Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl) arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: Potential substance abuse therapeutic agents

Article abstract of DOI:10.1021/jm0704200

Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-trans-but-2- enyl)-4-pyridine-2-ylben

Full text of DOI:10.1021/jm0704200

J. Med. Chem. 2007, 50, 4135-4146
4135
Heterocyclic Analogues of N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides
with Functionalized Linking Chains as Novel Dopamine D3 Receptor Ligands: Potential
Substance Abuse Therapeutic Agents
Peter Grundt,† Katherine M. Prevatt,† Jianjing Cao,† Michelle Taylor,‡ Christina Z. Floresca,‡ Ji-Kyung Choi,§
Bruce G. Jenkins,§ Robert R. Luedtke,‡ and Amy Hauck Newman*,†
Medicinal Chemistry Section, National Institute on Drug AbusesIntramural Research Program, National Institutes of Health, 5500 Nathan
Shock DriVe, Baltimore, Maryland 21224, Department of Pharmacology and Neuroscience, UniVersity of North Texas Health Science Center,
Fort Worth, Texas 76107, and Massachusetts General HospitalsNMR Center and HarVard Medical School, Boston, Massachusetts 02129
ReceiVed April 10, 2007
Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects
induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)-
piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylbenzamide)] and related analogues are currently being
evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding
affinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was to
examine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropyl
substitutions on the butylamide linking chain systematically coupled with 2-fluorenylamide or 2-pyridylphe-
nylamide and 2-methoxy- or 2,3-dichloro-substituted phenylpiperazines to measure the impact on binding
affinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated at
the human dopamine D3 (hD3) receptor (Ki ) 1-5 nM) as measured in competition binding assays. Several
analogues showed >100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while all
the derivatives with an olefinic linker were antagonists, in quinpirole-stimulated mitogenesis at hD3 receptors,
several of the hydroxybutyl-linked analogues (16, 17, 21) showed partial agonist activity. Finally, several
structural modifications reduced lipophilicities while retaining the desired binding profile.
Introduction
between the D2 and D3 dopamine receptor subtypes, has
provided a formidable challenge in the pursuit to discover
dopamine D3-selective compounds. Thus far, high dopamine
D2/D3 selectivity has typically been achieved with relatively
large molecules characterized by a heterocyclic moiety bridged
by an unsubstituted four-carbon chain or carbocycle to an
extended or substituted arylamide or a corresponding bioiso-
tere.7,11 Arylcarboxylamides connected through a butyl chain
to a 2,3-dichloro- or 2-methoxy-substituted phenylpiperazine
such as the compounds 2-4 depicted in Figure 1 are well-
studied examples of dopamine D3 receptor preferring com-
pounds. Analogues 5 and 6 featuring a trans-butenyl linker with
2,3-dichlorophenylpiperazine have also been examined and
found to display improved D2/D3 selectivity ratios compared
to their saturated butyl counterparts.15 The trans-cyclohexyl
derivatives of the 4-phenylpiperazines also showed promising
dopamine D3 receptor affinities.16 However, the incorporation
of shorter and longer linkers such as propyl and pentyl resulted
in reduced dopamine D3 receptor affinity and/or selectivity over
dopamine D2 or D4 receptors17-19
Nicotine, alcohol, cocaine, methamphetamine, and the opiates
can stimulate brain reward pathways that may lead to abuse
and addiction.1 The dopamine receptor system plays a key role
in numerous neuropsychiatric and neurological disorders, and
investigation into mechanistic underpinnings and neuroadapta-
tions within this family of receptors has been the focus of
intensive research over the past decade. Recently, the dopamine
D2-like receptor subtypes (D2, D3, D4) have been studied using
imaging techniques in animal models as well as in human
addicts to further delineate the molecular mechanisms respon-
sible for the reinforcing effects of psychostimulants.2-5
In this pursuit, the dopamine D3 receptor subtype has been
hypothesized to play a fundamental role in the abuse-related
effects of cocaine and other drugs of abuse.6-9 Hence, the need
to develop novel, selective, and bioavailable dopamine D3
receptor ligands has been recently emphasized.7,10-12 Further
support for pursuing dopamine D3 receptor selective ligands
as potential medications for drug abuse and addiction comes
from the brain localization of D3 receptors, which are primarily
expressed in limbic regions of the brain, including the nucleus
accumbens. It has been hypothesized that D3 receptor blockade
may antagonize drug reward and/or reinforcement while avoid-
ing the risk of extrapyramidal side effects associated with the
blockade of the more ubiquitous D2 receptors.13
In addition to optimizing pharmacological selectivity, it is
also important that these novel compounds be able to penetrate
the blood brain barrier (BBB) and have appropriate pharmaco-
kinetics to facilitate interpretation of in vivo results. Compounds
4 and 6 have been evaluated for D3 function in animal models
of cocaine abuse and demonstrate D3 antagonism in vivo.20,21
However, it has been our observation that relatively high doses
of these as well as other D3-selective agents including 1 and 3
(Figure 1) are required for behavioral activity.20,22,23 It is not
known whether these required high doses are due to a low
permeability surface area product of these agents for crossing
the BBB, high peripheral metabolism, large uptake in some other
The high degree of amino acid homology13,14 within the
binding sites of the dopamine D2-like receptors, especially
* To whom correspondence should be addressed. Phone: (410) 550-
6568,extension114.Fax: (410)550-6855.E-mail: anewman@intra.nida.nih.gov.
† National Institute on Drug AbusesIntramural Research Program.
‡ University of North Texas Health Science Center.
§ Massachusetts General HospitalsNMR Center and Harvard Medical
School.
10.1021/jm0704200 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/02/2007

4136 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Grundt et al.
Figure 1. Selective pharmacological tools for the dopamine D3 receptor.
Figure 2. Maps of the hemodynamic response (rCBV) to 2 mg/kg iv compound 6 in a rat. The slices cover an anterior to posterior direction from
Bregma +2.2 to -8.3. The color map shows statistically significant changes in cerebral blood volume (CBV). Also shown on the bottom left and
top right are zoomed slices A2 and A3 with an overlay from a Paxinos atlas corresponding to the appropriate slices. The D3 antagonist produces
rCBV changes in nucleus accumbens, islets of Calleja, and hippocampus consistent with the D3 receptor distribution. Note that there is little
activation in the caudate/putamen showing great selectivity of D3 over D2 receptors.
organ or compartment, or alternative mechanisms. Preliminary
evaluation of compound 6 and several related analogues for
activity in the spot Ames test and Herg assay and for CaCo-2
absorption potential suggests that these compounds may be
candidates for clinical development (personal communication
with Dr. Jane Acri). Nevertheless, their restricted aqueous
solubility may limit the validity of these predictive tests, and
thus, investigating structural modifications that retain the desired
pharmacological profile while reducing lipophilicity will likely
improve water solubility and other physicochemical properties.
entering the brain and occupying dopamine D3 receptor rich
regions using previously published methods.24,25 At a dose of
1.0 or 2.0 mg/kg (iv), 6 readily entered the brain and was
localized in D3 receptor rich brain regions such as the islets of
Calleja and the nucleus accumbens shell while eliciting much
smaller changes in the caudate/putamen consistent with the much
higher ratio of D3 receptors in the accumbens compared to the
caudate/putamen13 (Figure 2). In addition, the increases in
regional cerebral blood volume (rCBV) in these regions
established this agent as a D3 antagonist, comparable to 126
because D3 and D2 agonists lead to decreases in rCBV and
D2/D3 antagonists lead to increases in rCBV.24,25 In Figure 2,
the average of five rats at a dose of 2 mg/kg iv of compound 6
is shown. In these animals the average rCBV change integrated
Pharmacologic Magnetic Resonance Imaging (phMRI)
Pharmacologic magnetic resonance imaging studies (phMRI)
were undertaken to determine whether or not compound 6 was

Analogues of Carboxamides as Receptor Ligands
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4137
Scheme 1. Synthesis of the 3-Hydroxylamines 27a
a Reagents and conditions: (a) phthalimid potassium salt, DMF, microwave, 100 °C, 20 min; (b) 1-(2,3-dichlorophenyl)- or 1-(2-methoxyphenyl)piperazine,
2-PrOH, microwave, 90 °C, 20 min; (c) hydrazine, ethanol, microwave, 90 °C, 20 min.
