2-
phthalimido)alkyl]-4-(benzocycloalkyl)piperazines (8a -
f). The removal of phthalimide group32 by treatment
with hydrazine led to the primary amines 9a -f.
† Cooperation Pharmaceutique Franc¸aise.
‡ Les Algorythmes.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
S0022-2623(95)00759-X CCC: $14.00 © 1997 American Chemical Society

New Benzocycloalkylpiperazines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 953
Ch a r t 1
O
OH
R=
R=
R=
N
buspirone
gepirone
N
O
O
8-OH-DPAT
CH3
CH3
N
N
N
O
N
N
H
F
F
O
N
O
H
H
F
CH3
(CH2)4-R
N
tandospirone
O
fluoxetine
O
R=
N
ipsapirone
S
O
O
H
R3
R2
R1
(CH2)m
N
N
(CH2)n
N
N
N
F
O
O
I(19–51)
MB 35
m = 0, 1, 2; n = 2, 3
R1, R3 = H, OCH3
R2 = H, Cl, F, CH3, OCH3, Ph
Sch em e 1
X
O
(1) NaBH4
(2) SOCl2
(CH2)m
(CH2)m
2a–c (X = OH)
3a–c (X = Cl)
1a–c
a: m = 0
b: m = 1
c: m = 2
O
HN
N
O
C2H5
4
O
O
KOH
(CH2)m
N
N
(CH2)m
N
N
H
C2H5
5a–c
6a–c
O
(CH2)n–Br
N
O
7
O
NH2NH2
(CH2)m
N
N
(CH2)n
N
(CH2)m
N
N (CH2)n NH2
O
8a–f
9a–f
m
n
0
2
a
R1
0
1
3
b
R2
R3
c
2
3
2
process A
d
e
f
1
2
O
2
3
Cl
10
I(19–51)
Other routes were used to prepare the (benzocy-
cloalkyl)piperazines (19-51). As described in the Scheme
2 for the synthesis of compound 33 (m ) 1, n ) 2, R1 )
R3 ) H, R2 ) F), the condensation of 1-chlorotetralin
(3b) with 1-[2-(4-fluorobenzamido)-1-ethyl]piperazine
(16) led to compound 33 (process B).

954 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
El Ahmad et al.
Sch em e 2
Cl
CH2 H2C
N
11
N
CH2 CN
CH2
NH2
14
O
C
F
AlLiH4
Cl
F
17
N
N
(CH2)2 NH2
H2C NH
CH2
ClCH2
O
15
12
process C
process E
process D
17
6b
N
N H
CH2
18
33
C
O
F
N
N
(CH2)2 HN
CH2
13
F
H2, Pd/C
H
N
N
(CH2)2 HN
O
16
3b
process B
F
N
N
(CH2)2 HN
O
33
1-[2-(4-Fluorobenzamido)-1-ethyl]piperazine (16) was
Resu lts a n d Discu ssion
prepared by debenzylation of 4-benzyl-1-[2-(4-fluoroben-
zamido)ethyl]piperazine (13), under palladium on active
carbon.33 Piperazine 13 was obtained either by reduc-
Thirty-three 1-(benzocycloalkyl)-4-(benzamidoalkyl)-
piperazine derivatives I (19-51) were prepared and
evaluated in vitro, in a preliminary binding screening,
for their affinity for 5-HT1A receptors, and their selec-
tivities were compared to those of three other receptors,
5-HT2, D2, and R1. Products exhibiting an inhibition
lower than 30% at 10-7 M for all receptors were
considered as inactive. Products showing an inhibition
more than 30% at 10-7 M for one of the four examined
receptors in the preliminary binding screening are
reported in Table 1.
34
tion of the nitrile 11 with AlLiH4 followed by amidi-
fication of the amine 12 with 4-fluorobenzoyl chloride
(17) (process D) or by amidification of 2-chloroethy-
lamine (14) with 17 followed by the reaction of the
amide 15 with 1-benzylpiperazine (18) (process E).
The condensation of N-(2-chloroethyl)-4-fluorobenza-
mide (15) with tetralinylpiperazine (6b) afforded com-
pound 33 (process C).
All synthesized compounds are described in Table 5.
The yields reported were referring to the process A.
The influence of the stereochemistry on the activity
was studied for three tetralin derivatives (m ) 1), which
were the most potent 5-HT1A ligands. The two enanti-
omers were obtained from the (()-1-(1,2,3,4-tetrahy-
dronaphthyl)piperazine (6b). The levo isomer was
obtained by the treatment of the racemic 6b with 1
equiv of (+)-aspartic acid, the liberation of the crude
base, and then, the crystallization of the oxalate.
Mother liquors were neutralized with sodium hydroxide,
and treated with (+)-tartric acid, and the dextro enan-
tiomer was purified by the crystallization of oxalate salt.
The products selected on the preliminary binding
screening and their enantiomers were tested on an
extended binding screening. Affinity constants (Ki) for
11 central receptors have been determined and com-
pared to those for agonists 8-OH-DPAT, buspirone, and
MB 35. The results obtained for 5-HT1A,1C,1D,2,3,R1, H1,
D
1,2,3, and σ receptors are reported in Table 2.
In this work we studied (a) the influence of modifica-
tions of the ring size (m), (b) the length of the alkyl side
chain (n), (c) the substitutions on the aromatic ring (R1,
R2, R3), and (d) the stereochemistry of the benzocy-
cloakyl ring.

