Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2- ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration

Article abstract of DOI:10.1021/jm070860r

This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the ph

Full text of DOI:10.1021/jm070860r

J. Med. Chem. 2008, 51, 101–117
101
Further Structure–Activity Relationships Study of Hybrid
7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-
5,6,7,8-tetrahydronaphthalen-2-ol Analogues: Identification of a High-Affinity D3-Preferring
Agonist with Potent in Vivo Activity with Long Duration of Action
Swati Biswas,† Suhong Zhang,† Fernando Fernandez,† Balaram Ghosh,† Juan Zhen,§ Eldo Kuzhikandathil,#
Maarten E. A. Reith,§ and Aloke K. Dutta*,†
Department of Pharmaceutical Sciences, Wayne State UniVersity, Detroit, Michigan 48202, Millhauser Laboratories, Department of Psychiatry,
New York UniVersity School of Medicine, New York, New York 10016, and Department of Pharmacology and Physiology, UMDNJsNew
Jersey Medical School, Newark, New Jersey 07103
ReceiVed July 16, 2007
This paper describes an extended structure–activity relationships study of aminotetralin-piperazine-based
hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers
have been developed where location of the phenolic hydroxyl group has been varied on the aromatic ring.
Between two catechol derivatives, compound 6e with a two methylene linker length exhibited higher affinity
and selectivity for D3 over D2 receptors over compound 6f with four methylene linkers (D2/D3 ) 50.6 vs
7.51 for 6e and 6f, respectively). In general, the (-)-isomer was more potent than the (+)-isomeric counterpart.
Binding results indicated highest selectivity for D3 receptors in compound (-)-10 (Ki ) 0.35 nM; D2/D3
) 71). In the 5-hydroxy series, highest selectivity for D3 receptors was exhibited by compound (-)-25 (Ki
) 0.82 nM; D2/D3 ) 31.5). Most potent compounds exhibited binding and functional affinities at the sub-
nanomolar level for the D3 receptor. Binding assays were carried out with HEK-293 cells expressing either
D2 or D3 receptors by using tritiated spiperone as radioligand for competition studies to evaluate inhibition
constants (Ki). A functional assay of selected compounds for stimulating GTPγS binding was carried out
with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. The
functional assay results indicated partial to full agonist characteristics of test compounds. Compound (-)-
25 was selected further for in vivo study to evaluate its potency in producing contralateral rotations in rats
with unilateral lesion in the nigrostriatal region induced by neurotoxin 6-OHDA, a Parkinsonian animal
model. Compound (-)-25 at 5 µmol/kg exhibited rotational activity that lasted beyond 12 h, whereas at a
1 µmol/kg dose the rotations lasted beyond 8 h.
Introduction
highest expression of D3 receptor was found in the area of the
ventral striatum and associated striatum.10,11 The D3 receptor
has been suggested as an interesting target for the development
of potential atypical antipsychotic agents, antiparkinsonian
drugs, and pharmacotherapeutics for treatment of drugs of
abuse.12–14 Cloning of D2 and D3 receptors revealed a molecular
structural sequence containing 50% homology between these
two receptor subtypes. A higher homology of 75–80% was
found in the helical transmembrane spanning regions between
these two receptor subtypes, where agonist binding sites are
believed to be located.3,15
The dopamine (DA)a receptor system has been targeted for
drug development for treatment of psychiatric illness, neuro-
degeneration, drug abuse, and other therapeutic areas.1–3 The
DA receptor system, a G-protein-coupled receptor (GPCR), in
the central nervous system (CNS) was initially classified into
two main classes, D1 and D2.4 So far, five subtypes of DA
receptor have been discovered, and they are grouped into two
main classes as D1-type and D2-type. D2-type receptors include
D2, D3, and D4 receptors, whereas D1-type receptors include
D1 and D5.5–9 Interestingly, it was discovered that the DA D3
receptor had a different distribution in the brain compared to
the D2 receptor.5,6 The DA D3 receptor was found to be located
predominantly in the limbic region, which has been implicated
in a number of psychiatric disorders.10 In the human brain, the
DA receptor agonists have been used frequently in the therapy
of Parkinson’s disease (PD), which is a progressive, chronic
neurodegeneration disorder and is characterized by a gradual
loss of dopaminergic neurons in the par compacta of the
substantia nigra.16 It is estimated that PD affects approximately
1% of people older than 65 years of age. As mentioned above,
dopaminergic agents have been used more extensively in the
therapy for PD than any other class of drug molecules.17,18
Development of DA agonists started with the goal to address
the shortcomings of L-dopa therapy, specifically, the problems
associated with development of dyskinesia and its implication
in toxicity to dopaminergic cells.19 DA agonists are known to
provide neuroprotection.13,20 Neuroprotection by DA agonists
might be derived from the following effects: (a) Stimulation of
DA autoreceptors results in decreased DA synthesis, release,
and turnover. This leads to production of less DA-related
* Address correspondence to this author at the Department of Pharma-
ceutical Sciences, Room 3128, Applebaum College of Pharmacy and Health
Sciences, Wayne State University, Detroit, MI 48202 [telephone (313) 577-
1064; fax (313) 577-2033; e-mail adutta@wayne.edu].
†
Wayne State University.
New York University School of Medicine.
UMDNJsNew Jersey Medical School.
§
#
aAbbreviations: DA, dopamine; CNS, central nervous system; GPCR,
G-protein-coupled receptor; PD, Parkinson’s disease; ROS, reactive oxygen
species; SAR, structure-activity relationship; GTPγS, guanosine 5′-[γ-
thio]triphosphate; 7-OH-DPAT, 7-hydroxy-2-(dipropylamino)tetralin; 6-O-
HDA, 6-hydroxydopamine; CHO, Chinese hamster ovary; HEK, human
embryonic kidney; PMA, phosphomolybdic acid.
10.1021/jm070860r CCC: $40.75
2008 American Chemical Society
Published on Web 12/12/2007

102 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
Figure 1. Molecular structures of selective D3 receptor agonists and antagonists.
neurotoxicity by reducing production of reactive oxygen species
(ROS).20 (b) DA agonists will reduce the need for L-dopa and,
thus, will reduce the production of ROS.21 (c) DA agonist
therapy causes a lower incidence of motor complications when
compared to L-dopa therapy.22,23 (d) DA agonists have longer
plasma half-lives than L-dopa. (e) DA D3 receptor preferring
agonists were shown to provide additional neuroprotective
effects relative to DA D2 receptor agonists, possibly via
production of neurotrophic factors.24–26 Furthermore, it has been
demonstrated in a primate model that L-dopa-induced dyskinesia
can be reduced by treatment with a D3 partial agonist.27–29 This
may indicate a superior property of D3 selective agonist or
partial agonist in adjunct therapy with levodopa.
An enormous amount of work has already been performed
in developing selective agonists and antagonists for the D3
receptor.12,30,31 Aminotetralin derivatives were among the
earliest classes of molecules that were investigated for D3
activity.32 7-OH-DPAT (Figure 1), an aminotetralin derivative,
was analyzed in various binding assays to evaluate its binding
activity for D2/D3 receptors. From these studies, 7-OH-DPAT
was shown to exhibit preferential affinity for the D3 receptor
even though the selectivity ratio varied among different
laboratories, largely due to different assay conditions, radioli-
gands, and transfected cell lines applied.33 Recently, a bioiso-
steric analogue of 7-OH-DPAT, pramipexole, was developed
by replacing the phenolic group by a more metabolically stable
thiazolidinium moiety (Figure 1). Pramipexole represents one
of the highest D3 selective agonists reported to date.34 Numerous
other aminotetralins have been developed including structurally
constrained version analogues, which exhibited a wide array of
activity. In another recent study, the aminotetralin moiety was
combined with substituted benzamides, which led to the
development of a series of molecules as both agonists and
antagonists exhibiting high affinity for D2, D3, and 5HT1a
receptors.35 Compound 1 (Figure 1) represents the prototypical
structure derived from this class of molecules. Besides ami-
notetralin derivatives, other structural classes of D2/D3 agonists
have also been developed. Ropinirole is one such example,
which is also a D3 preferring agonist and is used in the therapy
for PD.36 Similar to the development of agonists, numerous
antagonists, for example, SB-277011, selective for the D3
receptor have been developed over the years.37 The majority
of the highly selective D3 antagonists thus far developed contain
a piperazine moiety.12,38–40 Interestingly, compound BP 897,
which was initially identified as a partial agonist but later
displayed antagonist property in other experiments, could reduce
cocaine-seeking behavior in rats.41,42
In our previous effort to develop selective molecules for the
D3 receptor, we adopted a hybrid approach by which the
aminotetralin moiety and the piperazine fragment were fused
together to develop the target molecules. It was perceived that
the aminotetralin moiety will interact with the agonist binding
sites in the DA receptor and that the piperazine fragment will
interact with the accessory binding sites in the D3 receptor to
provide selectivity. Our initial work in this area led to the
development of selective ligands for the D3 receptor compared
to the D2 receptor.43,44 Measurement of thymidine incorporation
by mitogenesis, a functional activity assay, indicated agonist
activity in these hybrid molecules. One of the lead compounds,
compound 2 (D-74) in Figure 1, exhibited high D3 selectivity
and produced potent in vivo contralateral rotational activity in
unilaterally lesioned 6-OHDA-treated rats, indicating good
blood-brain barrier crossing ability of the drug.44
In our current study, we have explored the hybrid structure
template in greater detail to delineate molecular determinants
that can be attributed toward selectivity of these compounds
for the D3 receptor. Specifically, we wanted to explore the
positional effect of the hydroxyl functionality in the aromatic
ring in binding interaction with the receptors. We also wanted
to observe the effect of replacement of the phenolic aromatic
moiety by a bioisosteric indol-2-one derivative on affinity for
the DA receptors. We have also introduced different linker
lengths between aminotetralin and piperazine moieties to further
establish the role of linker size in affinity and selectivity for
the D3 receptor. In addition, for the most active racemic
compounds, their enantiomers were synthesized in enantiomeric
purity. Finally, a selective compound was evaluated in 6-OHDA
unilaterally lesioned rats to observe its ability to produce
contralateral rotations.
Chemistry
Syntheses of the target compounds are described in Schemes
1-5. Synthesis of intermediate amines 2a-c was accomplished
by first treating phenylpiperazine with appropriate chloroaceto-
nitrile in the presence of a base followed by reduction of the
acetonitrile group with Raney nickel to provide intermediates
2a-c.
Scheme 2 describes the synthesis of the final targets 6a-f.
Appropriate 2-tetralone reacted with amines under reductive
Scheme 1a
a a, K2CO3, toluene, reflux, 3 h; b, Raney nickel, H2, 60 psi, 8 h.

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 103
Scheme 2a
a a, NaCNBH3, AcOH, dichloroethane, RT, overnight; b, Et3N, CH2Cl2, 0 °C to RT, 4 h; c, 1-bromopropane, K2CO3, DMF, reflux, 3 h; d, LiAlH4, THF,
reflux, 4 h; e, BBr3, CH2Cl2, -40 °C to RT, overnight; f, 48% aq HBr, 4 h.
amination reaction condition to yield compounds 3a-f in good
yields. Amines were next acylated with appropriate acyl chloride
to yield 4a-d, which were then reduced by LAH to produce
5a-d. Compounds 3e and 3f were directly converted to 5e and
5f by N-alkylation. Final targets 6a-f were produced by
demethylation of the methoxy group either by boron tribromide
or by 48% HBr.
Next, in Scheme 3 the enantiomeric compounds (+)-10, (-)-
10, (+)-13, and (-)-13 were synthesized by following our
published procedure to yield the respective target molecules.44
In Scheme 4, we describe the synthesis of amino and 1,3-
dihydro-2H-indol-2-one derivatives. 2-Tetralone was mononi-
trated in the presence of nitric acid to produce nitro derivative
14. Compound 14 was next reacted with piperazine amine 2a
under reductive amination condition to yield 15. Acylation of
the free amine followed by reduction of the nitro and acyl groups
produced intermediate 18. This compound was next treated with
chloral hydrate and hydroxyl amine to produce an intermediate
that was cyclized under acidic condition to generate benzo[e]
indole-1,2(3H)-dione derivative 19.45 Reduction with hydrazine
produced the second target molecule, 20.46
Scheme 5 describes the synthesis of both the optically active
5-hydroxy derivatives and the corresponding racemic versions.
5-Methoxy-2-tetralone under reductive amination condition
produced compound 21. Treatment of intermediate 21 with a
chiral 4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-dioxa-
phophorinane 2-oxide agent, prepared by following the literature
procedure,47 followed by hydrolysis provided two pure enan-
tiomers of 21 in good yield. To synthesize the final target
2-methoxy derivative 24a and its enantiomers, compounds (()-
21, (+)-21, and (-)-21 were first reacted with boron tribromide
to yield (()-21a, (+)-21a, and (-)-21a, which were treated with
chloroacetyl chloride to produce (()-22a and its enantiomers.
Reaction of these intermediates with appropriate aryl-piperazine
derivatives yielded racemic (()-23a and its enantiomers,
respectively, in good yields. The final targets (()-24a, (+)-
24a, and (-)-24a were produced by reducing the amide
intermediate with LAH. The other target molecules were
synthesized by treating the enantiomers and the racemic mixtures
of compound 21 with chloroacetyl chloride follwed by N-
alkylation and reduction in the similar way as described for
compound 24a. In the final step, the methyl group was removed

104 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
Scheme 3a
a a, NaCNBH3, dichloroethane, AcOH, RT, overnight; b, (R)-(-)-R-methoxyphenylacetic acid, EDCI, HOBT, ET3N, CH2Cl2; c, preparative HPLC; d, (i)
t-BUOK, THF, overnight, (ii) MeLi, THF, 30 min; e, propargyl bromide, NaH, THF, DMF, 50 °C, 6 h; f, BBr3, CH2Cl2, -40 °C to RT, overnight; g,
propionyl chloride, Et3N, CH2Cl2, 0 °C to RT, 2 h; h, LiAlH4, THF, reflux, 4 h.
by standard methods to produce the targets (+)-25, (-)-25, and
(()-25b in good yield.
over (-)-13 (Ki ) 0.748 vs 1.22 nM). Similar to 13, both
enantiomers of compound 10 exhibited sub-nanomolar affinity
for the D3 receptor. However, like enantiomers of 13, both (-)-
10 and (+)-10 exhibited comparable potencies at the D3 receptor
(Ki ) 0.35 and 0.76 nM).
Results and Discussion
Our earlier paper on a hybrid drug development approach
for D2/D3 receptors described the development of aminotetralin–
piperazine-based hybrid derivatives exhibiting D3 preferential
activity both in binding and in functional assays. One of the
enantiomerically pure lead molecules, 2 (Figure 1), indicated
good blood-brain barrier penetrability as it produced potent
contralateral rotations in rats with 6-OHDA-induced unilateral
lesions in the nigrostriatal DA system.44 The results from the
in vivo study thus indicated site-specific agonist activity of 2
in the CNS.
In our current structure-activity relationship (SAR) work we
wanted to evaluate the binding activity of enantiomers of the
racemates 13 and 10, which were evaluated earlier in both
binding and functional assays.44 Both racemates exhibited high-
affinity binding for the D3 receptor with moderate selectivity
for the D3 over D2 receptor. In the functional assay these
racemic compounds were agonists with preferential affinity for
the D3 receptor.44 The enantiomers derived from these two
racemates in the current study displayed differential potencies
for DA receptors. In the case of compound 13, the (+)- and
(-)-isomers were almost equipotent at D2/D3 receptors, with
(+)-13 exhibiting slightly higher potency for the D3 receptor
Next, the positional effect of the hydroxyl functionality on
the aromatic moiety of our lead derivative was explored in
binding interaction. This modification was also accompanied
with other molecular alterations involving changes in methylene
linker length, introduction of a thiophene moiety on the N-alkyl
side chain, and addition of one more hydroxyl group in the
tetrahydrophenol moiety. Thus, compounds 6a-f were designed
and synthesized. In this regard, for the sake of consistency with
the literature references and to avoid any confusion, we are
referring to compound 6a and the corresponding analogues as
5-hydroxy-, 6b as 6-hydroxy-, and 6c as 7-hydroxy-substituted
derivatives throughout this paper. It is evident from Table 1
that when the hydroxyl group was moved to the 5-position as
in compound 6a, an enhancement of potency took place
compared to our original lead 2 (0.82 vs 1.56 nM). However,
it was less selective for the D3 receptor compared to 2. The
change of the hydroxyl group to position 6 yielded compound
6b, which was less potent and selective at the D3 compared to
2 and 6a (Ki ) 11.2 nM, D2/D3 ) 57.9 for 6b). To evaluate
the effect of a three-methylene linker size, compound 6c was
designed and synthesized. This compound exhibited similar

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 105
Scheme 4a
a a, HNO3, -30 °C, 8 min; b, NaCNBH3, dichloroethane, AcOH, RT, overnight; c, propionyl chloride, Et3N, CH2Cl2, 0 °C to RT, 2 h; d, H2 1 atm, 10%
Pd/C, MeOH, RT, 4 h; e, LiAlH4, THF, reflux, 4 h; f, (i) chloral hydrate, Na2SO4, NH2OH·H2O·HCl, 60-80 °C, (ii) H2SO4, 80 °C, 20 min; g, NH2NH2,
reflux, 30 min, (ii) EtOH, EtONa, 80 °C, 30 min.
Scheme 5a
a a, n-Propylamine, NaCNBH3, AcOH, dichloroethane, RT, overnight; b, (+)- or (-)-chlocyphos, ethanol, recrystallized from isopropanol; c, 20% NaOH,
RT, 2 h; d, BBr3, CH2Cl2, -40 °C, overnight; e, Et3N, CH2Cl2, 0 °C to RT, 2 h; f, K2CO3, CH3CN, 60 °C, 4 h; g, LiAlH4, reflux, 4 h; h, BH3, THF, reflux,
6 h; i, 48% aq HBr, reflux, 3 h.