Scheme 2. Synthesis of the 2-Hydroxylamines 30a
a Reagents and conditions: (a) 1-(2,3-dichlorophenyl)- or 1-(2-methoxyphenyl)piperazine, potassium carbonate, acetone, reflux, 24 h; (b) sodium azide,
ammonium chloride, DMF, 100 °C; 5 h; (c) triphenylphosphine, THF, room temperature, 16 h.
from 0 to 30 min was 8.9% in the accumbens versus 3.2% in
the caudate/putamen (a ratio of 2.8). In addition, there was
significant activation in the hippocampus as expected based on
D3 receptor expression.27 It was noted that there was an apparent
discrepancy between the dose of compound 6 required for
behavioral activity (e.g., 30-56 mg/kg)20 compared to the dose
that showed D3 receptor blockade in the phMRI studies.
Although the behavioral studies used the sc route of administra-
tion while the phMRI studies used the iv route, there still seemed
to be a significant dose difference. These results combined with
the high D3 receptor affinity (Ki(D3) ) 0.7 nM) in vitro
suggested that either suboptimal pharmacokinetics were respon-
sible or another mechanism may be involved in the behavioral
actions of these dopamine D3 receptor antagonists.
In order to further address these possibilities, new ligands
were designed with modifications of the amide linking chain
incorporated to preserve and/or increase high affinity and
dopamine D3 receptor selectivity while potentially improving
the pharmacokinetics of these agents. Thus far, the optimal
length and conformation of the linking chains have been
established, but appended functionality on the linker has not
been explored except recently.19 The high lipophilicity of these
drugs was our primary concern, and as such, we considered
substitutions that might provide some additional polarity and
thus reduce lipophilicity.28 Using the established pharmacophore
of the dopamine D3 selective ligands 329 and 6,15 and the
2-methoxy substituted phenylpiperazine moiety, first introduced
in the D3 partial agonist, 213 (Figure 1), we investigated
systematic substitutions on the saturated butyl linking chain
while comparing the 2-methoxy- and 2,3-dichloro-substituted
phenylpiperazines and the 2-pyridylphenyl to the 2-fluorenyl
ring systems in the arylamide portion of the molecule. Several
substitution patterns on the 2-pyridyl group of 6 were also
investigated. Binding data at human dopamine D2-like receptors
and D2/D3 selectivity for all analogues were compared to those
for the parent ligands. For selected compounds, D2 and D3
functional data using the quinpirole-stimulated mitogenesis assay
and binding data for the serotonin receptors 5HT1A, 5HT2A, and
5HT2C were also obtained.
Chemistry
The racemic hydroxybutylamine intermediates 27 and 30
needed to prepare the 3-hydroxy derivatives 16-19 and
2-hydroxy analogues 21-23 were synthesized as depicted in
Schemes 1 and 2. In both cases, the synthetic routes used
bifunctional 2-(2-bromoethyl)oxirane (24)30 as starting material.
All key steps were found to be regioselective, and only the
products depicted were isolated. The amines 27 (Scheme 1) were
synthesized via a modified Gabriel synthesis. No side products
were observed in the alkylation reaction to form the phthalimide
25. The opening of the oxirane moiety occurred selectively at
the least substituted side to yield the 3-hydroxyphthalimides 26,
which were then deprotected with hydrazine to afford the
hydroxylamines 27. In the case of the 2-hydroxylamines (30,
Scheme 2) the butylpiperazine bond was formed first, followed
by a regioselective opening of the epoxide with sodium azide
and a Schlesinger-type reduction. The general reaction sequence
was used to prepare the dopamine D3 receptor preferring
analogues 2-23 incorporating a butyl, butenyl, or hydroxybutyl
linking chain as depicted in Scheme 3. The required carboxylic
acids were prepared according to literature procedures.17,31 The
general syntheses of the butylamines and the butenylamines have
been described earlier.15,17,32,33 Because of constraints of readily
available starting material, the synthesis of the cyclopropyl

4138 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Scheme 3. Synthesis of Compounds 2-23a
Grundt et al.
a Reagents and conditions: (a) CDI, pyridine or DCC, HOBt, DMF. 13 was prepared from 6 by N-oxidation (mCPBA, CH2Cl2, room temperature, 16 h).
20 was prepared from 16 by acetylation (NEt3, CH3COCl, room temperature, 16 h).
Scheme 4. Synthesis of the Dimethylcyclopropyl Analogues 33 and 34a
a Reagents and conditions: (a) CDI, 4-pyridin-2-ylbenzoic acid, pyridine, room temperature; (b) trifluoromethanesulfonic anhydride, CH2Cl2, room
temperature, 4 h; (c) 2,3-dichlorophenylpiperazine, sodium bicarbonate, acetonitrile, reflux, 16 h.
derivatives 33 and 34 (Scheme 4) featured a formation of the
amide bond prior to the addition of the phenylpiperazine moiety.
Both the trans amide 32a and its cis isomer 32b were prepared
from the corresponding cyclopropylamines 31.34 Conversion of
the hydroxyl group to a triflate leaving group followed by
alkylation with 2,3-dichlorophenylpiperazine gave the isomeric
cyclopropyl derivatives 33 and 34 in good yield.
than 6 and thus a 221-fold 5HT1A/D3 selectivity. Interestingly,
compared to 6 (IC50(D2) ) 80.0 nM), the 6-methyl substituted
analogue 10 was 16-fold less potent at the dopamine D2 receptor
(EC50(D2) ) 1300 nM), making it the most functionally D3
selective analogue (194-fold) in the series (Table 2).
Pyridyl N-oxidation (12) retained high dopamine D3 affinity
(Ki ) 1.1 nM) comparable to the parent compound 6. However,
as was observed with the 6-oxa analogue 9, an oxa modification
of the pyridyl moiety led to a 4-fold higher binding affinity for
12 at the dopamine D2 receptor compared to 6, thus reducing
D2/D3 selectivity (3-fold). In contrast, the 1-piperazine N-oxide
13 showed a 70-fold lower binding affinity at the dopamine
D3 receptor and a 12-fold lower binding affinity at the dopamine
D2 receptor. Hence, these results show that while the oxidation
products of the pyridyl moiety negatively affect D2/D3 selectiv-
ity, oxidation of the 1-nitrogen of the piperazine ring is most
detrimental to high binding affinity at both D2 and D3 receptors.
These analogues could be oxidative metabolites of 6, and thus
this information may be important for determining pharmaco-
logical effects due to drug metabolism in vivo.
Pharmacological Results and Discussion
All ligands were evaluated in competition binding assays in
HEK 293 cells transfected with human D2L, D3, or D4
dopamine receptors.15 The displaced radioligand was the high-
affinity, selective D2-like receptor antagonist 2,3-dimethoxy-
5-(125I)-iodo-N-(9-benzyl-9-azabicyclo(3.3.1)nonan-3-yl) ben-
zamide (125I-IABN).35 In addition, clogP values and polar surface
areas (PSA) were calculated to provide a measure of lipophilicity
and predicted brain penetration, respectively.36,37 These data are
presented in Table 1. Selected compounds were also evaluated
in a quinpirole-stimulated mitogenesis assay for functional
activity at dopamine D2 and D3 receptors (Table 2) and for
binding affinities at the serotonin 5HT1A, 5HT2A, and 5HT2C
receptors (Table 3).
Substituent effects at the 2-pyridyl moiety of 6 on D2 and
D3 receptor binding affinities and D2/D3 selectivities were
examined with analogues 9-12. As depicted in Table 1, the
6-oxa derivative 9 was equiactive to 6 at D3 receptors. However,
9 had a 4-fold higher affinity at dopamine D2 receptors, resulting
in a lower D2/D3 selectivity ratio than 6. On the other hand,
compared to 6, the 6-methyl substituted analogue 10 had little
effect on binding at either dopamine D2 or dopamine D3
receptors. Indeed, the effects of the 6-methyl substitution were
mostly directed toward the serotonin 5HT1A subtype (Table 3).
Compound 10 showed a nearly 4-fold lower binding affinity
The olefinic linked derivatives with the 2-methoxy substituted
phenylpiperazine (14 and 15) were less D2/D3 selective (up to
6-fold) than their corresponding 2,3-dichloro analogues (6 and
5). For example, the 2-methoxyphenyl analogue 14 demon-
strated a 4-fold lower binding affinity at the dopamine D3
receptor than the corresponding 2,3-dichloro derivative 6. On
the other hand, in the fluorenylamide series the 2-methoxy
compound 15 had a >3-fold higher binding affinity at the
dopamine D2 receptor than the 2,3-dichloro analogue 5,
while the binding affinity at the dopamine D3 receptor was
unaffected by this modification. The compounds with a sat-
urated butyl linking chain showed similar structure-activity
relationships (SAR). No difference was observed in the

Analogues of Carboxamides as Receptor Ligands
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4139
Table 1. Human D2-like Family Receptor Subtype Binding Data in HEK Cells
a 4-(2,3-Dichlorophenyl)piperazine 1-oxide.

