Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl) piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor

Article abstract of DOI:10.1021/jm049465g

Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological investigations have been hampered by the lack of highly D3 receptor selective compounds that can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist NGB 2904 (1, 9H-fluorene-2-carboxylic acid {4-[(2,3-dichlorophenyl)-piperazin-1-yl]- butyl}-amide, K_i (hD3) = 2.0 nM, K_i (hD2_L) = 112 nM, D2/D3 selectivity ratio of 56) was chosen as a lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D = 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30 novel analogues were synthesized, and their binding affinities were evaluated in competition binding assays in HEK 293 cells transfected with either D2_L, D3, or D4 human dopamine receptors using the high affinity, selective D2-like receptor antagonist ¹²⁵I-IABN. Structural diversity in the aryl amide end of the molecule was found to have a major influence on (sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent ligand. Compound 29 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl} -4-pyridine-2-yl-benzamide) displayed the most promising pharmacological profile (K_i (hD3) = 0.7 nM, K_i (hD2_L) = 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells, with an EC₅₀ value of 3.0 nM. Compound 29 was a nearly 5 times more potent antagonist at the D3 receptor than 1 (EC₅₀ = 14.4 nM). Moreover, a decrease in c log D value of ～2 orders of magnitude was determined for this novel D3-receptor-preferring ligand, compared to 1. In summary, chemical modification of 1 has resulted in compounds with high affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo.

Full text of DOI:10.1021/jm049465g

J. Med. Chem. 2005, 48, 839-848
839
Novel Heterocyclic Trans Olefin Analogues of
N-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as Selective
Probes with High Affinity for the Dopamine D3 Receptor
Peter Grundt,† Erin E. Carlson,† Jianjing Cao,† Christina J. Bennett,† Elizabeth McElveen,‡ Michelle Taylor,‡
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, and Department of Pharmacology and Neuroscience, University of
North Texas Health Science Center, Fort Worth, Texas 76107
Received July 5, 2004
Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating
the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological
investigations have been hampered by the lack of highly D3 receptor selective compounds that
can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist
NGB 2904 (1, 9H-fluorene-2-carboxylic acid {4-[(2,3-dichlorophenyl)-piperazin-1-yl]-butyl}-
amide, Ki (hD3) ) 2.0 nM, Ki (hD2L) ) 112 nM, D2/D3 selectivity ratio of 56) was chosen as a
lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D
) 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30
novel analogues were synthesized, and their binding affinities were evaluated in competition
binding assays in HEK 293 cells transfected with either D2L, D3, or D4 human dopamine
receptors using the high affinity, selective D2-like receptor antagonist 125I-IABN. Structural
diversity in the aryl amide end of the molecule was found to have a major influence on
(sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more
rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues
demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent
ligand. Compound 29 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-
2-yl-benzamide) displayed the most promising pharmacological profile (Ki (hD3) ) 0.7 nM, Ki
(hD2L) ) 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole
stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster
ovary (CHO) cells, with an EC50 value of 3.0 nM. Compound 29 was a nearly 5 times more
potent antagonist at the D3 receptor than 1 (EC50 ) 14.4 nM). Moreover, a decrease in c log D
value of ∼2 orders of magnitude was determined for this novel D3-receptor-preferring ligand,
compared to 1. In summary, chemical modification of 1 has resulted in compounds with high
affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is
currently being evaluated in animal models of cocaine abuse and will provide an important
tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo.
Introduction
tions for neurological and neuropsychiatric disorders,
in addition to drug abuse, has been made and recently
reviewed.9 However, chemical modification of the first
generation drugs has been required to improve bio-
availability for in vivo evaluation. For example, it was
discovered that 3 was subject to metabolism by aldehyde
oxidase, which predicts that this compound would be
poorly bioavailable in humans, despite early preclinical
success in animal models.10 By replacement of the
arylcyano moiety, which was subject to metabolism,
with bioisosteres, GlaxoSmithKline recently reported a
second generation D3 receptor antagonist with high
pharmacological specificity that is metabolically stable,
orally active, and CNS penetrant.10
In the 4-phenylpiperazine class of D3-receptor-selec-
tive ligands, significant structure-activity relationships
(SAR) have been described wherein optimal D3-recep-
tor-binding affinities were obtained when the phenyl-
piperazine moiety is linked to an aryl amide via a butyl
chain.11-14 Substitution of the phenylpiperazine ring
was optimized with a 2,3-dichloro-substitution pattern,
The D3 receptor, first described in 1990,1 is a member
of the D2-like receptor family, and possesses ∼50%
overall homology to the D2 receptor subtype.2 D3
receptors are localized in the limbic areas of the brain,
specifically the islands of Calleja and the nucleus
accumbens.3 The discovery of D3-receptor-selective an-
tagonists and partial agonists has received particular
attention for the potential treatment of cocaine abuse
since the compound BP 897 (2, Figure 1) was first
reported to block cue-controlled cocaine seeking in rats.4
Additional studies with 25 and the potent and selective
D3 antagonist SB-277011 (3)6-8 further support the
development of D3-receptor-selective ligands as poten-
tial cocaine abuse medications. Considerable progress
in developing D3 receptor ligands as potential medica-
* Author to whom correspondence should be addressed. Phone:
(410)-550-6568 Ext. 114. Fax: (410)-550-6855. E-mail: anewman@
intra.nida.nih.gov.
† National Institutes of Health.
‡ University of North Texas Health Science Center.
10.1021/jm049465g CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/12/2005

840 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3
Grundt et al.
N-phthalimido-protected trans-butenyl bromide 4 was
linked to 2,3-dichlorophenylpiperazine. Deprotection of
the intermediate 5 to the primary amine 6 was achieved
by treatment with hydrazine. Amidation either using
the acid chloride under Schotten-Baumann conditions
(method A) or using 1,1-carbonyldiimidazole (CDI,
method B) gave the desired products generally in
moderate to good yields. Compounds 42, 43,11,12 and
4411,12 were prepared according to previously described
methods15,17 and analogous to their olefinic derivatives
except the fully saturated derivative of 6 was used. All
carboxylic acids were either commercially available or
were prepared by literature methods. The resulting
amides were converted to their appropriate salts for
biological testing.
Results and Discussion
Thirty three novel ligands and several previously
reported ligands15 were evaluated in competition bind-
ing assays in HEK 293 cells transfected with either D2L,
D3, or D4 human dopamine receptors. 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-3â-yl] benzamide (125I-
IABN).18 In addition, c log D values were calculated to
provide a quantitative measure of lipophilicity to use
in our drug design. These data are presented in Tables
1 and 2.
The effect on the binding affinities at the D2 and D3
receptors and D2/D3 selectivities induced by a substitu-
ent on the phenyl ring in the benzamides 7-25 is shown
by comparison with the unsubstituted derivative 37 in
Table 1. Generally, phenyl-ring substitution was well-
tolerated at the D3 receptor (Ki ) 0.4-3.8 nM). How-
ever, for these simple substituted benzamides, D2/D3
receptor binding selectivities were low to modest (D2/
D3 ) 2-34-fold). A small halogen substituent at the
para-position on the phenyl ring did not have a signifi-
cant impact on D2/D3 selectivity. However, the other
substituents in the para position of the benzamide
appeared to be the favored site for D2/D3 selectivity,
and a para > meta > ortho pattern of D2/D3 receptor
Figure 1. Some examples of D3 receptor selective ligands.
and the aryl amide functional group gave pharmacologi-
cal selectivity when extended to a di- or triaryl ring
system.13,15 However, it was discovered that many of the
most potent D3 receptor ligands were also highly
lipophilic (c log D > 6),15 which limited solubility and
might compromise in vivo testing. Encouraging initial
results with structurally more rigid analogues15 ob-
tained by unsaturation of the butyl linker and hetero-
cyclic analogues of 116 led us to investigate the combi-
nation of heterocyclic and substituted phenyl trans
olefins as potential potent and selective probes for the
dopamine D3 receptor that were less lipophilic than the
first generation ligands.
