Structure-affinity relationship study on N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides as potent and selective dopamine D3 receptor ligands

Article abstract of DOI:10.1021/jm020952a

The benzamide PB12 (N- [2-[4-(4-chlorophenyl)piperazin-1-yl] ethyl]-3-methoxybenzamide) (1), already reported as potent and selective dopamine D₄ receptor ligand, has been modified searching for structural features that could lead to D₃

Full text of DOI:10.1021/jm020952a

J . Med. Chem. 2002, 45, 5727-5735
5727
Str u ctu r e-Affin ity Rela tion sh ip Stu d y on
N-[4-(4-Ar ylp ip er a zin -1-yl)bu tyl]a r ylca r boxa m id es a s P oten t a n d Selective
Dop a m in e D3 Recep tor Liga n d s
Marcello Leopoldo,* Francesco Berardi, Nicola A. Colabufo, Paola De Giorgio, Enza Lacivita,
Roberto Perrone, and Vincenzo Tortorella
Dipartimento Farmaco-Chimico, Universita` degli Studi di Bari, via Orabona, 4, 70126 Bari, Italy
Received J une 4, 2002
The benzamide PB12 (N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide) (1),
already reported as potent and selective dopamine D4 receptor ligand, has been modified
searching for structural features that could lead to D3 receptor affinity. Changes in the aromatic
ring linked to N-1 piperazine ring led to the identification of 2-methoxyphenyl and 2,3-
dichlorophenyl derivatives (compounds 6 and 13) displaying moderate D3 affinity (Ki ) 145
and 31 nM, respectively). Intermediate alkyl chain elongation in compounds 1, 6, and 13
improved binding affinity for the D3 receptor and decreased the D4 affinity (compounds 18-
26). Among these latter compounds, the N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-3-
methoxybenzamide (19) was further modified with the replacement or of the 2,3-dichlorophenyl
moiety (compounds 27-30) or of the 3-methoxyphenyl ring (compounds 31-41). In this way,
we identified several high-affinity D3 ligands (0.13 nM < Ki’s < 4.97 nM) endowed with high
selectivity over D2, D4, 5-HT1A, and R1 receptors. In addition, N-[4-[4-(2,3-dimethylphenyl)-
piperazin-1-yl]butyl]-3-methoxybenzamide (27) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-
butyl]-7-methoxy-2-benzofurancarboxamide (41) appear to be valuable candidates for positron
emission tomography (PET) because of their affinity values, lipophilicity properties, and liability
of 11C labeling in the O-methyl position.
In tr od u ction
cocaine-seeking behavior,6 although a recent study
suggested that it may be the dopamine D3 receptor
antagonist properties of BP 897 which have potential
in the treatment of addiction and withdrawal.7 Despite
the early encouraging results with 7-OH-DPAT, BP 897,
and other D3 agents, presently, the in vivo function of
the D3 receptor and its role in cocaine’s actions remains
debatable because of the lack of D3-receptor selectivity
of these agents.
The cloning of the gene for dopamine D3 receptor and
subsequent identification of its distribution in brain and
pharmacology allowed for serious consideration of the
possibility that might be a target for antipsychotic and
antiparkinsonian drugs. As early as 1990, the D3
receptor was considered a potential target for developing
antipsychotic agents because dopamine (DA) antago-
nists used in the treatment of schizofrenia were not
selective for the D2 receptor, but they also exhibited high
affinity for the D3 receptor.1 Because D3 receptor is
highly expressed in limbic regions of the brain, but
exhibited low expression in motor divisions, it would be
a target for antipsychotics potentially devoid of un-
wanted motor side effects.2 Another therapeutic use of
D3 agents is for treatment of Parkinson’s disease (PD)
because DA agonists used in PD therapy have, in many
cases, as high or higher affinity for the D3 receptor.3
Therefore, it remains tenable that the mesolimbic D3
receptor could play a role in antiparkinsonian relief, and
recently the D3 preferring agonists pramipexole and
ropinirole (Chart 1) have been introduced in therapy for
effective treatment of PD.
Therefore, D3 ligands having subnanomolar affinities,
high receptor subtype specificity, and improved bio-
availability would greatly aid in understanding the role
of the D3 receptor. Additionally, the presence in the
structure of such ligands of methoxy or N-methyl groups
would give access to 11C radioligands suitable for
positron emission tomography (PET).8,9 To date, no
effective D3-preferring PET radioligand for in vivo D3
receptor imaging has been reported.10
In recent years, we have been interested in SAFIR
studies on D4 ligands represented by the potent and
selective PB12 (1) (Table 1).11,12 From a survey of the
literature dealing with D3 ligands, it emerged that
compounds structurally related to PB12 were able to
bind to D3 receptor.13 This ability depended upon the
nature of the aromatic ring linked to the piperazine N-1
position. On the basis of this observation, a first set of
compounds (derivatives 6-17) was designed by chang-
ing the aromatic ring linked to the piperazine ring.
Some aromatic rings, such as phenyl, 2,3-diCl-phenyl,
and 2-CH3O-phenyl, were selected because they were
displayed by known arylpiperazine D3 ligands.13-15
Among these analogues of compound 1, only 2,3-diCl-
The D3 receptor subtype would also be involved in the
pharmacological effects of psychostimulant drugs.1,4 An
early study on the D3-selective agonist 7-OH-DPAT
suggested that D3 receptors played a modulatory role
in the self-administration of cocaine.5 Also, the selective
D3 partial agonist BP 897 was found to attenuate
* To whom correspondence should be addressed. Phone: +39-080-
5442798. Fax: +39-080-5442231. E-mail: leopoldo@farmchim.uniba.it.
10.1021/jm020952a CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/22/2002

5728 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Ch a r t 1. Dopamine D3 Agents
Leopoldo et al.
phenyl and 2-CH3O-phenyl derivatives (6 and 13,
respectively) displayed moderate D3 receptor affinity,
along with high D4 receptor affinity. Then, the effect of
intermediate alkyl chain elongation on D3 receptor
affinity was evaluated by preparing a set of homologues
of compounds 1, 6, and 13 (derivatives 18-26). This
modification was considered because three high affinity
D3 ligands (i.e., BP 897, NGB 2904,16 and SB 27701117)
(Chart 1) displayed the four carbon butyl chain and also
because alkyl chain elongation of compound 1 resulted
in a decrease in D4 receptor affinity.12 In line with the
above considerations, D3 affinity values of compounds
18-26 indicated that the four carbon alkyl chain was
an important requisite for high D3 affinity. Conse-
quently, several n-butyl chain containing 1-arylpipera-
zine derivatives (compounds 27-41) were evaluated in
the search for structural features that could enhance
the selectivity over the other receptors capable of
binding 1-arylpiperazines (i.e., D2, 5-HT1A, and R1
receptors). In particular, we prepared some compounds
related to N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-
butyl]-3-methoxybenzamide (19) by replacing the 2,3-
dichlorophenyl group with the 2,3-dimethylphenyl group
(compound 27) or with a bicyclic aromatic nucleus
(compounds 28-30). Then, we also prepared N-[4-[4-
(2,3-dichlorophenyl)piperazin-1-yl]butyl]arylcarboxam-
ides 31-41, bearing an aryl group other than the
3-methoxyphenyl. These groups were chosen for their
different contribution to lipophilicity (expressed as
ClogP values18) and also among those displayed by
already reported D3 ligands (i.e., 4-bromo-1-methoxy-
2-naphthalenyl,19 1-methoxy-2-naphthalenyl,20 1,1′-bi-
phenyl,21 4-quinolyl17).
Ch em istr y
Benzamides 8-17 were prepared by reacting the
appropriate 1-arylpiperazine with N-(2-chloroethyl)-3-
methoxybenzamide (2),11 as depicted in Scheme 1.
Similarly, benzamide 18 was prepared by condensing
1-(2,3-dichlorophenyl)piperazine with N-(3-chloropro-
pyl)-3-methoxybenzamide (3). This latter compound was
obtained by acylating 3-chloropropylamine with 3-meth-
oxybenzoyl chloride. The synthesis of the benzamides
19, 20, 22, 23, 27-41 (Scheme 2) required the inter-
mediate amines 5a -j. Among these, amines 5a -d were
prepared by alkylating the appropriate 1-arylpiperazine
with 4-chlorobutanenitrile or 5-chloropentanenitrile and
subsequent reduction of nitriles 4a -d with borane-
methyl sulfide complex,22 whereas amines 5e-j were
synthesized according to literature methods, as detailed
in Experimental Section. Final compounds were achieved
by condensing the amines 5a -j with appropriate acyl
chloride or carboxylic acid in the presence of 1,1′-
carbonyldiimidazole as condensing agent.