4140 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Grundt et al.
Table 2. In Vitro Functional Data at D2-like Receptors for Selected
Pairs of D3 compounds with an aliphatic linker and varied
substituents on the phenylpiperazine (2-methoxy vs 2,3-dichloro)
have been synthesized previously, and for example, Chu et al.
have demonstrated that the 2-benzofuranylamides showed no
difference in binding profiles regardless of the substitution of
the phenylpiperazine.38 On the other hand, Bettinetti et al.,18
using somewhat different assay conditions, reported a more than
3-fold higher binding affinity at the dopamine D2 receptors for
the 2-methoxy compared to the 2,3-dichloro analogues for the
same compounds, while the binding affinities at the dopamine
D3 receptor were unaffected. On the basis of these and the
present studies, it is clear that both the 2-methoxy and the 2,3-
dichlorophenyl substitutions give high D3 binding affinities and,
depending on the linking chain and the nature of the arylamide,
varying selectivities over the other dopamine and serotonin
receptors are achieved. These findings are important for
radioligand and imaging agent development39-41 but may also
affect ligand selection for in vivo studies, as the most D3-
selective compound might not be the best candidate if other
physicochemical properties are determined to be superior for
another analogue.42
Ligandsa
In the mitogenesis assay (Table 2), both fluorenylamides 3
and 7 were determined to be antagonists at D3 receptors, and
corresponding with the binding data, the 2-methoxyphenylpip-
erazine 7 (IC50(D3) ) 2.2 nM) was 7 times more potent
functionally than the corresponding 2,3-dichloro substituted
analogue 3 (IC50(D3) ) 14.4 nM). Incidentally, 3 and 7 were
found to have similar D2/D3 selectivities of 89-fold and 102-
fold, respectively, in the mitogenesis assay. In contrast to the
2,3-dichloro substituted partial agonist 4, the corresponding
2-methoxy derivative 8 demonstrated antagonism in the func-
tional assay at the dopamine D3 receptor.
In the 5-HT binding assays (Table 3), the 2,3-dichloro
derivatives generally showed lower 5-HT1A receptor binding
affinities, resulting in somewhat higher 5-HT1A/D3 selectivities
than the corresponding the 2-methoxy analogues. However, the
2-methoxy derivatives with saturated linking chains (7 and 8)
were at least 5-fold more 5-HT2C/D3 selective than the corre-
sponding 2,3-dichloro compounds (3 and 4), an observation that
had been reported earlier.38 In contrast, in the olefinic series of
analogues (14, 6, 15, 5), selectivities of the 5-HT2C receptor
over the dopamine D3 receptor were essentially unaffected by
the substitution pattern on the phenylpiperazine moiety.
Overall, the hydroxybutyl linker was well tolerated at the
dopamine D3 receptor, resulting in up to 177-fold dopamine
D2/D3 selectivity (e.g., compound 17). Binding affinities at the
dopamine D3 receptor and D2/D3 selectivity of the 3-hydroxy-
butyl derivatives were determined by the arylamide moiety and
were independent of the substitution on the phenylpiperazine
(2,3-dichloro vs 2-methoxy). The 2-pyridylphenyl analogues 16
and 18 not only showed similar binding affinities at D3 receptors
but also displayed no difference in binding affinity at the 5HT1A
receptor, resulting in similarly low 5HT1A/D3 selectivities (<13-
fold). However, in line with the aliphatic analogues 4 and 8,
the 2-methoxy derivative 18 demonstrated 18-fold higher 5HT2A/
D3 and 37-fold higher 5HT2C/D3 selectivities than 16. Acety-
lation (20) of the hydroxyl group of 16 was not well tolerated
at the dopamine D3 receptor presumably because of steric
hindrance.
a Data were obtained through the NIDA Addiction Treatment Discovery
Program contract with SRI (N01DA-1-8816). b Partial agonist activity: EC50
(% stimulation). c This compound is a very weak partial agonist and likely
functions as an antagonist in vivo.
binding profile at dopamine D2 and D3 receptors within the
saturated 2-pyridylphenyl analogues 4 and 8, regardless of the
substituent on the phenylpiperazine. However, the 2-methoxy-
fluorenyl derivative 7 was found to have both high affinity at
the dopamine D3 receptor (Ki(D3) ) 0.3 nM) and lower affinity
at D2 (Ki ) 55.4 nM), resulting in the highest (185-fold) D2/
D3 selectivity ratio of the series.
Compared to the 3-hydroxybutyl analogue 16, the 2-hydroxy-
butyl derivative 21 was determined to have higher binding
affinities at both D2 and D3 receptors, by 9- and 6-fold,
respectively. Interestingly, the 2-hydroxybutyl analogue 21 and
the butyl analogue 4 shared a very similar binding profile,

Analogues of Carboxamides as Receptor Ligands
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4141
Table 3. Binding Affinities for Serotonin Receptor Subtypes for Selected Ligandsa
a Data were obtained through the NIDA Addiction Treatment Discovery Program contract with SRI (N01DA-1-8816). b 4-(2,3-Dichlorophenyl)piperazine
1-oxide.
suggesting that the 2-OH may not provide a point of contact at
predicting decreased lipophilicity, compared to the correspond-
ing parent olefinic or aliphatic compounds. The calculated polar
surface area (PSA)36 was significantly increased (by 20 Å2).
Values less than 75 Å2 are considered as being favorable for
brain penetration. Coupled with their favorable binding profiles,
several of these new analogues have been selected for in vivo
evaluation.
the receptor binding site, in potential contrast to substitution in
the 3-position. This observation appears to be independent of
the structure of the arylamide compared to 3. The 2-hydroxy
analogue 22 also showed a similar binding profile.
As expected, the introduction of a hydroxyl group into the
butyl linking chain resulted in somewhat lower clogP values,

4142 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Grundt et al.
The trans-cyclopropyl linking chain was found to be well
tolerated at the dopamine D3 receptor. Compound 33 (Ki(D3)
) 1.0 nM) showed a similar binding profile compared to the
trans-olefin 6 (Ki(D3) ) 0.7 nM), not only at the dopamine D3
receptor but also at the serotonin 5HT1A, 5HT2A, and 5HT2C
receptors. In contrast, the cis-cyclopropyl analogue 34 demon-
strated a 160-fold lower binding affinity at the dopamine D3
receptor than the trans-isomer 33. Interestingly, the binding
affinities at the dopamine D2 receptor and the serotonin
receptors were somewhat less affected by the cis conformation
of the linker, up to 19-fold lower compared to the trans
derivative. Thus, the D2/D3 selectivity of 34 was low (7-fold),
indicating that a trans geometry of the linker is pivotal to
achieving optimal dopamine D3 affinity and D2/D3 selectivity.
This correlates well with results reported earlier for other
phenylpiperazines with an olefinic linking chain, where a trans
olefin was the preferred conformation compared to the cis
olefin.19,33 Thus, the difference in the observed binding affinities
at dopamine D3 receptors may further support the hypothesis
that an extended linear arrangement is the most probable
bioactive conformation of the phenylpiperazine class of dopam-
ine D3 receptor preferring ligands.43
predict “druglike” properties. These compounds will provide
novel tools with which to further elucidate the role of dopamine
D3 receptors in drug abuse, in vivo, and may serve as leads for
therapeutic agents for the treatment of addiction.
Experimental Methods
All melting points were determined on a Thomas-Hoover melting
point apparatus and are uncorrected. The 1H and 13C NMR spectra
were recorded on a Varian Mercury Plus 400 instrument. Proton
chemical shifts are reported as parts per million (δ ppm) relative
to tetramethylsilane (0.00 ppm) as an internal standard. Coupling
constants are measured in hertz (Hz). Chemical shifts for 13C NMR
spectra are reported as δ relative to the deuterium signal of the
solvent (CDCl3, 77.5 ppm; CD3OD, 49.3 ppm). Microanalyses were
performed by Atlantic Microlab, Inc. (Norcross, GA) and agree
within 0.4% of calculated values. If not stated otherwise, all final
compounds were purified by column chromatography (silica gel,
Merck, 230-400 mesh, 60 Å) or thin layer chromatography (silica
gel, Analtech, 1000 µm) using EtOAc/CHCl3 (5:5:1), 1% triethy-
lamine or CHCl3/MeOH (10:1), 1% triethylamine as an eluent.