Chemistry
The synthesis of the novel olefin analogues of N-{4-
[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarbox-
amides 7-36 was achieved by following a previously
reported pathway.15,17 As depicted in Scheme 1, the
Scheme 1. Synthetic Strategy for Novel D3 Receptor Ligands

Trans Olefin Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3 841
Table 1. Human D2-Family Receptor Subtype Binding Data in HEK Cells for trans-Butenyl Benzamide Analogues
a The methods for the binding assays are described in the Experimental Methods section.18 Ki values are the mean of at least three
independent determinations. b Calculated partition coefficients at physiological pH (7.4); ACD/LogD Suite, Advanced Chemistry
Development Inc., Toronto, Canada.
binding selectivities was generally followed. The iodo-
benzamides (13-15) had somewhat lower D3 receptor
binding affinities than the unsubstituted derivative 37
(∼4-5-fold). For these iodo-substituted derivatives, the
binding affinities at the D3 receptor appeared to be
generally unaffected by the position of the substituent.

842 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3
Grundt et al.
Table 2. Human D2-Family Receptor Subtype Binding Data in HEK Cells for trans-Butenyl Heterocyclic Analoguesa
a Ki and c log D values were obtained as described in Table 1.
However, at the D2 receptor, the 2-iodo derivative 13
(Ki ) 10.6 nM) showed a higher binding affinity than
the 3-iodo benzamide 14 (Ki ) 28.1 nM) and 4-iodo
ligand 15 (Ki ) 35.4 nM). The nitro derivatives (21-
23) and the methoxylated ligands (16-18) exhibited
similar SAR dependence on the position of substituent
on the phenyl ring as the iodo-benzamides (13-15) at
the D2 receptor. This effect was most pronounced for
the methoxylated derivatives, wherein the 4-methoxy
analogue 18 had a 10-fold lower affinity at the D2
receptor than the 2-methoxy ligand 16. The 4-methoxy
ligand 18 showed a comparable affinity at the D3
receptor (Ki ) 1.2 nM) to the unsubstituted phenyl
derivative 37, resulting in a D2/D3 selectivity of 26. The
4-hydroxy 20 and the 4-nitro 23 derivatives demon-
strated similar D2/D3 ratios of 34 and 28, respectively.
Thus, the demethylation of 18 to form the 4-hydroxy
ligand 20 led to higher affinities at both the D2 and the
D3 receptors of Ki ) 13.7 nM and Ki ) 0.4 nM,
respectively but did not significantly improve the D2/
D3 selectivity.
38.15 The simple pyridine-substituted amides (26-28)
were found to have low D2/D3 selectivities. All of these
derivatives demonstrated similar binding affinities at
the D3 receptor (Ki ) 2.0-2.6 nM). However, moving
the nitrogen atom around the pyridine ring appeared
to follow a similar pattern as described above for the
phenyl-substituted benzamides wherein the 4-pyridine-
amido derivative exhibited the highest D2/D3 binding
selectivity (16-fold). A phenyl spacer was introduced
between the pyridine system and amide moiety to form
the pyridine-benzamides 29-31. Overall, these ligands
exhibited significantly enhanced D2/D3 selectivities.
Compared to the simple pyridine-amides (26-28), the
affinities at D3 receptors improved slightly (Ki ) 0.7-
0.9 nM). Interestingly, the order of D2/D3 binding
selectivity dependent on the nitrogen position on the
pyridine moiety appeared to be reversed, whereas the
2-pyridylphenylbenzamide 29 showed the highest D2/
D3 binding selectivity (133-fold).
To further improve the hydrophilicity of 29, a second
nitrogen was introduced into the 5-position of the
pyridine moiety or the pyridine moiety was replaced
with an imidazole system. However, the 2,5-pyrimidine-
benzamide derivative 32 as well as the imidazole ligand
The binding affinities at the human D2L and D3
receptors for the heterocyclic analogues with the trans-
butenyl linker are depicted in Table 2 and compared to

Trans Olefin Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3 843
Table 3. Human D2-Family Receptor Subtype Binding Data in
compared to the respective compounds with the butyl
linker (4115 and 42). Within both sets of pyridine-
benzamides, the affinities at the D3 receptor were
similar, for example, for the 2-pyridine-benzamides 29
and 41, the Ki ) 0.7 and 0.5 nM, respectively. However,
there was a significant difference for the binding affini-
ties at the D2 receptor. Compound 41 (Ki ) 24.8 nM)
had a nearly 4-fold higher affinity at this receptor than
29 (Ki ) 93.3 nM), resulting in an overall improved D2/
D3 selectivity for the trans-butenyl derivative. The
trans-butenyl vs butyl ligand pairs 38/1 and 35/43
showed a similar relationship with the saturated de-
rivative having higher binding affinities at the D2
receptor while the binding affinity at D3 receptor was
similar or unaffected. Though, as can be shown for the
saturated analogue 43 (Ki (D2L) ) 64.7 nM) and the
olefinic derivative 35 (Ki (D2L) ) 149 nM), the effect on
D2 binding affinity was somewhat less pronounced than
that for 41 vs 29. However, the 4-iodo benzamide 39
(Ki (D3) ) 1.6 nM), which featured a butyl linker
between the amide moiety and the piperazine system,
had a ∼2-fold higher affinity at the D3 receptor than
the trans-butenyl ligand 15 (Table 1, Ki ) 3.4 nM). Both
ligands demonstrated similar binding affinities at the
D2 receptor of 39.3 and 35.4 nM. So that overall, for
olefinic ligand 15, the D2/D3 binding selectivity was
reduced. Other examples were the benzofuran pairs (36
and 44) and the quinoxaline derivatives (34 and 40),
where the introduction of the trans olefinic linker has
a small but negative impact on binding affinity at D3.
The saturated benzothiophen 43 and the benzofuran 44
analogues were previously reported to have extraordi-
nary D3 affinities and D2/D3 selectivities.11,12 However,
under our assay conditions, these analogues demon-
strated significantly lower D2/D3 selectivities. Although
introduction of the trans-olefinic linker to give 36 did
not serve to improve binding affinity or selectivity at
D3 receptors, this modification to the benzothiophen
analogue resulted in one of the most potent and selective
analogues in the series, 35. In total, the replacement of
the saturated butyl linker with a trans olefin did not
uniformly improve D3 binding affinity and selectivity.
The impact of saturation was thus dependent on the aryl
terminus of the individual compound. Nevertheless, the
compounds of most interest for further investigation,
in terms of pharmacological profile and lipophilicity,
possessed the trans-olefin linker.
HEK Cells for Selected Butyl Analoguesa
a Ki values were obtained as described in Table 1.
33 showed a remarkable effect of the second nitrogen
in reducing D2/D3 binding selectivity as compared to
that of 29, which was primarily due to an increase in
binding affinities at D2 receptors. Although both com-
pounds showed similar D2/D3 selectivities, their binding
affinities at the D3 receptor were quite different.
Compound 33 had a 4-fold higher binding affinity at the
D3 receptor than that of 32 and was one of the most
potent D3 ligands in the series. Its binding profile at
both D2 and D3 receptors appeared to be similar to that
of the 4-phenolic derivative 20 (Table 1).
Additional rigid heterocyclic derivatives were further
investigated wherein the 2-quinoxaline carboxylic acid
derivative 34 showed relatively low affinity (Ki ) 3.8
nM) at the D3 receptor and was only moderately D2/
D3 selective. The benzothiophen analogue 35 showed
higher selectivity than the benzofuran 36, D2/D3 ) 135
and 36, respectively. Thus, the D2/D3 binding profile
for the benzothiophen derivative 35 was similar to that
for the 2-pyridine-benzamide 29. However, its relatively
high lipophilicity (c log D ) 7.10) would likely reduce
its viability for further in vivo development.