Resu lts a n d Discu ssion
Affinity values of the target compounds 6-41 for D3,
D4, D2, 5-HT1A, and R1 receptors are listed in Table 2.

Potent and Selective Dopamine D3 Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5729
Ta ble 1. Physical Properties of Target Compounds
compd
n
Ar
Ar′
formulaa
mp, °C
CLogP
1b (PB12)
6b
2
2
2
2
2
2
2
2
2
2
2
2
2
3
4
5
3
4
5
3
4
5
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
4-Br-1-CH3O-2-naphthalenyl
1-CH3O-2-naphthalenyl
2-naphthalenyl
4-quinolyl
1,1′-biphenyl
2-benzofuranyl
1H-indol-2-yl
1H-indol-3-yl
3-indazolyl
2-benzo[b]thienyl
7-CH3O-2-benzofuranyl
4-Cl-Ph
2-CH3O-Ph
2-Py
2-Cl-Ph
3-Cl-Ph
4-CH3-Ph
4-CH3O-Ph
4-F-Ph
2,3-di-Cl-Ph
Ph
1-naphthalenyl
4-Cl-2-Py
4-CH3-2-Py
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2-CH3O-Ph
2-CH3O-Ph
2-CH3O-Ph
4-Cl-Ph
3.72
2.86
1.89
3.72
3.72
3.33
2.71
3.15
4.36
2.83
4.01
2.67
2.38
4.57
4.50
5.03
3.08
3.00
3.53
3.93
3.86
4.93
3.92
4.15
3.20
2.85
6.60
5.61
5.28
4.74
6.00
4.67
4.70
4.36
4.46
5.33
4.98
7b
8
9
C20H24ClN3O2
C20H24ClN3O2
C21H27N3O2‚HCl
C21H27N3O3‚2HCl
C20H24FN3O2
C20H23Cl2N3O2‚HCl
C20H25N3O2‚HCl
C24H27N3O2‚(COOH)2‚H2O
C19H23ClN4O2‚(COOH)2
C20H26N4O2‚2HCl
C21H25Cl2N3O2‚HCl‚4/5H2O
C22H27Cl2N3O2‚HCl
C23H29Cl2N3O2‚HCl
116-118
147-149
229-231
223-225
157-159
254-256
234-236
177-179
239-240
221-224
184-187
218-220
188-189
10
11
12
13
14
15
16
17
18
19
20
21c
22
23
24c
25c
26c
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
C23H31N3O3‚2HCl
C24H33N3O3‚2HCl
185-186
189-191
4-Cl-Ph
4-Cl-Ph
2,3-di-CH3-Ph
1-naphthalenyl
1-isoquinolyl
1,2-benzisoxazol-3 -yl
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
C24H33N3O2‚HCl
185-187
184-186
163-164
111-113
204-206
190-192
217 dec
150-153
245 dec
236 dec
245 dec
265 dec
267 dec
228 dec
212-214
C26H31N3O2‚HCl‚1/2H2O
C25H30N4O2‚2(COOH)2
C23H28N4O3‚HCl
C26H28BrCl2N3O2‚HCl
C26H29Cl2N3O2‚HCl‚1/5H2O
C
C
C
C
C
C
C
C
25H27Cl2N3O‚HCl
24H26Cl2N4O‚(COOH)2
27H29Cl2N3O‚HCl
23H25Cl2N3O2‚HCl
23H26Cl2N4O‚2HCl
23H26Cl2N4O‚HCl
22H25Cl2N5O‚HCl‚H2O
23H25Cl2N3OS‚HCl
C24H27Cl2N3O3‚HCl
a
All compounds were recrystallized from CH3OH/Et2O except 8, 9, 12 (from CHCl3/ n-hexane), and 15, 16, 29 (CH3OH). Analysis for
C,H,N; results were within (0.4% of the theoretical values for the formulas given. See ref 11. c See ref 12.
b
Sch em e 1a
as high-affinity D4 ligands. In particular, compounds 8,
10, and 13 were equipotent to 1, showing subnanomolar
D4 affinity values (Ki’s ranging between 0.018 and 0.040
nM). Compounds 6-17 did not bind to D2 receptor and
displayed a wide range of 5-HT1A and R1 receptor
affinities. Subsequently, we evaluated the effect on D3
affinity of alkyl chain elongation in compounds 6 and
13. This modification was also aimed at decreasing the
D4 affinity, because in a previous study12 we observed
that elongation of the alkyl chain in 1 resulted in a
decrease in D4 affinity (compounds 24-26). The results
made clear different structural requirements between
D3 and D4 receptors. In fact, the D3 affinities of
compounds 18-26, that are homologues of compounds
6, 13, and 1, were ranked as follows: butyl > pentyl g
propyl > ethyl. In particular, butyl derivatives 19, 22,
and 25 displayed D3 affinities ranging between 0.27 and
1.7 nM. On the other hand, D4 affinity values are
ordered oppositely: ethyl > propyl g butyl > pentyl.
These opposite trends resulted in an increasing in
specificity for the D3 receptor, especially in compounds
a
Reagents: (A) thionyl chloride; (B) 2-chloroethylamine or
3-chloropropylamine; (C) 1-arylpiperazine.
The variation of the aromatic group linked to the
piperazine ring N-1 position of compound 1 led to
compounds 6-17 that were devoid of D3 receptor
affinity, except for compounds 6, 8, 13, 15, that showed
moderate D3 affinity (Ki’s ranging between 31 and 146
nM). These compounds are characterized by a 2- or 2,3-
di-substituted phenyl ring or by a 1-naphthalenyl ring.
On the other hand, compounds 6-17 can be considered
19 and 25, which were also selective versus D2, 5-HT1A
,
and R1 receptors. The observed lack of selectivity of
compounds 6 and 21-23 over 5-HT1A receptors should
be mainly due to the 1-(2-methoxyphenyl)piperazine

5730 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Leopoldo et al.
Sch em e 2a
a
Reagents: (A) 4-chlorobutanenitrile or 5-chloropentanenitrile; (B) borane-methyl sulfide complex; (C) acyl chloride or carboxylic acid
and 1,1′-carbonyldiimidazole.