106 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
Table 1. Affinity for Cloned D2L and D3 Receptors Expressed in
Human Embryonic Kidney Cells Measured by Inhibition of
[3H]Spiperone Bindinga
method of separation of enantiomers for these compounds as
the initial binding results from the lead 6a looked promising
for in vivo study. Thus, in Scheme 5 the amine intermediate
(()-21 was selected for chiral separation. The three racemic
derivatives belonging to the 5-hydroxy series displayed high
potency for the D3 receptor with low to sub-nanomolar potency
(Ki ) 0.80, 2.80, and 0.45 nM for (()-6a, (()-24a, and (()-
25b, respectively). All three compounds also exhibited ap-
preciable affinity for the D2 receptor. Among the three racemic
compounds, 6a exhibited maximum selectivity for the D3. The
two enantiomers of 6a exhibited differential activity for the
dopamine receptors with (-)-25 more potent and selective for
the D3 (Ki ) 0.82 nM; D2/D3 ) 31.5). Similarly, enantiomers
of the 2-methoxy derivative (()-24a also exhibited differential
activity, with (-)-24a being the most potent and selective for
the D3 receptor (Ki ) 0.45 nM; D2/D3 ) 20.9). It is evident
that in the 5-hydroxy series the (-)-enantiomer exhibited the
higher potency. The racemic dichloro derivative (()-25b was
the most potent among the three analogues.
Ki (nM), D2L
Ki (nM), D3
compd
[3H]spiperone
[3H]spiperone
D2L/D3
(D-74) 2
7-OH-DPAT
6a
6b
6c
6d
6e
6f
(-)-10
(+)-10
(-)-13
(+)-13
18
142 ( 23
202 ( 34
58.6 ( 7.1
649 ( 96
167 ( 40
24.6 ( 4.0
70.3 ( 16.8
21.7 ( 4.8
25.2 ( 7.3
32.9 ( 8.6
19.4 ( 1.3
19.3 ( 1.5
638 ( 40
1.56 ( 0.36
2.35 ( 0.29
0.80 ( 0.27
11.2 ( 2.0
10.3 ( 1.5
23.9 ( 6.1
1.39 ( 0.14
2.89 ( 0.52
0.35 ( 0.03
0.76 ( 0.079
1.22 ( 0.37
0.74 (0.069
22.2 ( 3.8
10.9 ( 2.5
18.8 ( 4.2
2.80 ( 0.71
0.46 ( 0.12
0.45 ( 0.16
18.4 ( 1.0
0.82 ( 0.13
91
86
72.9
57.9
16.2
1.03
50.6
7.51
71.0
43.2
15.9
25.8
28.7
8.27
4.72
12.8
20.9
32.2
12.9
31.5
20
90.6 ( 21.0
88.7 ( 3.1
35.8 ( 6.3
9.56 ( 2.29
14.6 ( 1.7
238 ( 14
(+)-24a
(()-24a
(-)-24a
(()-25b
(+)-25
(-)-25
On the basis of the binding results, compounds (-)-25, (-)-
24a, and 2 were selected for the GTPγS binding functional assay
for D2 and D3 receptors. In this assay, stimulation of the binding
of nonhydrolyzable [35S]GTPγS by agonist was measured and
compared with the full agonist DA. The results indicated, as
shown in Table 2, that compounds (-)-24a and (-)-25 are
highly potent partial to full agonists at the D2 and D3 receptors
and that both of them exhibited similar selectivities for the D3
receptor (D2/D3 ) 19.4 and 18.3, respectively). The half-
maximal stimulation (EC50) for theD3 receptor of these com-
pounds was in the sub-nanomolar range [EC50 ) 0.08 and 0.12
nM for (-)-24a and (-)-25, respectively]. On the other hand,
compound 2 turned out to be a potent partial agonist with high
receptor maximum stimulation potency for the D3 receptor. The
functional selectivity of compound 2 for the D3 receptor was
comparable with to those of (-)-24a and (-)-25 as shown above
(D2/D3 ) 17.6 for 2). The compounds were considerably more
potent in stimulating [35S]GTPγS binding than in inhibiting
[3H]spiperone binding.
26.0 ( 7.5
a Results are means ( SEM for three to seven experiments, each
performed in triplicate.
affinity and selectivity to 6b and was less potent compared to
2 and 6a. Thus, it further demonstrates that the optimal
methylene linker size is 2 in a similarly substituted series of
this hybrid template, unlike reported with other classes of D3
selective molecules.48 In a further structural modification, the
propyl group was replaced by a 2-thiophene ethyl fragment,
which resulted in the development of 6d. Compound 6d
interestingly exhibited good potency for both D2 and D3
receptors (Ki ) 24.6 and 23.9 nM for D2 and D3, respectively),
even though it lacked a propyl group. In the next two
compounds, 6e and 6f, 6,7-dihydroxy functionalities were
introduced in our lead structure with the variation of the
methylene linker length. In agreement with our earlier results,
compound 6e with the two methylene linker size was more
potent and selective for the D3 receptor although both com-
pounds were very potent at D3 (Ki ) 1.39 and 2.89 nM and
D2/D3; 50.6 and 7.5 for 6e and 6f, respectively). Thus,
compound 6e represents addition of one extra hydroxyl func-
tionality into the structure of 2, which resulted in retention of
almost identical affinity at D3 with slightly higher affinity for
D2, resulting in lower selectivity of 6e for D3 compared to 2.
To evaluate the effect of bioisosteric replacement of the
hydroxyl moiety in 2 on affinity and selectivity, compounds 18
and 20 were designed and synthesized. In 18, the hydroxyl
functionality was replaced by an amino group, whereas in
compound 20, the amino group has been converted into the
benzo[e]indole-1,2(3H)-dione derivative. It is expected that in
both cases H-bonding interaction of parent hydroxyl group
should be maintained with much retention of affinity and
selectivity. Replacement of the hydroxyl group by amino in
compound 18 produced considerably less potency at D3
compared to 2 (Ki ) 22.2 vs 1.56 nM for 18 and 2, respectively)
with lowering of affinity for D2 as well. However, conversion
of 18 into its 2-oxoindole derivative resulted in regaining of
some of its potency. The gain of potency was 2-fold at the D3
receptor, and in case of D2 the increase of potency was 7-fold
(Ki ) 10.9 vs 22.2 nM for D3 and 638 vs 90 nM for D2).
Finally, the 5-hydroxy derivative 6a was further explored as
it exhibited high selectivity and potency for the D3 receptor in
the current series. In this regard, we have developed an efficient
In Vivo Rat Rotational Study. Next compound (-)-25 was
evaluated in vivo in the 6-OHDA-lesioned rat rotational model.
In this animal model, the DA neurons of one side of the
nigrostriatal DA system are selectively and completely degener-
ated by intracebral injection of the neurotoxin 6-OH-DA. This
will induce a postsynaptic supersensitivity to develop on the
lesioned side. DA agonist when administered systemically will
produce contralateral rotations in the rat, that is, toward the
nonlesioned side.49 As the unilaterally lesioned 6-OH-DA rat
represents a well-accepted rodent model for PD, the results from
this experiment will indicate a potential future applicability of
these drugs in PD and an implication of the relative role of D3
receptors in inducing antiparkinsonian effect.36 Furthermore, the
results from this experiment will indicate in vivo agonist potency
of test compounds and, thus, may serve as a further screening
device for developing PD treatment compounds. In addition,
results from this experiment will also indicate whether a drug
is able to cross the blood- brain barrier efficiently or not.
Compound (-)-25 was selected for evaluation in this rat
rotational model to determine its potency in producing con-
tralateral rotations. Two different doses of (-)-25 were tested.
At 5 µmol/kg (2.87 mg/kg), compound (-)-25 produced potent
rotations that lasted beyond 12 h and produced more than 4319
total number of rotations. At a lower dose of 1 µmol/kg (0.53
mg/kg), (-)-25 exhibited rotational activity lasting for 9 h with
a total number of rotations of 3609. It is evident that the higher

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 107
Table 2. Stimulation of [35S]GTPγS Binding to the Cloned hD2 Receptor Expressed in CHO Cells and Cloned hD3 Receptor Expressed in AtT-20
Cells
CHO-D2L
EC50 (nM) [35S]GTPγS
AtT-20-D3
EC50 (nM) [35S]GTPγS
compound
% Emax
100
32.1 ( 2.8
63.4 ( 3.5
61.8 ( 1.0
% Emax
100
40.5 ( 7.5
78.5 ( 9.5
78.0 ( 3.4
D2/D3
dopamine
2
(-)-25
(-)-24a
209 ( 29
8.53 ( 0.62
0.69 ( 0.39
0.12 ( 0.002
0.080 ( 0.041
24.5
17.6
18.3
19.4
12.2 ( 0.9
2.22 ( 0.27
1.56 ( 0.72
a EC50 is the concentration producing half-maximal stimulation; for each compound, maximal stimulation (Emax) is expressed as percent of the Emax
observed with 1 mM (D2) or 100 µM (D3) of the full agonist DA (% Emax). Results are means ( SEM for three or four experiments, each performed in
triplicate.
high in vivo stability or formation of an active metabolite. This
will be investigated in more detail in a future study.
Conclusion. In this paper we describe a SAR study on an
aminotetralin and piperazine hybrid template, which yielded
some highly potent agonists for D2 and D3 receptors. 5-Hydroxy
derivatives proved to be the most potent agonists for DA D2/
D3 receptors in the current series of compounds. Conversion
of the phenolic hydroxyl group in the 2-oxoindole derivative
retained most of its potency. For the most potent compounds,
potency was at the sub-nanomolar level. In the GTPγS stimula-
tion binding functional assay, selected compounds exhibited
partial agonist to full agonist characteristics with preferential
affinity for the D3 receptor. Interestingly, even though the
7-hydroxy compound 2 exhibited a potent EC50 value, it was
much less active in producing maximum stimulation and in this
respect was less intrinsically active than the 5-hydroxy derivative
(-)-25. Thus, compound 2 displays a partial agonist character.
Figure 2. Effect on turning behavior of (-)-25a, 2, apomorphine (0.05
Compound (-)-25 exhibited potent and extended I rotational
activity in rats with unilateral 6-OHDA lesions in the striatum.
Future pharmacokinetic analysis will increase our understanding
of its mechanism of in vivo action.
mg/kg or 0.16 µmol/kg), and vehicle in unilaterally 6-OH-DA-lesioned
rats studied over 12 h. Each point is the mean ( SEM of four to five
rats. All drugs were administered ip. One-way ANOVA analysis
demonstrates significant effect among treatments: F (5,95) ) 19.14 (P
< 0.0001). Dunnett’s analysis showed that the effect of (-)-25 on
rotations at two doses (5 and 1 µmol/kg) was statistically significant
different compared to vehicle (P < 0.01). The effect of 2 (5 µmol/kg)
on rotation was statistically significantly different from that of vehicle
(P < 0.01).
Experimental Section
Analytical silica gel-coated TLC plates (silica gel 60 F254) were
purchased from EM Science and were visualized with UV light or
by treatment with phosphomolybdic acid (PMA). Flash chroma-
tography was carried out on Baker silica gel 40 mM. 1H NMR
spectra were routinely obtained on GE-300 MHz and Varian 400
MHz FT NMR equipment. The NMR solvent used was either
CDCl3 or CD3OD as indicated. TMS was used as an internal
standard. Elemental analyses were performed by Atlantic Microlab,
Inc., and were within (0.4% of the theoretical value. Optical
rotations were recorded on a Perkin-Elmer 241 polarimeter.
[3H]Spiperone (15.0 Ci/mmol) and [35S]GTPS (1250 Ci/mmol)
were from Perkin-Elmer (Boston, MA). 7-OHDPAT, quinpirole,
and (+)-butaclamol were from Sigma-Aldrich (St. Louis, MO).
dose was more potent in producing contralateral rotations. For
comparison with the 7-hydroxy compound, 2 was also tested
at 5 µmol/kg (2.51 mg/kg), which produced a rotational profile
similar to that produced by 1 µmol/kg of (-)-25. The control
vehicle under the same experimental condition produced no
rotation. It is evident from the results that at a similar dose,
(-)-25 is more potent in producing contralateral rotations
compared to 2. Interestingly, (-)-25 at a lower dose of 1 µmol/
kg and 2 at a dose of 5 µmol/kg, produced initial increases of
rotational motor activity followed by a brief decrease of activity
before a steady increase of rotational activity took place. At
present, the reason for such initial biphasic activity is unknown.
The standard reference compound used for comparison purposes
was apomorphine (Figure 2), which exhibited a much shorter
duration of action. Compound (-)-25 thus exhibited potent in
vivo activity with a long duration of action, and in this regard,
it is one of the most potent DA agonists known to date. A higher
dose of (-)-25 produced an activation profile that stayed on a
plateau for the entire duration of the study (>12 h).
Additionally, it is interesting to observe different rotational
activity profiles for 2 and (-)-25, with the latter compound
exhibiting higher potency and longer duration of action.
Aminotetralins have been known to produce poor oral activity
and bioavailability due to their inactivation by glucuronidation
in the metabolism process.50 In that context, it is interesting to
see that hybrid tetralin derivative (-)-25 exhibited such a long
duration of activity at a low dose, which indicates either its
Procedure A. Synthesis of 1-(4-Phenylpiperazin-1-yl)aceto-
nitrile (1a). A suspension of 1-phenylpiperazine (10 g, 61.64
mmol), potassium carbonate (4.26 g, 30.82 mmol), and chloroac-
etonitrile (4.50 mL, 70.88 mmol) in toluene was refluxed for 3 h.
Toluene was removed under reduced pressure, and the residue was
diluted with ethyl acetate, washed with water and brine, dried over
sodium sulfate (Na2SO4), concentrated, and purified by column
chromatography (ethyl acetate/hexane ) 1:1) to afford the product
1
1a as a thick yellow solid (11.24 g, 90%): H NMR (400 MHz,
CDCl3) δ 2.77 (t, 4H, J ) 4.8 Hz), 3.24 (t, 4H, J ) 4.8 Hz, Ph-
N(CH2)2), 3.58 (s, 2H), 6.87 (t, 1H, J ) 7.4 Hz, Ar-H), 6.94 (d,
2H, J ) 8.8 Hz, Ar-H), 7.26–7.30 (m, 2H, Ar-H).
Synthesis of 3-(4-Phenylpiperazin-1-yl)-propanenitrile (1b).
Compound 1b was synthesized from 1-phenylpiperazine (12 g,
73.96 mmol) and 3-chloropropionitrile (17.4 mL, 221.88 mmol)
according to procedure A to afford product 1b (12.42 g, 78%): 1H
NMR (400 MHz, CDCl3) δ 2.44–2.48 (t, 2H, J ) 7.2,
N-CH2CH2CN), 2.49–2.53 (t, 2H, J ) 7.2 Hz, CH2CH2CN), 2.61(t,
4H, J ) 4.8 Hz, CH2N(CH2)2), 3.20 (t, 4H, J ) 4.8 Hz,