Selected compounds with high D3 affinities were
evaluated for binding at human D4 receptors. None of
the compounds tested (Table 2) showed high binding
affinities (Ki ) 375-1770 nM) at D4 receptors and
displayed D4/D3 selectivities in the range of 292-1610.
The question arose as to whether the introduction of
a trans-butenyl linker between aryl amide and piper-
azine moiety uniformly improved D3 receptor binding
affinity and D2/D3 selectivity. For comparison, binding
affinities at the D2L and D3 human dopamine receptor
for selected derivatives with a saturated butyl linker
are depicted in Table 3. The trans-butenyl pyridine-
benzamides derivatives 29 and 30 (Table 2) were
Binding affinities have commonly been used to predict
SAR for the D3 receptor and D2/D3 selectivities. Gener-
ally, if in vitro functional data is obtained, then only
the D3 receptor activity is reported. The reasons for
evaluating D2 intrinsic activity were twofold: (1) to
determine if selectivity based on potencies in the
functional assay corresponded to in vitro binding selec-
tivity and (2) when these compounds are evaluated
behaviorally, it will be important to know their intrinsic
activity at D2 receptors as this will likely play a role in
vivo, especially at the higher doses. In this study,
intrinsic activities for selected compounds were deter-
mined in functional assays using stimulation (agonist)
or inhibition of quinpirole stimulation (antagonist) of
mitogenesis in human dopamine D3 or D2 receptors
transfected into Chinese hamster ovary (CHO) cells
(Table 4). All of the compounds evaluated were antago-

844 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3
Grundt et al.
Table 4. Functional Assays Using Inhibition of Quinpirole
Stimulation in Cloned Human Dopamine D2 and D3 Receptors
Transfected into CHO Cells for Selected Analogues
selective in this functional assay. A substitution in the
4-position improved D2/D3 selectivity based on potencies
in the functional assay. The 4-methoxy derivative 18
was found to be 6-fold more D2/D3 selective than 37.
The 4-hydroxy derivative 20 was the most potent
antagonist prepared in this series (EC50 ) 1.0 nM), but
it lacked significant D2/D3 selectivity (D2/D3 ) 8). At
this time, we are unclear as to whether the in vitro
binding or functional assays have greater predictive
power for in vivo potency and selectivity. As these
assays are performed in cell lines, under nonphysiologi-
cal conditions, it is imperative to further evaluate these
compounds in vivo and perhaps in additional in vitro
functional tests in an attempt to bring clarity to the
current D2/D3 selectivity inconsistencies.
Conclusions
Thirty three novel heterocyclic or substituted aryl-
amides were prepared with either a saturated or a trans
olefinic butyl linking chain and a 2,3-dichlorophenyl-
piperazine terminus. These compounds were evaluated
in vitro for both binding and function at hD2L and hD3
receptors, and selected analogues were tested for bind-
ing at hD4 receptors. Most of these novel analogues
displayed high affinities for D3 receptors (Ki ) 0.3-3.8
nM), and all of the compounds synthesized were D3
receptor selective in both binding and function as D3
antagonists.
For selected compounds, the affinities at the hD4
receptor were low, and thus the D4/D3 selectivity was
>290-fold. Discrepancies in Ki values across laboratories
appear to be dependent on cell lines, radioligands, and
assay conditions, which make comparisons to literature
values difficult. This conundrum has been noted for D3
agonists, as well.3,19 Likewise, a lack of correspondence
between binding affinities and the commonly used
mitogenesis assay also provides a complication to drug
design in this area. Hence, compounds that have been
reported in other laboratories to have extraordinarily
high binding affinities and selectivities (1, 43, and 44)
were discovered to have comparable pharmacological
profiles in our binding assays to several of our analogues
and significantly reduced selectivities in this functional
assay. Overall, compound 29 demonstrated the most
interesting pharmacological profile, in this series, and
is currently being evaluated in a number of in vivo
models of drug abuse. In summary, the design and
synthesis of high-affinity D3 receptor ligands has been
accomplished in this structural class and several related
structural classes of D3 receptor ligands.11-14 D3 recep-
tor selectivity will have to be further determined in
additional in vitro and, importantly, in vivo assays to
further elucidate the role of the D3 receptor in neuro-
psychiatric disorders and drug abuse.
a These data were obtained through the service of CTDP,
Division of Treatment Research and Development, NIDA, using
a contract (N01DA-1-8816) protocol.
nists in these functional tests. Although the D2/D3
selectivities established in the binding assays for these
novel trans-butenyl analogues corresponded to the D2/
D3 selectivities found in this functional assay, the ratios
depicting selectivity were significantly lower (up to
6-fold) than those in the binding assays.
All olefinic derivatives were found to be antagonists
at the D3 as well as at the D2 receptors. The pyridine-
benzamido derivatives 29 and 30 showed similar poten-
cies of EC50 ) 3.0 and 2.9 nM, respectively. In this in
vitro bioassay both compounds were nearly 5-fold more
potent as D3 receptor antagonists than the parent
compound 1. As in the binding assays, the differences
between the pyridine-benzamide 29 and 30 were more
pronounced at the D2 receptor. Further, both com-
pounds were also more potent than 1 at the D2 receptor,
16-fold and 35-fold, respectively. Although 29 appeared
to be moderately D3-selective (D2/D3 ) 27), the D2/D3
selectivity for 30 was lower (13-fold). Thus, overall D2/
D3 selectivity was found to be lower for 29 than for the
parent compound 1 even though it was ∼5-fold more
potent as a D3 receptor antagonist. The thiophene
derivative 35 displayed a similar D2/D3 selectivity
based on potencies in the functional assay to 29 but was
somewhat less potent as a D3 receptor antagonist (∼3-
fold). Replacement of the sulfur by an oxygen atom in
the furan derivative 36 resulted in a 4-fold loss of D2/
D3 selectivity. As in the binding assay, the furan
derivative 36 was less potent at the D3 receptor but
more potent at the D2 receptor than 35. The unsubsti-
tuted benzamide 37 was found to be essentially non-
Experimental Methods
Chemistry. All chemicals and reagents were purchased
from Aldrich Chemical Co. or Lancaster Synthesis, Inc. and
used without further purification. All melting points were
determined on a Thomas-Hoover melting point apparatus and
1
are uncorrected. The H and 13C NMR spectra were recorded
on Bruker AC-300 or 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).

Trans Olefin Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3 845
Chemical shifts for 13C NMR spectra are reported as δ relative
to deuterated chloroform (CDCl3, 77.5 ppm, CD3OD 49.3).
Infrared spectra were recorded as a neat film on NaCl plates
with a Perkin-Elmer Spectrum RX I FT-IR system. Micro-
analyses were performed by Atlantic Microlab, Inc. (Norcross,
GA) and agree within (0.4% of calculated values. All column
chromatography was performed using the silica gel (Merck,
230-400 mesh, 60 Å) and CHCl3/CH3OH 10:1) as eluting
solvent unless otherwise indicated. For the amide formation
reactions, absolute amylene-stabilized chloroform was used.
If not otherwise stated, then all spectroscopic data and yields
refer to the free base. Compounds 43 and 44 were prepared
according to literature procedures11,12 and were tested as
oxalate salts.
General Procedures. Procedure A. The appropriate
benzoic acid was converted into its corresponding acid chloride
by treatment with thionyl chloride, and this intermediate was
reacted with 6 in a Schotten-Baumann-type reaction as
described previously.17 The crude product was purified either
by chromatography or by recrystallization of its appropriate
salt.