Ta ble 2. Binding Affinities of Target Compounds
Ki ( S.E.M., nM
compd
n
Ar
Ar′
D3
D4
D2
5-HT1A
R1
1 (PB12)
6
7
8
9
2
2
2
2
2
2
2
2
2
2
2
2
2
3
4
5
3
4
5
3
4
5
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
3-CH3O-Ph
4-Cl-Ph
2-CH3O-Ph
2-Py
2-Cl-Ph
3-Cl-Ph
4-CH3-Ph
4-CH3O-Ph
4-F-Ph
2,3-di-Cl-Ph
Ph
1-naphthalenyl
4-Cl-2-Py
4-CH3-2-Py
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2-CH3O-Ph
2-CH3O-Ph
2-CH3O-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
2,3-di-CH3-Ph
1-naphthalenyl
1-isoquinolyl
1,2-benzisoxazol-3-yl
>1000 (28%)a 0.040 ( 0.002
1900 ( 250
467 ( 33
147 ( 14
0.060 ( 0.004
27 ( 4
245 ( 30
180 ( 20
283 ( 15
18 ( 2
145 ( 16
>850 (16%)
146 ( 24
1.1 ( 0.3
0.63 ( 0.04
>1000 (35%)
0.040 ( 0.007 >1000 (19%)
27 ( 4
472 ( 30
0.26 ( 0.02
>1000 (24%)
7460 ( 320
>1000 (15%)
>1000 (13%)
3680 ( 120
>8300 (26%)
>1000 (12%)
>1000 (17%)
>1000 (26%)
1130 ( 120
1410 ( 80
35 ( 9
224 ( 12
454 ( 25
5900 ( 350
134 ( 15
425 ( 52
197 ( 20
7.3 ( 0.6
115 ( 19
2900 ( 180
66.7 ( 6.0
134 ( 9
92.1 ( 4.0
61.4 ( 8.0
26.4 ( 2.2
16.2 ( 2.4
437 ( 31
406 ( 40
470 ( 25
717 ( 24
57 ( 3
1120 ( 120
3119 ( 125
>1000 (25%)
5100 ( 150
5 ( 5
138 ( 16
>1000 (43%)
236 ( 24
2050 ( 130
1880 ( 320
1120 ( 230
656 ( 20
110 ( 21
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
>850 (30%) 0.025 ( 0.007
432 ( 27
>850 (27%)
313 ( 22
29 ( 5
>850 (18%)
>850 (33%)
31 ( 7
22.3 ( 8.0
11 ( 2
0.018 ( 0.007
2.2 ( 0.8
0.21 ( 0.01
3.95 ( 0.80
23.9 ( 8.0
7.3 ( 0.6
9.0 ( 0.8
345 ( 25
1.8 ( 0.4
3.1 ( 0.7
55 ( 7
674 ( 35
59 ( 8
70 ( 5
0.60 ( 0.03
433 ( 17
58.6 ( 6.0
117 ( 20
123 ( 15
78.7 ( 7.3
19.8 ( 2.0
7.5 ( 1.1
4.5 ( 0.7
>850 (23%)
397 ( 92
>850 (44%)
268 ( 12
0.43 ( 0.06
12.7 ( 3.5
7730 ( 220
>1000 (22%)
>850 (33%)
2.3 ( 0.2
0.27 ( 0.03
3.0 ( 0.4
1560 ( 200
2990 ( 110
680 ( 18
124 ( 20
1.7 ( 0.5
5.3 ( 0.8
253 ( 12
586 ( 37
5.4 ( 0.7
25 ( 2
3960 ( 150
2350 ( 270
>850 (22%)
77.0 ( 5.2
0.41 ( 0.05
36 ( 3
241 ( 35
63.6 ( 8.0
2.3 ( 1.5
168 ( 18
7.58 ( 0.50
652 ( 85
720 ( 225
370 ( 80
604 ( 50
283 ( 15
890 ( 125
0.17 ( 0.05
0.54 ( 0.02
9.5 ( 0.8
46.5 ( 6.2
4.97 ( 0.30
0.60 ( 0.02
0.58 ( 0.02
0.72 ( 0.02
1.15 ( 0.30
0.62 ( 0.03
930 ( 30
770 ( 15
210 ( 24
4-Br-1-CH3O-2-naphthalenyl 2,3-di-Cl-Ph
3800 ( 130 >1000 (46%)
1-CH3O-2-naphthalenyl
2-naphthalenyl
4-quinolyl
1,1′-biphenyl
2-benzofuranyl
1H-indol-2-yl
1H-indol-3-yl
3-indazolyl
2-benzo[b]thienyl
7-CH3O-2-benzofuranyl
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
2,3-di-Cl-Ph
830 ( 120
5200 ( 350
430 ( 12
575 ( 230
335 ( 21
88.5 ( 8.2
>1000 (32%) >1000 (41%)
5740 ( 125
135 ( 14
63 ( 13
107 ( 18
170 ( 10
373 ( 20
0.12 ( 0.04
126 ( 20
1660 ( 140
1110 ( 170
621 ( 12
5500 ( 220
184 ( 16
0.62 ( 0.02 >800 (24%)
0.94 ( 0.02 >800 (30%)
0.18 ( 0.02 >800 (39%)
0.14 ( 0.01 >800 (38%)
0.13 ( 0.01
28 ( 2
720 ( 15
0.74 ( 0.08
30.0 ( 0.3
haloperidol
clozapine
8-OH-DPAT
phentolamine
2.1 ( 0.4
18 ( 3
a
Full Ki not obtained, percentage inhibition at the concentration shown given in parentheses.
moiety that is often present in 5-HT1A receptor ligands.23
Therefore, we have identified the structure of N-[4-(4-
further examination of the SAFIR was carried out on
compound 19 that showed the highest D3 affinity.
Changes were made by replacing either the 2,3-di-
chorophenyl moiety (compounds 27-30) or the 3-meth-
arylpiperazin-1-yl)butyl]-3-methoxybenzamide as
a
framework to obtain potent D3 ligands. At this point, a

Potent and Selective Dopamine D3 Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5731
assigned structures. Purity of target compounds was checked
by HPLC analysis on a Perkin-Elmer series 200 LC instrument
using a Phenomenex Prodigy ODS-3 RP-18 column (250 × 4.6
mm, 5 µ particle size) and equipped with a Perkin-Elmer 785A
UV/vis detector setting λ ) 254 nm. All compounds were eluted
with CH3OH/H2O/Et3N, 4:1:0.01, v/v, at a flow rate of 1 mL/
min. A standard procedure was used to transform final
compounds into their hydrochloride or oxalate salts that were
recrystallized as detailed in Table 1.
oxyphenyl group (compounds 31-41). For the first
modification, we replaced the two Cl atoms with two
CH3 groups (compound 27), or we used a bicyclic
aromatic ring to mimic the 2,3-dichlorophenyl group.
The 2,3-dimethylphenyl derivative 27 displayed slightly
higher D3 affinity than the parent 2,3-dichlorophenyl
derivative 19 and showed at least 300-fold selectivity
over D2, D4, 5-HT1A, and R1 receptors. Also, 1-naphtha-
lenyl derivative 28 displayed high D3 affinity (Ki ) 0.54
nM), but it proved to be nonselective over D4 and 5-HT1A
receptors. Isoquinoline 29 and 1,2-benzisoxazole 30 were
significantly less potent than 19 at D3 receptor. How-
ever, data concerning derivatives 27-30 did not provide
clear information for SAFIR on that part of the mol-
ecule.
1-(2,3-Dichlorophenyl)piperazine was a kind gift by Clariant
Life Science Molecules (Origgio, Varese, Italy). The following
compounds were synthesized according to published proce-
dures: 1-(1-naphthalenyl)piperazine,24 1-(4-chloro-2-pyridinyl)-
piperazine,25 1-(4-methyl-2-pyridinyl)piperazine,25 1-(isoquinolin-
1-yl)piperazine,27 4-bromo-2-methoxy-1-naphthoic acid,28 2-meth-
oxy-1-naphthoic acid,29 N-(2-chloroethyl)-3-methoxybenzamide
(2),11 4-(2,3-dichlorophenyl)-1-piperazinebutanamine (4e),16
3-[4-(4-aminobutyl)-1-piperazinyl]-1,2-benzisoxazole (4f),30 4-(2-
methoxyphenyl)-1-piperazinebutanamine (4g),31 4-(2-methox-
yphenyl)-1-piperazinepentanamine (4j).32
For the second modification, we replaced the 3-meth-
oxyphenyl ring of compound 19 with a variety of bicyclic
aromatic rings including 4-bromo-1-methoxy-2-naph-
thalenyl,19 1-methoxy-2-naphthalenyl,20 1,1′-biphenyl,21
4-quinolyl17 (compounds 31-41) that are present in
already reported D3 ligands. All these compounds pos-
sessed high D3 receptor affinity (0.13 nM < Ki < 4.97
nM) and high selectivity over D2, D4, 5-HT1A, and R1
receptors. Therefore, it seems clear that the replacement
of the 3-methoxyphenyl ring attached to the amide
moiety of compound 19 with a bicyclic aromatic ring did
not change the D3 affinity but greatly increased the
specificity for the D3 receptor.
N-(3-Ch lor opr opyl)-3-m eth oxyben zam ide (3). To a cooled
mixture containing 3-chloropropylamine hydrochloride (4.10
g, 31.5 mmol) in 1.2% aqueous NaOH (120 mL) was added
dropwise under vigorous stirring a CH2Cl2 solution (50 mL)
of 3-methoxybenzoyl chloride, prepared from the corresponding
acid (5.05 g, 33.2 mmol) and SOCl2 (10 mL). Then, the aqueous
layer was separated and extracted with CH2Cl2. The combined
organic layers were dried over Na2SO2 and evaporated to
dryness under reduced pressure. The crude residue was
chromatographed (CHCl3 as eluent) to give pure benzamide 3
as a solid (4.53 g, 63% yield). 1H NMR (90 MHz, CDCl3): δ
1.93-2.25 (m, 2H, CH2CH2CH2), 3.50-3.70 (m, 4H, CH2-
CH2CH2), 3.83 (s, 3H, CH3), 6.83 (br s, 1H, NH), 6.90-7.45
(m, 4H, aromatic); GC/MS m/z 229 (M+ + 2, 3), 227 (M+, 9),
192 (58), 164 (20), 135 (100).