108 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
Ar-N(CH2)2), 6.85–6.88 (t, 1H, J ) 7.6 Hz, Ar-H), 6.92–6.94 (d,
J ) 7.6 Hz, Ar-H), 7.25–7.29 (m, 2H, Ar-H).
mmol), NaCNBH3 (0.57 g, 9.12 mmol), and HOAc (0.14 mL) in
1,2-dichloroethane (20 mL) to yield compound 3c (1.42 g, 55%)
(procedure C): 1H NMR (400 MHz, CDCl3) δ 1.60–1.75 (m, 1H),
1.76–1.86 (m, 2H), 2.03–2.06 (m, 2H), 2.46–2.51 (m, 2H),
2.56–2.70 (m, 5H), 2.74–2.84 (m, 4H), 2.94–3.02 (m, 1H),
3.10–3.21 (m, 4H), 3.73–3.74 (m, 3H, -OCH3), 6.58-6.68 (m,
2H), 6.86–7.0 (m, 4H), 7.25–7.29 (m, 2H).
Synthesis of 4-(4-Phenylpiperazin-1-yl)butanenitrile (1c). 1-Phe-
nylpiperazine (12 g, 73.96 mmol) was treated with chlorobutyroni-
trile (21.28 mL, 221.89 mmol) (procedure A) to afford 1c (12.8 g,
75.6%): 1H NMR (400 MHz, CDCl3) δ 1.83–1.89 (q, 2H, J ) 6.8
Hz, CH2CH2CH2CN), 2.43–2.47 (t, 2H, J ) 7.2, N-CH2CH2-
CH2CN), 2.49–2.53 (t, 2H, J ) 7.2 Hz, CH2CH2CH2CN), 2.59–2.61
(t, 4H, J ) 4.8 Hz, CH2N(CH2)2), 3.19 (t, 4H, J ) 4.8 Hz, Ar-
N(CH2)2), 6.85–6.88 (t, 1H, J ) 7.6 Hz, Ar-H), 6.92–6.94 (d, J )
7.6 Hz, Ar-H), 7.25–7.29 (m, 2H, Ar-H).
Synthesis of 7-Methoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3d). Compound 2a (0.81
g, 3.95 mmol) was reacted with 7-methoxy-2-tetralone (0.73 g, 4.14
mmol), NaCNBH3 (0.99 g, 15.78 mmol), and HOAc (0.26 mL) in
1,2-dichloroethane (30 mL) to yield 3d (1.0 g, 69.44%) (procedure
Procedure B. Synthesis of 2-(4-Phenylpiperazin-1-yl)ethyl-
amine (2a). A solution of compound 1a in methanol (12.5 g, 62.1
mmol) was hydrogenated in a Parr hydrogenator apparatus in the
presence of Raney nickel catalyst at a pressure of 60 psi for 12 h.
The reaction mixture was passed through Celite, dried over Na2SO4,
evaporated, and purified over a silica gel column using the solvent
system ethyl acetate/methanol/triethylamine (80:15:5) to afford
1
C): H NMR (400 MHz, CDCl3) δ 1.60–1.68 (m, 2H), 2.60–2.63
(m, 6H, CH2N(CH2)2), 2.76–3.04 (m, 7H), 3.16–3.20 (t, J ) 4.8
Hz, N(CH2)2), 3.77 (s, 3H, OCH3), 6.62–6.71 (m, 2H, Ar-H),
6.64–7.02 (m, 4H, Ar-H), 7.24–7.30 (m, 2H, Ar-H).
Synthesis of 6,7-Dimethoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3e). 6,7-Dimethoxy-2-
tetralone was prepared from 2-(3,4-dimethoxyphenyl) acetic acid
by following a previously described procedure.51 Compound 2a
(0.358 g, 1.75 mmol) was reacted with 6,7-dimethoxy-2-tetralone
(0.3 g, 1.46 mmol), sodium triacetoxyborohydride (Na(OAc)3BH)
(0.925 g, 4.37 mmol), and HOAc (0.5 mL) in 1,2-dichloroethane
(30 mL) (procedure C). The crude product was purified by flash
chromatography (EtOAc/MeOH/Et3N ) 80:15:5) to yield com-
pound 3e (0.53 g, 92%): 1H NMR (400 MHz, CDCl3) δ 1.58–1.68
(m, 2H), 2.58–2.65 (m, 6H), 2.74–2.98 (m, 7H), 3.16–3.18 (t, J )
4.8 Hz, 4H, N(CH2)2), 3.81 (s, 3H, OCH3), 3.82 (s, 3H, OCH3),
6.56–6.57 (m, 2H, Ar-H), 6.82–6.87 (m, 1H, Ar-H), 6.90–6.92 (m,
2H, Ar-H), 7.23–7.27 (m, 2H, Ar-H).
1
compound 2a (8.9 g, 70%): H NMR (400 MHz, CDCl3) δ 2.48
(t, 2H, J ) 6.4 HZ), 2.69 (t, 4H, J ) 4.8 Hz), 2.89 (t, 2H, J ) 6.4
Hz), 3.14 (t, 4H, J ) 4.8 Hz, Ph-NCH2), 6.82 (t, 1H, J ) 8.0 Hz,
Ar-H), 6.89 (d, 2H, J ) 8.0 Hz, Ar-H), 7.21–7.27 (m, 2H, Ar-H).
Synthesis of 3-(4-Phenylpiperazin-1-yl)propan-1-amine
(2b). Compound 2b was synthesized from compound 1b (12 g,
55.74 mmol) according to procedure B to afford 2b (9.0 g, 74%):
1H NMR (400 MHz, CDCl3) δ 1.76–1.83 (q, 2H, J ) 6.4 Hz),
2.56 (t, 2H, J ) 6.4 Hz), 2.65 (t, 2H, J ) 5.2 Hz), 2.96 (t, J ) 6.0
Hz), 3.19 (t, 4H, J ) 5.2 Hz, Ph-NCH2), 6.86 (t, 1H, J ) 7.2 Hz,
Ar-H), 6.90–6.92 (d, 2H, J ) 8.4 Hz, Ar-H), 7.24–7.27 (m, 2H,
Ar-H).
Synthesis of 4-(4-Phenylpiperazin-1-yl)butan-1-amine (2c).
Compound 2c was synthesized from compound 1c (12 g, 52.33
mmol) according to procedure B to afford 2c (9.2 g, 75%): 1H
NMR (400 MHz, CDCl3) δ 1.45–1.61 (m, 4H), 2.39–2.42 (t, 2H,
J ) 7.2 Hz, NCH2), 2.59–2.62 (t, 4H, J ) 4.5 Hz, CH2N(CH2)2),
2.70–2.74 (t, 2H, CH2NH2), 3.19–3.22 (t, 4H, J ) 4.6 Hz, Ar-
N(CH2)2), 6.83–6.87 (t, 1H, J ) 7.2 Hz, Ar-H), 6.92–6.94 (d, J )
7.6 Hz, Ar-H), 7.24–7.28 (m, 2H, Ar-H).
Synthesis of 6,7-Dimethoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-1,2,3,4-tetrahydronaphthalen-2-amine (3f). Compound 2c
(0.340 g, 1.46 mmol) was reacted with 6,7-dimethoxy-2-tetralone
(0. 250 g, 1.21 mmol), Na(OAc)3BH (0.771 g, 3.64 mmol), and
HOAc (0.5 mL) in 1,2-dichloroethane (20 mL) (procedure C) to
furnish 3f (0.467 g, 91%): 1H NMR (400 MHz, CDCl3) 1.65 (br s,
6H), 2.44–2.48 (m, 2H), 2.63–2.65 (m, 4H), 2.76–2.81 (m, 4H),
2.99–3.01 (m, 2H), 3.19–3.22 (t, J ) 4.8 Hz, 4H, N(CH2)2), 3.82
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.55–6.57 (m, 2H, Ar-H),
6.84–6.87 (m, 1H, Ar-H), 6.91–6.93 (m, 2H, Ar-H), 7.24–7.28 (m,
2H, Ar-H).
Procedure D. Synthesis of N-(5-Methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]propi-
onamide (4a). Propionyl chloride (0.49 mL, 5.75 mmol) was added
into a solution of compound 3a (0.70 g, 1.92 mmol) and Et3N (2.0
mL) in anhydrous methylene chloride at 0 °C under N2 atmosphere
and then stirred at room temperature for 4 h. The reaction was
diluted with CH2Cl2 and washed with water and brine, and the
organic layer was dried over Na2SO4, evaporated, and purified by
flash chromatography (EtOAc/MeOH/Et3N ) 95:4:1) to yield 4a
(0.4 g, 59.5%): 1H NMR (400 MHz, CDCl3) δ 1.13–1.17 (t, 3H, J
) 7.2 Hz, -NCOCH2CH3), 1.85–2.04 (m, 2H), 2.36–2.46(m, 2H),
2.59–2.68 (m, 7H), 2.78–2.88 (td, 1H, J1 ) 16.6 Hz, J2 ) 4.0 Hz),
2.97–3.06 (m, 2H), 3.20 (t, 4H, J ) 4.8 Hz, Ar-N(CH2)2), 3.41–3.55
(m, 2H), 3.81–3.82 (d, 3H, J ) 5.6 Hz, -OCH3), 3.98–4.03 (m,
1H, -NCH), 6.65–6.71 (m, 2H), 6.82–6.93 (m, 3H), 7.07–7.15 (m,
1H), 7.23–7.28 (m, 2H).
Synthesis of N-(6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]propionamide (4b). Com-
pound 3b (0.29 g, 0.79 mmol) was reacted with propionyl chloride
(0.21 mL, 2.38 mmol) and Et3N (1.0 mL) in CH2Cl2 (10 mL)
(procedure D). The crude product was purified by flash chroma-
tography using solvent system EtOAc/MeOH ) 90:10 to yield pure
compound 4b (0.4 g, 90.64%): 1H NMR (400 MHz, CDCl3) δ
1.14–1.18 (t, 3H, J ) 7.6 Hz, -NCOCH2CH3), 1.93–2.00 (m, 2H),
2.39–2.45 (m, 2H), 2.56–2.99 (m, 10H), 3.19–3.26 (m, 4H, Ar-
N(CH2)2), 3.40–3.54 (m, 2H), 3.77–3.28 (d, 3H, J ) 4.8 Hz,
-OCH3), 4.01–4.05 (m, 1H, -NCH), 6.63–6.74 (m, 2H, Ar-H),
6.85–7.01 (m, 3H, Ar-H), 7.25–7.29 (m, 3H, Ar-H).
Procedure C. Synthesis of 5-Methoxy-N-[2-(4-phenylpiper-
azin-1-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-2-amine (3a). A
mixture of compound 2a (0.4 g, 1.95 mmol), 5-methoxy-2-tetralone
(0.38 g, 2.14 mmol), and glacial acetic acid (HOAc) (0.14 mL) in
1,2-dichloroethane (20 mL) was stirred at room temperature under
N2 atmosphere for 20 min. Sodium cyanoborohydride (NaCNBH3)
(0.49 g, 7.79 mmol) dissolved in a minimum volume of methanol
was added to the reaction mixture. The reaction mixture was stirred
at room temperature under nitrogen atmosphere for 12 h. The
solvent was evaporated, and saturated NaHCO3/H2O (20 mL) was
added to the mixture, which was then extracted with ethyl acetate
(3 × 100 mL). The combined organic phase was dried over Na2SO4
and evaporated to afford the crude product, which was purified by
flash chromatography (EtOAc/MeOH/Et3N ) 95:4:1) to give the
product 3a (0.65 g, 91.3%): 1H NMR (400 MHz, CDCl3) δ
1.73–1.83 (m, 1H), 2.02–2.09 (m, 1H), 2.23 (m, 1H), 2.6–2.78 (m,
5H), 2.87–3.22 (m, 7H), 3.31–3.33 (m, 1H), 3.76 (s, 2H), 3.8 (s,
3H, -OCH3), 4.05–4.15 (m, 1H, -NH-CH), 6.65–6.71 (m, 3H),
6.84–6.90 (m, 2H), 7.08–7.13 (td, 1H, J1 ) 7.8 Hz, J2 ) 2.8 Hz),
7.26 (t, 2H, J ) 7.2 Hz).
Synthesis of 6-Methoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3b). Compound 2a (0.28
g, 1.37mmol) was reacted with 6-methoxy-2-tetralone (0.27 g, 1.50
mmol), NaCNBH3 (0.34 g, 5.47mmol), and HOAc (0.09 mL) in
1,2-dichloroethane (20 mL) to yield 3b (0.45 g, 90%) (procedure
1
C): H NMR (400 MHz, CDCl3) δ 1.72–1.84 (m, 1H), 2.02–2.08
(m, 1H), 2.23 (m, 1H), 2.6–2.78 (m, 5H), 2.87–3.25 (m, 7H),
3.31–3.33 (m, 1H), 3.76 (s, 2H), 3.8 (s, 3H, -OCH3), 4.05–4.15
(m, 1H, -NH-CH), 6.63–6.74 (m, 2H), 6.85–7.01 (m, 3H),
7.25–7.29 (m, 3H).
Synthesis of 7-Methoxy-N-[3-(4-phenylpiperazin-1-yl)propyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3c). Compound 2b (0.50
g, 2.28 mmol) was reacted with 7-methoxy-2-tetralone (0.44 g, 2.51
Synthesis of N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-[3-(4-phenylpiperazin-1-yl)propyl]propionamide (4c). Com-

