Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl)ethyl] propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: Identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity

Article abstract of DOI:10.1021/jm701524h

In the current report, we extend the SAR study on our hybrid structure 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen- 2-ol further to include heterocyclic bioisosteric analogues. Binding assays were carried out with HEK-29

Full text of DOI:10.1021/jm701524h

J. Med. Chem. 2008, 51, 3005–3019
3005
Bioisosteric Heterocyclic Versions of 7-{[2-(4-Phenyl-piperazin-1-yl)ethyl]propylamino}-
5,6,7,8-tetrahydronaphthalen-2-ol: Identification of Highly Potent and Selective Agonists for
Dopamine D3 Receptor with Potent in Vivo Activity
Swati Biswas,† Stuart Hazeldine,† Balaram Ghosh,† Ingrid Parrington,‡ Eldo Kuzhikandathil,§ Maarten E. A. Reith,‡ and
Aloke K. Dutta*,†
Department of Pharmaceutical Sciences, Wayne State UniVersity, Detroit, Michigan 48202, Department of Psychiatry, Millhauser Laboratories,
New York UniVersity School of Medicine, New York, New York 10016, and Department of Pharmacology and Physiology, UMDNJ-New Jersey
Medical School, Newark, New Jersey 07103
ReceiVed December 6, 2007
In the current report, we extend the SAR study on our hybrid structure 7-{[2-(4-phenyl-piperazin-1-
yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol further to include heterocyclic bioisosteric analogues.
Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated
spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating
GTPγS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing
human D3 receptors. The highest binding affinity and selectivity for D3 receptors were exhibited by (-)-34
(Ki ) 0.92 nM and D2/D3 ) 253). In the functional GTPγS binding assay, (-)-34 exhibited full agonist
activity with picomolar affinity for D3 receptor with high selectivity (EC50 ) 0.08 nM and D2/D3 ) 248).
In the in vivo rotational study, (-)-34 exhibited potent rotational activity in 6-OH-DA unilaterally lesioned
rats with long duration of action, which indicates its potential application in neuroprotective treatment of
Parkinson’s disease.
Introduction
logical properties. They are known as D1-type and D2-type.
D1-type consists of D1 and D5 subtypes, whereas D2, D3, and
D4 receptors belong to D2-type.11–17 This classification was
based on distinct physiological and pharmacological properties
of these two receptors as stimulation of the D1-type receptor
leads to activation of adenylate cyclase, which promotes
synthesis of cAMP, whereas D2-type receptor activation leads
to inhibition of adenylate cyclase activity. In the CNS, D1-type
receptors are located postsynaptically, whereas D2-type recep-
tors are located both pre- and postsynaptically and have a high
affinity for dopamine.18
1Parkinson’s disease (PD) is a chronic progressive neurode-
generation disorder that is characterized by a gradual loss of
dopaminergic neurons in the pars compacta of the substantia
nigra.1 It is estimated that PD affects approximately 1-2% of
people older than 65 years of age. It is primarily a sporadic
disorder, although a rare subset of population (<10%) acquires
this disease because of several genetic defects.2,3 Some of the
symptoms associated with PD involve rigidity, bradykinesia,
resting tremor, and postural instability along with cognitive and
psychiatric complications.1,4,5 Several therapies are being used
in the clinic for symptomatic treatment of PD.6 The dopamine
precursor L-dopa has been used as a gold standard treatment
agent for PD since its discovery almost 40 years ago and is
still considered a main therapy.7 However, long-term use of
L-dopa gives rise to motor fluctuations with dyskinesias and
the decrease in duration of response to a given L-dopa dose.8
Prolong use of L-dopa also gives rise to “on” and “off” episodes
resulting in additional complications. It has also been speculated
that long-term exposure to L-dopa may be toxic to dopamine
neurons, hence accelerating the dopamine neurodegeneration
process.9,10
Since the discovery of the D3 receptor from molecular cloning
in early 1990s, there has been a great deal of interest in
understanding the functional properties of the D3 receptor to
delineate its role in different disease processes in the CNS.19
Neuroanatomical location of the D3 receptor is different from
D2 because it concentrates in the limbic regions, which have
been implicated in different psychiatric diseases.20 In human
brain, the highest expression of D3 receptor was found in the
area of the ventral striatum and associated striatum.21 The D3
receptor has been implicated in neuroprotection, as D3 preferring
agonists, e.g., pramipexole and ropinirole, could protect dopam-
ine neurons against MPTP and 6-OH-DAa neurotoxicity more
robustly than less selective D3 agonists.22–24 In another study,
it was demonstrated that clinically relevant low doses of
pramipexole effectively protected dopamine fibers from MPTP
neurotoxicity.25 A role of D3 receptor has also been implicated
in production of neurotrophic factors such as BDNF. In a recent
study, D3-preferring agonists have been demonstrated to induce
production of neurotrophic factors such as brain-derived neu-
rotrophic factor (BDNF) and glial cell line-derived factor
(GDNF) in cultured mesencephalic dopamine neurons and also
in differentiated SH-SY5Y cells.26–28 D3 agonist has also been
shown to play a role as a neurorestorative agent in some of
these experiments.29 Evidence from some of these early studies
Dopamine receptors, which belong to the G-protein-coupled
receptor (GPCR) class, in the brain have been studied exten-
sively over a period of several decades. Dopamine receptors
are classified into two main classes based on their pharmaco-
* To whom correspondence should be addressed. Address: Department
of Pharmaceutical Sciences, Room 3128, Applebaum College of Pharmacy
& Health Sciences, Detroit, MI 48202. Phone: 1-313-577-1064. Fax: 1-313-
577-2033. E-mail: adutta@wayne.edu.