New Benzocycloalkylpiperazines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 955
Ta ble 1. Preliminary Binding Studies (Percentage of Inhibition at 10-7 M)
compd
m
n
R1
R2
R3
5-HT1A
R1
5-HT2
D2
20
23
32
33
34
35
37
39
40
45
46
47
49
0
0
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
3
3
2
2
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
69 ( 0.8
45 ( 1.4
93 ( 1.3
88 ( 0.5
86 ( 0.4
42 ( 0.9
63 ( 2
39 ( 1.2
68 ( 1.8
51 ( 3.6
22 ( 2.9
0
36 ( 0.3
0
0
OCH3
H
F
6 ( 2.4
17 ( 3.8
0
11 ( 1
4 ( 1.3
3 ( 0.3
29 ( 2
5 ( 0.5
7 ( 1.5
2 ( 0.3
0
7 ( 0.7
31 ( 0.1
47 ( 1
60 ( 0.4
74 ( 0.3
4 ( 1.2
22 ( 2.3
17 ( 5.1
6 ( 0.2
6 ( 3.9
28 ( 2.2
17 ( 1.6
19 ( 1.8
37 ( 1.8
23 ( 0.9
14 ( 2.1
10 ( 1
20 ( 0.7
Cl
23 ( 2.1
CH3
OCH3
H
F
H
0
0
11 ( 0.8
6 ( 0.5
0
0
0
0
F
CH3
OCH3
11 ( 1.5
37 ( 1
MB 35
1 ( 0.5
In flu en ce of th e Cycloa lk yl Size (M). The affinity
for 5-HT1A receptors appeared when m ) 0 (compounds
20 and 23) was maximal for m ) 1 (compounds 32-35,
37, 39, and 40), and decreased for m ) 2 (compounds
45-47 and 49). Compound 45 was the only derivative
which showed affinity for the 5-HT2 receptors. Many
substituted benzocycloheptyl derivatives (m ) 2; com-
pounds 46, 47, and 49) are also bound to dopaminergic
D2 receptors, as MB 35. In this preliminary binding
screening, tetralin compounds (m ) 1) showed the
highest affinity for the 5-HT1A receptors.
In flu en ce of th e Alk yl Sid e Ch a in (n ). The results
reported in Table 1 showed that, except 39 (n ) 3) and
40 (n ) 3), the only compounds to be active were the
benzamidoethyl ones (n ) 2; compounds 20, 23, 32-
35, 37, 45-47, and 49). The benzamidopropyl analogs
(n ) 3; compounds 25-31, 41-44, and 51) did not
present any affinity for the selected receptors. These
results agreed with those obtained with MB 35 in which
distance between the aromatic ring and the nitrogen
atom of the piperazine is the same as in the benzami-
doethyl analogs.
showed affinity for 5-HT1A receptors better than that
of their dextro isomers and racemates. The chirality of
the benzocycloalkyl ring also had a great influence on
the selectivity for 5-HT1A receptors. (+)-33 and (+)-34
showed poor selectivity vs dopaminergic D2 and sero-
toninergic 5-HT receptors. In contrast, levorotatory
enantiomers, (-)-32, (-)-33, and (-)-34, presented a
high degree of selectivity (S > 100) for 5-HT1A receptors
compared to all the tested receptors and were more
selective than reference compound buspirone. Among
levorotatory enantiomers, (-)-32 possessed the highest
affinity and selectivity.
These preliminary structure-activity relationship
studies showed that the replacement of the butyrophe-
none moiety, found in the MB 35 structure, by a
benzamidoethyl group had a positive effect on the
5-HT1A selectivity. This structural modulation led to
the obtention of new identities among which the com-
pounds (-)-32, (-)-33, and (-)-34, with both greater
affinity and higher selectivity for 5-HT1A receptors than
MB 35 and buspirone.
P h a r m a cology
In flu en ce of th e Su bstitu en ts on th e Ar om a tic
Rin g (R1, R2, a n d R3). The highest affinity and
selectivity were obtained with the nonsubstituted de-
rivatives (R1 ) R2 ) R3 ) H, m ) 1, n ) 2, compound
32; m ) 1, n ) 3, compound 39; m ) n ) 2, compound
45). The substitution in para position of the aromatic
moiety by a halogen, fluorine (R1 ) R3 ) H, R2 ) F, m
) 0, n ) 2, compound 20; m ) 1, n ) 2, compound 33;
m ) 1, n ) 3, compound 40) or chlorine (R1 ) R3 ) H,
R2 ) Cl, m ) 1, n ) 2, compound 34), atoms led to
derivatives which presented a good affinity and selectiv-
ity for the 5-HT1A receptors. In the tetralyl series (m
) 1), the substitution in 4-position by a methoxy moiety
(R1 ) R3 ) H, R2 ) OCH3, m ) 1, n ) 2, compound 37)
led to an active compound but had an unfavorable effect
on the affinity and selectivity for 5-HT1A receptor. On
the other hand, 4-methyl (R1 ) R3 ) H, R2 ) CH3,
compounds 21, 28, 35, 41, and 47), 4-phenyl (R1 ) R3 )
H, R2 ) Ph; compounds 22, 29, 36, 42, and 48), or
trimethoxy derivatives (R1 ) R2 ) R3 ) OCH3, com-
pounds 24, 31, 38, 44, and 50) were less active or
inactive. The tested phthalimide derivatives 17a -f
were also inactive.
Owing to high 5-HT1A affinity and selectivity, com-
pounds 32, 33, 34, and their enantiomers were selected
for further evaluation (i) to determine in vitro their
postsynaptic agonist/antagonist profile on the adenylate
cyclase activity (inhibition cAMP forskolin induced in
hippocampus), (ii) to confirm in vivo their agonist/
antagonist profile, using the lower lip retraction test,
and (iii) to compare the potency of racemic compounds
and their enantiomers on these tests.
The results of these tests with 32, 33, 34, and their
enantiomers (+)-32, (-)-32, (+)-33, (-)-33, (+)-34, and
(-)-34 are shown in Table 3.