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 109
pound 3c (0.78 g, 2.06 mmol) was reacted with propionyl chloride
(0.54 mL, 6.18 mmol) and Et3N (2.0 mL) in CH2Cl2 (15 mL)
(procedure D). The crude product was purified by flash chroma-
tography using solvent system EtOAc/MeOH ) 90:10 to yield pure
compound 4c (0.8 g, 89.2%): 1H NMR (400 MHz, CDCl3) δ
1.14–1.18 (t, 3H, J ) 7.6 Hz, -NCOCH2CH3), 1.93–2.00 (m, 3H),
2.39–2.45 (m, 2H), 2.56–2.99 (m, 12H), 3.19–3.26 (m, 4H, Ar-
N(CH2)2), 3.42–3.54 (m, 2H), 3.77–3.28 (d, 3H, J ) 4.8 Hz,
-OCH3), 4.01–4.05 (m, 1H, -NCH), 6.63–6.74 (m, 2H), 6.85–7.01
(m, 3H), 7.25–7.29 (m, 3H).
Synthesis of N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]-2-(thiophen-2-yl)aceta-
mide (4d). Compound 3d (1.4 g, 3.83 mmol) was reacted with
2-thiophene acetyl chloride (0.47 mL, 3.83 mmol) and Et3N (2.0
mL) in CH2Cl2 (20 mL) (procedure D). The crude product was
purified by flash chromatography using solvent system EtOAc/
MeOH ) 90:10 to yield pure compound 4d (0.6 g, 32%): 1H NMR
(400 MHz, CDCl3) δ 1.84–2.0 (m, 2H), 2.6–2.90 (m, 9H), 2.96–3.02
(m, 1H), 3.18–3.22 (m, 4H), 3.41–3.56 (m, 2H), 3.76–3.77 (d, 3H,
J ) 6.0 Hz, -OCH3), 3.94–4.01 (m, 2H), 4.09–4.17 (m, 1H),
6.56–6.58 (m, 1H, Ar-H), 6.68–6.74 (m, 1H, Ar-H), 6.83–7.01 (m,
6H, Ar-H), 7.19–7.29 (m, 3H, Ar-H).
compound 5d (0.39 g, 87%): 1H NMR (400 MHz, CDCl3) δ
1.58–1.70 (m, 2H), 1.99–2.01 (m, 1H), 2.58–2.69 (m, 6H),
2.71–3.05 (m, 9H), 3.18–3.23 (m, 4H), 3.26–3.31 (m, 1H), 3.78
(s, 3H, -OCH3), 6.62 (br s, 1H, Ar-H), 6.67–6.69 (m, 1H, Ar-H),
6.82–7.01 (m, 6H, Ar-H), 7.23–7.28 (m, 3H, Ar-H).
Procedure F. Synthesis of 6,7-Dimethoxy-N-[2-(4-phenylpi-
perazin-1-yl)ethyl]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-
amine (5e). A mixture of amine 3e (510 mg, 1.29 mmol),
1-bromopropane (634 mg, 5.16 mmol), and K2CO3 (534 mg, 3.87
mmol) in dry DMF (10 mL) was stirred at 80 °C for 20 h. The
reaction mixture was poured into water (20 mL) and extracted with
Et2O (3 × 20 mL). The combined organic phase was washed with
brine and dried over Na2SO4. The solvent was removed by
evaporation, and the residue was purified by flash chromatography
(EtOAc/MeOH/ Et3N ) 80:8:4) to yield 5e (0.50 g, 89%): 1H NMR
(400 MHz, CDCl3) 0.87–0.91 (t, J ) 7.2 Hz, 3H, CH3CH2CH2N),
1.50–1.61 (m, 4H), 1.96–2.04 (m, 2H), 2.52–2.54 (br s, 2H, CH2N),
2.66–2.80 (br s, 4H, N(CH2)2), 2.88–2.96 (m, 7H), 3.20 (br s, 4H,
N(CH2)2), 3.78 (br s, 6H, CH3O), 6.58 (br s, 2H, Ar-H), 6.85 (brs,
1H, Ar-H), 6.92 (br s, 2H, Ar-H), 7.26–7.28 (m, 2H, Ar-H).
Synthesis of 6,7-Dimethoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (5f). Amine
3f (380 mg, 0.90 mmol) was reacted with 1-bromopropane (441
mg, 3.59 mmol) and K2CO3 (429 mg, 3.10 mmol) in DMF (10
mL) by following procedure F to obtain 5f (0.24 g, 57%): 1H NMR
(400 MHz, CDCl3) δ 0.90–0.94 (t, J ) 7.2 Hz, 3H, CH3CH2CH2N),
1.48–1.56 (m, 8H), 2.39–2.41 (m, 2H), 2.61–2.62 (m, 6H), 2.80
(br s, 4H), 2.99–3.01 (m, 2H), 3.20–3.22 (t, J ) 4.8 Hz, 4H,
N(CH2)2), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.56–6.57 (m,
2H, Ar-H), 6.83–6.87 (m, 1H, Ar-H), 6.92–6.94 (m, 2H, Ar-H),
7.24–7.28 (m, 2H, Ar-H).
Procedure E. Synthesis of 5-Methoxy-N-[2-(4-phenylpiper-
azin-1-yl)ethyl)]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-
amine (5a). Compound 4a (0.48 g, 1.14 mmol) in anhydrous THF
(20 mL) was added dropwise into a suspension of lithium aluminum
hydride (LiAlH4) (0.35 g, 9.11 mmol) in anhydrous THF (15 mL)
at 0 °C under N2 atmosphere. The reaction mixture was refluxed
for 8 h, cooled to room temperature, and then cooled further to 0
°C. Saturated NaOH/H2O (3 mL) was added dropwise to quench
excess LiAlH4. The mixture was filtered, and the reaction mixture
was dried over Na2SO4. The solvent was removed under vacuum
to afford compound 5a (0.4 g, 87%): 1H NMR (400 MHz, CDCl3)
δ 0.90 (t, 3H, J ) 7.6 Hz, CH2CH2CH3), 1.44–1.60 (m, 3H),
2.07–2.09(m, 1H), 2.50–2.55 (m, 5H), 2.65 (t, 4H, J ) 5.2 Hz,
CH2N(CH2)2), 2.72–3.02 (m, 6H), 3.2 (t, 4H, J ) 4.8 Hz,
Ar-N(CH2)2), 3.81 (s, 3H, -OCH3), 6.65 (d, 1H, J ) 7.6 Hz), 6.71
(d, 1H, J ) 7.6 Hz), 6.85 (t, 1H, J ) 8.0 Hz), 6.93 (d, 2H, J ) 8.0
Hz), 7.09 (t, 1H, J ) 7.6 Hz), 7.24–7.28 (m, 2H, J ) 7.2 Hz).
Synthesis of 6-Methoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (5b). Compound
4b (0.303 g, 0.72 mmol) was reacted with LiAlH4 (0.27 g, 7.19
mmol) in THF (20 mL) by following procedure E. The crude
product was purified by flash chromatography using solvent system
EtOAc/MeOH/Et3N ) 95:4:1 to yield compound 5b (0.26 g,
Procedure G. Synthesis of 6-[(2-(4-Phenylpiperazin-1-yl)eth-
yl)(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol (6a). Boron
tribromide (1 M solution in dichloromethane) (3.24 mL, 3.24 mmol)
was added into a solution of 5a (0.44 g, 1.08 mmol) in anhydrous
methylene chloride (CH2Cl2) (20 mL) at -40 °C under N2
atmosphere. The reaction mixture was stirred at -40 °C for 2 h
and was continued overnight at room temperature. The reaction
was quenched by the addition of saturated NaHCO3 solution, and
the mixture was extracted with CH2Cl2. The combined organic layer
was dried over Na2SO4 and evaporated under vacuum, and the crude
product was purified by flash chromatography (EtOAc/MeOH )
1
95:5) to afford compound 6a (0.2 g, 47%): H NMR (400 MHz,
CDCl3) δ 0.88 (t, 3H, J ) 7.2 Hz, CH2CH2CH3), 1.36–1.51 (m,
3H), 1.93–1.97 (m, 1H), 2.40–2.54 (m, 6H), 2.64–2.68 (m, 3H),
2.73 (t, 4H, J ) 4.8 Hz, CH2N(CH2)2), 2.82–2.94 (m, 2H), 3.26 (t,
4H, J ) 5.6 Hz, Ar-N(CH2)2), 6.46–6.48 (d, 1H, J ) 8.0 Hz),
6.55–6.57 (d, 1H, J ) 7.6 Hz), 6.86 (t, 1H, J ) 7.2 Hz), 6.91–6.95
(m, 3H), 7.24–7.28 (m, 2H).
1
87.4%): H NMR (400 MHz, CDCl3) δ 0.90 (t, 3H, J ) 7.6 Hz,
CH2CH2CH3), 1.46–1.70 (m, 3H), 2.01–2.05 (m, 1H), 2.52–2.57
(m, 4H), 2.65–2.86 (m, 10H), 2.97–2.99 (m, 1H), 3.2 (t, 4H, J )
4.8 Hz, Ar-N(CH2)2), 3.77 (s, 3H, -OCH3), 6.62 (d, 1H, J)2.8
Hz), 6.68–6.70 (dd, 1H, J1 ) 8.4 Hz, J2 ) 2.4 Hz), 6.85 (t, 1H, J
) 7.2 Hz), 6.93 (d, 2H, J ) 8.0 Hz), 7.00 (d, 1H, J ) 8.0 Hz),
7.26 (t, 2H, J ) 7.2 Hz).
The product was converted into the corresponding dioxalate salt,
mp 130–132 °C. Anal. Calcd for C25H35N3O·2C2H2O4: C, H, N.
Synthesis of 6-[(2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino]-
5,6,7,8-tetrahydronaphthalen-2-ol (6b). Compound 5b (0.26 g,
0.63 mmol) was reacted with 1 M BBr3/CH2Cl2 (1.88 mL, 1.88
mmol) in CH2Cl2 (20 mL) by following procedure G to furnish 6b
Synthesis of 7-Methoxy-N-[3-(4-phenylpiperazin-1-yl)propyl]-
N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (5c). Compound
4c (0.90 g, 2.06 mmol) was reacted with LiAlH4 (0.47 g, 12.3
mmol) in THF (30 mL) by following procedure E. The crude
product was purified by flash chromatography using solvent system
EtOAc/MeOH/Et3N ) 95:4:1 to yield compound 5c (0.54 g, 63%):
1H NMR (400 MHz, CDCl3) δ 0.90 (t, 3H, J ) 7.8 Hz,
CH2CH2CH3), 1.43–1.75 (m, 5H), 1.98–2.02 (m, 1H), 2.41–2.51
(m, 4H), 2.55–2.62 (m, 6H), 2.74–2.85 (m, 4H), 2.93–3.0 (m, 1H),
3.2 (t, 4H, J ) 4.8 Hz, Ar-N(CH2)2), 3.77 (s, 3H, -OCH3),
6.62–6.63 (d, 1H, J ) 2.8 Hz), 6.66–6.69 (dd, 1H, J1 ) 8.4 Hz, J2
) 2.4 Hz), 6.85 (t, 1H, J ) 7.2 Hz), 6.93 (d, 2H, J ) 8.0 Hz), 6.98
(d, 1H, J ) 8.0 Hz), 7.26 (t, 2H, J ) 8.0 Hz).
Synthesis of 7-Methoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
N-[2-(thiophen-2-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-2-
amine (5d). Compound 4d (0.46 g, 0.94 mmol) was reacted with
LiAlH4 (0.29 g, 7.52 mmol) in THF (30 mL) by following
procedure E. The crude product was purified by flash chromatog-
raphy using solvent system EtOAc/MeOH/Et3N ) 95:4:1 to give
1
(0.074 g, 30%): H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J )
7.2 Hz, CH2CH2CH3), 1.30–1.50 (m, 3H), 1.81–1.84 (bd, 1H, J )
10.8 Hz), 2.41–2.80 (m, 15H), 3.26 (t, 4H, J ) 4.8 Hz, Ar-N(CH2)2),
6.43 (bs, 1H), 6.51–6.54 (dd, 1H, J1 ) 8.4 Hz, J2 ) 2.4 Hz),
6.82–6.88 (m, 2H), 6.91–6.93 (d, 2H, J ) 7.6 Hz), 7.24–7.28 (m,
2H).
The product was converted into the corresponding trihydrochlo-
ride salt, mp 155–158 °C. Anal. Calcd for C25H35N3O·3HCl: C,
H, N.
Synthesis of 7-[(3-(4-Phenylpiperazin-1-yl)propyl)(prop-
yl)amino]-5,6,7,8-tetrahydronaphthalen-2-ol (6c). Compound 5c
(0.54 g, 1.28 mmol) was reacted with 1 M BBr3/CH2Cl2 (3.85 mL,
3.85 mmol) in CH2Cl2 (20 mL) by following procedure G to yield
1
6c (0.32 g, 61.1%): H NMR (400 MHz, CDCl3) δ 0.90 (t, 3H, J
) 7.2 Hz, CH2CH2CH3), 1.45–1.65 (m, 4H), 1.70–1.88 (m, 4H),
2.45–2.82 (m, 14H), 3.24 (t, 4H, J ) 4.8 Hz, Ar-N(CH2)2), 6.52

110 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
(d, 1H, J ) 2.4 Hz), 6.58–6.60 (dd, 1H, J1 ) 8.4 Hz, J2 ) 2.4 Hz),
6.84–6.87 (t, 2H, J ) 7.2 Hz), 6.89–6.94 (m, 2H), 7.26(t, 2H, J )
7.2 Hz).
The product was converted into the corresponding trihydrochlo-
ride salt, mp 122–125 °C. Anal. Calcd for C26H37N3O·3HCl: C,
H, N.
Synthesis of 7-[(2-(4-Phenylpiperazin-1-yl)ethyl)(2-(thiophen-
2-yl)ethyl)amino]-5,6,7,8-tetrahydronaphthalen-2-ol (6d). Com-
pound 5d (0.41 g, 0.86 mmol) was reacted with 1 M BBr3/CH2Cl2
(2.58 mL, 2.58 mmol) in CH2Cl2 (20 mL) following procedure G
to yield 6d (0.15 g, 38%): 1H NMR (400 MHz, CDCl3) δ 1.45–1.49
(m, 1H), 1.91–1.93 (m, 1H), 2.54–2.98 (m, 17H), 3.24 (t, 4H, J )
4.4 Hz, Ar-N(CH2)2), 6.43–6.55 (m, 2H, Ar-H), 6.80–6.94 (m, 6H,
Ar-H), 7.11–7.12 (d, 1H, J ) 5.2 Hz, Ar-H), 7.23–7.27 (m, 2H,
Ar-H).
using the solvent system ethyl acetate/methanol/triethylamine
(95:4:1) to afford 1.22 g of compound 8 (1.22 g, 74%), which is
a mixture of two diastereomers.
Separation of Diastereomers of Compounds 8a and 8b. The
diastereomeric mixture of compound 8 (1.22 g) was separated into
the corresponding pure diasteriomers 8a and 8b by semipreparative
HPLC using a normal phase column (Nova-Pak silica 6 µm). The
mobile phase used was 6.5% isopropanol in hexane with a flow
rate of 16 mL/min. Two fractions were eluted with a retention times
of 11.5 min for (+,-)-8a and 14.5 min for (-,-)-8b. Final purity
of the separated diasterieomers was checked by an analytical normal
phase column (Nova-Pak silica 60 Å, 4 µm) using the same mobile
phase with a flow rate of 1 mL/min. Pure diasteriomers 8a and 8b
were eluted from the analytical column at 9.5 and 12.0 min,
respectively. Compound 8a was isolated in 0.57 g (34.54%), and
compound 8b was isolated in 0.46 g (28%).
The product was converted into the corresponding trioxalate salt,
mp 147–151 °C. Anal. Calcd for C28H35N3OS·2C2H2O4: C, H, N.
Procedure H. Synthesis of 6-[(2-(4-Phenylpiperazin-1-yl)eth-
yl)(propyl)amino]-5,6,7,8-tetrahydronaphthalene-2,3-diol (6e).
A mixture of 580 mg (1.33 mmol) of 3 and 10 mL of 48% HBr
was refluxed under N2 for 3 h. The reaction mixture was then
evaporated to dryness. The resulting solid was then crystallized
with acetone/methanol to get a white solid of 6e in HBr salt form
8a: 1H NMR (400 MHz, CDCl3) δ 1.36–1.80 (m, 6H), 2.26–2.38
(m,1H), 2.39–2.48 (t, 2H, J ) 6.4 Hz), 2.49–2.64 (m, 6H),
2.75–2.94 (m, 2H), 3.10–3.34 (m, 6H), 3.53 (s, 3H), 3.74 (s, 3H),
5.09 (s, 1H), 6.52 (d, 1H, J ) 2.4 Hz), 6.68 (d, 1H, J ) 8.4 Hz),
6.85 (t, 1H, J ) 7.2 Hz), 6.91 (d, 2H, J ) 7.6 Hz), 6.96 (m, 1H),
7.20–7.50 (m, 7H).
8b: 1H NMR (400 MHz, CDCl3) δ 1.35–1.79 (m, 6H), 2.26–2.38
(m,1H), 2.39–2.49 (t, 2H, J ) 6.4 Hz), 2.51–2.64 (m, 6H),
2.75–2.94 (m, 2H), 3.11–3.34 (m, 6H), 3.46 (s, 3H), 3.74 (s, 3H),
5.03 (s, 1H), 6.45 (d, 1H, J ) 2.4 Hz), 6.67 (d, 1H, J ) 8.4 Hz),
6.85 (t, 1H, J ) 7.2 Hz), 6.90 (d, 2H, J ) 7.6 Hz), 6.96 (m, 1H),
7.20–7.50 (m, 7H).
1
(0.691 mg, 80%): H NMR (400 MHz, CDCl3) δ 0.88–0.93 (t, J
) 7.2 Hz, 3H, CH3CH2CH2N), 1.35–150 (m, 4H), 1.71–1.85 (m,
2H), 2.41–2.60 (br s, 2H, CH2N), 2.65 (br s, 4H, N(CH2)2),
2.70–2.73 (m, 7H), 3.25 (br s, 4H, N(CH2)2), 6.45–6.48 (m, 2H,
Ar-H), 6.84–6.87 (m, 1H, Ar-H), 6.89–6.92 (m, 2H, Ar-H),
7.23–7.27 (m, 2H, Ar-H).
Synthesis of (+)-7-Methoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-7). Potassium
tert-butoxide (0.57 g, 5.09 mmol) was added into a solution of 8a
(0.46 g, 0.85 mmol) in THF at room temperature under nitrogen
atmosphere and stirred overnight. TLC revealed complete consump-
tion of the starting material. The solvent was removed, and the
residue was suspended in EtOAc and washed with water, NH4Cl
solution, and brine. The solution was dried and concentrated under
vacuum. Into the solution of this mixture in dry THF was added a
solution of MeLi (0.074 g, 3.39 mmol) at room temperature under
nitrogen atmosphere and stirred for 0.5 h when TLC revealed
completion of the reaction. The mixture was quenched with water,
the solvent was evaporated, and the residue was suspended in
EtOAc. The organic layer was washed with water and brine and
dried over Na2SO4. The solution was concentrated under vacuum,
and the product was purified by column chromatography using the
solvent system EtOAc/MeOH/Et3N (90:10:1) to afford the optically
pure amine (+)-7 (0.29 g, 86.94%). Optical rotation of (+)–7 was
The product was converted into the corresponding trihydrobromide
salt, mp 185–188 °C. Anal. Calcd for C25H35N3O2 ·3HBr·H2O: C, H,
N.
Synthesis of 6-[(4-(4-Phenylpiperazin-1-yl)butyl)(propyl)amino]-
5,6,7,8-tetrahydronaphthalene-2,3-diol (6f) (Procedure H). Com-
pound 5f (240 mg, 0.52 mmol) and 10 mL of 48% HBr was refluxed
by following procedure H to provide 6f in HBr salt form (0.265 g,
1
75%): H NMR (400 MHz, CD3OD) δ 1.04–1.08 (t, J ) 7.2 Hz,
3H, CH3CH2CH2N), 1.81–1.94 (m, 8H), 2.83–2.85 (m, 2H),
2.99–3.05 (m, 6H), 3.09–3.21 (m, 4H), 3.40 (br s, 2H), 3.73–3.8
(t, J ) 4.8 Hz, 4H, N(CH2)2), 6.52–6.5 (m, 2H, Ar-H), 6.95–6.98
(m, 1H, Ar-H), 7.06–7.08 (m, 2H, Ar-H), 7.28–7.32 (m, 2H, Ar-
H).
The product was converted into the corresponding trihydrobromide
salt, mp 180–183 °C. Anal. Calcd for C27H39N3O2 ·3HBr·1.5H2O: C,
H, N.
Synthesis of 7-Methoxy-N-[4-(4-phenylpiperazin-1-yl)butyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (7). Compound 2c (2.56
g, 10.97 mmol) was reacted with 7-methoxy-2-tetralone (2.32 g,
13.16 mmol) and Na(OAc)3BH (6.98 g, 32.91 mmol) and HOAc
(0.4 mL) in 1,2-dichloroethane (30 mL) by following procedure
C. The crude product was purified by flash chromatography (ethyl
acetate/methanol/triethylamine ) 85:10:5) to afford the product 7
(2.72 g, 60%): 1H NMR (400 MHz, CDCl3) δ 1.48–1.56 (m, 4H),
1.95–1.97 (m,2H), 2.33–2.36 (t, 2H, J ) 6.8 Hz), 2.52–2.55 (m,
5H), 2.64–2.79 (m, 4H), 2.82–2.94 (m, 2H), 3.12–3.15 ((t, 4H, J
) 4.8 Hz, Ar-N(CH2)2), 3.68 (s, OCH3), 6.54–6.63 (m, 2H, Ar-H),
6.76–6.93 (m, 4H, Ar-H), 7.17–7.21 (m, 2H, Ar-H).
Synthesis of 2-Methoxy-N-(7-methoxy-1,2,3,4-tetrahydronaph-
thalen-2-yl)-2-phenyl-N-[4-(4-phenylpiperazin-1-yl)butyl]acet-
amide (8). A mixture of (R)-(-)-R-methoxyphenylacetic acid (1.013
g, 6.09 mmol), 1,3-(dimethylamino)propyl]-3-ethylcarbodiimide-
hydrochloride (EDCI) (1.17 g, 6.09 mmol), 1-hydroxybenzotriazole
(HOBT) (0.87 g, 6.40 mmol), and Et3N (0.85 mL, 6.09 mmol) in
anhydrous methylene chloride (50 mL) was stirred at room
temperature under nitrogen atmosphere for 1 h. A solution of
compound 7 (1.20 g, 3.05 mmol) in anhydrous methylene chloride
was added into the reaction mixture under nitrogen at room
temperature and stirred for 20 h. The mixture was diluted with
CH2Cl2 and washed with 5% HCl acid solution, sodium bicarbonate,
and brine. The solvent was removed under vacuum, dried over
Na2SO4, and purified by column chromatography over silica gel
1
[R]D ) +10.95 (c 1 in MeOH): H NMR (400 MHz, CDCl3) δ
1.40–1.80 (m, 6H), 2.00–2.10 (m, 1H), 2.42 (t, 2H, J ) 6.8 Hz),
2.52–2.66 (m, 5H), 2.68–2.87 (m, 4H), 2.88–3.05 (m, 2H), 3.21 (t,
4H, J ) 4.8 Hz), 3.77 (s, 3H), 6.61 (d, 1H, J ) 2.4 Hz), 6.69 (dd,
1H, J ) 2.4 Hz, J ) 8.0 Hz), 6.85 (t, 1H, J ) 7.2 Hz), 6.93 (d,
2H, J ) 7.6 Hz), 7.00 (d, 1H, J ) 8.4 Hz), 7.26 (t, 2H, J ) 8.0
Hz).
Synthesis of (-)-7-Methoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-1,2,3,4-tetrahydronaphthalen-2-amine ((-)-7). Compound 8b
(0.45 g, 0.85 mmol) was hydrolyzed under similar conditions as
described above to afford the optically pure amine (-)-7 (0.28 g,
85%). Optical rotation of (–)-7 was [R]D ) -10.3 (c 1 in MeOH):
1H NMR (400 MHz, CDCl3) δ 1.48–1.56 (m, 4H), 1.95–1.97 (m,
2H), 2.33–2.36 (t, 2H, J ) 6.8 Hz), 2.52–2.55 (m, 5H), 2.64–2.79
(m, 4H), 2.82–2.94 (m, 2H), 3.12–3.15 ((t, 4H, J ) 4.8 Hz, Ar-
N(CH2)2), 3.68 (s, OCH3), 6.54–6.63 (m, 2H, Ar-H), 6.76–6.93 (m,
4H, Ar-H), 7.17–7.21 (m, 2H, Ar-H).
Synthesis of (+)-7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl-[4-(4-phenylpiperazin-1-yl)butyl]prop-2-ynylamine ((+)-9). A
solution of (+)-7 (0.17 g, 0.43 mmol) in a mixture of THF and
DMF (5:1) at 24 °C under nitrogen was treated with NaH (0.072
g, 3 mmol). The reaction mixture was stirred for 30 min before
propargyl bromide (0.31 g, 2.58 mmol) was added. The reaction
mixture was stirred for 6 h at 50 °C and then was poured onto
water (15 mL). THF was removed under vacuum, and the reaction