Microwave reactions were performed in a CEM Discover Labmate
system equipped with a 80 mL pressure vessel. Yields and reaction
conditions are not optimized. Generally, yields and spectroscopic
data refer to the free base. The procedures to determine the binding
affinities at the human dopamine D2-like receptors15 and the binding
affinities at the serotonin 5HT1A, 5HT2A, and 5HT2C receptors45
and the functional mitogenesis assay45 have been published earlier.
General Procedure for the Synthesis of Carboxylic Acid
Amides. The 1-imidazole adduct appropriate carboxylic acid was
reacted with the suitable secondary amine derivative as described
previously.15 The crude product was purified by chromatography,
structurally characterized, and then converted into its oxalate or
hydrochloride salt for biological evaluation.
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-9H-fluorene-
2-carboxamide (7). 7 was prepared from 9H-fluorene-2-carboxylic
acid and 4-(4-(2-methoxyphenyl)piperazin-1-yl)butylamine32 ac-
cording to the general procedure. Yield: 74%. Mp (hydrochlo-
ride): 208-210 °C. 1H NMR (CDCl3): δ 1.67-1.73 (m, 4H), 2.47
(t, J 6.7, 2H), 2.65 (s, 4H), 3.04 (s, 4H), 3.51 (q, J 6.1, 2H), 3.84
(s, 3H), 3.91 (s, 2H), 6.82-6.88 (m, 4H), 6.98 (dt, J 7.8, 4.6, 1H),
7.35 (td, J 7.4, 1.2, 1H), 7.40 (t, J 7.0, 1H), 7.55 (d, J 7.0, 1H),
7.75-7.77 (m, 2H), 7.81 (d, J 8.0, 1H), 7.96 (s, 1H). 13C NMR
(CDCl3): δ 25.0, 27.9, 37.3, 40.5, 50.93, 53.9, 55.8, 58.5, 111.5,
118.6, 120.1, 121.0, 121.4, 123.4, 124.4, 125.6, 126.3, 127.4, 128.0,
133.8, 141.2, 141.6, 143.8, 144.4, 145.1, 152.7, 168.6. Anal.
(C29H33N3O2‚2HCl‚0.5H2O) C, H, N.
Summary and Conclusions
On the basis of the parent compounds 3 and 6, a series of
analogues were prepared to further explore SAR at dopamine
D3 receptors and to optimize “druglike” properties44 without
significantly modifying the pharmacological profile. Modifica-
tions to the 2-pyridylphenylamide of 6 were generally well
tolerated at D3 receptors but had a small detrimental effect on
D2/D3 selectivity. The 2-methoxy vs 2,3-dichloro substitution
on the phenylpiperazine moiety was equally tolerated at the
dopamine D3 receptors, although modifications to the rest of
the molecule caused changes in selectivities. Hydroxyl substitu-
tions in the linking butyl chain were also well tolerated and
produced one of the most selective compounds in this structural
class reported to date (17). This substitution provided a H-bond
donor moiety in a part of the molecule that did not adversely
affect binding but does reduce lipophilicity, which may be
important for improved solubility and permeability of these
molecules for in vivo studies.44 Limited steric tolerance at the
3-position of the linking chain was suggested on the basis of
the significant decrease in binding affinity of the acetylated
analogue. This corresponds to a similar finding with methyl
substitution at this position19 in a related series of dopamine
D3 antagonists. The cyclopropyl analogues do not provide any
improvement over the olefin analogues but served to further
confirm the trans conformation of the linker as being optimal
at dopamine D3 receptors. Both partial agonists and antagonists
were identified in the mutagenesis assay for function at
dopamine D3 receptors. At this time, the only consistent
structural feature that predicts efficacy is structural rigidity in
the linking chain. As with other D3 agents with structurally
rigid linkers, such as in 1, all of the olefins and cyclopropyl
analogues were D3 antagonists, whereas compounds with
saturated linkers were either antagonists or partial agonists in
the mitogenesis assay. Although the arylamide portion of a
similar series of molecules has been suggested to predict
efficacy,43 our combined studies of >100 related analogues to
date have not confirmed this finding. Whether or not the
mitogenesis or other in vitro functional tests can predict D3
efficacy in vivo will be the topic of future investigation because
this information will be instructive for medication development.
In summary, a series of novel high affinity and D3 selective
compounds have been synthesized whose clogP and PSA values
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-4-pyridin-2-
ylbenzamide (8). 8 was prepared from 4-pyridin-2-ylbenzoic acid
hydrochloride and 4-(4-(2-methoxyphenyl)piperazin-1-yl)buty-
lamine32 according to the general procedure. Yield: 53%. Mp
1
(oxalate): foam. H NMR (CDCl3): δ 1.67-1.74 (m, 4H), 2.49
(t, J 6.84, 2H), 2.67 (s, 2H), 3.07 (s, 2H), 3.51 (q, J 6.0, 2H), 3.84
(s, 3H), 6.83 (m, 5H), 7.26 (m, 1H), 7.73-7.79 (m, 2H), 7.89 (d,
J 8.2, 2H), 8.06 (d, J 8.6, 2H), 8.71 (dt, J 4.7, 1.3, 1H). 13C NMR
(CDCl3): δ 24.8, 27.9, 40.4, 50.8, 53.9, 55.8, 58.5, 111.6, 118.7,
121.3, 121.4, 123.1, 123.4, 127.4, 127.9, 135.6, 137.3, 142.5, 150.3,
152.7, 156.7, 167.8. Anal. (C27H32N4O2‚(COOH)2‚0.75H2O) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-
4-(6-oxo-1,6-dihydropyridin-2-yl)benzamide (9). A suspension of
0.12 g (0.53 mmol) of 4-(6-oxo-1,6-dihydropyridin-2-yl)benzoic
acid, 0.13 g (0.64 mmol) of dicyclohexylcarbodiimide, 0.1 g (0.7
mmol) of 1-hydroxbenzotriazole hydrate in 15 mL of DMF was
treated at 0 °C with 0.16 g (0.53 mmol) of 4-(4-(2,3-chlorophenyl)-
piperazin-1-yl)-trans-but-2-enylamine15 and 0.17 mL (1.2 mmol)
of triethylamine. The reaction mixture was stirred at room tem-
perature for 3 days and filtered. The solvent was removed in vacuo,
and the residue was taken up in saturated sodium bicarbonate and
CHCl3. The combined organics were dried with sodium sulfate and
concentrated, and the crude product was purified by thin layer
chromatography. Yield: 0.10 g (38%). 1H NMR (CDCl3): δ 2.67

Analogues of Carboxamides as Receptor Ligands
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4143
(s, 4 H), 3.06 (s, 6 H), 4.11 (m, 2H), 5.74-5.83 (m, 2H), 6.51-
6.54 (m, 2H), 6.70 (t, J 5.3, 1 H), 6.95 (dd, J 6.7, 2.9, 1H), 7.11-
7.17 (m, 2H), 7.50 (dd, J 9.1, 7.0, 1H), 7.72 (d, J 8.3, 2 H), 7.85
(d, J 8.4, 2 H). 13C NMR (CDCl3): δ 40.6, 50.2, 52.3, 59.4, 105.9,
17.9, 118.1, 124.1, 126.3, 126.6, 126.7, 127.0, 127.3, 130.2, 133.2,
135.0, 135.7, 141.6, 145.6, 150.4, 164.5, 167.0. Anal. (C26H26-
Cl2N4O2‚1.5(COOH)2) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-
4-(6-methylpyridin-2-yl)benzamide (10). 10 was prepared from
4-(6-methylpyridin-2-yl)benzoic acid hydrochloride and 4-(4-(2,3-
chlorophenyl)piperazin-1-yl)-trans-but-2-enylamine15 according to
the general procedure. Yield: 18%. Mp (oxalate): 125-126 °C.
1H NMR (CDCl3): δ 2.63 (s, 7H), 3.08 (s, 6H), 4.12 (m, 2H),
5.78-5.80 (m, 2H), 6.42 (s, br, 1H), 6.95 (d, J 6.7, 2.7, 1H), 7.11-
7.16 (m, 3H), 7.55 (d, J 7.7, 1H), 7.65 (t, J 7.6, 1H), 7.87 (d, J 8.7,
2H), 8.05 (d, J 8.3, 2H). 13C NMR (CDCl3): δ 25.2, 42.0, 51.7,
53.7, 60.7, 118.3, 119.1, 122.8, 125.0, 127.5, 127.8, 127.9, 129.4,
130.2, 134.4, 134.7, 137.5, 143.1, 151.7, 156.0, 159.0, 167.4. Anal.