The racemates 32, 33, 34, and the enantiomers (-)-
32, (+)-33, (-)-33, (+)-34, and (-)-34 inhibited forsko-
lin-activated adenylate cyclase in rat hippocampi in a
concentration-dependent manner, with a similar maxi-
mal effect (maximal inhibition ) -25%) for the eight
compounds. This potency is correlated with the affinity
for 5-HT1A receptors. The enantiomers (-)-32 and (-)-
33 were the most potent compounds with respective IC50
) 14 ( 2 and 15 ( 2 nM; their activity was similar to
the activity of 8-OH-DPAT. These data suggest that
these compounds acted by the stimulation of postsyn-
aptic 5-HT1A receptors as described by Podona et al.35
In the lower lip retraction (-)-32, (-)-33, and (-)-34
induced a clear lower lip retraction at 2.75, 2.25, and
2.50 mg/kg, respectively. In this test, the levo isomers
In flu en ce of th e Ster eoch em istr y of th e Ben zo-
cycloa lk yl R in g. The chiral resolution of the high-
affinity compounds (32, 33, and 34) was performed, and
enantiomers were tested on an extended binding screen-
ing (Table 2). The levo enantiomers (-)-33 and (-)-34

956 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
El Ahmad et al.
Ta ble 3. Effects of 32, 33, 34, and Their Enantiomers on
Electrophysiological and Behavioral Studies
in vitro tests
affinity for
5-HT1A
receptors
Ki (nM)
agonist
activity
in vivo behavioral test
LLRb msad
IC50 (nM)
compd
forskolina
(mg/kg ip) rats
32
(-)-32
33
1.1 ( 0.1
0.4 ( 0.02
1.5 ( 0.1
50 ( 3
0.5 ( 0.04
10 ( 0.4
210 ( 13
4 ( 0.3
36 ( 6
14 ( 2
52 ( 8.6
1450 ( 90
15 ( 2
75 ( 8
1500 ( 110
38 ( 3
210 ( 18
14 ( 2
52 ( 7
NT
2.75
NT
NT
2.25
NT
(+)-33
(-)-33
34
(+)-34
(-)-34
MB 35
8-OH-DPAT
buspirone
NT
2.50
>64
2.20
NT
17 ( 0.3
0.5 ( 0.04
7.1 ( 1
a
b
Inhibition of forskolin-activated adenylate cyclase. Lower lip
retraction (msad ) minimum significant active dose).
Ta ble 4. Comparison between Literature Data for Reference
Compounds and Ki (nM) and S Values for (-)-32 and (-)-33a
compd
(-)-32
0.4 ( 0.02 0.5 ( 0.04
(1) (1)
(-)-33
8-OH DPAT buspirone
5-HT1A
(rat)
5-HT1A
0.5 ( 0.136
(1)
9.3 ( 0.436
(1)
1.937
1537
(human)
5-HT2
NT
1380 ( 110 >100036
178 ( 2336
(19)
(2760)
10 ( 8
(140)
(>2000)
84 ( 636
(168)
D2
130 ( 4
(270)
NT
100036
(1.4)
D1
3090 ( 150 100036
100036
(>107)
>242736
(>261)
(6180)
124 ( 5
(250)
(> 2000)
R1
190 ( 4
(380)
>242736
(>4850)
a
NT ) not tested. Selectivity values for 5-HT1A receptors (S )
Ki receptor/Ki 5-HT1A) are given in parentheses.
(-)-32, (-)-33, and (-)-34 are almost as potent as
8-OH-DPAT and acted in vivo as agonists on the
postsynaptic 5-HT1A receptors.
In comparison with literature data for reference
compounds, reported in Table 4, the preferred deriva-
tives (-)-32 and (-)-33 showed affinity and selectivity
higher than those of buspirone and were comparable to
those of 8-OH-DPAT.
As there was no notable difference between affinity
for cloned human and rat 5-HT1A receptors as for 8-OH-
DPAT and buspirone, it may be suggested that (-)-32
and (-)-33 would have a similar affinity for human
5-HT1A receptors and in consequence would present
some clinical interest.
Con clu sion
The proposed chemical modulation confirmed that the
5-HT1A receptor affinity was supported by the (benzo-
cycloalkyl)piperazinyl moiety. These studies showed
that tetralyl (m ) 1) compounds were more active than
phenylindanyl (m ) 0) and benzocycloheptanyl (m ) 2)
derivatives. The levo enantiomers of selected tetralyl
compounds presented the highest affinity and selectivity
and were comparable, in vitro as well as in vivo, to
reference compound 8-OH-DPAT. Finally, the replace-
ment of the butyrophenone group found in the MB 35
structure by a benzamidoethyl group permitted us to
obtain the expected gain of selectivity in regard to D2,
5-HT2, and R1 receptors. The benzamidopropyl deriva-
tives appeared less potent than ethyl analogs.