†
Wayne State University.
New York University School of Medicine.
UMDNJ-New Jersey Medical School.
‡
§
a Abbreviations: GTPγS, guanosine 5′-[γ-thio]triphosphate; 7-OH-DPAT,
7-hydroxy-2-(dipropylamino)tetralin; 6-OH-DA, 6-hydroxydopamine; CHO,
Chinese hamster ovary; HEK, human embryonic kidney.
10.1021/jm701524h CCC: $40.75
2008 American Chemical Society
Published on Web 04/12/2008

3006 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
Figure 1. Molecular structures of dopamine D3 receptor selective agonists and antagonists.
indicates that selective D3-preferring agonists not only will have
potential to alleviate motor dysfunction in PD patients but also
will have a potential to provide neuroprotective effect in
restoration of lost dopaminergic function. Furthermore, it has
been increasingly evident from primate and rodent experiments
that treatment with L-dopa leads to overexpression of D3
receptor in the basal ganglia and the development of dyskinesia
due to treatment with L-dopa can be reduced significantly by
treatment with D3 preferring agonist.30,31 Consequently, high
affinity agonist for D3 receptor with high selectivity will be
able to delineate more effectively roles of functional properties
of D3 receptor and its importance in various neurodisorders.
Since the discovery of the D3 receptor, an intensive effort
has been directed toward development of selective ligands for
this receptor. A large number of molecules have been developed
with various selectivities for the D3 receptor.32,33 The task of
developing selective ligands has been particularly challenging
considering the fact that D2 and D3 receptors share considerable
homology in their molecular structures. In the primary structure
sequence the extent of homology is greater than 50% which
when extended to the transmembrane domains, the homology
increases to greater than 90%, and both receptors share very
similar active binding sites.34 Therefore, it is challenging to
develop drugs, either agonist or antagonist, selective for D3
compared to D2, which becomes especially difficult when
development of a selective agonist is considered. This is due to
the fact that both receptors share nearly identical active binding
sites for agonist interaction. Numerous ligands as antagonists
have been developed so far with a number of lead compounds
showing high selectivity for the D3 receptor. Most of these
compounds contain a piperazine ring connected to a suitable
benzamide-type moiety via variable linker size.32,33,35 Some of
the most selective molecules derived from this template are
shown in Figure 1. On the other hand, selectivities of agonists
developed so far have not been very high for the reason
described above. Some of the agonists with the highest D3
selectivity are pramipexole, ropinirole, and 7-OH-DPAT. Most
of the agonists developed so far are based on the aminotetralin
structure.
in aminotetralins is known to possess poor in vivo stability due
to formation of metabolites via conjugation with glucuronic acid,
also resulting in poor oral bioavailability.38 In our current
studies, we have included a number of heterocyclic moieties
including 2-aminothiazole, pyrazole, isoxazole, and thia- and
selenodiazole rings.
Chemistry
Syntheses of the target molecules are shown in Schemes 1-5.
Scheme 1 describes the synthesis of 6a-f. Appropriately
substituted amines 1a-d were prepared by following our
previously described procedure.39 Reductive amination of these
amines with 1,4-cyclohexanedione monoethylene ketal in the
presence of sodium triacetoxyborohydride produced compounds
3a-d. N-Alkylation of amine with propyl bromide in the
presence of a base produced 4a-d in good yield. Similarly,
N-alkylation of 3b,c with propargyl bromide in the presence of
sodium hydride produced 4e-f. Next, hydrolysis of ketal in
the presence of 2 N HCl produced keto derivatives 5a-f. The
final target 2-aminothiazol derivatives 6a-f were produced by
first reacting 5a-f with pyrrolidine to produce the enamine
intermediate followed by reaction with sulfur and cyanamide
at room temperature overnight.40
Scheme 2 describes the synthesis of number of heterocyclic
target derivatives. Ketone 5a was reacted with ethyl formate in
the presence of sodium ethoxide to produce hydroxymethylene
derivative 7, which on treatment with semicarbazide followed
by treatment with concentrated H2SO4 produced pyrazole
analogue 8.41 The isoxazole derivative 9b was synthesized by
treating 7 with hydroxylamine hydrochloride in acetic acid, and
the isomeric isoxazole 9a was produced by treatment of 7 with
hydroxylamine in pyridine. In the next reaction, compound 5a
was converted into semicarbazone 10 by reacting with semi-
carbazide hydrochloride in the presence of sodium acetate in
methanol. Semicarbazone 10 was next treated with thionyl
chloride to produce target 11.41 Similarly, selenium derivative
12 was produced by treating compound 10 with selenium
dioxide.
Scheme 3 describes synthesis of pyrazole derivative target
19. The starting 3-ethoxy-2-cyclohexen-1-one was first con-
verted into 6-hydroxymethylene derivative followed by its
conversion into pyrazole derivative 14 on treatment with
hydrazine.42 Protection of pyrazole N-atom with mesitylene-
sulfonyl chloride followed by acid catalyzed hydrolysis of enol
ether yielded compound 16.43 Reductive amination with amine
1a produced compound 17 in good yield. Intermediate 17 on
reaction with propionyl chloride followed by reduction with
LAH produced the final compound 19.