(C27H28Cl2N4O)‚2(COOH)2) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-
4-(3-methylpyridin-2-yl)benzamide (11). 11 was prepared from
4-(3-methylpyridin-2-yl)benzoic acid hydrochloride and 4-(4-(2,3-
chlorophenyl)piperazin-1-yl)-trans-but-2-enylamine15 according to
the general procedure. Yield: 55%. Mp (oxalate): foam. 1H NMR
(CDCl3): δ 2.34 (s, 3H), 2.65 (s, 4H), 3.07-3.10 (m, 6H), 6.12
(m, 2H), 5.78-5.82 (m, 2H), 6.49 (t, J 5.5, 1H), 6.95 (dd, J 6.5,
2.9, 1H), 7.12-7.16 (m, 2H), 7.21 (dd, J 7.6, 4.8, 1H), 7.57-7.62
(m, 3H), 7.86 (dt, J 8.6, 2.0, 2H), 8.53 (dt, J 4.2, 0.8, 1H). 13C
NMR (CDCl3): δ 20.4, 42.0, 51.7, 53.7, 60.7, 119.1, 123.0, 125.0,
127.3, 127.9, 129.4, 129.7, 130.3, 131.4, 134.2, 134.4, 139.2, 144.1,
147.5, 151.6, 158.0, 167.5. Anal. (C27H28Cl2N4O‚1.5(COOH)2‚
0.5C3H7OH‚0.5H2O) C, H, N.
127.5, 127.9, 129.1, 130.5, 135.0, 137.4, 141.6, 142.7, 150.3, 152.7,
156.7, 167.4. Anal. (C27H30N4O2‚3HCl‚4H2O) C, H, N.
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)-trans-but-2-enyl)-
9H-fluorene-2-carboxamide (15). 15 was prepared from 9H-
fluorene-2-carboxylic acid and 4-(4-(2-methoxyphenyl)piperazin-
1-yl)-trans-but-2-enylamine according to the general procedure.
Yield: 61%. Mp (hydrochloride): 224-226 °C. 1H NMR
(CDCl3): δ 2.68 (s, 4H), 3.09-3.10 (m, 6H), 3.86 (s, 3H), 3.94 (s,
2H), 4.13 (m, 2H), 5.81-5.83 (m, 2H), 6.32 (t, J 5.4, 1H), 6.85
(dd, J 8.2, 1.2, 1H), 6.89-6.96 (m, 2H), 7.00 (m, 1H), 7.35 (td, J
7.3, 1.3, 1H), 7.40 (td, J 7.4, 1.6, 1H), 7.57 (d, J 7.4, 1H), 7.78-
7.83 (m, 3H), 7.99 (s, 1H). 13C NMR (CDCl3): δ 37.4, 42.0, 51.0,
53.8, 55.8, 60.8, 111.6, 118.7, 120.2, 121.0, 121.4, 123.4, 124.3,
125.7, 126.2, 127.5, 128.1, 129.3, 130.4, 133.1, 141.1, 141.7, 143.9,
144.5, 145.4, 152.7, 168.0. Anal. (C29H31N3O2‚3HCl) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
4-pyridin-2-ylbenzamide (16). 16 was prepared from 4-pyridin-
2-ylbenzoic acid hydrochloride and 27a according to the general
procedure. Yield: 52%. Mp (hydrochloride): foam. 1H NMR
(CDCl3): δ 1.62 (m, 1H), 1.83 (m, 1H), 2.39-2.46 (m, 2H), 2.58
(m, 2H), 2.82 (m, 2H), 3.05 (s, 4H), 3.45 (m, 1H), 3.89 (m, 2H),
4.00 (s, 1H), 6.91 (dd, J 7.1, 2.5, 1H), 7.08-7.15 (m, 2H), 7.23
(ddd, J 5.89, 4.83, 2.58, 1H), 7.50 (dd, J 5.9, 3.7, 1H), 7.70-7.76
(m, 2H), 7.88 (d, J 8.3, 2H), 8.02 (d, J 8.3, 2H), 8.67 (dt, J 4.8,
1.2, 1H). 13C NMR (CDCl3): δ 33.7, 38.8, 51.6, 53.5, 63.9, 66.6,
118.3, 120.5, 122.3, 124.3, 126.6, 127.1, 127.1, 133.6, 134.4, 136.4,
141.5, 149.3, 150.5, 155.7, 166.3. Anal. (C26H28Cl2N4O2‚2HCl‚0.5-
(2-PrOH)‚1.5H2O) C, H, N.
N-(3-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
9H-fluorene-2-carboxamide (17). 17 was prepared from 9H-
fluorene-2-carboxylic acid and 27a according to the general
procedure. Yield: 58%. Mp (oxalate): 188-190 °C. 1H NMR
(oxalate, CDCl3, 5% D2O): δ 1.60-1.69 (1H, m), 1.83-1.87 (1H,
m), 2.42-2.50 (2H, m), 2.61 (2H, m), 2.86-2.87 (2H, m), 3.07
(4H, s), 3.45-3.52 (1H, m), 3.87-3.94 (4H, m), 6.94-8.00 (10H,
m). 13C NMR (oxalate, CDCl3, 5% D2O): δ 33.6, 37.2, 38.6, 51.6,
53.5, 63.9, 66.7, 118.8, 119.9, 120.8, 124.1, 125.0, 125.4, 126.0,
127.2, 127.7, 127.8, 127.8, 133.1, 134.3, 141.0, 143.6, 144.3, 145.0,
151.3, 167.4, 167.8. Anal. (C28H29Cl2N3O2‚(COOH)2) C, H, N.
N-(3-Hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-
4-pyridin-2-ylbenzamide (18). 18 was prepared from 4-pyridin-
2-ylbenzoic acid hydrochloride and 27b according to the general
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-
4-(pyridin-N-oxide-2-yl)benzamide (12). 12 was prepared from
4-(pyridin-N-oxide-2-yl)benzoic acid and 4-(4-(2,3-dichlorophenyl)-
piperazin-1-yl)-trans-but-2-enylamine15 according to the general
procedure. Yield: 27%. 1H NMR (CDCl3): δ 2.91 (s, br, 4H), 3.06
(m, 6H), 4.07 (m, 2H), 5.71-5.82 (m, 2H), 6.93-6.96 (m, 2H),
7.12-7.15 (m, 2H), 7.27-7.31 (m, 1H), 7.36 (t, J 7.54, 1H), 7.45
(d, J 7.83, 1.74, 1H), 7.86 (m, 4H), 8.33 (d, J 6.65, 0.78, 1H). 13
C
NMR (CDCl3): δ 41.8, 51.4, 53.4, 60.4, 118.9, 124.8, 125.4, 126.5,
127.3, 127.7, 127.7, 128.9, 129.7, 130.3, 134.2, 135.5, 135.6, 140.7,
148.7, 151.39, 166.9. Anal. (C26H26Cl2N4O2‚1.5(COOH)2) C, H, N.
1
procedure. Yield: 47%. Mp (oxalate): foam. H NMR (CDCl3):
δ 1.63 (m, 1H), 1.84 (m, 1H), 2.43 (m, 2H), 2.64 (m, 2H), 2.88
(m, 2H), 3.11 (s, 4H), 3.46 (m, 1H), 3.86 (s, 3H), 4.94 (m, 2H),
6.86 (dd, J 7.4, 1.2, 1H), 6.92-6.94 (m, 2H), 7.01 (m, 1H), 7.23
(m), 7.52 (dd, J 5.9, 3.7, 1H), 7.74-7.79 (m, 2H), 7.91 (d, J 8.3,
2H), 8.05 (d, J 8.3, 2H), 8.71 (dt, J 4.8, 1.2, 1H). 13C NMR
(CDCl3): δ 33.0, 38.3, 50.5, 53.2, 55, 63.5, 66.3, 110.9, 117.9,
120.6, 120.7, 122.4, 122.8, 126.7, 127.2, 134.6, 136.6, 140.8, 141.7,
149.6, 152.0, 156.1, 166.7. Anal. (C27H32N4O2‚2(COOH)2‚0.5H2O)
C, H, N.