New Benzocycloalkylpiperazines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 957
Ta ble 5. Physical and Spectrochemical Data of Compounds I (19-51)
compd
m
n
R1
R2
R3
compositiona
mp (°C)
yield (%)
19
20
21
22
23
24
25
26
27
28
29
30
31
32b
33b
34b
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
2
2
2
2
2
2
2
3
3
3
3
3
3
2
2
2
2
2
2
3
H
H
H
H
H
CH3O
H
H
H
H
H
H
CH3O
H
H
H
H
H
H
CH3O
H
H
H
H
H
CH3O
H
H
H
H
H
CH3O
H
H
F
CH3
Ph
CH3O
CH3O
H
H
H
H
H
H
CH3O
H
H
H
H
H
H
CH3O
H
H
H
H
H
H
CH3O
H
H
H
H
H
CH3O
H
H
H
H
H
CH3O
H
C22H27N3O‚2HCl
238
230
193
222
172
207
223
198
225
228
235
203
211
232
220
225
210
243
195
215
193
183
222
208
212
176
194
233
214
221
212
194
180
72
71
60
75
73
72
75
75
78
61
75
72
62
83
83
80
71
70
56
78
74
62
61
54
61
59
58
62
70
65
67
52
55
C
22H26FN3O‚2HCl
C23H29N3O‚2HCl
C
28H31N3O‚2HCl
C23H29N3O2‚2HCl
C25H33N3O4‚2HCl
C
C
C
23H29N3O‚2HCl
23H28FN3O‚2HCl
23H28ClN3O‚2HCl
F
Cl
CH3
Ph
CH3O
CH3O
H
C24H31N3O‚2HCl
C29H33N3O‚2HCl
C24H31N3O2‚2HCl
C26H35N3O4‚2HCl
C23H29N3O‚2HCl
C23H28FN3O‚2HCl
C23H28ClN3O‚2HCl
C24H31N3O‚2HCl
C29H33N3O‚2HCl
C24H31N3O2‚2HCl
C26H35N3O4‚2HCl
F
Cl
CH3
Ph
CH3O
CH3O
H
F
CH3
Ph
CH3O
CH3O
H
F
CH3
Ph
C
C
24H31N3O‚2HCl
24H30FN3O‚2HCl
C25H33N3O‚2HCl
C30H35N3O‚2HCl
C25H33N3O2‚2HCl
C27H37N3O4‚2HCl
C
C
24H31N3O‚2HCl
24H30FN3O‚2HCl
C25H33N3O‚2HCl
C30H35N3O‚2HCl
OCH3
CH3O
F
C25H33N3O2‚2HCl
C27H37N3O4‚2HCl
C
25H32FN3O‚2HCl
a
b
Satisfactory elemental analyses ((0.4%) for C, H, N were obtained for all compounds. (+)-32: mp 215 °C; yield 82%; [R]22 ) +60°
D
(c ) 0.62, MeOH). (-)-32: mp 215 °C; yield 83%; [R]22D ) -64° (c ) 0.65, MeOH). (+)-33: mp 223 °C; yield 85%; [R]22D ) +80° (c ) 0.73,
MeOH). (-)-33: mp 223 °C; yield 79%; [R]22 ) -77° (c ) 0.71, MeOH). (+)-34: mp 232 °C; yield 82%; [R]22 ) +75° (c ) 0.70, MeOH).
D
D
(-)-34: mp 232 °C; yield 78%; [R]22 ) -71° (c ) 0.66, MeOH).
D
15.9 mmol), potassium carbonate (5.55 g, 40 mmol), and
sodium iodide (0.5 g, 3.3 mmol) in 150 mL of methyl ethyl
ketone was refluxed for 24 h. The solution was then evapo-
rated to dryness, and the residue was taken up with water
and extracted with ethyl acetate. The organic layer was
separated, dried, and evaporated, and the residue was purified
by chromatography on a silica column (eluent, 0.5% Et3N/ethyl
acetate) to yield 3.3 g (54%) of pure product 33.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Bu¨chi
535 apparatus and are uncorrected. 1H-NMR spectra of crude
bases were recorded on a Hitachi 1500 FT spectrometer (60
MHz). Chemical shifts are given as δ values with reference
to Me4Si as internal standard. Infrared spectra of the bases
of final products were performed on a Perkin-Elmer 1500 FT
spectrometer. Specific absorptions are given in cm-1
. Thin
P r ocess C. A mixture of 1-(1,2,3,4-tetrahydronaphth-1-yl)-
piperazine (6b) (5.4 g, 25 mmol), N-(2-chloroethyl)-4-fluoroben-
zamide (15) (5.04 g, 25 mmol), and 8 mL of triethylamine in
100 mL of DMF was heated at 60 °C for 48 h. After cooling,
the reaction mixture was poured all at once into 200 mL of
water and then extracted with ethyl acetate. The organic
phase was dried and evaporated under vacuum. The residue
was purified by chromatography on a silica column (eluent,
0.5% Et3N/ethyl acetate) to yield 3g (31%) of a pure product
33.
P r ep a r a tion of th e Dih yd r och lor id e. The base dissolved
in alcohol was added with alcoholic solution of hydrogen
chloride and the salt crystallized out. Physicochemical data
are shown in Table 5. Spectral data are available as Sup-
porting Information.
E t h yl 4-(Ben zocycloa lk yl)p ip er a zin e-1-ca r b oxyla t e
(5a -c). A mixture of 1-chlorobenzocycloalkane (3a -c) (0.65
mol), ethyl piperazine-1-carboxylate (4) (124.8 g, 0.79 mol),
potassium carbonate (197.34 g, 1.43 mol), and sodium iodide
(10 g, 0.06 mol) in 1 L of acetonitrile was refluxed for 24 h.
After cooling, the mixture was filtered and the solvent was
evaporated off. The residual oil was taken up with ice-water,
and the product was extracted three times with ethyl acetate.
A solution of hydrogen chloride was then added. The hydro-
chloride formed was filtered off. The base was displaced from
its salt with sodium carbonate in a dichloromethane/water
mixture. The organic layer was separated, dried, and evapo-
rated under vacuum to give an oil. 5a : m ) 0; 70% yield; 1H
layer chromatography was performed on Merck silica gel 60
plates with fluorescent indicator, and the plates were visual-
ized with UV light (254 nm). Flash chromatography was
conducted on Merck Kieselgel 60 (0.040-0.063). Elemental
analyses were carried out by the Microanalysis Laboratory of
the Faculty of Pharmacy in Chatenay-Malabry, France, and
agreed to within (0.4% of calculated values. The optical
purity of enantiomers was determined by an HPLC method
using a chiral column SCI ULTRON (ES-OVM 4.6 × 150)
performed on a L 4500 Hitachi spectrometer. Optical rotation
(R) of the pure enantiomers was measured by an AA10 optical
activity polarimeter.