0.34 (CHCl3/CH3OH 10:1). Mp (hydrochloride, methanol/di-
ethyl ether) 124-126 °C. IR (film): ν 3314, 1643. 1H NMR
(CDCl3): δ 2.63 (s, 4H), 3.05-3.07 (m, 6H), 4.08 (m, 2H), 5.76-
5.78 (m, 2H), 6.62 (t, J 5.4, 1H), 6.96 (m, 1H), 7.10-7.22 (m,
3H), 7.37 (m, 1H), 7.50-7.57 (m, 2H). 13C NMR (CDCl3): δ
42.32, 51.88, 53.88, 60.78, 114.54 (JCF ) 23), 118.67 (JCF
)
21), 118.72, 122.45 (JCF ) 3), 124.68, 127.50, 129.13, 129.56,
130.26 (JCF ) 8), 133.99, 136.63 (JCF ) 6), 151.00, 162.48 (JCF
) 246), 165.74. Anal. (C21H22Cl2FN3O‚HCl‚0.25H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-fluorobenzamide (9) was prepared from 4-fluoro-
benzoic acid and 6 according to procedure B. Yield: 73%. Mp
(hydrochloride, methanol/diethyl ether) 56 °C. IR (film):
ν
1
3302, 1645. H NMR (CDCl3): δ 2.64 (s, 4H), 3.06-3.08 (m,
6H), 4.08 (m, 2H), 5.76 (s, 1H), 6.19 (s, 1H), 6.93 (m, 1H), 7.36-
7.40 (m, 4H), 7.76 (m, 2H). 13C NMR (CDCl3): δ 41.93, 51.55,
53.53, 60.46, 115.44 (JCF ) 22), 118.43, 124.39, 127.23, 128.74,
129.02 (JCF ) 8), 129.44, 130.32, 133.71, 150.75, 164.19 (JCF
) 249), 165.72. Anal. (C21H22Cl2FN3O‚1.5HCl‚H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-2-chlorobenzamide (10) was prepared from 2-chloro-
benzoic acid and 6 according to procedure A. Yield: 67%. Rf )
0.37 (CHCl3/CH3OH 10:1). Mp (hydrochloride, methanol/di-
Procedure B. In a typical conversion, CDI (0.11 g, 0.66
mmol) was added to a solution of the appropriate benzoic acid
(0.66 mmol) in 2 mL of absolute pyridine, and the mixture was
stirred under argon for 1 h. After that time, a solution of 6
(0.20 g, 0.66 mmol) in 5 mL of absolute chloroform was added,
and the mixture was stirred overnight. All volatiles were
removed in vacuo, and the residue was purified by chroma-
tography to give the title compound.
1
ethyl ether) 64 °C. IR (film): ν 3282, 1645. H NMR (CDCl3):
δ 2.65 (s, 4H), 2.92-3.08 (m, 6H), 4.08 (s, 2H), 5.79 (s, 2H),
6.55 (m, 1H), 6.94 (m, 1H), 7.10-7.14 (m, 2H), 7.27-7.37 (m,
2H), 7.60 (d, J ) 7.1, 1H), 7.73 (d, J ) 8.3, 1H). 13C NMR
(CDCl3): δ 39.85, 49.58, 51.51, 58.53, 116.98, 122.92, 123.64,
125.43, 126.56, 127.37, 127.50, 127.78, 128.41, 128.55, 128.96,
129.64, 132.33, 133.42, 149.55, 164.72. Anal. (C21H22Cl3N3O‚
HCl‚1.25H2O) C, H, N.
4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-2-
enylamine (6). A suspension of 4-(2,3-dichlorophenyl)-pip-
erazine (7.55 g, 32.8 mmol), 2-(4-trans-bromo-but-2-enyl)-
isoindole-1,3-dione (4)20 (9.19 g, 32.8 mmol), and sodium
bicarbonate (13.7 g, 161 mmol) in acetonitrile (100 mL) was
heated to 80 °C under an atmosphere of argon for 5 h.
Subsequently, most of the inorganic salts were removed by
filtration of the hot (CAUTION!) reaction mixture. The N-
protected intermediate 5 crystallized out of the filtrate and
was taken up in a minimum amount of chloroform. After
filtration and evaporation of the solvent, 10.9 g (77%) was
obtained as a solid. Rf ) 0.45 (ethyl acetate). Mp 144-146 °C
(CHCl3). IR (film): ν 1714. 1H NMR (CDCl3): δ 2.62 (s, br.,
4H), 3.05-3.06 (m, 6H), 4.31 (m, 2H), 5.69-5.82 (m, 2H), 6.95
(m, 1H), 7.10-7.16 (m, 2H), 7.69-7.75 (m, 2H), 7.81-7.88 (m,
2H). 13C NMR (CDCl3): δ 39.04, 51.21, 53.18, 60.09, 118.60,
123.31, 124.54, 127.17, 127.44, 127.47, 129.91, 132.12, 133.99,
151.21, 167.90. Deprotection of 5 was achieved in a solution
(5.12 g, 11.9 mmol) of absolute ethanol (150 mL) under an
atmosphere of argon, to which hydrazine (0.75 mL, 24 mmol)
was added, and the reaction mixture was allowed to stir at
reflux for 2.5 h. The reaction mixture was cooled (0 °C) and
filtered, and solvent was removed under reduced pressure. The
residue was purified by column chromatography to give the
title compound (2.71 g, 76%) as an oil. Rf ) 0.49 (CHCl3/
CH3OH/N(C2H5)3 10:1:1). IR (film): ν 3358. 1H NMR (CDCl3):
δ 1.50 (s, br., 2H), 2.64 (s, br., 4H), 3.06 (m, 6H), 3.34 (m, 2H),
5.64-5.84 (m, 2H), 6.96 (m, 1H), 7.11-7.17 (m, 2H). 13C NMR
(CDCl3): δ 43.50, 51.24, 53.15, 60.38, 118.58, 124.53, 126.56,
127.42, 127.46, 133.97, 134.71, 151.22.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-2-fluorobenzamide (7) was prepared from 2-fluoro-
benzoic acid and 6 according to procedure A. Yield: 96%. Rf )
0.34 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp (hydrochloride,
methanol/diethyl ether) 164 °C. IR (film): ν 3354, 1649. 1H
NMR (CDCl3): δ 2.66 (s, 4H), 3.09 (s, 6H), 4.13 (m, 2H), 5.72-
5.85 (m, 2H), 6.94 (m, 1H), 7.07-7.19 (m, 2H), 7.26 (m, 1H),
7.43-7.54 (m, 2H), 8.05-8.15 (m, 2H). 13C NMR (CDCl3): δ
41.34, 46.26, 52.17, 56.67, 115.94 (JCF ) 25), 118.57, 120.87
(JCF ) 11), 124.52, 124.78 (JCF ) 3), 127.41, 128.72, 129.60,
132.04 (JCF ) 2), 133.28 (JCF ) 9), 133.94, 151.16, 160.55 (JCF
) 247), 163.01. Anal. (C21H22Cl2FN3O‚2HCl) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-3-chlorobenzamide (11) was prepared from 3-chloro-
benzoic acid and 6 according to procedure A and purified by
recrystallization of its oxalate from acetone. Yield: 66%. Rf )
0.48 (CHCl3/CH3OH 10:1). Mp (oxalate, acetone) 108-111 °C.