Our hybrid drug development approach, combining aminote-
tralin and piperazine moieties together via a linker, resulted in
a number of potent agonists exhibiting high affinities for D2/
D3 receptors with preferential affinity for the D3 receptor. Some
of these molecules also exhibited good selectivity for the D3
receptor.36,37 So far, structurally, we have focused on compounds
with an aminotetralin moiety containing phenolic or equivalent
moiety. However, in this report, we wanted to explore the
replacement of the catechol ring by several bioisosteric moieties
to observe the effect of such replacement on both affinity and
selectivity for the D3 receptor. A catechol or phenolic moiety
Schemes 4 and 5 describe synthesis of various enantiomeric
analogues of 2-aminothiazole derivatives. A new synthesis of

Tetrahydronaphthalen-2-ols as Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 3007
Scheme 1a
a (a) 1,4-Cyclohexanedione monoethylene ketal, Na(OAc)3BH, AcOH, dichloroethane, room temp, overnight; (b) bromopropane, K2CO3, DMF, reflux,
3 h; (c) propargyl bromide, NaH, THF/DMF ) 5:1, room temp to 60 °C, 3 h; (d) 2 N HCl, THF, reflux, 4 h; (e) (i) pyrolidine,TsOH, benzene, Dean-Stark
reflux,1.5 h; (ii) S8, MeOH, NH2CN, room temp, overnight.
pramipexole was devised by us, which involved protection of
amino group in intermediate 20 by mesitylenesulfonyl chloride
followed by hydrolysis of ketal and conversion into 2-ami-
nothiazole derivative 23.44 Deprotection of protected group
yielded racemic pramipexole in good yield. Racemic prami-
pexole was next resolved by following a patent procedure with
some modification.45 Separated enantiomers (+)-24 and (-)-
24 were then used in the synthesis of various optically active
2-aminothiazole derivatives as described in Scheme 5.
Various substituted phenyl piperazine derivatives 25a-d were
treated with chloroacetyl chloride to provide substituted pip-
erazine derivatives 26a-d. N-Alkylation of enantiomeric prami-
pexole with various chloropiperazine derivatives in the presence
of a base and potassium iodide yielded enantiomeric substituted
amides 27-30. Reduction of amide with borane produced the
final optically active targets (+)-31, (-)-31, (+)-32, (-)-32,
(+)-33, (-)-33, and (-)-34.
characterized. In this regard, we first wanted to optimize
2-aminothiazole ring-based derivatives as one of our target
molecules. To this end, a series of racemic derivatives 6a-f
were synthesized and characterized. In an earlier report, we
described the development of compound 6a.36 In this report,
we resynthesized the compound because we wanted to rechar-
acterize it with our new cell lines. In the 6a-f series of
compounds, N-aromatic and N-alkyl substitutions were explored.
The two principle aromatic substitutions were 2-methoxy- and
2,3-dichlorophenyl groups. The N-alkyl substitutions mainly
consisted of propyl and propargyl groups. The dichloro deriva-
tive 6c was the most potent with moderate selectivity for the
D3 receptor (Ki ) 1.82 nM for D3; D2/D3 Ki ratio ) 37.6,
Table 1). The 2-methoxy substituted compound 6b was some-
what less potent compared to 6c; however, the selectivity for
D3 receptor was similar to that of 6c (D2/D3: 32.6 and 37.6
for 6b and 6c, respectively, Table 1). In accordance to our
previous results with compounds containing four methylene
linker, compound 6d produced lower potency at both D2 and
D3 receptors compared to 6a.36,39 This result indicates that the
mode of interaction of our hybrid derivatives may not be
identical with the other class of molecules interacting with D2/
D3 receptors. Next, in compounds 6e and 6f the N-propyl group
was replaced by an N-propargyl group, which for the most part
Results and Discussion
One of our main goals in this structure-activity relationship
(SAR) study is to delineate an optimum pharmacophoric
structure with bioisosteric heterocyclic moieties in the hybrid
structure backbone for high D3 selectivity. Several structurally
different heterocyclic derivatives have been synthesized and

3008 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
Scheme 2a
a (a) NaOEt, ethyl formate, benzene, room temp, overnight; (b) (i) semicarbazide HCl, sodium acetate, EtOH, 0 °C, 1 h; (ii) concentrated H2SO4/H2O
(1:3), reflux, 15 min; (c) NH2OH·HCl, AcOH, 80 °C, 1 h; (d) NH2OH·HCl, pyridine, reflux, 6 h; (e) semicarbazide HCl, sodium acetate, MeOH, reflux,4
h; (f) thionyl chloride, -10 °C to room temp, 30 min; (g) SeO2, AcOH, room temp, 30 min.
Scheme 3a
a (a) NaOEt, ethyl formate, benzene, room temp, overnight; (b) NH2NH2, ethanol, reflux, 6 h; (c) 2-mesitylenesulfonyl chloride, NaOH, dichloromethane;
reflux, overnight; (d) 3 N HCl, THF, room temp, 16 h; (e) 1a, NaCNBH3, AcOH, dichloroethane, room temp, overnight; (f) propionyl chloride, Et3N,
dichloromethane, 0 °C to room temp, 4 h; (g) LiAlH4, THF, reflux, 4 h.
maintained the potency with less selectivity for the D3 receptor.
Interestingly, N-propargyl substituted compounds 6e and 6f
exhibited higher affinity for the D2 receptor compared to their
corresponding N-propyl substituted compounds (81.2 and 34.9
nM for 6e and 6f vs 166 and 68.4 nM for 6b and 6c).