In conclusion, structural modifications of the high-
affinity D4 ligand PB12 (1) have led to the identification
of several N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxa-
mides with high affinity for D3 receptor. Moreover, the
benzamides derived from aromatic bicyclic carboxylic
acid were also highly selective over D2, D4, 5-HT1A, and
R1 receptors. Finally, the in vitro binding profiles of
compounds 27, 32, and 41 suggest that these highly
potent and selective D3 receptor ligands may be par-
ticularly attractive potential candidates for receptor
imaging with PET. Moreover, it is generally more
desirable to perform PET studies with competitive
receptor antagonists, and compounds 27, 32, and 41
should also possess this property. In fact, they are
structurally closely related to the D3 receptor antago-
nists NGB 2904 and NGB 2849.16 The phenolic precur-
sors of compounds 27, 32, and 41 will provide 11C
radiolabeled derivatives that will be tested in PET
studies for their ability of in vitro imaging of primate
brain D3 receptor.
4-(2,3-Dich lor oph en yl)-1-piper azin epen tan en itr ile (4a).
A stirred mixture of 1-(2,3-dichlorophenyl)piperazine (1.71 g,
7.4 mmol), 5-chloropentanenitrile (0.70 mL, 6.2 mmol), and
an excess of anhydrous Na2CO3 in acetonitrile (50 mL) was
refluxed overnight. After cooling, the mixture was evaporated
to dryness and water was added to the residue. The aqueous
phase was extracted with CH2Cl2 (2 × 30 mL) and the collected
organic layers were dried over Na2SO4 and evaporated under
reduced pressure. The crude residue was chromatographed
(CHCl3/AcOEt, 1:1 as eluent) to yield pure 4a as a white
semisolid (1.6 g, 86% yield). 1H NMR (90 MHz, CDCl3): δ
1.50-1.85 [m, 4H, (CH2)2CH2CN], 2.25-2.70 [m, 8H, (CH2)2-
NCH2, CH2CN], 3.03 [br t, 4H, ArN(CH2)2], 6.80-7.25 (m, 3H,
aromatic); GC/MS m/z 313 (M+ + 2, 18), 312 (M+ + 1, 7), 311
(M+, 27), 245 (72), 243 (100).
4-(2,3-Dim eth ylph en yl)-1-piper azin ebu tan en itr ile (4b).
As above, the title compound was obtained in 38% yield
starting from 1-(2,3-dimethylphenyl)piperazine and 4-chloro-
butanenitrile. 1H NMR (90 MHz, CDCl3): δ 1.75-2.10 (m, 2H,
CH2CH2CN), 2.27 and 2.33 (2 s, 6H, 2 CH3), 2.37-2.75 [m,
8H, (CH2)2NCH2, CH2CN], 2.95 [br t, 4H, ArN(CH2)2], 6.85-
7.25 (m, 3H, aromatic); GC/MS m/z 259 (M+ + 2, 2), 258 (M+
+ 1, 20), 257 (M+, 100), 217 (87), 203 (35).
Exp er im en ta l Section
4-(1-Naph th alen yl)-1-piper azin ebu tan en itr ile (4c). Title
compound was prepared as above in 85% yield starting from
1-(1-naphthalenyl)piperazine and 4-chlorobutanenitrile.1H NMR
(90 MHz, CDCl3): δ 1.80-2.07 (m, 2H, CH2CH2CN), 2.27-
3.17 [m, 8H, (CH2)2NCH2, CH2CN], 3.60 [br t, 4H, ArN(CH2)2],
7.05-8.30 (m, 7H, aromatic); GC/MS m/z 281 (M+ + 2, 3), 280
(M+ + 1, 25), 279 (M+, 100), 239 (49), 154 (53).
4-(1-Isoqu in olyl)-1-p ip er a zin ebu ta n en itr ile (4d ). As for
compound 4a , nitrile 4d was prepared from 1-(1-isoquinolyl)-
piperazine and 4-chlorobutanenitrile. The crude residue was
chromatographed with CHCl3/ CH3OH, 19:1, as eluent, in 28%
yield. 1H NMR (90 MHz, CDCl3): δ 1.75-2.05 (m, 2H, CH2-
CH2CN), 2.33-2.75 [m, 8H, (CH2)2NCH2, CH2CN], 3.45 [br t,
4H, ArN(CH2)2], 7.17-8.20 (m, 6H, aromatic); GC/MS m/z 281
(M+ + 1, 3), 280 (M+, 11), 171 (20), 157 (100), 144 (40).
Ch em istr y. Column chromatography was performed with
1:30 ICN silica gel 60A (63-200 µm) as the stationary phase.
Melting points were determined in open capillaries on a
Gallenkamp electrothermal apparatus. Elemental analyses (C,
H, N) were performed on Eurovector Euro EA 3000 analyzer
or on a Carlo Erba model 1106 instrument; the analytical
results were within (0.4% of the theoretical values for the
1
formula given. H NMR spectra were recorded at 90 MHz on
a Varian EM-390 spectrometer or at 300 MHz on a Bruker
AM 300 WB spectrometer or on a Varian Mercury-VX spec-
trometer. All chemical shift values are reported in ppm (δ).
Recording of mass spectra was done on an HP6890-5973 MSD
gas chromatograph/mass spectrometer; only significant m/z
peaks, with their percentage of relative intensity in paren-
theses, are reported. All spectra were in accordance with the

5732 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Leopoldo et al.
Gen er a l P r oced u r e for th e Syn th esis of Am in es 5a -
d . Borane-methyl sulfide complex as 10.0 M BH3 in excess
methyl sulfide (1.6 mL, 16 mmol) was dropped into an ice-
cooled solution of nitrile (5.1 mmol) in anhydrous THF (10 mL),
under stirring. After being refluxed for 4 h, the reaction
mixture was cooled at -10 °C and MeOH was added dropwise
very carefully until gas evolution ceased. The mixture was
treated with 3 N HCl (20 mL) and was refluxed for 1 h. After
cooling, the mixture was alkalized with 3 N NaOH and
extracted with CH2Cl2 (2 × 50 mL). The collected organic
layers were dried over Na2SO4 and the solvent was evaporated
under reduced pressure to give the pure amine as a colorless
oil.
4-(2,3-Dich lor op h en yl)-1-p ip er a zin ep en ta n a m in e (5a ).
Nearly quantitative yield.1H NMR (90 MHz, CDCl3): δ 1.25-
1.80 [m, 8H, (CH2)3CH2NH2, 2H D2O exchanged], 2.15-2.80
[m, 8H, (CH2)2NCH2, CH2NH2], 3.15 [br t, 4H, ArN(CH2)2],
6.80-7.30 (m, 3H, aromatic); GC/MS m/z 315 (M+, 1), 245 (68),
243 (100), 200 (29), 172 (25), 141 (76).
aromatic, NH, 1H D2O exchanged); GC/MS m/z 371 (M+ + 2,
1), 370 (M+ + 1, 8), 369 (M+, 35), 205 (100), 135 (20).
N-[2-[4-(4-F lu or op h en yl)p ip er a zin -1-yl]eth yl]-3-m eth -
oxyben za m id e (12). Eluted with CHCl3/CH3OH, 19:1, in 72%
yield. 1H NMR (300 MHz, CDCl3): δ 2.63-2.69 [m, 6H, CH2N-
(CH2)2], 3.12 [br t, 4H, (CH2)2NAr], 3.57 (q, 2H, J ) 5.6 Hz,
NHCH2), 3.82 (s, 3H, CH3), 6.82-7.38 (m, 9H, aromatic, NH,
1H D2O exchanged); GC/MS m/z 358 (M+ + 1, 2), 357 (M+,
10), 193 (100), 150 (26).