IR (film): ν 3309, 1641. 1H NMR (CDCl3): δ 2.64 (s, 4H), 3.07-
3.08 (m, 6H), 4.07 (m, 2H), 5.75-5.77 (m, 2H), 6.28 (m, 1H),
6.93 (dd, J ) 6.7, 2.7, 1H), 7.09-7.14 (m, 2H), 7.34 (t, J ) 7.6,
1H), 7.44 (dd, J ) 7.4, 1.6, 1H), 7.62 (d, J ) 7.4, 1H), 7.74 (t,
J ) 1.6, 1H). 13C NMR (CDCl3) δ 42.20, 51.77, 53.76, 60.68,
118.66, 124.63, 125.05, 127.29, 127.46, 129.15, 129.46, 129.89,
131.52, 133.96, 134.69, 136.11, 150.98, 165.65. Anal. (C21H22-
Cl3N3O‚(COOH)2‚CH3COCH3) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-chlorobenzamide (12) was prepared from 4-chloro-
benzoic acid and 6 according to procedure A. Yield: 79%. Rf )
0.39 (CHCl3/CH3OH 10:1). Mp (hydrochloride, methanol/di-
ethyl ether) 69 °C. IR (film): 3310, 1642. 1H NMR (CDCl3): δ
2.64 (s, 4H), 3.06-3.07 (m, 6H), 4.07 (m, 2H), 5.76-5.77 (m,
2H), 6.68 (t, J ) 5.2, 1H), 6.95 (m, 1H), 7.10-7.16 (m, 2H),
7.36 (d, J ) 8.6, 2H), 7.73 (d, J ) 8.6, 2H). 13C NMR (CDCl3)
δ 41.52, 51.12, 53.18, 60.14, 118.61, 124.63, 127.46, 128.41,
128.78, 129.83, 132.74, 133.99, 137.71, 151.09, 166.24. Anal.
(C21H22Cl3N3O‚HCl‚0.5H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-2-iodobenzamide (13) was prepared from 2-iodo-
benzoic acid and 6 according to procedure B. Yield: 54%. Rf )
0.47 (CHCl3/CH3OH 10:1). Mp (hydrochloride, methanol/di-
ethyl ether) 121-123 °C. IR (film): ν 3272, 1644. 1H NMR
(CDCl3): δ 2.65 (s, 4H), 3.06-3.10 (m, 6H), 4.09 (m, 2H), 5.75-
5.89 (m, 2H), 6.00 (m, 1H), 6.95 (m, 1H), 7.06-7.17 (m, 3H),
7.34-7.41 (m, 2H), 7.85 (d, J ) 7.7, 1H). 13C NMR (CDCl3): δ
41.35, 51.10, 53.02, 60.10, 92.45, 118.49, 124.41, 127.31,
127.76, 128.02, 129.19, 130.85, 132.52, 133.80, 139.65, 141.13,
142.03, 151.05, 169.10. Anal. (C21H22Cl2IN3O‚HCl‚H2O) C, H,
N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-3-iodobenzamide (14) was prepared from 3-iodo-
benzoic acid and 6 according to procedure A and purified as
its oxalate from acetone. Yield: 56% (oxalate). Rf ) 0.38
1
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-3-fluorobenzamide (8) was prepared from 3-fluoro-
benzoic acid and 6 according to procedure A. Yield: 67%. Rf )
(CHCl3/CH3OH 10:1). Mp (oxalate, acetone) 138-142 °C. H
NMR (CDCl3): δ 2.48 (s, 4H), 3.02 (s, 6H), 4.05 (m, 2H), 5.74-
5.75 (m, 2H), 6.92 (m, 1H), 7.04-7.14 (m, 4H), 7.77 (t, J 7.7,

846 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3
Grundt et al.
1H), 8.13 (t, J 1.5, 1H). 13C NMR (CDCl3): δ 41.45, 51.03,
52.99, 60.12, 94.09, 118.45, 124.35, 126.14, 127.21, 127.32,
128.79, 129.36, 129.98, 133.74, 135.91, 136.25, 140.07, 150.99,
165.73. Anal. (C21H22Cl2IN3O‚(COOH)2) C, H, N.
124.75, 124.93, 126.66, 127.35, 127.51, 129.00, 131.27, 133.93,
150.74, 160.43, 167.71. Anal. (C21H23Cl2N3O2‚2HCl‚0.5H2O) C,
H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-2-nitrobenzamide (21) was prepared from 2-nitro-
benzoic acid and 6 according to procedure A. Yield: 90%. Rf )
0.42 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp (hydrochloride,
methanol/diethyl ether) 144 °C. IR (film): ν 3272, 1649. 1H
NMR (CDCl3): δ 2.51 (s, 4H), 2.93-2.94 (m, 6H), 3.90 (m, 2H),
5.59-5.73 (m, 2H), 6.74 (t, J 5.7, 1H), 6.83 (m, 1H), 7.00-
7.07 (m, 2H), 7.35-7.54 (m, 3H), 7.85 (dd, J ) 8.0, 1.0, 1H).
13C NMR (CDCl3): δ 41.34, 50.97, 52.92, 59.94, 118.47, 124.20,
124.34, 127.12, 127.36, 128.55, 128.99, 129.01, 130.23, 132.57,
133.48, 133.68, 146.19, 150.97, 166.24. Anal. (C21H22Cl2N4O3‚
HCl‚1.5H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-iodobenzamide (15) was prepared from 4-iodo-
benzoic acid and 6 according to procedure A and purified as
its oxalate salt from acetone. Yield: 96% (oxalate). Rf ) 0.37
1
(CHCl3/CH3OH 10:1). Mp (oxalate, acetone) 181-183 °C. H
NMR (CDCl3): δ 2.62 (m, 4H), 3.04-3.06 (m, 6H), 4.06 (m,
2H), 5.75 (m, 2H), 6.50 (t, J ) 5.4 Hz, 1H), 6.94 (dd, J ) 6.1,
3.5 Hz, 1H), 7.15 (m, 2H), 7.50 (d, J ) 8.5 Hz, 2H), 7.76 (d, J
) 8.5 Hz, 2H). 13C NMR (CDCl3): δ 41.51, 51.20, 53.17, 60.15,
98.44, 118.57, 124.54, 127.43, 128.54, 129.12, 129.42, 133.74,
133.94, 137.68, 151.14, 166.49. Anal. (C21H22Cl2IN3O‚(COOH)2)
C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-3-nitrobenzamide (22) was prepared from 3-nitro-
benzoic acid and 6 according to procedure A. Yield: 71%. Rf )
0.37 (CHCl3/CH3OH 10:1). Mp (hydrochloride, methanol/di-
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-2-methoxy-benzamide (16) was prepared from
2-methoxybenzoic acid and 6 according to procedure A. Yield:
78%. Rf ) 0.56 (CH3Cl/CH3OH 10:1, 1% NH4OH). Mp (fuma-
rate, ethanol) 189 °C. IR (film): ν 3401, 1653. 1H NMR
(CDCl3): δ 2.51-2.65 (m, 4H), 2.97-3.10 (m, 6H), 3.93 (s, 3H),
4.11 (m, 2H), 5.68-5.86 (m, 2H), 6.84-7.14 (m, 5H), 7.48 (m,
1H), 8.20 (dd, J 7.8, 1.9, 1H). 13C NMR (CDCl3): δ 40.96, 51.03,
55.77, 60.07, 111.17, 118.52, 121.13, 121.25, 24.43, 127.30,
127.35, 127.58, 130.49, 132.14, 132.66, 133.81, 151.06, 157.32,
164.99. Anal. (C22H25Cl2N3O2‚(CHCOOH)2‚0.5H2O) C, H, N.
1
ethyl ether) 158 °C. IR (film): ν 3307, 1645, 1529, 1349. H
NMR (CDCl3): δ 2.67 (s, 4H), 3.07-3.10 (m, 6H), 4.12 (m, 2H),
5.74-5.87 (m, 2H), 6.58 (t, J ) 5.0, 1H), 6.95 (m, 1H), 7.10-
7.17 (m, 2H), 7.65 (t, J ) 7.9, 1H), 8.18 (“d”, J ) 7.7, 1H), 8.35
(ddd, J ) 8.2, 2.1, 1.0, 1H), 8.61 (t, J ) 1.9, 1H). 13C NMR
(CDCl3): δ 41.81, 51.22, 53.25, 60.15, 118.62, 121.75, 124.64,
126.11, 127.48, 129.11, 129.66, 129.90, 133.31, 134.02, 136.01,
148.16, 151.15, 164.86. Anal. (C21H22Cl2N4O3‚2HCl) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-3-methoxy-benzamide (17) was prepared from
3-methoxybenzoic acid and 6 according to procedure A and
purified by recrystallization as its fumarate from acetone.