In our next SAR exploration, several bioisosteric heterocyclic
derivatives were designed and synthesized as described in
Schemes 2 and 3. A suitably substituted pyrazole ring is a well-
known bioisosteric equivalent of the catechol moiety for agonist
interaction with dopamine receptors; thus, quinpirole and other
related pyrazole derivatives have been developed as agonist for
D2/D3 receptors.42 In the design of heterocyclic analogues, we
wanted to introduce pyrazole, isoxazoles, and thia- and sele-
nodiazole heterocyclic ring systems into our hybrid template.
As expected from our previous results on bioisosteric deriva-
tives, pyrazole derivative 8 exhibited good potency for the D3
receptor but was weak at D2 with overall good selectivity for
the D3 receptor (Ki ) 46.7 nM, D2/D3 ) 39.3, Table 1). On
the other hand, neither isoxazole 9b nor its isomer 9a was very
active at the D2/D3 receptor, indicating nonsuitability of these

Tetrahydronaphthalen-2-ols as Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 3009
Scheme 4a
a (a) n-Propylamine, NaCNBH3, AcOH, dichloroethane, room temp, overnight; (b) 2-mesitylenesulfonyl chloride, NaOH, dichloromethane, reflux, overnight;
(c) 2 N HCl, THF, reflux, 6 h; (d) pyrollidine, TsOH, benzene, Dean-Stark reflux, 1.5 h; (ii) S8, MeOH, NH2CN, room temp, overnight; (e) 33% HBr in
AcOH, phenol, ethyl acetate, 0 °C to room temp, 10 h; (f) HCl, methanol, L-(+)- or D-(-)-tartaric acid, MeOH, recrystallized from MeOH.
Scheme 5a
a (g) Chloroacetyl chloride, Et3N, dichloromethane, 0 °C to room temp, 2 h; (h) (+)-24 or (-)-24, K2CO3, KI, acetonitrile, 60 °C, 4 h; (i) BH3 in THF,
THF, room temp, 36 h.
hetero rings as bioisosteres for dopamine D2/D3 receptors.
Similarly, thiadiazolo derivative 11 and the selenium analogue
12 were weak at the D2/D3 receptors. Isomeric pyrazole
derivative 19 likewise was also weak at both dopamine
receptors. Thus, the heterocyclic rings other than pyrazole
moiety were not suitable for interaction with D2/D3 receptors.
In Schemes 4 and 5 we describe synthesis of enantiomers of
the racemic compounds shown in Scheme 1. In general the (-)-
isomer was more active than the (+)-isomer. The two enanti-
omers of 6a, (+)-31 and (-)-31, exhibited differential activity
with higher potency, and selectivity for the D3 receptor resided
in (-)-31 (Ki ) 4.15 nM for D3 and D2/D3 ) 58.6). It is
important to point out that the racemic mixture 6a exhibited
somewhat greater selectivity for D3 receptor than (-)-31 (D2/
D3) 107 vs 58.6 for 6a and (-)-31, respectively). This could
be due to the presence of complex interaction with the D2
receptor. However, such anomaly was not observed with the
enantiomers of 6b and 6c. Among these enantiomers, (-)-33
exhibited the most potent affinity for the D3 receptor (Ki )
1.80 nM for D3).
A recent publication has demonstrated that N-substituted fused
aromatic rings substituted piperazine moiety is well tolerated
by the D3 receptor, indicating the possible existence of a
hydrophobic binding pocket.46 These results further indicate that
the bicyclic system is tolerated well on either side of those
molecules. In our further exploration to evaluate the effect of
an additional hydrophobic interaction in developing molecules
with higher selectivity for the D3 receptor, we decided to replace
the N-phenyl moiety by a linearly fused biphenyl moiety in (-)-
34. In this regard such a linearly fused biphenyl moiety has
been shown to introduce higher potency and selectivity for D3
receptors in other molecular structures.32 The biphenyl derivative
(-)-34 exhibited subnanomolar potency and high selectivity for
the D3 receptor (Ki ) 0.92 nM for D3 and D2/D3 ) 248).
Compound (-)-34 was most potent and selective for D3 in the
current series of molecules.
Next, the two compounds (-)-33 and (-)-34 were selected
based on the binding results for evaluation in 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 assays were carried out with the cloned human D2 and D3
receptors expressed in CHO and AtT cells.47 The half-maximal
stimulation (EC50) of (-)-33 and (-)-34 along with percent of
maximal stimulation compared with a maximal efficacious (Emax
) 100%) concentration of dopamine indicated full agonist
activity of both compounds at D2 and D3 receptors. Both
compounds exhibited extremely high affinity in the picomolar
range for stimulating the D3 receptor and are two of the most
potent agonists for the D3 receptor known to date (EC50 ) 0.089
and 0.060 nM for (-)-34 and (-)-33). They also exhibited high
selectivity toward preferential stimulation of D3 compared to
D2 receptor (D2/D3 EC50 ) 248 and 223 for (-)-34 and (-)-
33, respectively). In this regard, compound (-)-34 exhibited
greater functional selectivity than 7-OH-DPAT in GTPγS
binding assay (D2/D3 ) 248 vs 74.95 for (-)-34 and 7-OH-
DPAT (Table 2), respectively).
In Vivo Pharmacology with 6-OH-DA Lesioned Rats.