N-[2-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]et h yl]-3-
m eth oxyben za m id e (13). Eluted with CHCl3/AcOEt, 1:1, in
11% yield. 1H NMR (300 MHz, CDCl3): δ 2.67 [br t, 6H, CH2N-
(CH2)2], 3.07 [br s, 4H, (CH2)2NAr], 3.57 (q, 2H, J ) 5.6 Hz,
NHCH2), 3.83 (s, 3H, CH3), 6.82 (br s, 1H, NH, D2O ex-
changed), 6.91-7.38 (m, 7H, aromatic); GC/MS m/z 409 (M+
+ 2, 1), 407 (M+, 1), 245 (64), 243 (100).
N-[2-(4-P h en ylp ip er a zin -1-yl)eth yl]-3-m eth oxyben za -
m id e (14). Eluted with CHCl3/AcOEt, 1:1, in 11% yield. 1H
NMR (300 MHz, CDCl3): δ 2.64-2.69 [m, 6H, CH2N(CH2)2],
3.21 [br t, 4H, (CH2)2NAr], 3.58 (q, 2H, J ) 5.6 Hz, NHCH2),
3.83 (s, 3H, CH3), 6.82-7.38 (m, 10H, aromatic, NH, 1H D2O
exchanged); GC/MS m/z 340 (M+ + 1, 1), 339 (M+, 6), 175 (100),
132 (24).
4-(2,3-Dim eth ylp h en yl)-1-p ip er a zin ebu ta n a m in e (5b).
77% Yield. 1H NMR (90 MHz, CDCl3): δ 1.53-2.10 [m, 6H,
(CH2)2CH2NH2, 2H D2O exchanged], 2.27 and 2.33 (2 s, 6H, 2
CH3), 2.50-2.80 [m, 8H, (CH2)2NCH2, CH2NH2], 3.00 [br t, 4H,
ArN(CH2)2], 6.90-7.30 (m, 3H, aromatic); GC/MS m/z 262 (M+
+ 1, 1), 261 (M+, 3), 203 (79), 160 (62), 146 (78), 132 (84), 127
(100).
N-[2-[4-(1-Na p h th a len yl)p ip er a zin -1-yl]eth yl]-3-m eth -
oxyben za m id e (15). Eluted with CHCl3/AcOEt, 1:1, in 10%
1
yield. H NMR (300 MHz, CDCl3): δ 2.77 [t, 2H, J ) 5.9 Hz,
CH2N(CH2)2], 2.84 [br s, 4H, CH2N(CH2)2], 3.17 [br s, 4H,
(CH2)2NAr], 3.63 (q, 2H, J ) 5.6 Hz, NHCH2), 3.85 (s, 3H, CH3),
6.99-8.19 (m, 12H, aromatic, NH, 1H D2O exchanged); GC/
MS m/z 391 (M+ + 2, 1), 390 (M+ + 1, 4), 389 (M+, 14), 225
(100).
N-[2-[4-(4-Ch lor o-2-p yr id in yl)p ip er a zin -1-yl]et h yl]-3-
m eth oxyben za m id e (16). Eluted with CHCl3/CH3OH, 19:1,
in 11% yield. 1H NMR (300 MHz, CDCl3): δ 2.60-2.67 [m,
6H, CH2N(CH2)2], 3.49 [br t, 4H, (CH2)2NAr] 3.58 (q, 2H, J )
5.6 Hz, NHCH2), 3.83 (s, 3H, OCH3), 6.59 (d, 1H, J ) 8.7 Hz,
CCldCH), 6.89 (br s, 1H, NH, D2O exchanged), 6.99-7.38 (m,
5H, aromatic), 8.01 (d, 1H, J ) 1.8 Hz, NdCH); GC/MS m/z
375 (M+ + 1, 1), 374 (M+, 4), 246 (31), 221 (21), 212 (31), 210
(100), 181 (33), 155 (35).
4-(1-Na p h th a len yl)-1-p ip er a zin ebu ta n a m in e (5c). 74%
Yield. 1H NMR (90 MHz, CDCl3): δ 1.45-1.98 [m, 6H, (CH2)2-
CH2NH2, 2H D2O exchanged], 2.30-2.90 [m, 8H, (CH2)2NCH2,
CH2NH2], 3.15 [br t, 4H, ArN(CH2)2], 7.10-8.35 (m, 7H,
aromatic); GC/MS m/z 284 (M+ + 1, 2), 283 (M+, 8), 225 (33),
182 (31), 154 (50), 127 (100).
4-(1-Isoqu in olyl)-1-p ip er a zin ebu ta n a m in e (5d ). 34%
Yield. 1H NMR (90 MHz, CDCl3): δ 1.40-2.03 [m, 6H, (CH2)2-
CH2NH2, 2H D2O exchanged], 2.33-3.00 [m, 8H, (CH2)2NCH2,
CH2NH2], 3.35 [br t, 4H, ArN(CH2)2], 7.10-8.15 (m, 6H,
aromatic); GC/MS m/z 284 (M+, 0.3), 157 (100).
Gen er a l P r oced u r e for th e Syn th esis of Ben za m id es
8-18. A stirred solution of the appropriate 1-arylpiperazine
(6.0 mmol), chloroderivative 2 (5.0 mmol) (or compound 3 in
the case of the benzamide 18), and triethylamine (4 mL) in
toluene (50 mL) was refluxed for 20 h. Then the solvent was
evaporated under reduced pressure and the residue taken up
with a 20% aqueous Na2CO3 and extracted with AcOEt. The
organic layer was dried (Na2SO4) and evaporated to dryness.
The crude residue was chromatographed as detailed below to
give target benzamides as pale yellow oils or solids.
N-[2-[4-(2-Ch lor op h en yl)p ip er a zin -1-yl]eth yl]-3-m eth -
oxyben za m id e (8). Eluted with CHCl3/AcOEt, 1:1, in 59%
yield. 1H NMR (300 MHz, CDCl3): δ 2.68 [br t, 6H, CH2N-
(CH2)2], 3.08 [br s, 4H, (CH2)2NAr], 3.57 (q, 2H, J ) 5.6 Hz,
NHCH2), 3.84 (s, 3H, CH3), 6.84 (br s, 1H, NH, D2O ex-
changed), 6.92-7.38 (m, 8H, aromatic); GC/MS m/z 373 (M+,
1), 211 (36), 209 (100).
N-[2-[4-(4-Meth yl-2-p yr id in yl)p ip er a zin -1-yl]eth yl]-3-
m eth oxyben za m id e (17). Eluted with CHCl3/CH3OH, 19:1,
in 23% yield. 1H NMR (300 MHz, CDCl3): δ 2.19 (s, 3H, CH3),
2.62-2.67 [m, 6H, CH2N(CH2)2], 3.48-3.61 [m, 6H, (CH2)2NAr,
NHCH2], 3.84 (s, 3H, OCH3), 6.59 (d, 1H, J ) 8.4 Hz, CdCH),
6.90 (br s, 1H, NH, D2O exchanged), 7.00-7.39 (m, 5H,
aromatic), 8.01-8.02 (m, 1H, NdCH); GC/MS m/z 355 (M+
+
1, 2), 354 (M+, 9), 246 (74), 190 (100), 178 (22), 161 (44), 135
(99), 121 (99).
N-[3-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]p r op yl]-3-
m eth oxyben za m id e (18). Eluted with CHCl3/CH3OH, 19:1,
in 56% yield. 1H NMR (300 MHz, CDCl3): δ 1.88-1.95 (m,
2H, NHCH2CH2), 2.65-2.90 [m, 6H, CH2N(CH2)2], 3.10 [br s,
4H, (CH2)2NAr], 3.60 (q, 2H, J ) 5.4 Hz, NHCH2), 3.82 (s, 3H,
CH3), 6.90-7.48 (m, 7H, aromatic), 8.32 (br s, 1H, NH, D2O
exchanged); GC/MS m/z 423 (M+ + 2, 1), 421 (M+, 3), 386 (23),
245 (50), 243 (78), 221 (100), 192 (63).
Gen er a l P r oced u r e for th e Syn th esis of Ben za m id es
19, 20, 22, 23, 27-30, 32, 33, 35. To a cooled mixture
containing the appropriate amine (5.0 mmol) in 1.2% aqueous
NaOH (20 mL) was added dropwise under vigorous stirring a
CH2Cl2 solution (50 mL) of acyl chloride, prepared from the
corresponding acid (6.0 mmol) and SOCl2 (5 mL). Then, the
aqueous layer was separated and extracted twice with CH2-
Cl2. The combined organic layers were dried over Na2SO4 and
evaporated to dryness under reduced pressure. The crude
residue was chromatographed as detailed below to give target
benzamide as a pale yellow liquid.