1-[2-(4-F lu or ob en za m id o)-1-et h yl]-4-(1,2,3,4-t et r a h y-
d r on a p h th -1-yl)p ip er a zin e Dih yd r och lor id e (33). P r o-
cess A. A mixture of 1-(2-amino-1-ethyl)-4-(1,2,3,4-tetrahy-
dronaphth-1-yl)piperazine (9c) (2.59 g, 10 mmol), triethylamine
(2 mL), and 50 mL of chloroform was cooled to 5 °C. 4-Fluo-
robenzoyl chloride (17) (1.58 g, 10 mmol) in 20 mL of
chloroform was added dropwise to the mixture at t < 10 °C.
Then the reaction mixture was stirred for 4 h. The solvent
was evaporated to dryness, the residue was taken up with
water, and extracted with dichloromethane, and the organic
phase was washed with 2 M NaOH. The product was purified
by chromatography on a silica column (eluent, 0.5% Et3N/ethyl
acetate) to yield 3.16 g (83%) of a pure product 33. Compounds
I (19-51) were prepared according this process.
P r ocess B. A mixture of 1-[2-(4-fluorobenzamido)ethyl]-
piperazine (16) (4 g, 15.9 mmol), 1-chlorotetralin (3b) (2.65 g,

958 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6
Ta ble 6. Physicochemical Properties of Compounds 8a -f
El Ahmad et al.
mp (°C)
yield
compd
m
n
(salt, 2HCl) (%)
NMR (CDCl3) (base) δ
8a
8b
8ca
8d
8e
8f
0
0
1
1
2
2
2
3
2
3
2
3
252
243
231
169
249
254
72
74
72
68
65
69
2.1 (q, 2H, J ) 7 Hz), 2.4-3 (m, 12H), 3.8 (t, 2H, J ) 7.3 Hz), 4.3 (t, 1H, J ) 7 Hz), 7.2-7.8 (m, 8H)
1.65-2.1 (m, 4H), 2.4-2.9 (m, 12H), 3.8 (t, 2H, J ) 7.3 Hz), 4.3 (t, 1H, J ) 7 Hz), 7.2-7.8 (m, 8H)
1.6-1.9 (m, 4H), 2.3-2.8 (m, 12H), 3.75 (t, 1H, J ) 7 Hz), 3.85 (t, 2H, J ) 7.5 Hz), 7-7.9 (m, 8H)
1.6-2.1 (m, 6H), 2.4-2.9 (m, 12H), 3.75 (t, 1H, J ) 7 Hz), 3.85 (t, 2H, J ) 7.5 Hz), 7-7.9 (m, 8H)
1.5-2.15 (m, 6H), 2.25-2.8 (m, 12H), 3.1 (t, 1H, J ) 7 Hz), 3.8 (t, 2H, J ) 7.3 Hz), 7-7.8 (m, 8H)
1.45-2.1 (m, 8H), 2.3-2.85 (m, 12H), 3.1 (t, 1H, J ) 7 Hz), 3.75 (t, 2H, J ) 7.3 Hz), 7-7.9 (m, 8H)
a
(+)-8c: mp 223 °C; [R]25 ) +96.3° (c ) 2.49, MeOH). (-)-8c: mp 222 °C; [R]25 ) -104.5° (c ) 2.58, MeOH).
D
D
NMR (CDCl3) δ 1.25 (t, 3H, J ) 7 Hz), 2.1 (q, 2H, J ) 7 Hz),
2.3-2.9 (m, 6H), 3.5 (t, 4H, J ) 6 Hz), 4.15 (q, 2H, J ) 7 Hz),
4.35 (t, 1H, J ) 7 Hz), 7-7.7 (m, 4H). 5b: m ) 1; 63% yield;
1H NMR (CDCl3) δ 1.25 (t, 3H, J ) 7 Hz), 1.6-2.1 (m, 4H),
2.3-2.9 (m, 6H), 3.5 (t, 4H, J ) 6 Hz), 3.8 (t, 1H, J ) 7 Hz),
4.15 (q, 2H, J ) 7 Hz), 7-7.75 (m, 4H). 5c: m ) 2; 61% yield;
1H NMR (CDCl3) δ 1.25 (t, 3H, J ) 7 Hz), 1.4-2 (m, 6H), 2.4-
2.9 (m, 6H), 3.15 (t, 1H, J ) 7 Hz), 3.45 (t, 4H, J ) 6 Hz), 4.15
(q, 2H, J ) 7 Hz), 7-7.2 (m, 4H).
led to an oil (3.05 g, 14 mmol) of (+)-6b: [R]25 ) +99° (c )
D
1.62; 95% EtOH); ee ) 81%.
A solution of this impure (+)-6b (3 g, 14 mmol) in 120 mL
of ethanol (95%) was treated with oxalic acid dihydrate (1.76
g, 14 mmol). The oxalate obtained was filtered off and dried
to give 3.25 g (76%): [R]25 ) +29° (c ) 1.52; H2O); ee ) 97%.
D
The free (+)-6b was obtained by decomposing the oxalate with
3 N NaOH.
1-(2-P h t h a lim id o-1-a lk yl)-4-(ben zocycloa lk yl)p ip er a -
zin e (8a -f). A mixture of 1-(benzocycloalkyl)piperazine (6a -
c) (50 mmol), (bromoalkyl)phthalimide (7) (65 mmol), potas-
sium carbonate (17.25 g, 125 mmol), and sodium iodide (1 g,
6 mmol) in 200 mL of acetonitrile was refluxed for 24 h. The
solvent was evaporated off to dryness. The residue was taken
up with water and extracted with dichloromethane. The
organic layer was separated, dried, and evaporated, and the
residue was purified by chromatography on a silica column
(eluent, 35% ethyl acetate/cyclohexane). Physicochemical
properties are reported in Table 6.