Compounds (-)-33 and (-)-34 were chosen for in vivo
evaluation in rats carrying unilateral lesion in the medial

3010 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
Table 1. Affinity for Cloned D2L and D3 Receptors Expressed in HEK
Cells Measured by Inhibition of [3H]Spiperone Bindinga
[3H]spiperone
compd
D2L Ki (nM)
D3 Ki (nM)
D2L/D3 (Ki ratio)
7-OH-DPAT
D-74
6a
202 ( 34
142 ( 23
2.35 ( 0.29
1.56 ( 0.36
5.96 ( 1.60
5.09 ( 0.51
1.82 ( 0.43
12.4 ( 2.2
34.8 ( 6.4
7.10 ( 0.63
46.7 ( 12.6
155 ( 47
86
91
107
639 ( 98
6b (D-210)
6c (D-219)
6d (D-203)
6e (D-218)
6f (D-220)
166 ( 19
32.6
37.6
62.0
2.33
4.92
39.3
5.90
3.20
4.66
4.64
13.7
45.0
58.6
2.40
41.1
3.68
31.6
253
68.4 ( 25.9
769 ( 173
81.2 ( 11.1
34.9 ( 1.3
1835(5) ( 445
915 ( 165
813 ( 182
746 ( 173
189 ( 55
8 (D-189)
9b (D-193)
9a (D-192)
11 (D-191)
12 (D-190)
19 (D-201)
(+)-31 (D-255)
(-)-31 (D-258)
(+)-32 (D-257)
(-)-32 (D-259)
(+)-33 (D-256)
(-)-33 (D-260)
(-)-34 (D-264)
254 ( 99
160 ( 15
40.7 ( 17.5
188 ( 23
Figure 2. Effect on turning behavior of (-)-33 and (-)-34 and vehicle
in 6-OH-DA unilaterally lesioned rats studied over 12 h. Each point is
the mean ( SEM for four rats. All drugs were administered sc. One
way ANOVA analysis demonstrates a significant effect among treat-
ments: F(3,95) ) 29.48 (P < 0.0001). Dunnett’s analysis shows that
the effect of (-)-33 and (-)-34 on rotations at a dose of 2.5 µmol/kg
is statistically significantly different compared to vehicle (P < 0.01).
2,570 ( 620
1979 ( 567
243 ( 65
44.0 ( 10.6
4.15 ( 0.76
101 ( 41
243 ( 47
288 ( 86
7.01 ( 1.16
12.0 ( 2.9
1.80 ( 0.32
0.92 ( 0.23
44.2 ( 6.9
56.8 ( 15.4
264 ( 40
a Results are the mean ( SEM for three to seven experiments each
performed in triplicate.
forebrain bundle induced by application of the neurotoxin
6-hydroxydopamine (6-OH-DA). This results in destruction of
dopamine neurons and development of high supersensitivity of
dopamine receptors on the lesioned side. Such surgically
modified rats when challenged with direct acting dopamine
agonists produce contralateral rotations away from the lesioned
side. This rat model is considered to be one of the standard
models for preclinical screening of drugs for possible antipar-
kinsonian property.48 Two different doses (2.5 and 5 µmol/kg)
of each compound were tested to observe their effect in
producing contralateral rotations. At the 5 µmol/kg dose, both
(-)-33 (2.96 mg /kg) and (-)-34 (3.58 mg/kg) produced potent
rotations that lasted for more than 10 h (Figure 3). Compound
(-)-34 was more potent in producing maximum rotations
compared to (-)-33 (3866 vs 2766 for (-)-34 and (-)-33,
respectively). Peak effects of both compounds were reached at
around 7.4 h. This indicates long duration of action of both
compounds in producing contralateral rotations. When tested
at a lower dose (2.5 µmol/kg), these two compounds, (-)-33
(1.48 mg/kg) and (-)-34 (1.79 mg/kg), produced lower number
of rotations, indicating dose dependency for the effect. The total
number of rotations produced by these two compounds at the
lower dose (2.5 µmol/kg) was comparable (2092 vs 2281 for
(-)-34 and (-)-33, respectively). The rotations in this case
lasted for more than 8 h (Figure 2).
Figure 3. Effect on turning behavior of (-)-33 and (-)-34 and vehicle
in 6-OH-DA unilaterally lesioned rats studied over 12 h. Each point is
the mean ( SEM for four rats. All drugs were administered sc. One
way ANOVA analysis demonstrates significant effect among treatments:
F(3,95) ) 33.58 (P < 0.0001). Dunnett’s analysis shows that the effect
of (-)-33 and (-)-34 on rotations at a dose of 5 µmol/kg is statistically
significantly different compared to vehicle (P < 0.01).
5,6,7,8-tetrahydronaphthalen-2-ol have been developed. Among
various heterocyclic derivatives, only pyrazole and 2-aminothia-
zole compounds exhibited potent affinity and selectivity for the
D3 receptor. Several enantiomers of 2-aminothiazole compounds
were synthesized and characterized. Higher affinity and selectiv-
ity mainly resided in the (-)-isomer. Compound (-)-34 turned
out to be the most potent and D3 selective compound in the
binding assay. In the GTPγS functional assay, both (-)-33 and
(-)-34 exhibited high selectivity for the D3 receptor with
Conclusion
Novel heterocyclic analogues based on our earlier lead
molecule 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-
Table 2. Stimulation of [35S]GTPγS Binding to the Cloned hD2 Receptor Expressed in CHO Cells and Cloned hD3 Receptor Expressed in AtT-20
Cellsa
CHO-D2
35S]GTPγS (nM)
AtT-D3
35S]GTPγS (nM)
compd
EC50
[
Emax (%)
100
EC50
[
Emax (%)
100
D2/D3
24.50
dopamine
209(4) ( 29
8.53 ( 0.62
(definition)
61.4 ( 8.6
78.8 ( 0.8
119 ( 6
(definition)
45.3 ( 2.3
95.7 ( 10.7
102 ( 19
7-OH-DPAT
(-)-33
(-)-34
39.8 ( 19.4
13.4 ( 2.4
19.9 ( 0.9
0.531 ( 0.042
0.06 ( 0.015
0.085 ( 0.016
74.95
223
248
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 the mean ( SEM for three to four experiments each performed in
triplicate.