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 111
mixture was extracted with ether (3 × 100 mL); the combined
organic layer was washed thoroughly with brine, dried over Na2SO4,
and evaporated under vacuum. The crude mass was purified by
column chromatography on a silica gel column using the solvent
system ethyl acetate/methanol/triethylamine ) 95:4:1 to yield pure
Compound (+)-11 (0.13 g, 0.29 mmol) was reacted with LiAlH4
(0.06 g, 1.58 mmol) in dry THF (15 mL) by following procedure
E. The crude product was purified by flash chromatography using
the solvent system EtOAc/MeOH ) 90:10 to afford compound (+)-
1
12 (0.12 g, 94%): [R]D ) +0.77 (c 19.5 mg/mL in MeOH); H
1
compound (+)-9 (0.11 g, 52%): H NMR (400 MHz, CDCl3) δ
NMR (400 MHz, CDCl3) δ 0.89 (t, 3H, J ) 7.2 Hz), 0.93–1.00
(m, 1H), 1.40–1.70 (m, 8H), 1.95–2.05 (m, 1H), 2.41 (t, 2H, J )
6.8 Hz), 2.48 (t, 2H, J ) 6.8 Hz), 2.54 (t, 2H, J ) 6.8 Hz), 2.61
(t, 4H, J ) 5.2 Hz), 2.68–2.90 (m, 4H), 3.21 (t, 4H, J ) 5.2 Hz),
3.76 (s, 3H), 6.62 (d, 1H, J ) 3.0 Hz), 6.68 (dd, 1H, J ) 2.8 Hz,
J ) 8.4 Hz), 6.85 (t, 1H, J ) 7.2 Hz), 6.93 (d, 2H, J ) 7.6 Hz),
6.98 (d, 1H, J ) 8.0 Hz), 7.26 (t, 1H, J ) 7.6 Hz).
Synthesis of (-)-7-Methoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine ((-)-12).
Compound (-)-11 (0.13 g, 0.29 mmol) was reacted under similar
condition as reported in procedure E to afford the optically pure
(-)-12 (0.10 g, 78%): 1H NMR (400 MHz, CDCl3) δ 0.89 (t, 3H,
J ) 7.2 Hz), 0.92–1.00 (m, 1H), 1.40–1.80 (m, 8H), 1.94–2.10 (m,
1H), 2.41 (t, 2H, J ) 7.2 Hz), 2.48 (t, 2H, J ) 6.8 Hz), 2.54 (t,
2H, J ) 6.8 Hz), 2.61 (t, 4H, J ) 4.8 Hz), 2.66–2.88 (m, 4H), 3.21
(t, 4H, J ) 4.8 Hz), 3.77 (s, 3H), 6.62 (d, 1H, J ) 2.8 Hz), 6.67
(dd, 1H, J ) 2.8 Hz, J ) 8.4 Hz), 6.85 (t, 1H, J ) 7.2 Hz), 6.93
(d, 2H, J ) 8.0 Hz), 6.98 (d, 1H, J ) 8.0 Hz), 7.26 (t, 1H, J ) 7.6
Hz).
1.55–1.67 (m, 5H), 2.11–2.18 (m, 2H), 2.41 (t, 2H, J ) 6.4 Hz),
2.58–2.66 (m, 5H), 2.68–2.86 (m, 4H), 2.96–2.98 (m, 2H),
3.18–3.21 (t, 4H, J ) 5.2 Hz), 3.51–3.52 (m, 2H, -NCH2CCH),
3.75 (s, 3H, -OCH3), 6.62–6.69 (m, 2H, Ar-H), 6.82–6.97 (m, 4H),
7.32–7.27 (t, 2H, J ) 8.4 Hz, Ar-H).
Synthesis of (-)-7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl-[4-(4-phenylpiperazin-1-yl)butyl]prop-2-ynylamine ((-)-9).
Compound (-)-7(0.15 g, 0.38 mmol) was reacted under similar
conditions as described above to afford the optically pure amine
(-)-9 (0.12 g, 55%): 1H NMR (400 MHz, CDCl3) δ 1.55–1.66
(m, 5H), 2.11–2.20 (m, 2H), 2.42 (t, 2H, J ) 6.4 Hz), 2.58–2.70
(m, 5H), 2.68–2.85 (m, 4H), 2.96–2.98 (m, 2H), 3.18–3.21 (t, 4H,
J ) 5.2 Hz), 3.51–3.53 (m, 2H, -NCH2CCH), 3.75 (s, 3H,
-OCH3), 6.62–6.71 (m, 2H, Ar-H), 6.82–6.96 (m, 4H), 7.33–7.27
(t, 2H, J ) 8.4 Hz, Ar-H).
Synthesis of (+)-7-{[4-(4-Phenylpiperazin-1-yl)butyl]prop-2-
ynylamino}-5,6,7,8-tetrahydronaphthalen-2-ol ((+)-10). Boron
tribromide (1 M solution in dichloromethane) (0.83 mL, 0.834
mmol) was added into a solution of (+)-9 (0.12 g, 0.28 mmol) in
anhydrous CH2Cl2 (20 mL) at -40 °C for 2 h and then at overnight
at room temperature to give product (+)-10 (0.08 g, 67%)
(procedure G): 1H NMR (400 MHz, CDCl3) δ 1.51–1.64 (m, 5H),
2.05–2.11 (m, 2H), 2.42–2.46 (t, 2H, J ) 8.0), 2.64–2.97 (m, 11H),
3.21–3.23 (t, 4H, Ph-N(CH2)2, J ) 6.0 Hz), 3.45–3.49 (m, 2H,
-NCH2CCH), 6.48–6.66 (m, 2H, Ar-H), 6.84–6.93 (m, 4H, Ar-
H), 7.23–7.27 (m, 2H, Ar-H).
Synthesis of (+)-7-[(4-(4-Phenylpiperazin-1-yl)butyl)(prop-
yl)amino]-5,6,7,8-tetrahydronaphthalen-2-ol ((+)-13). Compound
(+)-12 (0.1 g, 0.23 mmol) was reacted with boron tribromide (1
M solution in dichloromethane, 0.70 mL, 0.70 mmol) in dry CH2Cl2
(10 mL) at -40 °C by following procedure G. The crude product
was purified by flash chromatography using the solvent system
EtOAc/MeOH/Et3N ) 95:4:1 to afford compound (+)-13 (0.07 g,
1
73%): H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J ) 7.6 Hz),
The product was converted into the corresponding trihydrobro-
mide salt. Anal. Calcd for C27H35N3O·3HBr·2H2O: C, H, N.
Compound was highly hygroscopic.
1.40–1.64 (m, 7H), 1.94–2.03 (m, 1H), 2.38–2.58 (m, 6H), 2.64 (t,
4H, J ) 4.4 Hz), 2.66–2.84 (m, 4H), 2.88–3.00 (m, 1H), 3.22 (t,
4H, J ) 4.8 Hz), 6.49 (d, 1H, J)2.0 Hz), 6.55 (dd, 1H, J ) 2.4
Hz, J ) 8.0 Hz), 6.82–6.96 (m, 4H), 7.25 (t, 2H, J ) 8.4 Hz).
Free base was converted into its HCl salt, mp 110–113 °C. Anal.
Calcd for (C27H39N3O·3HCl·0.8H2O: C, H, N.
Synthesis of (-)-7-[(4-(4-Phenylpiperazin-1-yl)butyl)(prop-
yl)amino]-5,6,7,8-tetrahydronaphthalen-2-ol ((-)-13). Compound
(-)-12 (0.14 g, 0.32 mmol) was reacted with 1 M BBr3/CH2Cl2
(1.0 mL, 1.0 mmol) (procedure G) to give (-)-13 (0.95 g, 70%):
1H NMR (400 MHz, CDCl3) δ 0.88 (t, 3H, J ) 7.6 Hz), 1.40–1.66
(m, 7H), 1.94–2.06 (m, 1H), 2.38–2.58 (m, 6H), 2.64 (t, 4H, J )
4.4 Hz), 2.66–2.84 (m, 4H), 2.88–3.06 (m, 1H), 3.22 (t, 4H, J ) 4.8
Hz), 6.53 (d, 1H, J ) 2.0 Hz), 6.58 (dd, 1H, J ) 2.4 Hz, J ) 8.0 Hz),
6.80–6.98 (m, 4H), 7.26 (t, 2H, J ) 8.4 Hz).
Synthesis of (-)-7-{[4-(4-Phenylpiperazin-1-yl)butyl]prop-2-
ynylamino}-5,6,7,8-tetrahydronaphthalen-2-ol ((-)-10). Com-
pound (-)-9 (0.15 g, 0.35 mmol) was reacted under similar
conditions as described in procedure G to afford the optically pure
amine (-)-10 (0.083 g, 70%): 1H NMR (400 MHz, CDCl3) δ
1.51–1.68 (m, 5H), 2.05–2.10 (m, 2H), 2.42–2.48 (t, 2H, J ) 8.0),
2.64–2.97 (m, 11H), 3.21–3.23 (t, 4H, Ph-N(CH2)2, J ) 6.0 Hz),
3.45–3.50 (m, 2H, -NCH2CCH), 6.48–6.67 (m, 2H, Ar-H),
6.84–6.95 (m, 4H, Ar-H), 7.23–7.30 (m, 2H, Ar-H).
The product was converted into the corresponding trihydrobro-
mide salt. Anal. Calcd for C27H35N3O·3HBr·2.2 H2O: C, H, N.
Compound was highly hygroscopic.
Synthesis of (+)-N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-
2-yl)-N-[4-(4-phenylpiperazin-1-yl)butyl]propionamide ((+)-11).
Compound (+)-7 (0.17 g, 0.44 mmol) was reacted with propionyl
chloride (0.1 mL, 1.15 mmol) and Et3N (1.0 mL) in dry CH2Cl2
(10 mL) by following procedure D. The crude product was purified
by flash chromatography using the solvent system EtOAc/MeOH
) 95:5 to afford (+)-11 (0.16 g, 85%): 1H NMR (400 MHz, CDCl3)
δ 1.10–1.22 (m, 3H), 1.48–1.74 (m, 4H), 1.86–2.04 (m, 2H),
2.32–2.48 (m, 4H), 2.52–2.68 (m, 4H), 2.74–3.06 (m, 4H),
3.12–3.36 (m, 6H), 3.74–3.76 (s, 3H), 6.58–6.60 (d, 1H, J ) 2.4
Hz), 6.69–6.73 (dd, 1H, J ) 2.4 Hz, J ) 8.0 Hz), 6.81–6.90 (m,
1H), 6.92 (d, 2H, J ) 8.4 Hz), 6.96–7.06 (m, 1H), 7.20–7.32 (m,
1H).
Free base was converted into its HCl salt, mp 112–115 °C. Anal.
Calcd for C27H39N3O·3HCl·0.6H2O: C, H, N.
Synthesis of 7-Nitro-2-tetralone (14). Into cold (-30 °C)
concentrated nitric acid (8 mL, 90%) was added 2-tetralone
dropwise (0.66 mL, 5.0 mmol) with vigorous stirring under N2.
The reaction mixture was stirred for 8 min and poured into a beaker
containing a solution of 4.0 M NaOH (40 mL) and ice. The solution
was decanted, and the yellow precipitate was dissolved in EtOAC
(50 mL), washed with water (2 × 50 mL), and dried over MgSO4.
The crude product was purified by flash chromatography over a
silica gel column using hexane/ethyl acetate (4:1) to afford the title
compound 14 (0.102 g, 11%): 1H NMR (CDCl3, 400 MHz) δ 2.60
(t, J ) 6.4 Hz, 2H), 3.18 (t, J ) 6.4 Hz, 2H), 3.69 (s, 2H), 7.42 (d,
J ) 8.4 Hz, 1H), 8.03 (d, J ) 2.4 Hz, 1H), 8.10 (dd, J ) 2.4 Hz,
J ) 8.8 Hz, 1H); 13C NMR (CDCl3, 400 MHz) δ 28.64, 37.43,
44.98, 95.00, 122.38, 123.51, 128.85.
Synthesis of (-)-N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-
2-yl)-N-[4-(4-phenylpiperazin-1-yl)butyl]propionamide ((-)-11).
Compound (-)-7 (0.20 g, 0.52 mmol) was reacted under similar
conditions as described above to afford the optically pure amine
Synthesis of 7-Nitro-N-[2-(4-phenylpiperazin-1-yl)ethyl)]-
1,2,3,4-tetrahydronaphthalen-2-amine (15). Into a solution of
7-nitro-2-tetralone (0.29 g, 1.52 mmol) and acetic acid (0.3 mL) in
1,2-dichloroethane (40 mL) was added a solution of 2-(4-phe-
nylpiperazin-1-yl)ethanamine 2a (0.37 mg, 1.80 mmol) in 1,2-
dichloroethane (10 mL). The reaction mixture was stirred for 1 h
at room temperature under N2, followed by the addition of a solution
of NaBH3CN (0.30 g, 4.77 mmol) in MeOH (3 mL). The reaction
1
(-)-11 (0.18 g, 80%): H NMR (400 MHz, CDCl3) δ 1.10–1.22
(m, 3H), 1.46–2.04 (m, 6H), 2.33–2.52 (m, 4H), 2.54–2.70 (m, 4H),
2.76–3.06 (m, 4H), 3.10–3.36 (m, 6H), 3.75–3.77 (s, 3H), 6.56–6.64
(d, 1H, J ) 8.0 Hz), 6.66–6.76 (m, 1H), 6.82–6.90 (m, 1H), 6.92
(d, 2H, J ) 8.0 Hz), 6.96–7.05 (m, 1H), 7.20–7.30 (m, 1H).
Synthesis of (+)-7-Methoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-12).