4-(2,3-Dichlorophenyl)-1-(4-(4-(pyridin-2-yl)benzamido)-trans-
but-2-enyl)piperazine 1-Oxide (13). A solution of 6 (288 mg, 0.60
mmol) in 10 mL of dichloromethane was treated at 0 °C with
m-chloroperbenzoic acid (0.16 g, 77%, 0.72 mmol). After being
stirred for 16 h at room temperature, the reaction mixture was
successively washed with saturated sodium bicarbonate solution,
H2O, and brine and dried with sodium sulfate. The volatiles were
removed in vacuo, and the residue was purified by preparative thin
layer chromatography. Yield: 93 mg (32%). Mp (hydrochloride):
N-(3-Hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-
9H-fluorene-2-carboxamide (19). 19 was prepared from 9H-
fluorene-2-carboxylic acid and 27b according to the general
1
foam. H NMR (CD3OD): δ 3.23-3.29 (m, 4H), 3.50-3.61 (m,
4H), 3.99 (d, J 6.5, 1H), 4.13 (d, J 4.6, 1H), 6.04-6.18 (m, 2H),
7.18 (dd, J 7.8, 3.9, 1H), 7.24-7.28 (m, 2H), 7.40 (m, 1H), 7.91-
7.93 (m, 2H), 7.99 (d, J 8.4, 2H), 8.06 (d, J 8.7, 2H), 8.64 (dt, J
4.8, 1.2, 1H). 13C NMR (CDCl3): δ 41.0, 45.5, 63.5, 72.0, 119.3,
120.0, 121.6, 123.1, 125.4, 127.0, 127.3, 127.7, 128.0, 133.8, 134.6,
137.8, 137.9, 142.2, 149.3, 150.1, 156.4, 168.3. Anal. (C26H26-
Cl2N4O2‚2HCl‚0.5H2O) C, H, N.
1
procedure. Yield: 45%. Mp (oxalate): foam. H NMR (CDCl3):
δ 1.64 (m, 1H), 1.83 (m, 1H), 2.43 (m, 2H), 2.87 (m, 2H), 3.10 (s,
4H), 3.47 (m, 1H), 3.86 (s, 3H), 3.89-3.99 (m, 6H), 6.86 (d, J 7.4,
1H), 6.91-6.94 (m, 2H), 7.01 (m, 1H), 7.32-7.41 (m, 2H), 7.45
(dd, J 5.9, 3.5, 1H), 7.55 (d, J 7.4, 1H), 7.77-7.83 (m, 3H), 8.00
(s, 1H). 13C NMR (CDCl3): δ 33.3, 36.9, 38.5, 50.7, 55.3, 63.8,
66.6, 111.1, 118.1, 119.6, 120.5, 120.9, 123.1, 123.8, 125.2, 125.8,
126.9, 127.5, 133.0, 140.7, 141.0, 143.3, 144.0, 144.6, 152.2, 167.5.
Anal. (C29H33N3O3‚(COOH)2‚H2O) C, H, N.
1-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-4-(4-(pyridin-2-yl)-
benzamido)butan-2-yl Acetate (20). A solution of 16 (0.25 g, 0.5
mmol) in 10 mL of CH2Cl2 was treated with 70 µL (0.75 mmol)
of acetic anhydride followed by 140 µL (1.0 mmol) of triethylamine.
After being stirred for 16 h, the mixture was washed with sodium
bicarbonate solution, dried with sodium sulfate, and purified by
flash chromatography. Yield: 0.22 g (82%). Mp (oxalate): foam.
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)-trans-but-2-enyl)-
4-pyridin-2-ylbenzamide (14). 14 was prepared from 4-pyridin-
2-ylbenzoic acid hydrochloride and 4-(4-(2-methoxyphenyl)-
piperazin-1-yl)-trans-but-2-enylamine according to the general
procedure. Yield: 65%. Mp (hydrochloride): 168-170 °C. 1H
NMR (400 MHz, CDCl3): δ 2.70 (s, 4H), 3.12 (s, 6H), 3.86 (s,
3H), 4.13 (m, 2H), 5.78-5.85 (m, 2H), 6.43 (m, 1H), 6.85-7.02
(m, 4H), 7.27 (s, 2H), 7.77 (s, 2H), 7.90 (d, J 7.5, 2H), 8.06 (d, J
8.1, 2H), 8.72 (d, J 3.1, 1H). 13C NMR (101 MHz, CDCl3): δ
41.0, 50.9, 53.7, 55.8, 60.7, 111.6, 118.7, 121.3, 121.4, 123.2, 123.5,

4144 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17
Grundt et al.
1H NMR (CDCl3): δ 1.84 (m, 1H), 2.05 (m, 1H), 2.12 (s, 3H),
2.52 (dd, J 13.2, 5.2, 1H), 2.65 (m, 5H), 2.99 (s, 4H), 3.25 (dq, J
9.7, 5.00, 1H), 3.81 (dt, J 12.3, 5.7, 1H), 5.19 (m, 1H), 6.89 (dd,
J 7.7, 1.8, 1H), 7.06-7.17 (m, 3H), 7.26 (ddd, J 6.1, 4.8, 2.44,
1H), 7.73-7.76 (m, 2H), 7.93 (d, J 8.6, 2H), 8.07 (d, J 8.6, 2H),
8.70 (td, J 4.83, 1.50, 1.50, 1H). 13C NMR (CDCl3): δ 21.0, 32.4,
36.1, 51.3, 53.7, 61.5, 69.6, 118.6, 120.8, 122.7, 124.5, 127.0, 127.4,
127.5, 133.9, 134.7, 136.9, 142.1, 149.8, 151.1, 156.2, 167.1, 171.5,
Anal. (C28H30Cl2N4O3‚1.5(COOH)2‚H2O) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-2-hydroxybutyl)-
4-(pyridin-2-yl)benzamide (21). 21 was prepared from 4-pyridin-
2-ylbenzoic acid and 30a according to the general procedure.
Yield: 52%. Mp (oxalate): foam. 1H NMR (CDCl3): δ 1.63 (ddd,
J 14.6, 6.0, 3.4, 1H), 1.81 (dtd, J 14.5, 10.9, 10.8, 3.9, 1H), 2.72
(m, 6H), 3.07 (s, 4H), 3.34 (ddd, J 13.4, 7.6, 4.6, 1H), 3.77 (ddd,
J 13.4, 6.7, 3.4, 1H), 4.07 (m, 1H), 6.77 (t, J 5.3, 1H), 6.93 (dd, J
7.4, 2.2, 1H), 7.13-7.19 (m, 2H), 7.28 (m, 1H), 7.76-7.81 (m,
2H), 7.91 (d, J 8.6, 2H), 8.07 (d, J 8.6, 2H), 8.72 (td, J 4.8, 1.4,
1.4, 1H). 13C NMR (CDCl3): δ 28.8, 45.8, 51.4, 53.3, 57.5, 72.7,
118.7, 120.9, 122.8, 125.0, 127.1, 127.5, 127.6, 127.7, 134.2, 134.8,
137.0, 142.2, 149.9, 150.9, 156.3, 167.3. Anal. (C26H28Cl2N4O2‚
(COOH)2‚H2O), C, H, N.
7.81 (m, 2H). 13C NMR (CDCl3): δ 33.9, 35.3, 51.4, 53.4, 63.8,
64.5, 118.2, 122.7, 124.1, 127.0, 131.6, 133.4, 133.4, 150.4, 167.7.
2-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-
isoindoline-1,3-dione (26b). 26b was prepared from 1-(2-meth-
oxyphenyl)piperazine and 25 in a fashion similar to that described
1
above for 26. Yield: 28%. Mp: 192-194 °C. H NMR (CDCl3):
δ 1.79 (q, J 6.8, 2H), 2.41 (m, 2H), 2.61 (s, 2H), 2.85 (s, 2H), 3.07
(s, 4H), 3.77 (m, 1H), 3.85 (s, 3H), 3.91 (m, 2H), 6.86 (d, J 7.0,
1H), 6.91-6.95 (m, 2H), 7.00 (m, 1H), 7.85 (dd, J 5.5, 3.0, 2H),
7.71 (dd, J 5.4, 3.1, 2H). 13C NMR (CDCl3): δ 33.8, 35.4, 50.9,
53.6, 55.6, 64.1, 64.7, 111.3, 118.4, 121.2, 123.2, 123.4, 132.4,
134.1, 141.4, 152.4.