Tetrahydronaphthalen-2-ols as Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 3011
1,2-dichloroethane (10 mL) (procedure A). Purification by column
chromatography was done over silica gel by using solvent system
dichloromethane/methanol (100:2) to afford 0.75 g of product 3d
(82%). 1H NMR (400 MHz, CDCl3): δ 1.53-1.61 (m, 2H),
1.74-1.96 (m, 8H), 2.09-2.15 (m, 2H), 2.52-2.58 (m, 2H),
2.71-2.73 (t, 2H, J ) 4.8 Hz), 2.77-2.79 (t, 2H, J ) 4.8 Hz),
2.93-2.96 (t, 2H, J ) 6.0 Hz), 3.20-3.22 (t, 1H, J ) 5.2 Hz),
3.25-3.27 (t, 4H, J ) 4.4 Hz), 3.74 (s, 4H), 6.88-6.96 (m, 3H),
7.25-7.30 (m, 2H).
Procedure B. Synthesis of N-(2-(4-Phenylpiperazin-1-yl)-
ethyl)-N-propyl-1,4-dioxaspiro[4.5]decan-8-amine (4a). Com-
pound 3a (2.05 g, 5.93 mmol), 1-bromopropane (3) (2.93 g, 23.83
mmol), and K2CO3 (17.87 mmol) in dry DMF (20 mL) were stirred
at 60 °C for 10 h, and the mixture was poured into water (60 mL)
and extracted with Et2O (3 × 100 mL). The combined organic layer
was washed with brine, dried over MgSO4, evaporated, and the
residue was purified by flash chromatography using solvent system
ethyl acetate/methanol/ triethylamine (95:4:1) to yield 2.12 g of
pure compound 4a (92%). 1H NMR (400 MHz, CDCl3): δ 0.86 (t,
3H, J ) 4.0 Hz, N-CH2CH2C H3), 1.43 (m, 2H, -CH2CH3),
1.54-1.61 (m, 4H), 1.71-1.80 (m, 5H), 2.4-2.67 (m, 10H), 3.19
(t, 4H, J ) 4.5 Hz, Ph-N(CH2)2), 3.94 (s, 4H, -O(CH2)2O-),
6.84 (t, 1H, J ) 8.0 Hz), 6.92 (d, 2H, J ) 8.0 Hz), 7.24-7.28 (m,
2H).
Synthesis of N-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)eth-
yl)-N-propyl-1,4-dioxaspiro[4.5]decan-8-amine (4b). Compound
3b (1.09 g, 2.90 mmol) was reacted with 1-bromopropane (3) (0.8
mL, 8.80 mmol) and K2CO3 (1.22 g, 8.8 mmol) in dry DMF (20
mL) by following procedure B. The residue was purified by flash
chromatography using solvent system ethyl acetate/methanol/
triethylamine (90:9:1) to yield 0.70 g of pure compound 4b (58%).
1H NMR (400 MHz, CDCl3): δ 1.03 (t, 3H, J ) 7.2 Hz), 1.65-2.03
(m, 8H), 2.31-2.33 (d, 2H, J ) 10.4 Hz), 3.04-3.1 (m, 2H), 3.43
(bs, 8H), 3.64-3.94 (m, 12H), 6.87-6.91 (m, 3H), 7.04-7.08 (m,
1H).
picomolar affinity in stimulating the binding of nonhydrolyzable
[35S]GTPγS and did so as full agonists. Thus, (-)-33 and (-)-
34 are two of the most potent agonists for D3 receptor known
to date.49 A PD animal model, based on measuring in vivo
rotational activity in 6-OH-DA induced unilaterally lesioned rats,
indicated potent activity of these two compounds with long
duration of action. **In this rotational study, both compounds
exhibited comparable activity at a dose of 2.5 µMol/kg but (-)-
34 was somewhat more active at a higher 5 µMol/kg dose.
Detailed pharmacological evaluation to evaluate relative con-
tribution of D2 and D3 receptors in rotation by (-)-33 and (-)-
34 will be done at some point of time in future.
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 either phosphomolybdic acid (PMA) or ninhydrin.
Flash chromatography 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 spectrometers. 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-OH-DPAT and (+)-butaclamol
were from Sigma-Aldrich (St. Louis, MO).
Procedure A. Synthesis of N-(2-(4-Phenylpiperazin-1-yl)-
ethyl)-1,4-dioxaspiro[4.5]decan-8-amine (3a). Amine 1a (1.0 g,
4.87 mmol), 1,4-cyclohexanedione monoethylene ketal 2 (0.84 g,
5.36 mmol), and a few drops of acetic acid (0.3 mL) in dichloro-
ethane (30 mL) were stirred under nitrogen atmosphere at 0 °C for
30 min before the addition of sodium triacetoxyborohydride (1.55
g, 7.31 mmol). The reaction mixture was stirred for 8 h at room
temperature under nitrogen atmosphere. The reaction mixture was
diluted with EtOAc (100 mL), quenched by addition of 10%
aqueous HCl (10 mL), followed by addition of saturated NaHCO3
solution (20 mL). The organic layer was washed with brine (25
mL), dried over Na2SO4, evaporated, and the crude product was
purified by flash chromatography by using solvent system ethyl
acetate/methanol/triethylamine (95:4:1) to yield 1.5 g of compound
3a (90%). 1H NMR (400 MHz, CDCl3): δ 1.42-1.49 (m, 3H),
1.53-1.60 (m, 3H), 1.69 (bs, 2H), 1.77 (d, 2H, J ) 12.0 Hz),
1.87-1.91 (m, 2H), 2.55 (t, 4H, J ) 4.0 Hz), 2.60 (t, 4H, J ) 4.4
Hz), 2.76 (t, 1H, J ) 8.0 Hz), 3.19 (t, 4H, J ) 4.0 Hz, Ph-NCH2),
6.84 (t, 1H, J ) 8.0 Hz), 6.92 (d, 2H, J ) 8.0 Hz), 7.24-7.28 (m,
2H).