(() 1-(Ben zocycloa lk yl)p ip er a zin es (6a -c). Potassium
hydroxide (300 g, 5.36 mol) was slowly added to a solution of
ethyl 4-(benzocycloalkyl)piperazine-1-carboxylate (5a -c) (0.46
mol), water (100 mL), and methanol (400 mL). The reaction
mixture was refluxed. The reaction was monitored by thin
layer chromatography. After the starting material had disap-
peared, the mixture was cooled, filtered, and extracted with
dichloromethane. The organic layer was separated, dried, and
evaporated. The residual oil was taken up with ethanol, and
oxalic acid (39.33 g, 0.44 mol) dissolved in ethanol was added.
The oxalate formed was filtered off, and the base was displaced
from its salt with sodium carbonate in a dichloromethane/
water mixture. The organic layer was dried, and the solvent
was evaporated under vacuum to give an oil. 6a : m ) 0; 83%
1-(Am in oa lk yl)-4-(ben zocycloa lk yl)p ip er a zin e (9a-f).
A mixture of 1-(2-phthalimido-1-alkyl)-4-(benzocycloalkyl)-
piperazine (8a -f) (29 mmol) and hydrazine hydrate (3.4 g, 68
mmol) in 200 mL of methanol was stirred at room temperature.
The reaction was monitored by thin layer chromatography.
After the starting material had disappeared, the solvent was
evaporated under vacuum, 150 mL of 2 M HCl was added, and
the mixture was stirred for 2 h. The solid formed was filtered
off, the filtrate was neutralized with sodium carbonate, and
the product was extracted with ethyl acetate to give a thick
1
yield; H NMR (CDCl3) δ 2.1 (t, 2H, J ) 7 Hz), 2.4-2.85 (m,
7H), 2.9 (t, 4H, J ) 6 Hz), 4.3 (t, 1H, J ) 7 Hz), 7-7.7 (m,
1
4H). 6b: m ) 1; 84% yield; H NMR (CDCl3) δ 1.5-2.1 (m,
4H), 2 (s, NH), 2.4-2.8 (m, 6H), 2.9 (t, 4H, J ) 6 Hz), 3,75 (t,
1H, J ) 7 Hz), 7-7.8 (m, 4H). 6c: m ) 2; 70% yield; 1H NMR
(CDCl3) δ 1.3-2.1 (m, 6H), 2.3-2.75 (m, 6H), 2.9 (t, 4H, J ) 6
Hz), 3.2 (t, 1H, J ) 7 Hz), 3.9 (s, NH), 7.1 (m, 4H).
1
oil. 9a : m ) 0; n ) 2; 70% yield; H NMR (CDCl3) δ 2.1 (q,
(-)-1-(1,2,3,4-Tetr a h yd r on a p h th -1-yl)p ip er a zin e ((-)-
6b). (+)-L-Aspartic acid (3.6 g, 27 mmol) was added to a
solution of racemic 6b (7.4 g, 34 mmol) in 70 mL of ethanol
(95%). The mixture was refluxed for a few minutes and then
left to stand at room temperature for 3 or 4 h. The precipitate
formed was filtered off and dried to give 4.67 g (13.3 mmol) of
aspartate (39% based on the 6b). The solid obtained was
decomposed with 150 mL of 3 M NaOH. The aqueous phase
was extracted with diethyl ether. The organic layer was dried
and evaporated under vacuum to give an oil (1.92 g, 8.8 mmol)
2H, J ) 7 Hz), 2.3-2.9 (m, 16H), 4.4 (t, 1H, J ) 7 Hz), 7.1-
7.9 (m, 4H). 9b: m ) 0; n ) 3; 80% yield; 1H NMR (CDCl3) δ
1.6-2.2 (m, 4H), 2.3-2.9 (m, 16H), 4.4 (t, 1H, J ) 7 Hz), 7.1-
1
7.85 (m, 4H). 9c: m ) 1; n ) 2; 81% yield; H NMR (CDCl3)
δ 1.6-2 (m, 4H), 2.1 (s, NH2), 2.4-3 (m, 14H), 3.8 (t, 1H, J )
7 Hz), 7-7.85 (m, 4H). 9d : m ) 1; n ) 3; 78% yield; 1H NMR
(CDCl3) δ 1.6-2 (m, 6H), 2.2-3 (m, 16H), 3.8 (t, 1H, J ) 7
1
Hz), 7-7.8 (m, 4H). 9e: m ) 2; n ) 2; 75% yield; H NMR
(CDCl3) δ 1.4-2.1 (m, 6H), 2.2-3 (m, 16H), 3.15 (t, 1H, J ) 7
Hz), 6.9-7.25 (m, 4H). 9f: m ) 2; n ) 3; 69% yield; 1H NMR
(CDCl3) δ 1.4-2.1 (m, 8H), 2.2-3 (m, 16H), 3.15 (t, 1H, J ) 7
Hz), 6.95-7.2 (m, 4H).
of impure (-)-6b (26% of the initial 6b): [R]25 ) -114° (c )
D
1.64; 95% EtOH); enantiomeric excess (ee) 41%.
A solution of the impure (-)-6b (1.92 g, 8.8 mmol) in 80 mL
of ethanol (95%) was treated with oxalic acid dihydrate (1.2
g, 9.5 mmol). The oxalate obtained was filtered and dried to
1-Hyd r oxyben zocycloa lk a n es (2a -c). Sodium borohy-
dride (2.32 g, 61 mmol) was added in portions with stirring at
15 °C to a solution of 1a -c (183 mmol) in methanol (500 mL).
The mixture was stirred at room temperature for 2 h and then
evaporated. The resulting oil was treated with water and
diethyl ether, and the organic phase was separated, washed
with water and 0.1 M HCl, dried, and evaporated to dryness.
give 2.1 g (6.8 mmol) of (-)-oxalate salt: 76% yield; [R]25
)
D
-32° (c ) 1.64; 95% H2O); mp 202-203 °C; ee ) 100%. The
free amine was obtained by decomposing the oxalate with 3
M NaOH.