Yield: 55% (fumarate). Rf ) 0.40 (CHCl3/CH3OH 10:1). Mp
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-nitrobenzamide (23) was prepared from 4-nitro-
benzoic acid and 6 according to procedure A and purified as
its oxalate from acetone. Yield: 72% (oxalate). Rf ) 0.35
1
(CHCl3/CH3OH 10:1). Mp (oxalate, acetone) 186-189 °C. H
1
(fumarate, acetone) 122-124 °C. IR (film): ν 3317, 1641. H
NMR (CDCl3): δ 2.81 (s, 4H), 3.08-3.13 (m, 6H), 4.13 (m, 2H),
5.81-5.83 (m, 2H), 6.64 (m, 1H), 6.95 (m, 1H), 7.11-7.17 (m,
2H), 7.95 (d, J ) 8.8, 2H), 8.25 (d, J ) 8.8, 2H). 13C NMR
(CDCl3): δ 41.71, 50.99, 53.07, 60.08, 109.56, 118.60, 123.74,
124.69, 127.42, 127.48, 128.18, 129.00, 129.49, 130.26, 133.98,
139.94, 149.52, 150.97, 165.25. Anal. (C21H22Cl2N4O3‚2(COOH)2‚
1.5H2O) C, H, N.
2-Amino-N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-
trans-but-2-enyl}-benzamide (24) was prepared from 2-
aminobenzoic acid and 6 according to procedure B. Yield: 46%.
Rf ) 0.36 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp (hydrochlo-
ride, methanol/diethyl ether) 122 °C. 1H NMR (CDCl3): δ 2.64
(s, 4H), 3.06-3.07 (m, 6H), 4.02 (m, 2H), 5.53 (s, br., 2H), 5.74-
5.77 (m, 2H), 6.30 (t, J ) 5.3, 1H), 6.59-6.96 (m, 2H), 6.94
(m, 1H), 7.09-7.22 (m, 3H), 7.33 (dd, J ) 7.9, 1.2, 1H). 13C
NMR (CDCl3): δ 40.99, 51.13, 53.11, 60.14, 115.76, 116.45,
117.22, 118.55, 124.50, 127.09, 127.37, 127.41, 128.53, 129.99,
132.26, 133.89, 148.69, 151.10, 169.07. Anal. (C21H24Cl2N4O‚
2HCl‚H2O) C, H, N.
3-Amino-N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-
trans-but-2-enyl}-benzamide (25) was prepared from 3-
aminobenzoic acid and 6 according to procedure B. Yield: 41%.
Rf ) 0.32 (CHCl3/CH3OH, 10:1). Mp (hydrochloride, chloroform/
diethyl ether) 131 °C. IR (film): ν 3340, 1639. 1H NMR
(CDCl3): δ 2.64 (s, 4H), 3.05-3.12 (m, 6H), 3.73 (s, br., 2H),
4.05 (m, 2H), 5.74-5.75 (m, 2H), 6.43 (t, J ) 5.5, 1H), 6.76
(m, 1H), 6.94 (m, 1H), 7.05-7.19 (m, 5H). 13C NMR (CDCl3):
δ 41.33, 51.12, 53.13, 60.16, 113.72, 116.22, 117.84, 118.58,
124.54, 127.39, 127.44, 128.49, 129.36, 130.00, 133.92, 135.55,
146.87, 151.11, 167.59. Anal. (C21H24Cl2N4O‚3HCl‚0.33CHCl3)
C, H, N.
Pyridine-2-carboxylic acid-{4-[4-(2,3-dichlorophenyl)-
piperazin-1-yl]-trans-but-2-enyl}-amide (26) was prepared
from pyridine-2-carboxylic acid and 6 according to procedure
A. Yield: 30%. Rf ) 0.41 (CHCl3/CH3OH 10:1, 1% NH4OH).
Mp (hydrochloride, methanol/diethyl ether) 171 °C. IR (film):
ν 3390, 1671. 1H NMR (CDCl3): δ 2.65 (s, 4H), 3.07-3.09 (m,
6H), 4.13 (m, 2H), 5.78-5.81 (m, 2H), 6.95 (m, 1H), 7.10-7.17
(m, 2H), 7.43 (m, 1H), 7.83 (m, 1H), 8.19-8.21 (m, 2H), 8.55
(d, J ) 4.8, 1H). 13C NMR (CDCl3): δ 40.75, 51.18, 53.16, 60.22,
118.56, 122.22, 124.51, 126.15, 127.41, 128.51, 129.78, 133.93,
NMR (CDCl3): δ 2.49 (s, 4H), 2.95 (s, 6H), 3.83 (s, 3H), 4.07
(s, 2H), 5.66-5.83 (m, 2H), 6.92 (m, 1H), 7.08-7.15 (m, 3H),
7.26-7.32 (m, 2H), 7.38 (m, 1H). 13C NMR (CDCl3): δ 41.35,
50.87, 52.91, 55.28, 59.93, 112.34, 117.48, 118.54, 118.70,
124.51, 127.31, 127.38, 128.07, 129.39, 130.26, 133.84, 135.75,
150.94, 159.64, 167.11. Anal. (C22H25Cl2N3O2‚(CHCOOH)2‚
0.5H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-methoxy-benzamide (18) was prepared from
4-methoxybenzoic acid and 6 according to procedure A and
purified by recrystallization of its oxalate salt from acetone.
Yield: 51% (oxalate). Rf ) 0.45 (CHCl3/CH3OH 10:1). Mp
(oxalate, acetone) 167-172 °C. IR (film): ν 3320, 1635. 1H
NMR (CDCl3): δ 2.51-2.71 (m, 4H), 2.97-3.13 (m, 6H), 3.79
(s, 3H), 3.94 (m, 2H), 5.75-5.83 (m, 2H), 6.50 (t, J ) 5.5, 1H),
6.96-6.85 (m, 3H), 7.09-7.28 (m, 2H), 7.98 (“d”, J ) 8.6, 2H).
13C NMR (CDCl3): δ 42.14, 51.91, 54.13, 56.29, 61.11, 114.19,
119.03, 124.96, 127.04, 127.82, 129.05, 129.07, 130.42, 134.30,
151.39, 162.27, 166.86. Anal. (C22H25Cl2N3O2‚(COOH)2‚H2O)
C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-2-hydroxy-benzamide (19) was prepared from 2-
hydroxybenzoic acid and 6 according to procedure B. Yield:
34%. Rf ) 0.47 (CHCl3/CH3OH 10:1). Mp (hydrochloride,
methanol/diethyl ether) 121 °C. IR (film): ν 3329, 1638. 1H
NMR (CDCl3): δ 2.63 (s, 4H), 3.05-3.07 (m, 6H), 4.08 (m, 2H),
5.75-5.78 (m, 2H), 6.80-6.97 (m, 4H), 7.10-7.16 (m, 2H), 7.37
(m, 1H), 7.45 (dd, J ) 8.0, 1.5, 1H). 13C NMR (CDCl3): δ 41.74,
51.84, 53.83, 60.68, 114.25, 118.65, 118.67, 118.71, 124.59,
125.40, 127.43, 128.94, 129.51, 133.91, 134.19, 150.93, 161.18,
169.35. Anal. (C21H23Cl2N3O2‚2HCl) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-hydroxy-benzamide (20) was prepared from 4-
hydroxybenzoic acid and 6 according to procedure B. Yield:
51%. Rf ) 0.42 (CHCl3/CH3OH 10:1). Mp (hydrochloride,
methanol/diethyl ether) 148 °C. IR (film): ν 3309, 1633. 1H
NMR (CDCl3): δ 2.69 (m, 4H), 3.05-3.08 (m, 6H), 4.01 (m,
2H), 5.70-5.75 (m, 2H), 6.67 (t, J ) 5.5, 1H), 6.76 (d, J ) 8.6,
2H), 6.88 (m, 1H), 7.07-7.19 (m, 2H), 7.56 (d, J ) 8.6, 2H).