Synthesis of N-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)eth-
yl)-1,4-dioxaspiro[4.5]decan-8-amine. (3b). Amine 1b (1.25 g,
5.31 mmol) was reacted with 1,4-cyclohexanedione monoethylene
ketal 2 (0.83 g, 5.31mmol), NaCNBH3 (1.0 g, 15.93 mmol), and
HOAc (0.3 mL) in 1,2-dichloroethane (20 mL) to yield 1.09 g of
compound 3b (55%) (procedure A). 1H NMR (400 MHz, CDCl3):
δ 1.52-1.63 (m, 3H), 1.78-1.81 (m, 2H), 1.94-1.97 (m, 1H),
2.63-2.69 (m, 9H), 2.86 (t, 2H, J ) 6.4 Hz), 3.10 (bs, 4H), 3.86
(s, 4H), 3.94 (s, 3H), 6.85-7.03 (m, 4H).
Synthesis of N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-
ethyl)-1,4-dioxaspiro[4.5]decan-8-amine (3c). Amine 1c (0.65 g,
2.37 mmol) was reacted with 1,4-cyclohexanedione monoethylene
ketal (0.37 g, 2.37mmol), NaCNBH3 (0.52 g, 8.30 mmol), and
HOAc (0.2 mL) in 1,2-dichloroethane (10 mL) to yield 1.09 g of
compound 3c (55%) (procedure A). 1H NMR (400 MHz, CDCl3):
δ 1.42-1.61 (m, 4H), 1.77-1.80 (m, 2H), 1.89-1.93 (m, 2H),
2.54-2.65 (m, 7H), 2.77-2.80 (t, J ) 6.0 Hz), 3.06 (bs, 4H), 3.94
(s, 4H), 6.95-6.97 (m, 1H), 7.14-7.16 (m, 2H).
Synthesis of N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-
ethyl)-N-propyl-1,4-dioxaspiro[4.5]decan-8-amine (4c). Com-
pound 3c (1.20 g, 2.90 mmol) was reacted with 1-bromopropane
(3) (0.8 mL, 8.80 mmol) and K2CO3 (1.22 g, 8.8 mmol) in dry
DMF (20 mL) by following procedure B. The residue was purified
by flash chromatography by using solvent system ethyl acetate/
methanol/triethylamine (90:9:1) to yield 0.60 g of pure compound
1
4c (45%). H NMR (400 MHz, CDCl3): δ 0.87 (t, 3H, J ) 7.2
Hz), 1.39-1.61 (m, 6H), 1.691.80 (m, 4H), 2.42-2.67 (m, 10 H),
3.06 (bs, 4H), 3.19 (t, 1H, J ) 5.2 Hz), 3.93 (s, 4H), 6.94-6.98
(m, 1H), 7.13-7.15 (m, 2H).
Synthesis of N-(4-(4-Phenylpiperazin-1-yl)butyl)-N-propyl-
1,4-dioxaspiro[4.5]decan-8-amine (4d). Compound 3d (0.91 g,
2.44 mmol) was reacted with 1-bromopropane (3) (0.67 mL, 7.32
mmol) and K2CO3 (1.01 g, 7.32 mmol) in dry DMF (20 mL) by
following procedure B. The residue was purified by flash chroma-
tography using solvent system ethyl acetate/methanol/triethylamine
(90:9:1) to yield 0.61 g of pure compound 4d (60%). 1H NMR
(400 MHz, CDCl3): δ 0.86 (t, 3H, J ) 7.2 Hz), 1.39-1.56 (m,
10H), 1.68-1.80 (m, 4H), 2.37-2.48 (m, 6H), 2.55-2.61 (m, 5H),
3.21 (t, 4H, J ) 5.2 Hz), 3.93 (s, 4H), 6.83-6.87 (m, 1H),
6.93-6.95 (d, 2H, J ) 8.0 Hz), 7.24-7.28 (t, 2H, J ) 8.8 Hz).
Procedure C. Synthesis of N-(2-(4-(2-Methoxyphenyl)piper-
azin-1-yl)ethyl)-N-(prop-2-ynyl)-1,4-dioxaspiro[4.5]decan-8-
amine (4e). Into a suspension of NaH (60% dispersion in mineral
oil) (1.4 g, 34.89 mmol) in 10 mL of anhydrous THF/DMF mixture
(5:1) at 0 °C was added compound 3b (1.31 g, 3.49 mmol) dissolved
in 5 mL of the same solvent under nitrogen atmosphere. Reaction
mixture was stirred for 30 min at 0 °C before propargyl bromide
(80 wt % dispersion in toluene) (3.11 g, 20.93 mmol) was added.