N-[2-[4-(3-Ch lor op h en yl)p ip er a zin -1-yl]eth yl]-3-m eth -
oxyben za m id e (9). Eluted with CHCl3/AcOEt, 1:1, in 18%
yield. 1H NMR (300 MHz, CDCl3): δ 2.65-2.69 [m, 6H, CH2N-
(CH2)2], 3.22 [br t, 4H, (CH2)2NAr], 3.59 (q, 2H, J ) 5.6 Hz,
NHCH2), 3.83 (s, 3H, OCH3), 6.75-7.38 (m, 9H, aromatic, NH,
1H D2O exchanged); GC/MS m/z 374 (M+ + 1, 1), 373 (M+, 4),
211 (34), 209 (100), 166 (21).
N-[2-[4-(4-Meth ylp h en yl)p ip er a zin -1-yl]eth yl]-3-m eth -
oxyben za m id e (10). Eluted with CHCl3/AcOEt, 1:1, in 10%
1
yield. H NMR (300 MHz, CDCl3): δ 2.27 (s, 3H, CH3), 2.64-
2.69 [m, 6H, CH2N(CH2)2], 3.17 [br t, 4H, (CH2)2NAr], 3.58 (q,
2H, J ) 5.6 Hz, NHCH2), 3.85 (s, 3H, OCH3), 6.84-7.39 (m,
9H, aromatic, NH, 1H D2O exchanged); GC/MS m/z 354 (M+
+ 1, 4), 353 (M+, 15), 189 (100).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-3-
m eth oxyben za m id e (19). Eluted with CHCl3/CH3OH, 19:1,
in 65% yield. 1H NMR (300 MHz, CDCl3): δ 1.63-1.71 [m,
4H, NHCH2(CH2)2], 2.46 [t, 2H, J ) 6.8 Hz, CH2N(CH2)2], 2.61
[br s, 4H, CH2N(CH2)2], 3.01 [br s, 4H, (CH2)2NAr], 3.45 (q,
2H, J ) 6.1 Hz, NHCH2), 3.83 (s, 3H, CH3), 6.72 (br t, 1H,
N-[2-[4-(4-Meth oxyph en yl)piper azin -1-yl]eth yl]-3-m eth -
oxyben za m id e (11). Eluted with CHCl3/CH3OH, 19:1, in 44%
yield. 1H NMR (300 MHz, CDCl3): δ 2.64-2.69 [m, 6H, CH2N-
(CH2)2], 3.11 [br t, 4H, (CH2)2NAr], 3.58 (q, 2H, J ) 5.6 Hz,
NHCH2), 3.77 and 3.84 (2 s, 6H, 2 CH3), 6.83-7.38 (m, 9H,

Potent and Selective Dopamine D3 Receptor Ligands
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5733
NH), 6.87-7.40 (m, 7H, aromatic); GC/ MS m/z 436 (M+ + 1,
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]bu tyl]-(1,1′-
bip h en yl)-4-ca r boxa m id e (35). Eluted with CHCl3/CH3OH,
19:1, in 38% yield. H NMR (300 MHz, CDCl3): δ 1.68-1.75
[m, 4H, NHCH2(CH2)2], 2.53 [t, 2H, J ) 6.7 Hz, CH2N(CH2)2],
2.68 [br s, 4H, CH2N(CH2)2], 3.05 [br t, 4H, (CH2)2NAr], 3.52
(q, 2H, J ) 6.0 Hz, NHCH2), 6.86-7.88 (m, 13H, aromatic,
NH).
1), 435 (M+, 2), 261 (32), 245 (50), 243 (79), 235 (100), 135 (53).
1
N-[5-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]p en t yl]-3-
m eth oxyben za m id e (20). Eluted with CHCl3/AcOEt, 1:1, in
1
93% yield. H NMR (300 MHz, CDCl3): δ 1.41-1.49 (m, 2H,
CH2CH2CH2), 1.59-1.71 (m, 4H, CH2CH2CH2), 2.50 [t, 2H, J
) 7.6 Hz, CH2N(CH2)2], 2.71 [br s, 4H, CH2N(CH2)2], 3.11 [br
s, 4H, (CH2)2NAr], 3.47 (q, 2H, J ) 6.4 Hz, NHCH2), 3.84 (s,
3H, CH3), 6.26 (br s, 1H, NH), 6.93-7.36 (m, 7H, aromatic);
GC/MS m/z 450 (M+ + 1, 1), 449 (M+, 2), 275 (30), 263 (20),
249 (100), 245 (65), 243 (99).
Gen er a l P r oced u r e for th e Syn th esis of Ben za m id es
31, 34, 36-41. A mixture of the appropriate carboxylic acid
(0.48 mmol) and 1,1′-carbonyldiimidazole (0.50 mmol) in 10
mL of anhydrous THF was stirred for 8 h. A solution of amine
5e (0.5 mmol) in 10 mL of anhydrous THF was added and the
resulting mixture was stirred for 1 h. The reaction mixture
was partitioned between AcOEt and H2O. The organic layer
was washed with aqueous Na2CO3 solution, dried (Na2SO4),
and concentrated in vacuo. The crude residue was chromato-
graphed with CHCl3/CH3OH, 19:1 to afford the pure benza-
mide.
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-4-
br om o-1-m eth oxy-2-n a p h th a len eca r boxa m id e (31). 36%
Yield. 1H NMR (300 MHz, CDCl3): δ 1.66-1.76 [m, 4H,
NHCH2(CH2)2], 2.49 [t, 2H, J ) 7.0 Hz, CH2N(CH2)2], 2.63 [br
s, 4H, CH2N(CH2)2], 3.01 [br t, 4H, (CH2)2NAr], 3.54-3.60 (m,
2H, NHCH2), 3.99 (s, 3H, CH3), 6.82-8.38 (m, 9H, aromatic,
NH).
N-[4-[4-(2-Meth oxyph en yl)piper azin -1-yl]bu tyl]-3-m eth -
oxyben za m id e (22). Eluted with CHCl3/CH3OH, 19:1, in 41%
yield. 1H NMR (300 MHz, CDCl3): δ 1.65-1.69 [m, 4H,
NHCH2(CH2)2], 2.48 [t, 2H, J ) 6.5 Hz, CH2N(CH2)2], 2.67 [br
s, 4H, CH2N(CH2)2], 3.07 [br s, 4H, (CH2)2NAr], 3.45-3.49 (m,
2H, NHCH2), 3.82 and 3.85 (2 s, 6H, 2 CH3), 6.83-7.36 (m,
9H, aromatic, NH); GC/MS m/z 398 (M+ + 1, 8), 397 (M+, 29),
382 (40), 235 (55), 205 (100), 190 (30).