4-Amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
(27a). A sample of 4.48 g (10.0 mmol) of 26a was fully dissolved
in 25 mL of EtOH and treated with 0.48 g (15.0 mmol) of hydrazine
in the microwave (pressure vessel, Pmax, 150 W, cooling, 90 °C,
20 min). The cooled reaction mixture was filtered, and the filtrate
was evaporated in vacuo. Both the distillation residue and the initial
precipitate were partitioned between CHCl3 and 20% potassium
carbonate solution. The layers were separated and the aqueous layer
was dried with sodium sulfate to give the title compound as an oil,
which was used without further purification. Yield: 2.25 g (71%).
1H NMR (CDCl3): δ 1.56 (m, 2H), 2.40 (m, 2H), 2.61 (s, 2H),
2.80 (s, 2H), 2.97-3.05 (m, 9H), 3.89 (m, 1H), 6.92 (dd, J 6.3,
3.1, 1H), 7.09-7.14 (m, 2H). 13C NMR (CDCl3): δ 37.4, 39.7,
51.5, 53.6, 64.5, 66.3, 118.3, 124.2, 127.1, 133.5, 150.6.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-2-hydroxybutyl)-
9H-fluorene-2-carboxamide (22). 22 was prepared from 9H-
fluorene-2-carboxylic acid and 30a according to the general
1
procedure. Yield: 68%. Mp (oxalate): foam. H NMR (CDCl3):
δ 1.63 (m, 1H), 1.78 (m, 1H), 2.63 (s, 2H), 2.72-2.84 (m, 2H),
2.87 (s, 2H), 3.07 (s, 4H), 3.34 (m, 1H), 3.77 (ddd, 13.7, 7.0, 3.5,
1H), 3.94 (s, 2H), 4.07 (m, 1H), 6.90 (dd, J 5.4, 2.0, 1H), 7.12-
7.18 (m, 2H), 7.36 (t, J 5.3, 1H), 7.37 (t, J 5.4, 1H), 7.41 (d, J 7.0,
1H), 7.81-7.82 (m, 3H), 8.00 (s, 1H). 13C NMR (CDCl3): δ 28.9,
37.0, 45.9, 51.4, 53.4, 57.5, 72.8, 118.7, 119.8, 120.7, 124.0, 125.0,
125.3, 126.0, 127.1, 127.6, 127.7, 127.8, 133.0, 134.2, 140.8, 143.6,
144.2, 145.0, 150.9, 168.0. Anal. (C28H29Cl2N3O2‚2.5HCl‚0.5EtOAc‚
1.75H2O) C, H, N.
4-Amino-1-(4-(2-methoxyphenyl)piperazin-1-yl)butan-2-ol (27b).
27b was prepared from 26b in a fashion similar to that described
above for 27a. Yield: 69%. Wax. H NMR (CDCl3): δ 1.59 (m,
2H), 2.41 (m, 2H), 2.57 (m, 2H), 2.79-2.81 (m, 9H), 3.86 (s, 3H),
3.91 (m, 1H), 6.86 (d, J 7.5, 1H), 6.91-6.96 (m, 2H), 6.98-7.03
(m, 1H). 13C NMR (CDCl3): δ 37.3, 39.7, 50.9, 53.6, 55.5, 64.5,
66.2, 111.2, 118.3, 121.1, 123.1, 141.3, 152.3.
1
1-(2,3-Dichlorophenyl)-4-(2-(oxiran-2-yl)ethyl)piperazine (28a).
An amount of 2.31 g (10.0 mmol) of 1-(2,3-dichlorophenyl)-
piperazine was added to a suspension of 2.27 g (15.0 mmol) of 24
and 4.15 g (30.0 mmol) of potassium carbonate in 150 mL of
acetone, and the reaction mixture was refluxed for 24 h. The reaction
mixture was filtered and the volatiles were removed in vacuo to
give an oil (2.86 g, 95%), which was used without further
purification. 1H NMR (CDCl3): δ 1.72 (m, 1H), 1.83 (m, 1H), 2.53
(dd, J 5.0, 2.7, 1H), 2.61 (ddd, J 8.3, 6.5, 3.0, 2H), 2.66 (s, 4H),
2.79 (dd, J 4.9, 4.0, 1H), 3.01 (m, 1H), 3.07 (s, 4H), 6.96 (dd, J
6.5, 3.1, 1H), 7.11-7.19 (m, 2H). 13C NMR (CDCl3): δ 30.2, 47.1,
51.0, 51.4, 53.3, 55.0, 118.6, 124.6, 127.5, 134.0, 151.3.
1-(2-Methoxyphenyl)-4-(2-(oxiran-2-yl)ethyl)piperazine (28b).
28b was prepared from 24 and 1-(2-methoxyphenyl)piperazine in
a fashion similar to that described above for 28a. Yield: 87%. 1H
NMR (CDCl3): δ 2.60 (m, 2H), 2.67 (s, 4H), 2.78 (dd, J 4.9, 4.0),
3.00 (m, 1H), 3.10 (s, 4H), 3.86 (s, 3H), 6.86 (dd, J 7.8, 1.3, 1H),
6.88-7.03 (m, 3H). 13C NMR (CDCl3): δ 30.2, 47.2, 50.7, 51.0,
53.5, 55.2, 55.4, 111.2, 118.3, 121.1, 123.0, 141.4, 152.3.
N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)-2-hydroxybutyl)-
9H-fluorene-2-carboxamide (23). 23 was prepared from 9H-
fluorene-2-carboxylic acid and 30b according to the general
1
procedure. Yield: 42%. Mp (oxalate): foam. H NMR (CDCl3):
δ 1.62 (ddd, J 9.9, 6.1, 3.4, 1H), 1.80 (m, 1H), 2.63 (s, 2H), 2.76
(m, 2H), 2.88 (s, 2H), 3.10 (s, 4H), 3.33 (ddd, J 13.4, 7.7, 4.5,
1H), 3.78 (ddd, J 13.4, 6.8, 3.4, 1 H), 3.80 (s, 3H), 3.91 (s, 2H),
4.06 (m, 1H), 6.83-6.87 (m, 2H), 6.89-6.92 (m, 2H), 7.01 (ddd,
J 8.0, 5.8, 3.3, 1H), 7.34 (td, J 7.4, 1.3, 1H), 7.39 (td, J 7.5, 1.3,
1H), 7.55 (d, J 7.5, 1H), 7.79 (dd, J 7.9, 0.5, 1H), 7.82 (dd, J 8.1,
1.5, 1H), 8.00 (d, J 0.7, 1H). 13C NMR (CDCl3): δ 28.8, 36.9,
45.8, 50.6, 53.5, 55.4, 57.4, 72.6, 111.2, 118.2, 119.7, 120.6, 121.0,
123.2, 123.9, 125.2, 125.9, 127.0, 127.6, 132.9, 140.7, 140.8, 143.4,
144.0, 144.8, 152.2, 167.9. Anal. (C29H33N3O3‚(COOH)2‚1.25H2O)
C, H, N.
2-(Oxiran-2-yl)ethylisoindoline-1,3-dione (25). A suspension
of 1.84 g (10.0 mmol) of phthalimid potassium salt in 20 mL of
DMF was treated with 2.27 g (15.0 mmol) of 2430 in the microwave
(pressure vessel, Pmax, 150 W, cooling, 100 °C, 20 min). The cooled
reaction mixture was filtered, diluted with EtOAc (20 mL), and
washed with H2O (2 × 10 mL). The organic phase was dried was
sodium sulfate and the volatiles were removed in vacuo to give 25
(1.68 g, 78%) as a foam, which was used without further
purification. 1H NMR (CDCl3): δ 1.86 (m, 1H), 2.00 (m, 1H), 2.46
(m, 1H), 2.73 (t, J 3.9, 1H), 3.00 (m, 1H), 3.89 (m, 2H), 7.70-
7.74 (m, 2H), 7.83-7.87 (m, 2H). 13C NMR (CDCl3): δ 31.7, 35.2,
46.5, 50.4, 123.4, 132.2, 134.1, 168.4.
1-Azido-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
(29a). A suspension of 0.75 g (2.5 mmol) of 28a, 0.24 g (3.8 mmol)
of sodium azide, and 0.27 g (5.0 mmol) of ammonium chloride in
5 mL of DMF was heated at 100 °C for 5 h. The reaction mixture
was partitioned between 10 mL of CHCl3 and 10 mL of H2O. The
aqueous organic layer was extracted twice with 10 mL of CHCl3
and dried over sodium sulfate, and the volatiles were removed in
vacuo. The residue was purified by flash chromatography to give
1
29a as an oil. Yield: 0.44 g (51%). H NMR (CDCl3): δ 1.56
(ddd, J 14.7, 6.5, 3.4, 1H), 1.81 (m, 1H), 2.62 (s, 2H), 2.75 (m,
2H), 2.87 (s, 2H), 3.07 (s, 4H), 3.27 (dd, J 5.1, 1.4, 2H), 4.04 (dtd,
J 7.9, 5.3, 2.6, 1H), 6.52 (s, 1H), 6.93 (dd, J 7.2, 2.4, 1H), 7.12-
7.19 (m, 2H). 13C NMR (CDCl3): δ 28.4, 51.3, 53.3, 56.5, 57.3,
73.0, 118.7, 124.9, 127.6, 134.1, 150.9.