1
(+)-1-(1,2,3,4-Tetr a h yd r on a p h th -1-yl)p ip er a zin e ((+)-
6b). Mother liquors of aspartate were evaporated to dryness
(7.14 g), and the residue was treated with 3 M NaOH. The
product was extracted with diethyl ether. The organic layer
was dried and evaporated to give an oil (5.02 g, 23 mmol) (69%)
2a : m ) 0; 88% yield; H NMR (CDCl3) δ 2.1 (q, 2H, J ) 7
Hz), 2.25 (s, 1H, OH), 2.9 (t, 2H, J ) 7 Hz), 5.2 (t, 1H, J ) 7
1
Hz), 7.25 (m, 4H). 2b: m ) 1; 97% yield; H NMR (CDCl3) δ
1.6 -2.3 (m, 5H), 2.8 (t, 2H, J ) 7 Hz), 4.95 (t, 1H, J ) 7 Hz),
1
7-7.6 (m, 4H).; 2c: m ) 2; mp 102 °C; 85% yield; H NMR
of impure (+)-6b: [R]25 ) +50° (c ) 1.38; 95% EtOH); ee )
(CDCl3) δ 1.4 -2.2 (m, 7H), 2.8 (t, 2H, J ) 7 Hz), 4.75 (t, 1H,
J ) 7 Hz), 7-7.4 (m, 4H)
D
41%.
A solution of this impure (+)-6b (5 g, 23 mmol) in 200 mL
of ethanol (95%) was treated with (+)-tartaric acid (3.47 g, 23
mmol). The mixture was refluxed for a few minutes and then
left to stand at room temperature for about 3 h. The
precipitated tartrate was filtered off and dried (5.5 g, 15 mmol;
65% yield). The tartrate was displaced with 3 M NaOH. The
base was extracted with diethyl ether. A chemical treatment
1-Ch lor oben zocycloa lk a n es (3a -c). Thionyl chloride (26
mL, 0.35 mol) was added at 15 °C to a solution of 2a -c (0.238
mol) in toluene (340 mL). The mixture was stirred at room
temperature for 30 min and then heated to 55 °C for 1 h. The
mixture was cooled, washed twice with ice-water, dried, and
evaporated to give quantitatively 3a -c as an oil, which was
used without further purification in the next step. 3a : m )

New Benzocycloalkylpiperazines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 6 959
Ta ble 7. Binding Conditions
ligands
concentration
reference
compounds (nM) prot/mL
Ki
incubation
conditions
receptor
structures
nonspecific
R1
[3H]prazozin 0.5 nM
[3H]SCH23390 0.5 nM
[3H]raclopride 1.2 nM
[3H]spiperone 1.2 nM
frontal cortex calf
striatum bovine
striatum bovine
cortex
hippocampus + frontal buspirone
cortex bovine
WB4101
fluanxol
pimozide
0.6 0.8 mg
40 min, 25 °C prazozine
D1
D2
D3
18
0.8 mg
60 min, 25 °C (+)butaclamol, 10-5
M
0.6 0.8 mg
0.5 mg
8.6 0.5 mg
60 min, 25 °C spiperone, 10-5
M
haloperidol 115
60 min, 25 °C haloperidol, 10-5
40 min, 23 °C buspirone
M
5-HT1A [3H]-8-OH-DPAT 0.5 nM
5-HT1C [3H]mesulergine 1.2 nM
choro¨ıd Plexus pig
mianserin
butotenin
3.8 0.2 mg
5.8 0.8 mg
60 min, 25 °C mianserin
5-HT1D [3H]-5-OH-tryptamine 2 nM striatum + frontal
30 min, 25 °C 5-HT, 10-5
M
Cortex pig
5-HT2
5-HT3
H1
[3H]ketanserin 0.8 nM
[3H]BRL43694 1 nM
[3H]pyrilamine 1 nM
[3H]DTG 4 nM
frontal cortex bovine
NG cells 108-15
cortex rat
spiperone
ICS 205930 33
tripolidine
haloperidol
5.3 0.6 mg
30 min, 37 °C ketanserin
10-6 cells 60 min, 25 °C ICS 205930
12
38
0.5 mg
0.6 mg
40 min, 25 °C tripolidine, 10-6
120 min, 23 °C haloperidol
M
σ
hippocampus rat
0; 1H NMR (CDCl3) δ 2.35 (q, 2H, J ) 7 Hz), 2.95 (t, 2H, J )
ature until the absorption of the theoretical hydrogen volume.
The reaction mixture was filtered, and the filtrate was
neutralized with 2 M NaOH and evaporated to dryness. The
residue was taken up with dichloromethane and filtered. The
filtrate was dried, filtered, and concentrated under vacuum
to give a pasty product: yield 91.3%; 1H NMR (CDCl3) δ 2.25
(NH amine), 2.3-2.65 (m, 6H), 2.75-3 (m, 4H), 3.5 (q, 2H, J
) 6 Hz), 7.05 (NH amide), 7.2-7.9 (m, 4H).
Biology: Bin d in g Exp er im en ts. Receptor preliminary
assays were carried out using methods described in the
literature. Three concentrations were tested: 10-5, 10-7, and
10-9 M. The serotoninergic 5-HT1A and 5-HT2, the dopamin-
ergic D2, and the adrenergic R1 receptors were examined in
the preliminary assays. 5-HT1A assays used rat hippocampal
membranes and [3H]-8-OH-DPAT,38 5-HT2 assays used bovine
frontal cortex preparations and [3H]ketanserin,39 D2 assays
used bovine striatal preparations and [3H]YM09151-2,40 and
R1 assays used calf frontal cortex preparations and [3H]-
prazosin.41 Results were expressed as inhibition percentage
compared to results without drug.