N -[5-[4-(2-Me t h oxyp h e n yl)p ip e r a zin -1-yl]p e n t yl]-3-
m eth oxyben za m id e (23). Eluted with CHCl3/CH3OH, 19:1,
in 46% yield. 1H NMR (300 MHz, CDCl3): δ 1.40-1.47 (m,
2H, CH2CH2CH2), 1.56-1.70 (m, 4H, CH2CH2CH2), 2.44 [t, 2H,
J ) 7.5 Hz, CH2N(CH2)2], 2.69 [br s, 4H, CH2N(CH2)2], 3.11
[br s, 4H, (CH2)2NAr], 3.45 (q, 2H, J ) 6.7 Hz, NHCH2), 3.83
and 3.85 (2 s, 6H, 2 CH3), 6.29 (br s, 1H, NH), 6.83-7.36 (m,
8H, aromatic); GC/MS m/z 412 (M+ + 1, 6), 411 (M+, 22), 396
(21), 249 (32), 205 (100), 135 (43).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-4-
qu in olin eca r boxa m id e (34). 49% Yield. 1H NMR (300 MHz,
CDCl3): δ 1.68-1.82 [m, 4H, NHCH2(CH2)2], 2.41-2.55 [m,
10H, CH2N(CH2)2, (CH2)2NAr], 3.52-3.58 (m, 2H, NHCH2),
6.44-8.91 (m, 10H, aromatic, NH); GC/MS m/z 458 (M+ + 2,
19), 457 (M+ + 1, 9), 456 (M+, 30), 256 (57), 245 (64), 243 (100).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-2-
ben zofu r a n ca r boxa m id e (36). 66% Yield. 1H NMR (300
MHz, CDCl3): δ 1.64-1.71 [m, 4H, NHCH2(CH2)2], 2.49 [t, 2H,
J ) 6.9 Hz, CH2N(CH2)2], 2.67 [br s, 4H, CH2N(CH2)2], 3.09
[br s, 4H, (CH2)2NAr], 3.51 (q, 2H, J ) 6.5 Hz, NHCH2), 6.90-
7.68 (m, 9H, aromatic, NH); GC/MS m/z 447 (M+ + 2, 1), 446
(M+ + 1, 1), 445 (M+, 2), 271 (21), 245 (100), 243 (62).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]bu tyl]-1H-
in d ole-2-ca r boxa m id e (37). 7% Yield. 1H NMR (300 MHz,
DMSO-d6): δ 1.45-1.62 [m, 4H, NHCH2(CH2)2], 2.36 [br t, 2H,
CH2N(CH2)2], 2.51 [br s, 4H, CH2N(CH2)2], 2.95 [br s, 4H,
(CH2)2NAr], 3.36-3.42 (m, 2H, NHCH2), 6.98-7.59 (m, 8H,
aromatic), 8.44 (br t, 1H, NH), 11.51 (s, 1H, indole NH, D2O
exchanged); GC/MS m/z 446 (M+ + 2, 11), 445 (M+ + 1, 7),
444 (M+, 19), 270 (24), 245 (72), 244 (100), 243 (94).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]bu tyl]-1H-
N-[4-[4-(2,3-Dim et h ylp h en yl)p ip er a zin -1-yl]b u t yl]-3-
m eth oxyben za m id e (27). Eluted with CHCl3/AcOEt, 1:1, in
1
30% yield. H NMR (300 MHz, CDCl3): δ 1.72-1.65 [m, 4H,
NHCH2(CH2)2], 2.20 and 2.26 (2 s, 6H, 2 CH3), 2.47 [t, 2H, J
) 6.9 Hz, CH2N(CH2)2], 2.61 [br s, 4H, CH2N(CH2)2], 2.87 [br
t, 4H, (CH2)2NAr], 3.45-3.51 (m, 2H, NHCH2), 3.83 (s, 3H,
OCH3), 6.80 (br t, 1H, NH), 6.85-7.36 (m, 7H, aromatic); GC/
MS m/z 397 (M+ + 2, 1), 396 (M+ + 1, 3), 395 (M+, 13), 380
(21), 235 (100), 203 (85).
N-[4-[4-(1-Na p h th a len yl)p ip er a zin -1-yl]bu tyl]-3-m eth -
oxyben za m id e (28). Eluted with CHCl3/AcOEt, 1:1, in 54%
yield. 1H NMR (300 MHz, CDCl3): δ 1.75-1.68 [m, 4H,
NHCH2(CH2)2], 2.54 [t, 2H, J ) 6.7 Hz, CH2N(CH2)2], 2.75 [br
s, 4H, CH2N(CH2)2], 3.12 [br s, 4H, (CH2)2NAr], 3.52 (q, 2H, J
) 5.6 Hz, NHCH2), 3.83 (s, 3H, CH3), 6.82 (br s, 1H, NH),
6.91-8.20 (m, 11H, aromatic); GC/MS m/z 419 (M+ + 2, 2),
418 (M+ + 1, 11), 417 (M+, 38), 402 (35), 235 (100), 225 (94).
N-[4-[4-(1-Isoqu in olyl)p ip er a zin -1-yl]bu tyl]-3-m eth ox-
yben za m id e (29). Eluted with CHCl3/AcOEt, 1:1, in 24%
1
in d ole-3-ca r boxa m id e (38). 11% Yield. H NMR (300 MHz,
1
yield. H NMR (300 MHz, CDCl3): δ 1.70 [br s, 4H, NHCH2-
DMSO-d6): δ 1.44-1.58 [m, 4H, NHCH2(CH2)2], 2.34 [br s, 2H,
CH2N(CH2)2], 2.50 [br t, 4H, CH2N(CH2)2], 2.92 [br s, 4H,
(CH2)2NAr], 3.20-3.28 (m, 2H, NHCH2), 7.00-8.10 (m, 9H,
aromatic, NH), 11.50 (s, 1H, indole NH, D2O exchanged).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]bu tyl]-1H-
in d a zole-3-ca r boxa m id e (39). 39% Yield. 1H NMR (300
MHz, DMSO-d6): δ 1.76 [br s, 4H, NHCH2(CH2)2], 2.15 [br s,
2H, CH2N(CH2)2], 2.80 [br s, 4H, CH2N(CH2)2], 3.18 [br s, 4H,
(CH2)2NAr], 3.24 (br s, 2H, NHCH2), 7.26-8.37 (m, 7H,
aromatic), 8.52 (br s, 1H, CONH), 13.60 (s, 1H, indazole NH).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]bu tyl]ben -
zo[b]th iop h en e-2-ca r boxa m id e (40). 66% Yield. 1H NMR
(300 MHz, CDCl3): δ 1.44-1.60 [m, 4H, NHCH2(CH2)2], 2.38
[t, 2H, J ) 6.5 Hz, CH2N(CH2)2], 2.54 [br s, 4H, CH2N(CH2)2],
2.94 [br s, 4H, (CH2)2NAr], 3.41 (q, 2H, J ) 6.0 Hz, NHCH2),
6.74-7.71 (m, 8H, aromatic), 8.74 (br t, 1H, NH); GC/MS m/z
463 (M+ + 2, 1), 462 (M+ + 1, 1), 461 (M+, 3), 287 (32), 261
(100), 245 (63), 243 (97).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-7-
m et h oxy-2-b en zofu r a n ca r b oxa m id e (41). 70% Yield. 1H
NMR (300 MHz, CDCl3): δ 1.64-1.73 [m, 4H, NHCH2(CH2)2],
2.48 [t, 2H, J ) 6.8 Hz, CH2N(CH2)2], 2.66 [br s, 4H, CH2N-
(CH2)2], 3.08 [br s, 4H, (CH2)2NAr], 3.51 (q, 2H, J ) 6.5 Hz,
NHCH2), 3.69 (s, 3H, CH3), 6.87-7.45 (m, 8H, aromatic, NH);
GC/MS m/z 477 (M+ + 2, 1), 476 (M+ + 1, 1), 475 (M+, 3), 301
(30), 275 (100), 245 (57), 243 (83).
(CH2)2], 2.51 [t, 2H, J ) 6.7 Hz, CH2N(CH2)2], 2.71 [br s, 4H,
CH2N(CH2)2], 3.43 [br s, 4H, (CH2)2NAr], 3.50 (q, 2H, J ) 5.6
Hz, NHCH2), 3.83 (s, 3H, CH3), 6.57 (br s, 1H, NH), 6.99-
8.14 (m, 10H, aromatic); GC/MS m/z 418 (M+, 2), 157 (100).
N-[4-[4-(1,2-Ben zisoxa zol-3-yl)p ip er a zin -1-yl]bu tyl]-3-
m eth oxyben za m id e (30). Eluted with CHCl3/AcOEt, 1:1, in
1
37% yield. H NMR (300 MHz, CDCl3): δ 1.62-1.69 [m, 4H,
NHCH2(CH2)2], 2.45 [t, 2H, J ) 6.9 Hz, CH2N(CH2)2], 2.62 [br
t, 4H, CH2N(CH2)2], 3.48 (q, 2H, J ) 6.2 Hz, NHCH2), 3.55 [br
t, 4H, (CH2)2NAr], 3.82 (s, 3H, CH3), 6.55 (br s, 1H, NH), 6.35-
7.69 (m, 8H, aromatic); GC/MS m/z 408 (M+, 14), 249 (63), 216
(40), 206 (28), 161 (33), 135 (100).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-1-
m eth oxy-2-n a p h th a len eca r boxa m id e (32). Eluted with
CHCl3/AcOEt, 19:1, in 45% yield. 1H NMR (300 MHz, CDCl3):
δ 1.67-1.77 [m, 4H, NHCH2(CH2)2], 2.50 [t, 2H, J ) 7.0 Hz,
CH2N(CH2)2], 2.65 [br s, 4H, CH2N(CH2)2], 3.02 [br s, 4H,
(CH2)2NAr], 3.55-3.61 (m, 2H, NHCH2), 4.00 (s, 3H, CH3),
6.84-8.17 (m, 10H, aromatic, NH).