112 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
mixture was stirred overnight and then neutralized with a solution
of NaHCO3. The organic phase was separated and dried over
MgSO4. The crude product was purified by flash chromatography
over a silica gel column using ethyl acetate/methanol (19:1) to afford
the title compound 15 (0.37 g, 65%): 1H NMR (CDCl3, 400 MHz)
δ 1.62–1.76 (m, 1H), 2.04–2.16 (m, 1H), 2.56–2.76 (m, 8H),
2.82–2.93 (m, 3H), 2.95–3.06 (m, 2H), 3.07–3.16 (m,1H), 3.16–3.25
(t, J ) 4.8 Hz, 4H), 6.86 (t, J ) 7.2 Hz, 1H), 6.92 (d, J ) 8.0 Hz,
2H), 7.21 (d, J ) 8.0 Hz, 1H), 7.26 (t, J ) 8.0 Hz, 2H), 7.93 (d,
J ) 2.0 Hz, 1H), 7.95 (s, 1H).
raphy over a silica gel column using ethyl acetate/methanol (19:1)
to afford the title compound 19 (0.03 g, 20%): H NMR (CDCl3,
1
400 MHz) δ 0.90 (t, J ) 7.2 Hz, 3H), 1.16–1.34 (br s, 1H),
1.42–1.54 (q, J ) 8.0 Hz, J ) 14.4 Hz, 2H), 1.55–1.70 (m, 1H),
1.96–2.08 (m, 1H), 2.46–2.60 (m, 4H), 2.61–2.90 (m, 9H),
2.92–3.04 (m, 1H), 3.20 (t, J ) 4.8 Hz, 4H), 6.62 (d, J ) 8.0 Hz,
1H), 6.85 (t, J ) 7.2 Hz, 1H), 6.92 (d, J ) 8.8 Hz, 2H), 7.21 (d,
J ) 8.0 Hz, 1H), 7.26 (t, J ) 8.0 Hz, 2H).
Synthesis of 8-[(2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino]-
6,7,8,9-tetrahydro-1H-benzo[e]indol-2(3H)-one (20). A solution
of 8-[(2-(4-phenylpiperazin-1-yl)ethyl)(propyl)amino]-6,7,8,9-tet-
rahydro-1H-benzo[e]indole-1,2(3H)-dione (19) (0.03 g, 0.06 mmol)
in hydrazine (98%) was refluxed for 30 min in an oil bath. The
reaction mixture was poured onto an ice–water bath, and ethyl
acetate was added (20 mL). The organic phase was separated and
dried over MgSO4. Evaporation of the solvent and purification by
column chromatography afforded the corresponding hydrazone,
which was dissolved in a previously prepared solution of sodium
metal (0.2 g) in absolute ethanol (5 mL). The reaction mixture was
stirred at 80 °C under N2 for 30 min, allowed to cool at room
temperature, and poured onto an ice–water bath. Ethyl acetate (2
× 30 mL) was added, and the organic phase was separated and
dried over MgSO4. The crude product was purified by flash
chromatography over a silica gel column using ethyl acetate/
methanol (19:1) to afford the target compound 20 (0.013 g, 45%):
1H NMR (CDCl3, 400 MHz) δ 0.84–0.96 (m, 3H), 1.20–1.30 (br
s, 1H), 1.44–1.68 (m, 3H), 1.98–2.10 (m, 1H), 2.44–2.60 (m, 4H),
2.62–2.92 (m, 9H), 2.94–3.08 (m, 1H), 3.21 (t, J ) 4.8 Hz, 4H),
3.31 (s, 2H), 6.65 (d, J ) 8.0 Hz, 1H), 6.85 (t, J ) 8.0 Hz, 1H),
6.88–7.00 (m, 3H), 7.26 (t, J ) 8.0 Hz, 2H), 8.47 (br s, 1H).
Synthesis of N-(7-Nitro-1,2,3,4-tetrahydronaphthalen-2-yl)-
N-[2-(4-phenylpiperazin-1-yl)ethyl]propionamide (16). Into a
solution of 7-nitro-N-[2-(4-phenylpiperazin-1-yl)ethyl]-1,2,3,4-tet-
rahydronaphthalen-2-amine (15) (0.31 g, 0.82 mmol) and Et3N (0.85
mL) in dry CH2Cl2 (40 mL) under N2 at 0 °C was added propionyl
chloride (0.16 mL, 1.83 mmol) dropwise. The solution was stirred
for 4 h followed by the addition of a saturated solution of NaCl.
The organic phase was separated and dried over MgSO4. The crude
product was purified by flash chromatography over a silica gel
column using ethyl acetate to afford the title compound 16 (0.27
1
g, 77%): H NMR (CDCl3, 400 MHz) δ 1.12 (m, 3H), 1.94–2.16
(m, 2H), 2.36–2.50 (m, 2H), 2.54–2.80 (m, 6H), 2.90–3.16 (m, 5H),
3.20 (t, J ) 4.8 Hz, 4H), 3.40–3.60 (m, 2H), 6.80–6.90 (dd, J )
7.2 Hz, 2H), 6.92 (d, J ) 8.0 Hz, 1H), 7.18–7.32 (m, 3H), 7.90–8.02
(m, 2H).
Synthesis of N-(7-Amino-1,2,3,4-tetrahydronaphthalen-2-yl)-
N-[2-(4-phenylpiperazin-1-yl)ethyl]propionamide (17). Into a
solution of N-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)-N-[2-(4-
phenylpiperazin-1-yl)ethyl]propionamide (16) (0.07 g, 0.15 mmol)
in dry methanol (10 mL) was added 10% Pd/C (0.02 g). The
reaction mixture was stirred under hydrogen for 4 h and filtered
through Celite. Solvent was evaporated to afford compound 17 (0.06
g, 93%): 1H NMR (CDCl3, 400 MHz) δ 1.10–1.22 (t, J ) 7.2 Hz,
3H), 1.86–2.08 (m, 2H), 2.34–2.50 (m, 2H), 2.56–3.10 (m, 11H),
3.16–3.26 (t, J ) 4.8 Hz, 1H), 3.26–3.50 (m, 4H), 3.56–3.78 (m,
2H), 3.94–4.08 (m, 1H), 6.41 (s, 1H), 6.46–6.56 (dd, J ) 2.0 Hz,
J ) 8.0 Hz, 1H), 6.80–7.00 (m, 4H), 7.27 (t, J ) 8.0 Hz, 2H).
Synthesis of N2-[2-(4-Phenylpiperazin-1-yl)ethyl]-N2-propyl-
1,2,3,4-tetrahydronaphthalene-2,7-diamine (18). Into a suspen-
sion of LiAlH4 (0.03 g, 0.74 mmol) in dry THF (20 mL) at 0 °C
under N2 was added N-(7-amino-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-(2-(4-phenylpiperazin-1-yl)ethyl)propionamide (17) (0.06 g,
0.15 mmol) in dry THF (10 mL) to afford compound 18 (0.05 g,
Free base was converted into the trihydrochloric salt, mp 133–136
°C. Anal. Calcd for C27H36N4O·3HCl·1.8H2O.
Synthesis of 5-Methoxy-N-propyl-1,2,3,4-tetrahydronaphtha-
len-2-amine ((()-21). n-Propylamine (9.33 mL, 1.75 mmol) was
reacted with 5-methoxy-2-tetralone (10 g, 56.75 mmol), NaCNBH3
(10.69 g, 170.24 mmol), and HOAc (8.4 mL) in 1,2-dichloroethane
(100 mL) by following procedure C. The crude product was
dissolved in ethanol and was converted into hydrochloride salt by
treatment with HCl in ether solution. The pure precipitated HCl
salt (()-21 (12.73 g, 88%) was filtered off and washed with ether
and dried under vacuum. This racemic salt was converted to free
base by using saturated NaHCO3 solution. Free base was extracted
with ethyl acetate and was subjected to resolution in the next step.
1H NMR (400 MHz, CDCl3) δ 0.98 (t, 3H, J ) 7.2 Hz, CH2CH3),
1.65–1.77 (m, 3H), 2.18–2.23 (m, 1H), 2.53-2.62 (m, 1H),
2.76–2.85 (m, 3H), 2.88-2.98 (dq, 1H, J1 ) 18 Hz, J2 ) 3.2 Hz),
3.06–3.15 (m, 2H), 3.8 (s, 3H, -OCH3), 5.07 (br s, 1H, -NH),
6.68 (t, 2H, J ) 8.8 Hz, -CHCHCH), 7.10 (t, 1H, J ) 2.4 Hz, J
) 8.0 Hz).
1
86%) (procedure E): H NMR (CDCl3, 400 MHz) δ 0.90 (t, J )
7.2 Hz, 3H), 1.40–1.52 (q, J ) 7.2 Hz, J ) 14.0 Hz, 2H), 1.94–2.04
(m, 1H), 2.46–2.56 (t, J ) 8.0 Hz, 4H), 2.60–2.84 (m, 11H),
2.88–3.00 (m 1H), 3.20 (t, J ) 4.8 Hz, 4H), 3.50 (br s, 2H), 6.44
(d, J ) 2.0 Hz, 1H), 6.46–6.50 (dd, J ) 2.4 Hz, J ) 8.0 Hz, 1H),
6.82–6.90 (m, 2H), 6.93 (d, J ) 8.0 Hz, 2H), 7.26 (t, J ) 8.0 Hz,
2H).
Free base was converted into the tetrahydrochloride salt, mp
117–120 °C. Anal. Calcd for C25H36N4 ·4HCl·0.4H2O: C, H, N.
Synthesis of 8-[(2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino]-
6,7,8,9-tetrahydro-1H-benzo[e]indole-1,2(3H)-dione (19). Chloral
hydrate (0.063 g, 0.38 mmol) and sodium sulfate (0.44 g, 3.08
mmol) were dissolved in 4 mL of water and warmed in an oil bath
at 60 °C. Then N2-[2-(4-phenylpiperazin-1-yl)ethyl]-N2-propyl-
1,2,3,4-tetrahydronaphthalene-2,7-diamine (18) (0.136 g, 0.35
mmol) in 1 N HCl (5 mL) and NH2OH·HCl (0.077 g, 1.10 mmol)
in water (2 mL) were successively added. After the addition was
completed, the reaction mixture was heated at 80 °C for 20 min
and allowed to cool to room temperature. Ethyl acetate was added
as well as diluted ammonium hydroxide solution (until pH 8). The
organic phase was separated and dried over MgSO4. The solution
was filtered and solvent evaporated to afford an off-white solid.
This product was added portion-wise to a rapidly stirred concen-
trated sulfuric acid (5 mL) at 80 °C. After 20 min, the reaction
mixture was allowed to cool at room temperature, poured onto
crushed ice, and basified with diluted ammonium hydroxide. Ethyl
acetate was added, and the organic phase was separated and dried
over MgSO4. The crude product was purified by flash chromatog-
Resolution of 5-Methoxy-N-propyl-1,2,3,4-tetrahydronaph-
thalen-2-amine ((()-20). Racemic (()-21 was resolved into its
(+)- and (-)-isomers by using both (-)- and (+)-isomers of the
synthetic resolving agent 4-(2-chlorophenyl)-5,5-dimethyl-2-hy-
droxy-1,3,2-dioxaphosphorinane 2-oxide. This optically active
resolving agent was prepared according to the published proce-
dure.47 Compound (()-21 (5.22 g, 23.80 mmol) and (+)-4-(2-
chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphorinane 2-ox-
ide (6.52 g, 23.56 mmol) were dissolved by warming in 25 mL of
ethanol. The solution was cooled to room temperature and then to
0 °C. The precipitated crystals were filtered off, washed with cold
ether to yield 5.07 g of the salt ([R]D ) -5.6°, c 1 in methanol).
Further recrystallization (two times) from hot isopropanol yielded
the salt, 4.5 g ([R]D ) -13.4°, c 1 in methanol) (yield ) 76.27%).
Further crystallization of the salt from hot isopropanol did not
change the optical rotation any further. The salt was then hydrolyzed
in the presence of 20% NaOH solution in water under stirring
conditions for 2 h at room temperature. The aqueous layer was
extracted with dichloromethane (3 × 100 mL), dried over Na2SO4,
and evaporated to dryness to yield (-)-21, 1.99 g (76.25%), [R]D
of the HCl salt of (-)-21 ) -70.6°, c 1 in methanol).