1
7 Hz), 5.4 (t, 1H, J ) 7 Hz), 7.1-7.5 (m, 4H). 3b: m ) 1; H
NMR (CDCl3) δ 1.7-2.5 (m, 4H), 2.8 (t, 2H, J ) 7 Hz), 5.3 (t,
1
1H, J ) 7 Hz), 7-7.3 (m, 4H). 3c: m ) 2; H NMR (CDCl3)
δ 1.4 -2.6 (m, 6H), 2.8 (t, 2H, J ) 7 Hz), 5.2 (t, 1H, J ) 7 Hz),
7.2 (m, 4H).
1-Ben zyl-4-(cya n om eth yl)p ip er a zin e (11). Bromoaceto-
nitrile (14.56 g, 0.12 mol) in 10 mL of DMF was added dropwise
to a mixture of 4-benzylpiperazine (17.6 g, 0.1 mol) and
potassium carbonate (17.6 g, 0.127 mol) in 100 mL of DMF.
The temperature rose to 35 °C. After the mixture was stirred
for 24 h at room temperature, 100 mL of water were added,
and the mixture was extracted twice with ethyl acetate, the
organic phase was washed twice with water, dried, and
evaporated to give an oil (85% yield): 1H NMR (CDCl3) δ 2.55
(m, 8H), 3.5 (s, 4H), 7.3 (m, 5H).
N-(2-Am in o-1-eth yl)-4-ben zylp ip er a zin e (12). 1-Benzyl-
4-(cyanomethyl)piperazine (11) (10.5 g, 0.049 mol) in 10 mL
of THF was added dropwise, at 10 °C, to a slurry of LiAlH4
(2.6 g, 0.068 mol) in 100 mL of THF, under a nitrogen
atmosphere. The mixture was then refluxed for 6 h, cooled to
0 °C, and hydrolyzed by the dropwise addition of 3 mL of ice-
water and then 3 mL of 15% NaOH. The solids were filtered
and rinsed with diethyl ether. The solution was dried, filtered,
and evaporated to yield 8.6 g (80%): 1H NMR (CDCl3) δ 1.9
(s, NH2), 2.5 (m, 10H), 2.7 (t, 2H, J ) 7 Hz), 3.5 (s, 2H), 7.3
(m, 5H).
N-(2-Ch lor oeth yl)-4-flu or oben zam ide (15). 4-Fluoroben-
zoyl chloride (17) (33.05 g, 0.21 mol) dissolved in 50 mL of
dichloromethane was added dropwise to an aqueous solution
(100 mL) of chloroethylamine hydrochloride (14) (26.6 g, 0.23
mol) and potassium carbonate (37.4 g, 0.27 mol). After being
stirred for 24 h, the reaction mixture was extracted with
dichloromethane. The organic layer was dried and then
concentrated under vacuum to give 40 g (83.5%) of a solid: mp
108 °C; 1H NMR (CDCl3) δ 3.65-3.85 (m, 4H), 6.75 (NH), 6.9-
7.9 (m, 4H).
The selected compounds were examined on a larger screen-
ing. Operating conditions and results obtained with reference
compounds are summarized in Table 7.
Only the results of the compounds for which inhibition was
superior to 30% at 10-7 M for one receptor are reported in
Table 1.
Ad en yla te Cycla se Activity. Hippocampi of Wistar rats
were dissected immediately after death, and the tissues were
homogeneizated and centrifuged. Proteins were dosed by the
Lowry’s protocol. The enzymatic activity was measured from
conversion of [32P]-R -ATP into [32P]cAMP at the end of a 20
min incubation at 30 °C, in the presence of forskolin, as
described by Salomon42 and Coll. Concentration-effect curves
were analyzed using a nonlinear regression computer program
and the results expressed as percentage of maximal inhibition
and IC50 values.
Low er Lip Retr a ction Test in Ra ts.43 Rats were admin-
istered ip with the tested compounds and immediately after-
ward were placed individually in transparent plexiglass cages
(20 × 10 × 10 cm). Lower lip retraction was scored every 15
min for 3 h after injection according to the following scale: 0
) lower incisors not visible, 1 ) lower incisors partly visible,
2 ) lower incisors completely visible. Scores were cumulated
per rat. Six rats were used per group. All quantitative data
were analyzed for their overall statistical significance using
the Wilcoxon test.
4-Be n zyl-1-[2-(4-flu or ob e n za m id o)-1-e t h yl]p ip e r a -
zin e Dih yd r och lor id e (13). P r ocess D. This procedure is
the same as the process A. Initial products were 12 and 17
(yield, 83%).
P r ocess E. Compound 15 (20.15 g, 0.1 mol) in solution in
50 mL of DMF was added dropwise to a mixture of 1-ben-
zylpiperazine (18) (35.2 g, 0.2 mol) and sodium iodide (1 g,
6.6 mmol) in 150 mL of DMF. The reaction mixture was
stirred for 4 h at room temperature and then for 2 h at 65 °C.
After the mixture was cooled, water was added and the
mixture was extracted with ethyl acetate. The organic layer
was washed several times with water, dried, and then evapo-
rated to give 29 g of crude base (85% yield). This base was
dissolved in ethanol, a solution of hydrogen chloride in ethanol
was then added, and the dihydrochloride crystallized out: mp
Ack n ow led gm en t. We thank Carole Lecinse for
linguistic advice.
Su p p or tin g In for m a tion Ava ila ble: Spectrochemical
data of compounds I (19-51) (2 pages). Ordering information
is given on any current masthead page.
1
201 °C; H NMR (base) δ 2.4-2.7 (m, 10H), 3.45 (s, 2H), 3.55
(q, 2H, J ) 6 Hz), 6.85 (NH), 7.2-7.8 (m, 9H).
1-[2-(4-Flu or oben zam ido)-1-eth yl]piper azin e (16). Com-
pound 13 (25 g, 0.06 mol) was dissolved in a mixture of 100
mL of water and 100 mL of ethanol. Then, 3 g of 10% Pd/C
was added. Hydrogenolysis was carried out at room temper-
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