N-[4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl]-2-
n a p h th a len eca r boxa m id e (33). Eluted with CHCl3/AcOEt,
1:1 in 48% yield. 1H NMR (300 MHz, CDCl3): δ 1.66-1.79 [m,
4H, NHCH2(CH2)2], 2.48 [t, 2H, J ) 6.7 Hz, CH2N(CH2)2], 2.62
[br s, 4H, CH2N(CH2)2], 2.97 [br s, 4H, (CH2)2NAr], 3.54 (q,
2H, J ) 6.2 Hz, NHCH2), 6.71-8.33 (m, 11H, aromatic, NH).

5734 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26
Leopoldo et al.
Biologica l Meth od s. 1. Gen er a l. Human recombinant D4.4
dopamine receptor expressed in CHO cells, human recombi-
nant D2L dopamine receptor expressed in Sf9 cells, and rat
recombinant D3 dopamine receptor expressed in Sf9 cells were
obtained from RBI (Research Biochemicals International,
Natick, MA). For receptor binding studies, the compounds were
dissolved in absolute ethanol. Male Wistar Hannover rats
(200-250 g) were from Harlan (S. Pietro al Natisone, Italy).
The animals were handled according to internationally ac-
cepted principles for care of laboratory animals (E. E. C.
Council Directive 86/609, O. J . No. L358, December 18, 1986).
8-OH-DPAT hydrobromide was from RBI (Research Biochemi-
cals International, Natick, MA); haloperidol, phentolamine
hydrochloride, and clozapine were from Sigma-Aldrich (Milan,
Italy); [3H]prazosin, [3H]8-OH-DPAT, and [3H]spiroperidol
were obtained from NEN Life Science Products (Milan, Italy).
2. Radioligan d Bin din g Assay at Rat-Clon ed D3 Dopam -
in er gic Recep tor s. Binding of [3H]spiroperidol at rat-cloned
D3 receptor was performed according to Swarzenski et al.33
with minor modifications. The reaction buffer consisted of 50
mM Tris, 5 mM MgCl2, 5 mM EDTA, 5 mM KCl, 1.5 mM
CaCl2, 120 mM NaCl (pH 7.4), including 100 µL of dopamine
D3 diluted membranes, 0.4 nM of [3H]spiroperidol (Kd ) 0.60
nM), and 100 µL of the drug solution (six to nine concentra-
tions) for a total volume of 1 mL. Samples were incubated at
27 °C for 60 min, then the incubation was stopped by rapid
filtration through Whatman GF/C glass fiber filters (presoaked
in 0.3% polyethylenimine). The filters were washed twice with
1 mL of ice-cold buffer (50 mM Tris, pH 7.4). Nonspecific
binding was defined in the presence of 10 µM haloperidol.
drugs studied were incubated. Nonspecific binding was defined
using 1 µM 8-OH-DPAT. Samples were incubated at 37 °C for
20 min and then filtered on Whatman GF/B glass microfiber
filters. The Kd value determined for 8-OH-DPAT was 8.8 nM.
6. Ra d ioliga n d Bin d in g Assa y a t Ra t Cor tica l Mem -
br a n es r1-Ad r en ocep tor s. Binding experiments were per-
formed according to Glossmann and Hornung36 with minor
modifications. Rats were killed by decapitation, the brain was
quickly removed, and the cerebral cortex was dissected. The
cerebral cortex (1.0 g) was homogenized with a Brinkman
Polytron (setting 5 for 3 × 15 s) in 25 mL of buffer (50 mM
Tris, 0.1 mM PMSF, pH 7.4). The homogenate was centrifuged
at 1000g for 15 min at 4 °C. The supernatant was recovered
and centrifuged at 50000g for 30 min at 4 °C. The final pellet
was stored at -80 °C until used. Each tube received in a final
volume of 1 mL of 50 mM Tris (pH 7.4) rat cerebral cortical
membranes suspension and 1 nM [3H]prazosin. For competi-
tive inhibition experiments, various concentrations of drugs
studied were incubated. Nonspecific binding was defined using
10 µM phentolamine. Samples were incubated at 25 °C for 50
min and then filtered on Whatman GF/B glass microfiber
filters. The filters were presoaked for 50 min in Tris-poly-
ethylenimine 0.5%. The Kd value determined for prazosin was
0.5 nM.
7. Sta tistica l An a lysis. The inhibition curves on the
different binding sites of the compounds reported in Table 2
were analyzed by nonlinear curve fitting utilizing the Graph-
Pad Prism program.37 The value for the inhibition constant,
Ki, was calculated by using the Cheng-Prusoff equation.38
3. Ra d ioliga n d Bin d in g Assa y a t Hu m a n -Clon ed D4.4
Dop a m in er gic Recep tor s. Binding of [3H]spiroperidol at
human-cloned D4.4 receptor was performed according to Hadley
et al.34 with minor modifications. The reaction buffer consisted
of 50 mM Tris, 5 mM MgCl2, 5 mM EDTA, 5 mM KCl, 1.5
mM CaCl2 (pH 7.4), including 500 µL of dopamine D4.4 diluted
membranes, 0.15 nM of [3H]spiroperidol (Kd ) 0.17 nM), and
100 µ L of the drug solution (six to nine concentrations) for a
total volume of 1 mL. Samples were incubated at 25 °C for 60
min, then the incubation was stopped by rapid filtration
through Whatman GF/A glass fiber filters (presoaked in 0.3%
polyethylenimine). The filters were washed twice with 1 mL
of ice-cold buffer (50 mM Tris, pH 7.4). Nonspecific binding
was defined in the presence of 10 µM clozapine.
4. Ra d ioliga n d Bin d in g Assa y a t Hu m a n -Clon ed D2L
Dop a m in er gic Recep tor s. Binding of [3H]spiroperidol at
human-cloned D2L receptor was performed according to Hadley
et al.34 with minor modifications. The reaction buffer consisted
of 50 mM Tris, 10 mM MgCl2, 1 mM EDTA (pH 7.4), including
500 µL of dopamine D2L receptor diluted membranes, 0.2 nM
[3H]spiroperidol (Kd ) 0.20 nM), and 100 µL of the drug
solution (six to nine concentrations) for a total volume of 1
mL. Samples were incubated at 27 °C for 60 min, then the
incubation was stopped by rapid filtration through Whatman
GF/C glass fiber filters (presoaked in 0.3% polyethylenimine).
The filters were washed twice with 1 mL of ice-cold buffer (50
mM Tris, pH 7.4). Nonspecific binding was defined in the
presence of 10 µM haloperidol.
5. Ra d ioliga n d Bin d in g Assa y a t Ra t Hip p oca m p a l
Mem br a n es 5-HT1A Recep tor s. Binding experiments were
performed according to Borsini et al.35 with minor modifica-
tions. Rats were killed by decapitation, the brain was quickly
removed, and the hippocampus was dissected. The hippocam-
pus (1.0 g) was homogenized with a Brinkman polytron
(setting 5 for 3 × 15 s) in 25 mL of 50 mM Tris buffer, pH 7.6.
The homogenate was centrifuged at 48000g for 15 min at 4
°C. The supernatant was discarded, and the pellet was
resuspended in 25 mL of buffer, then preincubated for 10 min
at 37 °C. The homogenate was centrifuged at 48000g for 15
min at 4 °C. The supernatant was discarded, and the final
pellet was stored at -80 °C until used. Each tube received in
a final volume of 1 mL of 50 mM Tris (pH 7.6) hippocampus
membranes suspension and 1 nM [3H]-8-OH-DPAT. For
competitive inhibition experiments, various concentrations of
Ack n ow led gm en t. This study was supported by
Research Grant No. 2001037552-003 from Universita`
degli Studi di Bari and MURST (Italy) for the scientific
program in CHIM/08 field (2002-2003).
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