13C NMR (CDCl3): δ 41.23, 50.62, 53.00, 60.01, 115.60, 118.65,

Trans Olefin Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3 847
137.31, 148.01, 149.75, 151.16, 164.06. Anal. (C20H22Cl2N4O‚
employing an alteration of procedure B as described for 29.
Yield: 33%. Rf ) 0.31 (CHCl3/CH3OH 10:1). Mp (hydrochloride,
3HCl) C, H, N.
1
methanol/diethyl ether) 186 °C. H NMR (CDCl3): δ 2.62 (s,
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-nicotinamide (27) was prepared from nicotinoyl
chloride hydrochloride and 6 according to procedure A. Yield:
61%. Rf ) 0.34 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp (hydro-
chloride, methanol/diethyl ether) 151 °C. IR (film): ν 3294,
4H), 3.05 (s, 6H), 4.10 (s, 2H), 5.72-5.82 (m, 2H), 6.53 (t, J )
5.2, 1H), 6.91 (dd, J ) 6.8, 2.5, 1H), 7.10-7.13 (m, 2H), 7.20
(t, J ) 4.7, 1H), 7.88 (d, J ) 8.2, 2H), 8.47 (d, J ) 8.2, 2H),
8.78 (d, J 4.7, 2H). 13C NMR (CDCl3): δ 42.23, 51.85, 53.82,
60.78, 118.71, 119.70, 124.64, 127.30, 127.50, 128.35, 129.07,
129.71, 133.94, 136.14, 140.32, 151.05, 157.14, 163.48, 166.66.
Anal. (C25H25Cl2N5O‚2HCl‚2H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-(1H-imidazol-2-yl)-benzamide (33) was prepared
from 4-(1H-imidazol-2-yl)-benzoic acid22 and 6 according to
procedure B. Yield: 32%. Rf ) 0.32 (CHCl3/CH3OH 10:1, 1%
NH4OH). Mp (oxalate, ethanol) 176 °C. IR (film): ν 3203, 1634.
1H NMR (CDCl3): δ 2.66 (m, 4H), 3.04-3.10 (m, 6H), 4.01 (d,
J 4.3, 2H), 5.72-5.83 (m, 2H), 7.04 (dd, J 6.8, 2.5, 1H), 7.15-
7.21 (m, 4H), 7.87-7.94 (m, 4H). 13C NMR (CDCl3): δ 42.60,
52.26, 54.34, 61.32, 119.84, 125.46, 125.87, 127.95, 128.66,
131.75, 133.87, 134.43, 134.86, 146.39, 151.91, 168.49. Anal.
(C24H25Cl2N5O‚2(COOH)2).
Quinoxaline-2-carboxylic acid-{4-[4-(2,3-dichlorophen-
yl)-piperazin-1-yl]-trans-but-2-enyl}-amide (34). Prepared
from quinoxaline-2-carboxylic acid and 6 according to proce-
dure B. Yield: 67%. Rf ) 0.44 (CHCl3/CH3OH 10:1, 1%
NH4OH). Mp. (oxalate, ethanol) 148 °C. IR (film): ν 3397, 1671.
1H NMR (CDCl3): δ 3.06-3.12 (m, 4H), 3.91 (s, 6H), 4.21 (m,
2H), 5.84-5.87 (m, 2H), 6.94 (m, 1H), 7.08-7.14 (m, 2H), 7.79-
7.89 (m, 2H), 8.09 (m, 1H), 8.14-8.20 (m, 2H), 9.68 (s, 1H).
13C NMR (CDCl3): δ 40.78, 51.02, 53.04, 60.02, 118.43, 124.37,
127.24, 127.30, 128.84, 129.26, 129.30, 129.41, 130.68, 131.42,
133.76, 140.01, 143.15, 143.67, 150.97, 162.92. Anal. (C23H23-
Cl2N5O‚(COOH)2‚0.25H2O) C, H, N.
1
1644. H NMR (CDCl3): δ 2.62 (s, br., 4H), 3.05 (s, br., 6H),
4.10 (m, 2H), 5.77-5.79 (m, 2H), 6.94 (m, 1H), 7.12-7.15 (m,
2H), 7.22 (t, J ) 5.4, 1H), 7.35 (dd, J ) 7.9, 4.8, 1H), 8.14 (d,
J ) 7.9, 1H), 8.68 (d, J ) 3.8, 1H), 9.03 (s, br, 1H). 13C NMR
(CDCl3): δ 41.42, 51.06, 53.04, 60.02, 118.46, 123.33, 124.41,
127.25, 127.34, 129.07, 129.25, 130.06, 133.79, 135.04, 147.92,
150.93, 151.93, 165.37. Anal. (C20H22Cl2N4O‚3HCl‚1.25H2O) C,
H, N.
Pyridine-4-carboxylic acid-{4-[4-(2,3-dichlorophenyl)-
piperazin-1-yl]-trans-but-2-enyl}-amide (28) was prepared
from pyridine-4-carboxylic acid and 6 according to procedure
A. Yield: 68%. Mp (hydrochloride, methanol/diethyl ether)
133-135. IR (film): ν 3308, 1651. 1H NMR (CDCl3): δ 2.63 (s,
4H), 3.06 (s, 6H), 4.10 (s, 2H), 5.77 (s, 2H), 6.94 (m, 1H), 7.13-
7.16 (m, 2H), 7.66 (d, J ) 5.6, 2H), 8.69 (d, J ) 5.6, 2H). 13C
NMR (CDCl3): δ 41.47, 51.01, 53.02, 59.97, 118.49, 120.93,
124.49, 127.26, 127.39, 129.09, 129.14, 133.81, 141.46, 150.29,
150.95, 165.28. Anal. (C20H22Cl2N4O‚3HCl‚0.5H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-pyridine-2-yl-benzamide (29). In alteration of
procedure B, 4-pyridine-2-yl-benzoic acid hydrochloride21 was
treated with 2 equiv of CDI in pyridine. After 1 h at room
temperature, the reaction mixture was hydrolyzed with water
and extracted with chloroform. The intermediate imidazoline
derivative was reacted with 6 in the usual manner. The crude
amide was purified by flash chromatography and was con-
verted into its hydrochloride for pharmacological evaluation.
Yield: 62%. Rf ) 0.51 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp
(hydrochloride, 2-propanol) 230-232 °C. IR (film): ν 3299,
Benzo[b]thiophene-2-carboxylic acid-{4-[4-(2,3-dichloro-
phenyl)-piperazin-1-yl]-trans-but-2-enyl}-amide (35) was
prepared from benzo[b]thiophene-2-carboxylic acid and 6 ac-
cording to procedure A. Yield: 92%. Rf ) 0.62 (CHCl3/CH3OH
10:1, 1% NH4OH). Mp (oxalate, ethanol) 78 °C. IR (film): ν
1
1638. H NMR (CDCl3): δ 2.62 (s, 4H), 3.06 (s, 6H), 4.11 (m,
2H), 5.76-5.79 (m, 2H), 6.78 (t, J ) 5.5, 1H), 6.92 (m, 1H),
7.09-7.16 (m, 2H), 7.26 (m, 1H), 7.74-7.76 (m, 2H), 7.90 (d,
J ) 8.3, 2H), 8.04 (d, J ) 8.2, 2H), 8.69 (d, J ) 4.6, 1H). 13C
NMR (CDCl3): δ 41.48, 51.16, 53.14, 60.17, 118.55, 120.79,
122.70, 124.49, 126.92, 127.37, 127.41, 128.84, 129.75, 133.89,
134.49, 136.86, 142.10, 149.73, 151.12, 156.08, 166.90. Anal.