2-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
isoindoline-1,3-dione (26a). A sample of 2.1 g (9.0 mmol) of
1-(2,3-dichlorophenyl)piperazine in 40 mL of 2-PrOH was reacted
in the microwave (pressure vessel, Pmax, 150 W, cooling, 90 °C,
20 min) with 2.0 g (9.0 mmol) of 25. The solvent was removed in
vacuo, and the foamy residue was washed with 10 mL of 2-PrOH.
Yield: 2.96 g (73%). 1H NMR (CDCl3): δ 1.79 (m, 2H), 2.42 (m,
2H), 2.56 (s, 2H), 2.79 (m, 2H), 3.02 (s, 4H), 3.60 (s, 1H), 3.74-
3.83 (m, 3H), 6.90 (m, 1H), 7.06-7.11 (m, 2H), 7.67 (m, 2H),
1-Azido-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-2-ol (29b).
29b was prepared from 28b in a fashion similar to that described
1
above for 29a. Yield: 15%. H NMR (CDCl3): δ 1.55 (ddd, J
14.6, 6.7, 3.6, 1H), 1.80 (m, 1H), 2.62 (s, 2H), 2.74 (m, 2H), 2.89
(s, 2H), 3.09 (s, 4H), 3.24 (dd, J 11.6, 4.1, 1H), 3.29 (dd, J 11.6,

Analogues of Carboxamides as Receptor Ligands
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 17 4145
4.9, 1H), 3.86 (s, 3H), 4.03 (dtd, J 9.8, 5.5, 2.5, 1H), 6.86 (d, J
8.0, 1H), 6.89-6.95 (m, 2H), 7.01 (ddd, J 8.0, 5.1, 4.1, 1H). 13C
NMR (CDCl3): δ 28.4, 50.7, 53.5, 53.5, 55.4, 56.6, 57.4, 73.0,
111.2, 118.3, 121.1, 123.2, 140.9, 152.3.
46.3, 50.8, 51.4, 63.7, 127.6, 127.7, 127.8, 128.4, 134.2, 137.1,
140.4, 150.0, 151.0, 156.6, 161.7. Anal. (C27H28Cl2N4O‚2(COOH)2)
C, H, N.
Acknowledgment. The research reported herein was sup-
ported by funds from the NIDA Intramural Research Program,
Grants DA13584-03S1 and DA13584-01. P.G. was supported
by a National Institutes of Health (NIH) Visiting Fellowship.
K.M.P. was supported by an NIH summer IRTA fellowship.
The authors acknowledge support and helpful discussions with
Dr. Jane Acri, NIDA Addiction Treatment Discovery Program,
Division of Pharmacotherapies and Medical Consequences of
Drug Abuse, NIDA.
1-Amino-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
(30a). A solution of 29a (0.41 g, 1.2 mmol) and 1.87 g (7.2 mmol)
of triphenylphosphine in 20 mL of a THF/H2O mixture (10:1 v/v)
was stirred at room temperature for 16 h. The volatiles were
removed in vacuo and the residue was taken up in 2-PrOH (5 mL)
and treated with ethereal hydrochloric acid to give the desired amine
as a hydrochloride (0.33 g, 77%). 1H NMR (CDCl3): δ 1.53 (ddd,
J 14.5, 6.8, 4.0, 1H), 1.71 (m, 1H), 2.61 (s, 2H), 2.65-2.77 (m,
4H), 2.84 (s, 2H), 3.07 (m, 4H), 3.77 (m, 1H), 6.93 (dd, J 7.0, 2.5,
1H), 7.12-7.17 (m, 2H). 13C NMR (CDCl3): δ 29.0, 48.3, 51.3,
53.3, 74.9, 118.6, 124.8, 127.5, 134.0, 150.9.
Supporting Information Available: Results from microanaly-
sis. This material is available free of charge via the Internet at http://
pubs.acs.org.
1-Amino-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-2-ol (30b).
30b was prepared from 29b in a fashion similar to that described
1
above for 30a. Yield: 13%. H NMR (CDCl3): δ 1.52 (ddd, J
14.5, 6.5, 3.9, 1H), 1.71 (m, 1H), 2.54-2.77 (m, 4H), 2.86 (s, 2H),
3.09 (s, 4H), 3.77 (m, 1H), 3.87 (s, 3H), 6.86 (d, J 7.9, 1H), 6.90-
6.95 (m, 2H), 7.00 (m, 1H). 13C NMR (CDCl3): δ 29.0, 48.4, 50.7,
53.6, 55.4, 57.6, 75.2, 111.2, 118.3, 121.1, 123.2, 141.0, 152.3.
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N-(2-Hydroxymethyl-trans-cyclopropylmethyl)-4-pyridin-2-
ylbenzamide (32a). 32a was prepared from 4-pyridin-2-ylbenzoic
acid hydrochloride and 31a34 according to the general procedure.
1
Yield: 43%. H NMR (CDCl3): δ 0.45 (m, 2H), 0.99 (m, 2H),
3.01-3.07 (m, 4H), 3.50 (dt, J 14.0, 5.5, 2H), 3.71 (dd, J 11.0,
4.7, 2H), 4.09 (s, 1H), 7.23 (m 1H), 7.40 (t, J 4.7, 1H), 7.67 (d, J
7.8, 1H), 7.71 (m, 1H), 7.87 (d, J 7.8, 2H), 7.94 (d, J 7.8, 2H),
8.65 (d, J 3.9, 1H). 13C NMR (CDCl3): δ 8.6, 16.9, 20.4, 44.2,
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benzamide (32b). 32b was prepared from 4-pyridin-2-ylbenzoic
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1
Yield: 55%. H NMR (CDCl3): δ 0.16 (t, J 5.4, 1H), 0.76 (m,
1H), 1.23 (m, 2H), 2.12 (m, 1H), 3.24 (t, J 11.0, 1H), 4.23 (m,
1H), 4.53 (m, 1H), 7.26 (m, 1H),), 7.68 (d, J 7.8, 1H), 7.74 (td, J
7.8, 16, 1H), 7.88 (d, J 8.6, 2H), 7.92 (d, J 8.6, 2H), 8.66 (d, J 3.9,
1H). 13C NMR (CDCl3): δ 8.3, 15.7, 39.8, 62.5, 121.4, 127.2, 127.7,
134.9, 137.3, 142.0, 149.8, 156.6, 167.0.
N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-ylmethyl)-trans-cy-
clopropylmethyl)-4-pyridin-2-ylbenzamide (33). To a solution of
32a (0.59 g, 2.1 mmol) and triethylamine (0.64 g, 6.3 mmol) in
CH2Cl2 (10 mL) was added methanesulfonic acid anhydride
(0.55 g, 3.2 mmol) at 0 °C, and the mixture was stirred at room
temperature for 4 h. All volatiles were removed in vacuo, and to
the residue was added 0.44 g (5.3 mmol) of sodium bicarbonate
and CH3CN (10 mL). The mixture was refluxed for 16 h, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography. Yield: 0.12 g, 20%. Mp (oxalate): foam. 1H NMR
(CDCl3): δ 0.48 (dt, J 8.3, 5.0, 1H), 0.60 (dt, J 8.5, 5.0, 1H), 0.96
(m, 1H), 2.25 (dd, J 12.7, 7.3, 1H), 2.49 (dd, J 12.7, 5.9, 1H), 2.70
(s, 4H), 3.03 (4, 1H), 3.40 (t, J 6.14, 2H), 6.58 (t, J 5.2, 1H), 6.89
(dd, J 7.96, 1.61, 1H), 7.07 (t, J 7.98, 1H), 7.13 (dd, J 8.0, 1.6,
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127.9, 134.4, 135.2, 137.4, 142.6, 150.3, 151.6, 156.6, 167.5. Anal.
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Mp (oxalate): foam. H NMR (CDCl3): δ 0.14 (dd, J 10.0, 5.0,
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