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 113
(()-21 (3.12 g, 14.23 mmol) was similarly treated by using (-)-
4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphori-
nane 2-oxide (3.94 g, 14.23 mmol). Recrystallization from hot
isopropanol yielded the salt, 3.94 g (56%), [R]D ) +13.2, c 1 in
methanol). Further crystallization of the salt from hot isopropanol
did not change the optical rotation to a significant extent. Hydrolysis
of the salt following the above-mentioned procedure yielded (+)-
21, 1.74 g, (56%), [R]D of the HCl salt of (+)-21 ) +69.4°, c 1 in
methanol).
Synthesis of 2-Chloro-N-(5-hydroxy-1,2,3,4-tetrahydronaph-
thalen-2-yl)-N-propylacetamide ((()-22a). Compound (()-21a
(1.64 g, 7.99 mmol) was reacted with chloroacetyl chloride (1.3
mL, 16.0 mmol) and Et3N (2.0 mL) in CH2Cl2 (20 mL) to yield
1
(()-22a (0.96 g, 43%) by following procedure D: H NMR (400
MHz, CDCl3) δ 0.90–0.98 (m, 3H, CH2CH3), 1.64–1.72 (m, 2H),
1.90–2.12 (m, 2H), 2.61-2.74 (m, 1H), 2.83–3.09 (m, 3H),
3.19–3.27 (m, 2H), 4.00–4.15 (m, 3H), 6.61–6.68 (m, 2H),
6.96–7.04 (m, 1H).
Synthesis of 6-(Propylamino)-5,6,7,8-tetrahydronaphthalen-
1-ol ((()-21a). Compound (()-21 (0.77 g, 3.51 mmol) was reacted
with boron tribromide (1 M solution in dichloromethane, 7.8 mL,
7.81 mmol) in dry CH2Cl2 (10 mL) at -40 °C by following
procedure G. The crude product was purified by flash chromatog-
raphy using the solvent system hexane/EtOAc ) 60:40 to afford
Synthesis of (+)-2-Chloro-N-(5-hydroxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-propylacetamide ((+)-22a). Compound
(+)-21a (2.0 g, 9.74 mmol) was reacted under similar conditions
as reported above (procedure D) to afford the optically pure (+)-
22a (1.38 g, 50.2%): 1H NMR (400 MHz, CDCl3) δ 0.90–0.98
(m, 3H, CH2CH3), 1.62–1.72 (m, 2H), 1.91–2.03 (m, 2H), 2.64-2.75
(m, 1H), 2.86–3.10 (m, 3H), 3.21–3.29 (m, 2H), 4.00–4.17 (m, 3H),
6.60–6.70 (m, 2H), 6.97–7.07 (m, 1H).
Synthesis of (-)-2-Chloro-N-(5-hydroxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-propylacetamide ((-)-22a). Compound
(-)-21a (1.5 g, 7.31 mmol) was reacted under similar conditions
as reported above (procedure D) to afford the optically pure (-)-
22a (0.82 g, 39.8%): 1H NMR (400 MHz, CDCl3) δ 0.90–0.98
(m, 3H, CH2CH3), 1.63–1.73 (m, 2H), 1.91–2.04 (m, 2H), 2.65-2.75
(m, 1H), 2.85–3.10 (m, 3H), 3.20–3.29 (m, 2H), 4.01–4.15 (m, 3H),
6.60–6.70 (m, 2H), 6.97–7.06 (m, 1H).
1
compound (()-21a (0.70 g, 97%): H NMR (400 MHz, CD3OD)
δ 1.05–1.08 (t, 3H, J ) 7.6 Hz, CH2CH3), 1.74–1.85 (m, 3H),
2.32–2.37 (m, 1H), 2.61-2.70 (m, 1H), 2.82–2.90 (m, 1H), 2.96
-3.03 (dq, 1H, J1 ) 17.6 Hz, J2 ) 3.6 Hz), 3.08–3.12 (m, 2H),
3.19–3.24 (m, 1H), 3.44–3.52 (m, 1H), 6.61–6.63 (d, 2H, J ) 8.0
Hz, -CHCHCH), 6.98 (t, 1H, J ) 2.4 Hz, J ) 8.0 Hz).
Synthesis of (+)-6-(Propylamino)-5,6,7,8-tetrahydronaphtha-
len-1-ol ((+)-21a). Compound (+)-21 (0.6 g, 2.74 mmol) was
reacted under similar conditions as reported above (procedure G)
to afford the optically pure (+)-21a (0.55 g, 98%): 1H NMR (400
MHz, CD3OD) δ 1.05–1.07 (t, 3H, J ) 7.6 Hz, CH2CH3), 1.74–1.85
(m, 3H), 2.32–2.39 (m, 1H), 2.61-2.69 (m, 1H), 2.82–2.92 (m,
1H), 2.96 -3.00 (dq, 1H, J1 ) 17.6 Hz, J2 ) 3.6 Hz), 3.09–3.14
(m, 2H), 3.19–3.25 (m, 1H), 3.44–3.50 (m, 1H), 6.61–6.63 (d, 2H,
J ) 8.0 Hz, -CHCHCH), 6.98 (t, 1H, J ) 2.4 Hz, J ) 8.0 Hz).
Synthesis of (-)-6-(Propylamino)-5,6,7,8-tetrahydronaphtha-
len-1-ol ((-)-21a). Compound (-)-21 (0.80 g, 3.65 mmol) was
reacted under similar conditions as reported above (procedure G)
to afford the optically pure (-)-21a (0.72 g, 96%): 1H NMR (400
MHz, CD3OD) δ 1.05–1.08 (t, 3H, J ) 7.6 Hz, CH2CH3), 1.74–1.85
(m, 3H), 2.32–2.38 (m, 1H), 2.61 -2.69 (m, 1H), 2.82–2.92 (m,
1H), 2.96-3.05 (dq, 1H, J1 ) 17.6 Hz, J2 ) 3.6 Hz), 3.10–3.12
(m, 2H), 3.19–3.24 (m, 1H), 3.44–3.53 (m, 1H), 6.61–6.63 (d, 2H,
J ) 8.0 Hz, -CHCHCH), 6.98 (t, 1H, J ) 2.4 Hz, J ) 8.0 Hz).
Synthesis of 2-Chloro-N-(5-methoxy-1,2,3,4-tetrahydronaph-
thalen-2-yl)-N-propylacetamide ((()-22). Compound (()-21 (1.58
g, 7.20 mmol) was reacted with chloroacetyl chloride (1.2 mL, 1.44
mmol) and Et3N (2.0 mL) in CH2Cl2 (20 mL) by following
procedure D. The crude product was purified by flash chromatog-
raphy using the solvent system hexane/EtOAc ) 90:10 to yield
pure compound (()-22 (2.03 g, 95%): 1H NMR (400 MHz, CDCl3)
δ 0.90–0.97 (m, 3H, CH2CH3), 1.62–1.73 (m, 2H), 1.85–2.14 (m,
2H), 2.60-2.71 (m, 1H), 2.84–2.91 (dd, 1H, J1 ) 16.0 Hz, J2 )
4.8 Hz), 3.00–3.12 (m, 2H), 3.15–3.29 (m, 2H), 3.80–3.82 (d, 3H,
-OCH3), 3.95–4.01 (m, 1H), 4.08–4.10 (m, 2H), 6.65–6.70 (m,
2H), 7.07–7.16 (m, 1H).
Procedure I. Synthesis of (+)-N-(5-Methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-2-(4-phenylpiperazin-1-yl)-N-propylaceta-
mide ((+)-23). Into a suspension of compound (+)-22 (0.76 g, 2.60
mmol), potassium carbonate (0.71 g, 5.14 mmol), and a catalytic
amount of potassium iodide (40 mg) in acetonitrile (30 mL) was
added 1-phenylpiperazine (0.60 g, 3.85 mmol) under nitrogen
atmosphere with stirring. The reaction mixture was refluxed for
3 h and cooled to room temperature, and the reaction solution was
filtered. Inorganic residue was washed with ethyl acetate. The
combined solvent was evaporated to obtain the crude product, which
was purified by flash chromatography using the solvent system
1
hexane/ethyl acetate (70:30) to afford (+)-23 (0.92 g, 85%): H
NMR (400 MHz, CDCl3) δ 0.89–0.95 (m, 3H, CH2CH3), 1.61–1.71
(m, 2H), 1.83–1.89 (m, 1H), 1.98–2.03 (m, 1H), 2.63–2.66 (t, 4H,
J ) 5.2 Hz), 2.73–2.74 (m, 1H), 2.82–2.88 (dd, 1H, J1 ) 15.8 Hz,
J2 ) 4.4 Hz)), 2.97–3.36 (m, 10H), 3.81 (d, 3H, -OCH3), 4.26–4.32
(m, 1H), 6.65–6.71 (m, 2H), 6.84–6.87 (t, 1H, J ) 7.2 Hz),
6.90–6.95 (t, 2H, J ) 8.0 Hz), 7.06–7.14 (m, 1H), 7.24–7.28 (m,
2H).
Synthesis of (-)-N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-
2-yl)-2-(4-phenylpiperazin-1-yl)-N-propylacetamide ((-)-23). Com-
pound (-)-22 (0.8 g, 2.70 mmol) was reacted under similar
conditions as reported above (procedure I) to afford the optically
pure (-)-23 (0.98 g, 86%): 1H NMR (400 MHz, CDCl3) δ
0.89–0.95 (m, 3H, CH2CH3), 1.61–1.71 (m, 2H), 1.83–1.89 (m,
1H), 1.98–2.03 (m, 1H), 2.63–2.66 (t, 4H, J ) 5.2 Hz), 2.73–2.74
(m, 1H), 2.82–2.88 (dd, 1H, J1)15.8 Hz, J2 ) 4.4 Hz)), 2.97–3.36
(m, 10H), 3.81 (d, 3H, -OCH3), 4.26–4.32 (m, 1H), 6.65–6.71
(m, 2H), 6.84–6.87 (t, 1H, J ) 7.2 Hz), 6.90–6.95 (t, 2H, J ) 8.0
Hz), 7.06–7.14 (m, 1H), 7.24–7.28 (m, 2H).
Synthesis of N-(5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-propylacetamide ((()-
23a). Compound (()-22a (0.96 g, 3.41 mmol) with potassium
carbonate (0.57 g, 10.22 mmol) was reacted with 1-(2-methox-
y)phenylpiperazine HCl (1.013 g, 4.43 mmol) in the presence of a
catalytic amount of potassium iodide by following procedure I. The
crude product was purified by flash chromatography using the
solvent system hexane/ethyl acetate ) 40:60 to afford (()-23a (1.09
g, 73.12%): 1H NMR (400 MHz, CDCl3) δ 0.88–0.95 (m, 3H,
CH2CH3), 1.64–1.72 (m, 2H), 1.83–2.05 (m, 2H), 2.63–3.52 (m,
16H), 3.83–3.85 (d, 3H, -OCH3), 4.28–4.34 (m, 1H), 6.61–6.63
(d, 1H, J ) 8.0 Hz), 6.69–6.71 (d, 1H, J ) 8.0 Hz), 6.83–6.86 (t,
1H, J ) 7.6 Hz), 6.90–7.02 (m, 4H).
Synthesis of (+)-2-Chloro-N-(5-methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-propylacetamide ((+)-22). Compound
(+)-21 (1.75 g, 7.98 mmol) was reacted under similar conditions
as reported above (procedure D) to afford the optically pure (+)-
22 (2.30 g, 97%): 1H NMR (400 MHz, CDCl3) δ 0.90–0.97 (m,
3H, CH2CH3), 1.61–1.72 (m, 2H), 1.83–2.10 (m, 2H), 2.58-2.71
(m, 1H), 2.84–2.90 (dd, 1H, J1 ) 16.0 Hz, J2 ) 4.8 Hz),
3.00–3.10 (m, 2H), 3.15–3.29 (m, 2H), 3.80–3.82 (d, 3H,
-OCH3), 3.95–4.02 (m, 1H), 4.08–4.10 (m, 2H), 6.65–6.70 (m,
2H), 7.07–7.14 (m, 1H).
Synthesis of (-)-2-Chloro-N-(5-methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-propylacetamide ((-)-22). Compound (-)-
21(1.20 g, 5.47 mmol) was reacted under similar conditions as
reported above (procedure D) to afford the optically pure (-)-22
1
(1.58 g, 97%): H NMR (400 MHz, CDCl3) δ 0.90–0.97 (m, 3H,
CH2CH3), 1.61–1.73 (m, 2H), 1.83–2.12 (m, 2H), 2.58-2.70 (m,
1H), 2.84–2.89 (dd, 1H, J1 ) 16.0 Hz, J2 ) 4.8 Hz), 3.00–3.10
(m, 2H), 3.15–3.26 (m, 2H), 3.80–3.82 (d, 3H, -OCH3), 3.95–4.03
(m, 1H), 4.08–4.12 (m, 2H), 6.65–6.71 (m, 2H), 7.07–7.15 (m,
1H).
Synthesis of (+)-N-(5-Hydroxy-1,2,3,4-tetrahydronaphthalen-
2-yl)-2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-propylaceta-