(C26H26Cl2N4O‚2HCl‚3H2O) C, H, N.
1
3304, 1628. H NMR (CDCl3): δ 2.65 (s, 4H), 3.05-3.07 (m,
6H), 4.10 (m, 2H), 5.73-5.79 (m, 2H), 6.74 (s, br., 1H), 6.90
(m, 1H), 7.08-7.16 (m, 2H), 7.34-7.42 (m, 2H), 7.51-8.12 (m,
3H). 13C NMR (CDCl3): δ 41.52, 50.96, 53.02, 60.00, 118.57,
122.63, 124.58, 124.84, 124.98, 125.25, 126.27, 127.42, 127.47,
128.60, 129.87, 133.91, 138.35, 139.03, 140.77, 150.99, 162.19.
Anal. (C23H23Cl2N3OS‚(COOH)2) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-pyridine-3-yl-benzamide (30) was prepared from
4-pyridine-3-yl-benzoic acid hydrochloride21 and 6 employing
an alteration of procedure B as described for 29. Yield: 31%.
Rf ) 0.42 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp (oxalate,
ethanol) 194-196 °C. IR (film): ν 3297, 1641. 1H NMR
(CDCl3): δ 2.64 (s, 4H), 3.06-3.10 (m, 6H), 4.14 (m, 2H), 5.79-
5.81 (m, 2H), 6.61 (t, J ) 5.6, 1H), 6.93-6.97 (m, 1H), 7.13-
7.16 (m, 2H), 7.39 (m, 1H), 7.62-7.65 (m 2H), 7.86-7.93 (m,
3H), 8.62 (dd, J ) 4.8, 1.5, 1H), 8.84 (d, J ) 2.0, 1H). 13C NMR
(CDCl3): δ 41.52, 51.21, 53.20, 60.21, 118.57, 123.66, 124.57,
127.17, 127.21, 127.44, 127.79, 128.97, 129.73, 133.96, 134.42,
135.49, 140.81, 148.21, 149.08, 151.14, 166.74. Anal. (C26H26-
Cl2N4O‚(COOH)2‚2H2O) C, H, N.
2-Benzofuran-2-carboxylic acid {4-[4-(2,3-Dichlorophen-
yl)-piperazin-1-yl]-trans-but-2-enyl}-amide (36) was pre-
pared from 2-benzofuran-2-carboxylic acid and 6 according to
procedure B. Yield: 70%. Rf ) 0.65 (CHCl3/CH3OH 10:1). Mp
(hydrochloride, methanol/diethyl ether) 242-244 °C. IR
1
(film): ν 3314, 1648. H NMR (CDCl3): δ 2.64 (s, 4H), 3.07-
3.90 (m, 6H), 4.13 (m, 2H), 5.71-5.82 (m, 2H), 6.83 (t, J )
5.4, 1H), 6.85 (m, 1H), 7.09-7.16 (m, 2H), 7.28 (m, 1H), 7.41
(m, 1H), 7.47-7.50 (m, 2H), 7.65 (d, J ) 7.7, 1H). 13C NMR
(CDCl3): δ 40.65, 51.18, 53.18, 60.14, 110.46, 111.65, 118.55,
122.68, 123.66, 124.51, 126.85, 127.41, 127.51, 129.10, 129.26,
133.92, 148.54, 151.13, 154.63, 158.60. Anal. (C23H23Cl2N3O2‚
HCl‚H2O) C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-pyridine-4-yl-benzamide (31) was prepared from
4-pyridine-4-yl-benzoic acid hydrochloride21 and 6 employing
an alteration of procedure B as described for 29. Yield: 57%.
Rf ) 0.40 (CHCl3/CH3OH 10:1, 1% NH4OH). Mp (oxalate,
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-butyl}-4-
pyridine-3-yl-benzamide (42) was prepared from 4-pyridine-
3-yl-benzoic acid hydrochloride21 and 4-[4-(2,3-dichlorophenyl)-
piperazin-1-yl]-butylamine15,17 employing an alteration of
procedure B as described for 29. Yield: 33%. Rf ) 0.44 (CHCl3/
CH3OH 10:1, 1% NH4OH). Mp (hydrochloride, chloroform/
diethyl ether) 189 °C. IR (film): ν 3299, 1640. 1H NMR
(CDCl3): δ 1.64-1.74 (m, 4H), 2.61 (s, 4H), 3.00 (s, 4H), 3.51
(q, J ) 6.1, 2H), 6.86 (dd, J ) 7.6, 2.0, 1H), 7.05-7.15 (m, 2H),
7.26 (t, J ) 5.3, 1H), 7.36 (dd, J ) 7.9, 4.8, 1H), 7.61 (d, J )
8.3, 1H), 7.85 (m, 1H), 7.90 (d, J ) 8.3, 1H), 8.60 (dd, J ) 4.8,
1.5, 1H), 8.81 (d, J ) 2.2, 1H). 13C NMR (CDCl3): δ 24.43,
27.48, 40.07, 51.09, 53.22, 58.02, 118.47, 123.66, 124.51,
127.07, 127.34, 127.42, 127.86, 133.90, 134.36, 134.55, 135.47,
140.45, 148.12, 149.00, 151.07, 167.21. Anal. (C26H28Cl2N4O‚
3HCl‚0.33CHCl3) C, H, N.
1
ethanol) 192 °C. IR (film): ν 3288, 1648. H NMR (CDCl3): δ
2.64 (s, 4H), 3.05-3.07 (m, 6H), 4.13 (m, 2H), 5.77-5.79 (m,
2H), 6.53 (s, 1H), 6.93 (m, 1H), 7.08-7.13 (m, 2H), 7.49 (m,
2H), 7.66 (m, 2H), 7.89 (m, 2H), 8.51 (m, 2H). 13C NMR
(CDCl3): δ 42.29, 51.90, 53.87, 60.82, 118.75, 121.78, 124.73,
127.29, 127.57, 127.92, 129.12, 129.76, 134.04, 134.86, 147.10,
150.30, 151.06, 166.41. Anal. (C26H26Cl2N4O‚(COOH)2‚0.5H2O)
C, H, N.
N-{4-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-trans-but-
2-enyl}-4-pyrimidin-2-yl-benzamide (32) was prepared
from 4-pyrimidine-2-yl-benzoic acid hydrochloride21 and 6

848 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3
Grundt et al.
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Dopamine Receptor Binding Assays. A filtration binding
assay was used to characterize the binding properties of
membrane-associated receptors. For human D2L, D3, and D4
dopamine receptors expressed in HEK 293 cells, tissue homo-
genates (50 mL) were suspended in 50 mM Tris-HCl/150 mM
NaCl/10 mM EDTA buffer pH 7.5 and incubated with 50 µL
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determined using 25 µM (+)-butaclamol. For competition
experiments, the radioligand concentration was generally
equal to 0.5 times the Kd value, and the concentration of the
competitive inhibitor ranged over 5 orders of magnitude.
Binding was terminated by the addition of cold wash buffer
(10 mM Tris-HCl/150 mM NaCl, pH 7.5) and filtration over
glass-fiber filters (Schleicher and Schuell No. 32). Filters were
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Competition curves were modeled for a single site, and the
IC50 values were converted to equilibrium dissociation con-
stants (Ki values) using the Cheng-Prusoff23 correction. Mean
Ki values SEM are reported for at least three independent
experiments.
Acknowledgment. The research reported herein
was supported by funds from the NIDA Intramural
Research Program and 1 DA 13584. P.G. was supported
by a National Institutes of Health (NIH) Visiting
Fellowship. E.E.C. and C.J.B. were supported by NIH
summer IRTA fellowships.
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Supporting Information Available: Elemental Analy-
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