114 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
mide ((+)-23a). Compound (+)-22a (0.42 g, 1.49 mmol) was
reacted under similar conditions as reported above (procedure I)
to afford the optically pure (+)-23a (0.48 g, 73.6%): 1H NMR (400
MHz, CDCl3) δ 0.88–0.97 (m, 3H, CH2CH3), 1.64–1.70 (m, 2H),
1.80–2.06 (m, 2H), 2.65–3.57 (m, 16H), 3.83–3.88 (d, 3H, -OCH3),
4.28–4.34 (m, 1H), 6.61–6.65 (d, 1H, J ) 8.0 Hz), 6.69–6.72 (d,
1H, J ) 8.0 Hz), 6.83–6.84 (t, 1H, J ) 7.6 Hz), 6.90–7.03 (m,
4H).
Synthesis of (-)-N-(5-Hydroxy-1,2,3,4-tetrahydronaphthalen-
2-yl)-2-[4-(2-methoxyphenyl)piperazin-1-yl]-N-propylaceta-
mide ((-)-23a). Compound (-)-22a (0.72 g, 2.55 mmol) was
reacted under similar conditions as reported above (procedure I)
to afford the optically pure (-)-23a (0.85 g, 76%): 1H NMR (400
MHz, CDCl3) δ 0.89–0.98 (m, 3H, CH2CH3), 1.61–1.72 (m, 2H),
1.82–2.10 (m, 2H), 2.58–3.38 (m, 16H), 3.78–3.88 (m, 3H,
-OCH3), 4.28–4.34 (m, 1H), 6.61–6.70 (m, 2H), 6.83–6.87 (t, 1H,
J ) 7.6 Hz), 6.90–7.02 (m, 4H).
N-[2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl]-N-(5-meth-
oxy-1,2,3,4-tetrahydronaphthalen-2-yl)propionamide (()-23b. A
mixture of compound (()-22 (0.4 g, 1.35 mmol) with potassium
carbonate (0.93 g, 6.76 mmol) was reacted with 1-(2,3-dichlo-
ro)phenylpiperazine HCl (0.72 g, 2.70 mmol) in the presence of a
catalytic amount of potassium iodide by following procedure I. The
crude product was purified by flash chromatography using the
solvent system hexane/ethyl acetate ) 40:60 to afford (()-23b (0.55
g, 83%): 1H NMR (400 MHz, CDCl3) δ 0.88–0.95 (m, 3H,
CH2CH3), 1.64–1.74 (m, 2H), 1.80–2.05 (m, 2H), 2.67–3.52 (m,
16H), 3.81 (s, 3H, -OCH3), 4.30–4.34 (m, 1H), 6.64–6.66 (d, 1H,
J ) 8.0 Hz), 6.69–6.71 (d, 1H, J ) 8.0 Hz), 6.90–6.93 (dd, 1H, J1
) 7.6 Hz, J2 ) 2.0 Hz), 7.06–7.10 (t, 1H, J ) 8.0 Hz), 7.14–7.21
(m, 2H).
Synthesis of (+)-5-Methoxy-N-[2-(4-phenylpiperazin-1-yl)
ethyl]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-24).
Compound (+)-23 (0.92 g, 2.18 mmol) was reacted with LiAlH4
(0.66 g, 17.46 mmol) in dry THF (40 mL) under refluxing
conditions for 4 h by following procedure E. The crude product
was purified by flash chromatography using the solvent system
hexane/EtOAc (1:1) to afford compound (+)-24 (0.67 g, 56%): 1H
NMR (400 MHz, CDCl3) δ 0.88–0.92 (t, 3H, J ) 7.2 Hz, CH2CH3),
1.41–1.60 (m, 3H), 2.04–2.05 (m, 1H), 2.50–2.60 (m, 5H),
2.64–2.68 (t, 4H, J ) 4.8 Hz), 2.74–2.80 (m, 3H), 2.83–3.05 (m,
3H), 3.19–3.20 (t, 4H, J ) 5.4 Hz), 3.80 (s, 3H, -OCH3), 6.64–6.69
(d, 1H, J ) 8.6 Hz), 6.71–6.73 (d, 1H, J ) 7.6 Hz), 6.83–6.86 (t,
1H, J ) 7.2 Hz), 6.91–6.94 (d, 2H, J ) 8.0 Hz), 7.07–7.10 (t, 1H,
J ) 8.0 Hz), 7.24–7.32 (m, 2H).
Synthesis of (+)-6-[(2-(4-(2-Methoxyphenyl)piperazin-1-yl)
ethyl)(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol ((+)-
24a). Compound (+)-23a (0.48 g, 1.10 mmol) was reacted under
similar conditions as reported above (procedure E) to afford the
optically pure (+)-24a (0.14 g, 30.43%): [R]D ) (+) -31.6°, c 1
in methanol; 1H NMR (400 MHz, CDCl3) δ 0.86–0.90 (t, 3H, J )
7.6 Hz, CH2CH3), 1.40–1.49 (m, 3H), 1.92–2.00 (m, 1H), 2.27–2.36
(m, 1H), 2.44–2.96 (m, 14H), 3.15 (br s, 4H), 3.87 (s, 3H, -OCH3),
6.49–6.51 (d, 1H, J ) 8.0 Hz), 6.55–6.60 (d, 1H, J ) 7.2 Hz),
6.85–7.02 (m, 5H).
The product was converted into the corresponding dioxalate salt,
mp 130–132 °C. Anal. Calcd for C26H37N3O2 ·2C2H2O4 ·0.5H2O:
C, H, N.
Synthesis of (-)-6-[(2-(4-(2-Methoxyphenyl)piperazin-1-yl)
ethyl)(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol ((-)-
24a). Compound (-)-23a (0.85 g, 1.94 mmol) was reacted under
similar conditions as reported above (procedure E) to afford the
optically pure (-)-24a (0.53 g, 64.4%): [R]D ) -33.4°, c 0.5 in
1
methanol; H NMR (400 MHz, CDCl3) δ 0.86–0.90 (t, 3H, J )
7.6 Hz, CH2CH3), 1.35–1.50 (m, 3H), 1.95–1.99 (m, 1H), 2.22–2.29
(m, 1H), 2.43–2.96 (m, 14H), 3.16 (br s, 4H), 3.87 (s, 3H, -OCH3),
6.47–6.49 (d, 1H, J ) 8.0 Hz), 6.53–6.55 (d, 1H, J ) 7.2 Hz),
6.85–7.02 (m, 5H).
The product was converted into the corresponding dioxalate salt,
mp 132–134 °C. Anal. Calcd for C26H37N3O2 ·2C2H2O4 ·0.8 H2O:
C, H, N.
Synthesis of N-[2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl]-
5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine ((()-
24b). Into a solution of (()-23b (1.05 g, 2.14 mmol) in dry THF
was added 21.4 mL of a solution of borane-THF complex (1 M
solution) with stirring under nitrogen atmosphere. The reaction
mixture was refluxed for 6 h, cooled to room temprature, and
quenched with methanol. The solvent was evaporated. The white
solid complex was suspended in 6 N HCl in methanol and stirred
for 2 h at 50 °C. Methanol was evaporated under vacuum. The
reaction mixture was made alkaline using saturated Na2CO3/
NaHCO3 solution. The aqueous layer was extracted with ethyl
acetate (3 × 100 mL), dried over Na2SO4, concentrated under
vacuum, and purified by flash chromatography using the solvent
system ethyl acetate/methanol (90:10) to afford (()-24b (0.8 g,
1
78%): H NMR (400 MHz, CDCl3) δ 0.88–0.92 (t, 3H, J ) 7.2
Hz, CH2CH3), 1.43–1.63 (m, 3H), 2.04–2.09 (m, 1H), 2.51–2.57
(q, 5H), 2.69–3.07 (m, 14H), 3.81 (s, 3H, -OCH3), 6.64–6.66 (d,
1H, J ) 8.4 Hz), 6.70–6.72 (d, 1H, J ) 7.6 Hz), 6.94–6.97 (dd,
1H, J1 ) 6.8 Hz, J2 ) 3.2 Hz), 7.07–7.16 (m, 3H).
Synthesis of (-)-5-Methoxy-N-[2-(4-phenylpiperazin-1-yl)
ethyl]-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine ((-)-24).
Compound (-)-23 (0.98 g, 2.32 mmol) was reacted under similar
conditions as reported above (procedure E) to afford the optically
pure (-)-24 (0.53 g, 56%): 1H NMR (400 MHz, CDCl3) δ
0.88–0.91 (t, 3H, J ) 7.2 Hz, CH2CH3), 1.43–1.62 (m, 3H),
2.04–2.09 (m, 1H), 2.50–2.56 (m, 5H), 2.64–2.67 (t, 4H, J ) 4.8
Hz), 2.72–2.79 (m, 3H), 2.83–3.02 (m, 3H), 3.19–3.21 (t, 4H, J )
5.2 Hz), 3.80 (s, 3H, -OCH3), 6.64–6.66 (d, 1H, J ) 8.4 Hz),
6.70–6.72 (d, 1H, J ) 7.6 Hz), 6.83–6.86 (t, 1H, J ) 7.2 Hz),
6.91–6.93 (d, 2H, J ) 8.0 Hz), 7.07–7.10 (t, 1H, J ) 8.0 Hz),
7.24–7.28 (m, 2H).
Synthesis of 6-[(2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)
(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol ((()-24a). Com-
pound (()-23a (1.09 g, 2.49 mmol) was reacted with LiAlH4 (0.76
g, 19.9 mmol) in dry THF (40 mL) under refluxing conditions for
4 h by following procedure E. The crude product was purified by
flash chromatography using solvent EtOAc to afford (()-24a (0.60
g, 57%): 1H NMR (400 MHz, CDCl3) δ 0.86–0.90 (t, 3H, J ) 7.6
Hz, CH2CH3), 1.31–1.48 (m, 3H), 1.92–1.95 (m, 1H), 2.22–2.29
(m, 1H), 2.43–2.96 (m, 14H), 3.16 (br s, 4H), 3.86 (s, 3H, -OCH3),
6.46–6.48 (d, 1H, J ) 8.0 Hz), 6.54–6.56 (d, 1H, J ) 7.2 Hz),
6.85–7.02 (m, 5H), 7.85–8.2 (bs, 1H, -OH).
Synthesis of (+)-6-[(2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)
amino]-5,6,7,8-tetrahydronaphthalen-1-ol ((+)-25). Compound
(+)-24 (0.67 g, 1.64 mmol) was refluxed in 20 mL of 48% aqueous
HBr solution for 3 h. The reaction mixture was evaporated under
vacuum. The crude HBr salt was converted to free base by using
a saturated Na2CO3 solution. The aqueous layer was extracted with
ethyl acetate (3 × 100 mL), dried (Na2SO4), concentrated under
vacuum, and purified by flash chromatography using the solvent
system ethyl acetate/methanol (90:10) to afford (+)-25 (0.39 g,
60%): [R]D ) +34.8°, c 1 in methanol; 1H NMR (400 MHz, CDCl3)
δ 1.06–1.10 (t, 3H, J ) 7.2 Hz, CH2CH3), 1.91–2.02 (m, 3H),
2.46–2.50 (m, 1H), 2.67–2.76 (m, 1H), 3.10–3.95 (m, 18H),
6.61–6.69 (m, 2H), 6.96–7.04 (m, 2H), 7.13–7.14 (m, 2H),
7.32–7.35 (t, 2H, J ) 7.2 Hz).
The product was converted into the corresponding dioxalate salt,
mp 120–123 °C. Anal. Calcd for C25H35N3O·2C2H2O4: C, H, N.
Synthesis of (-)-6-[(2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)
amino]-5,6,7,8-tetrahydronaphthalen-1-ol ((-)-25). Compound
(-)-24 (0.53 g, 1.3 mmol) was reacted under similar conditions as
reported above (procedure H) to afford the optically pure (-)-25
1
(0.32 g, 63%): [R]D ) -35.6°, c 1 in methanol; H NMR (400
MHz, CDCl3) δ 0.87–0.91 (t, 3H, J ) 7.2 Hz, CH2CH3), 1.40–1.52
(m, 3H), 1.96–2.03 (m, 1H), 2.32–2.75 (m, 13H), 2.86–2.95 (m,
2H), 3.25–3.27 (t, 4H, J ) 4.8 Hz), 6.49–6.51 (d, 1H, J ) 7.6 Hz),
6.53–6.55 (d, 1H, J ) 7.6 Hz), 6.84–6.88 (t, 1H, J ) 7.6 Hz),
6.92–6.96 (m, 3H), 7.24–7.28 (m, 2H).
The product was converted into the corresponding dioxalate salt,
mp 122–125 °C. Anal. Calcd for C26H37N3O2 ·2C2H2O4 ·0.5H2O:
C, H, N.

High-Affinity D3-Preferring Agonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1 115
The product was converted into the corresponding dioxalate salt,
mp 122–124 °C. Anal. Calcd for C25H35N3O·2C2H2O4: C, H, N.
Synthesis of 6-[(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)eth-
yl)(propyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol ((()-25b).
Compound (()-24b (1.1 g, 2.31 mmol) was stirred with boron
tribromide (1 M solution in dichloromethane, 7.0 mL, 7.0 mmol)
in dry CH2Cl2 (20 mL) at -40 °C following procedure G. The
crude product was purified by flash chromatography using the
solvent system hexane/EtOAc ) 60:40 to afford compound (()-
was a very small fraction (5% or less) of basal binding in the
absence of drug (vehicle) and did not affect the EC50 (concentration
producing half-maximal stimulation) of the test drug estimated by
nonlinear logarithmic fitting (logistics model) with OriginPro 7.0.
The plateau binding (maximal binding stimulation) with test drug
was expressed as percent of maximal binding observed with the
full agonist DA (% Emax); each filter mat used for harvesting and
scintillation counting contained varying concentrations of test drug
(for EC50 determination) and a fixed [DA] (see above, for maximally
achievable binding with full agonist under the conditions of a given
experiment).
1
25b (0.60 g, 56%): H NMR (400 MHz, CDCl3) δ 0.88–0.92 (t,
3H, J ) 7.6 Hz, CH2CH3), 1.45–1.55 (m, 3H), 1.98–2.00 (m, 1H),
2.42–2.64 (m, 6H), 2.72–2.96 (m, 9H), 3.12 (br s, 4H), 6.54–6.56
(m, 2H), 6.92–6.96 (m, 2H), 7.12–7.17 (m, 2H), 7.6–7.84 (bs, 1H,
-OH).
The product was converted into corresponding dihydrochloride
salt, mp 180–183 °C. Anal. Calcd for C25H33Cl2N3O·2HCl·H2O:
C, H, N.
In Vivo Rotational Experiment with 6-OH-DA-Lesioned
Rats. The lesioned rats were purchased from Taconic Biotechnology
(Rensselaer, NY), and their unilateral lesion was checked twice by
apomorphine challenge following the surgery.The first 14 days
postlesion challenge with apomorphine was done to observe a
complete rotation session postadministration. In the second chal-
lenge with apomorphine (0.05 mg/kg) 21 days postlesion, con-
tralateral rotations were recorded for 30 min; apomorphine produced
rotations in all four rats (average rotation > 250), indicating
successful unilateral lesion. In these rats, lesion was performed on
the left side with the rotations produced upon agonist challenge
occurring clockwise. In our current study, apomorphine was also
used as a reference compound. The test drugs were dissolved in
sterile water and were administered as water solution. The number
of rotations was measured over 12 h. For control, vehicle was
administered alone. Rotations were measured in the Rotomax
Rotometry System (AccuScan Instruments, Inc., Columbus, OH)
equipped with a Rotomax Analyzer, high-resolution sensor, and
animal chambers with harnesses. Data were analyzed with the
Rotomax Window software program. Test drugs (-)-25 (1 and 5
µmol/kg) and 2 (5 µmol/kg) were dissolved in sterile water and
were administered ip. Apomorphine (0.05 mg/kg) was also admin-
istered, in the same manner, as a reference compound. The rotations
were measured in a rotational chamber immediately after admin-
istration of drugs. The data were collected every 30 min. Data were
analyzed by Graph Pad (version 4, San Diego, CA) program.
Compounds (–)-25 and 2 produced contralateral rotations in all
lesioned rats, which lasted over 8–12 h. The reference drug
apomorphine (0.16 µmol/kg) exhibited a fast onset of action with
the peak effect occurring within the first 30 min. It exhibited a
short duration of action.
Measurement of Binding Potencies at DA D2 and D3
Receptors: [3H]Spiperone Binding. Binding affinities were as-
sessed according to the general procedure described in our previous
study.44 Briefly, membranes were prepared from human embryonic
kidney (HEK) 293 cells expressing human D2L and D3 receptors.
Approximately 20 (for D2L) or 50 (for D3) µg of protein was
incubated with each test compound and [3H]spiperone (0.4 nM)
for 1 h at 30 °C in 50 mM Tris-HCl (pH 7.4), with 0.9% NaCl and
0.025% ascorbic acid in the absence of GTP, in a total volume of
0.8 mL. (+)-Butaclamol (2 µM) was used to define nonspecific
binding. Assays were terminated by the addition of ice-cold buffer
and filtration through glass fiber filtermats with cold saline as wash
buffer in the MACH 3-96 Tomtec harvester (Wallac, Gaithersburg,
MD). IC50 values were estimated by nonlinear regression analysis
with the logistic model in the least-squares fitting program ORIGIN
and converted to inhibition constants (Ki) by the Cheng-Prusoff
equation.52 In this conversion, the Kd values for [3H]spiperone
binding were 0.057 nM for D2 receptors and 0.125 nM for D3
receptors.
Measurement of Stimulation of DA D2 and D3 Receptors:
[35S]GTPγS Binding. Chinese hamster ovary (CHO) cells express-
ing human D2 receptors were grown in Dulbecco’s modified Eagle’s
medium enriched with 5% bovine calf serum, 1% L-glutamine, 0.5%
penicillin/streptomycin, and 2 µg/mL puromycin. ATt-20 cells
expressing human D3 receptors were grown in Gibco F10 medium
with 10% horse serum, 5% fetal bovine serum, 1% L-glutamine,
50 µg/mL gentamicin, and 500 µg/mL G418. The general proce-
dures used for measuring [35S]GTPγS binding are modified from
protocols described for DA receptors53 and other G protein-coupled
receptors.54,55 To make membranes, cells were washed with
phosphate-buffered saline (PBS) and then centrifuged in PBS at
1000g for 5 min at 4 °C. The supernatant was removed, and cells
were resuspended in 50 mM Tris-HCl, 1 mM EDTA (pH 7.4)
(resuspension buffer), by polytron, and then centrifuged at 35000g
for 15 min at 4 °C. This was done once more, at which point cells
were resuspended with assay buffer (D2, 20 mM HEPES, 3 mM
MgCl2, 150 mM NaCl, 0.2 mM EGTA, 0.001% bovine serum
albumin (BSA); D3, 20 mM HEPES, 3 mM MgCl2, 100 mM NaCl,
0.2 mM EGTA, 0.001% BSA). The [35S]GTPγS binding assays
were performed in triplicates. The final 1 mL volume was composed
of 100 µL of 10% (v/v) dimethyl sulfoxide (DMSO) as vehicle,
drug dilution (in 10% DMSO), or DA (1 mM for D2 cells and 100
µM for D3 cells) as an indicator of binding plateau; 400 µL of
[35S]GTPγS dilution (4.3 pmol in 10 mL of assay buffer per 24
well filter mat); and 500 µL of cell suspension (cells suspended,
per 24 well filter, in 12.5 mL of assay buffer and 7.5 µL of GDP,
for a final concentration of 3 µM in assay). This solution was
incubated at room temperature in a shaking water bath for 60 min.
Cells were harvested using Brandel GF/B filter mats and a 24 pin
Brandel harvester (Biomedical Research and Development Labo-
ratories, Inc., Gaithersburg, MD) with cold resuspension buffer as
the washing fluid. A Beckman LS 6500 scintillation counter was
used to determine 35S radioactivity at 70% efficiency. Nonspecific
binding of [35S]GTPγS measured in the presence of 10 µM GTPγS
Acknowledgment. This work is supported by National
Institute of Neurological Disorders and Stroke/National Institute
of Health (NS047198, A.K.D.). We thank Ingrid Parrington for
performing the functional GTPγS assays with D2- and D3-
expressing cells. We are grateful to Prof. J. Shine, Garvan
Institute for Medical Research, Sydney, Australia, for D2L-
expressing CHO cells.
Supporting Information Available: Elemental analysis results.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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