The reaction mixture was stirred at 60 °C for 3 h. The reaction
mixture was cooled to room temperature. Drop by drop water was
added to quench the reaction mixture, and the solvent was removed
in vacuo. Reaction mixture was washed with 20 mL of water. The
aqueous layer was extracted with Et2O (3 × 50 mL). The combined
organic layer was washed with brine, dried over MgSO4, evaporated,
Synthesis of N-(4-(4-Phenylpiperazin-1-yl)butyl)-1,4-dioxa-
spiro[4.5]decan-8-amine (3d). Amine 1d (0.57 g, 2.44 mmol) was
reacted with 1,4-cyclohexanedione monoethylene ketal (0.42 g, 2.69
mmol), NaCNBH3 (0.34 g, 5.47 mmol), and HOAc (0.15 mL) in

3012 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
and the residue was purified by flash chromatography using solvent
system ethyl acetate/methanol (95:5) to yield 0.44 g of pure
compound 4e (31%). H NMR (400 MHz, CDCl3): δ 1.51-1.66
(m, 4H), 1.78-1.89 (m, 4H), 2.18 (t, 1H, J ) 2.4 Hz), 2.53-2.70
(m, 7H), 2.80 (t, 2H, J ) 8.0 Hz), 3.10 (bs, 4H), 3.50-3.51 (d,
2H, J ) 2.0 Hz), 3.86 (s, 3H, -OCH3), 3.93 (s, 4H), 6.85-7.01
(m, 4H).
Synthesis of 4-((2-(4-(2-Methoxyphenyl)piperazin-1-yl)eth-
yl)(prop-2-ynyl)amino)cyclohexanone (5e). Compound 4e (0.44
g, 1.06 mmol) dissolved in 5 mL of THF was hydrolyzed in the
presence of 2 N HCl (25 mL) by following procedure D. The
residue was purified by flash chromatography using solvent system
ethyl acetate/methanol/triethylamine (95:4:0.5) to yield 0.30 g of
pure compound 5e (76%). 1H NMR (400 MHz, CDCl3): δ
1.75-1.84 (m, 2H), 2.02-2.04 (m, 2H), 2.16 (bs, 1H), 2.20-2.28
(m, 2H), 2.36-2.42 (m, 2H), 2.48-2.52 (t, 2H, J ) 6.8 Hz), 2.63
(bs, 4H), 2.74-2.78 (t, 2H, J ) 7.2 Hz), 2.91-2.96 (m, 1H), 3.02
(bs, 4H), 3.49 (bs, 2H), 3.76 (s, 3H), 6.77-6.93 (m, 4H).
Synthesis of 4-((2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-
ethyl)(prop-2-ynyl)amino)cyclohexanone (5f). Compound 4f (0.31
g, 0.69 mmol) dissolved in 5 mL of THF was hydrolyzed in the
presence of 2 N HCl (25 mL) by following procedure D. The
residue was purified by flash chromatography by using solvent
system ethyl acetate/methanol/triethylamine (95:4:0.5) to yield
0.20 g of pure compound 5f (73%). 1H NMR (400 MHz, CDCl3):
δ 1.84-1.93 (m, 2H), 2.10-2.14 (m, 2H), 2.22 (t, 1H, J ) 2.4 Hz,
-NCH2CC H), 2.29-2.37 (m, 2H), 2.46-2.52 (m, 2H), 2.58 (t, 2H,
J ) 7.2 Hz), 2.69 (bs, 4H), 2.83 (t, 2H, J ) 7.2 Hz), 2.99-3.07
(m, 5H), 3.58 (d, 2H, J ) 2.0 Hz), 6.95-6.97 (dd, 1H, J1 ) 6.8
Hz, J2 ) 2.4 Hz), 7.14-7.17 (m, 2H).
1
Synthesis of N-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-
ethyl)-N-(prop-2-ynyl)-1,4-dioxaspiro[4.5]decan-8-amine (4f). Com-
pound 3c (0.73 g, 1.76 mmol) was reacted with propargyl bromide
(0.79 mL, 7.05 mmol) in the presence of NaH (0.42 g, 10.57 mmol)
in THF/DMF mixture (20 mL) by following procedure C. The
residue was purified by flash chromatography by using solvent
system hexane/ethyl acetate (50:50) to yield 0.31 g of pure
**compound 4f (39%). 1H NMR (400 MHz, CDCl3): δ 1.51-1.63
(m, 4H), 1.79-1.89 (m, 4H), 2.19 (t, 1H, J ) 2.4 Hz), 2.54-2.68
(m, 7H), 2.79 (t, 2H, J ) 7.6 Hz), 3.07 (s, 4H), 3.51-3.52 (d, 2H,
J ) 2.0 Hz), 3.94 (s, 4H), 6.94-6.97 (dd, 1H, J ) 6.4 Hz, J ) 3.2
Hz), 7.11-7.15 (m, 2H).
Procedure D. Synthesis of 4-((2-(4-Phenylpiperazin-1-yl)-
ethyl)(propyl)amino)cyclohexanone (5a). Into a solution of
compound 4a (2.05 g, 5.97 mmol) in 20 mL of THF was added 2
N HCl (50 mL), and the reaction mixture was stirred at 80 °C under
nitrogen atmosphere for 6 h. THF was removed under reduced
pressure. Reaction mixture was made alkaline by saturated NaHCO3
solution. The aqueous layer was extracted with EtOAc (3 × 100
mL) and the combined organic layer was washed with brine, dried
over Na2SO4, and evaporated to yield crude product which was
purified by flash chromatography on silica gel using solvent system
ethyl acetate/methanol/triethyl amine (95:4:1) to yield 0.96 g of
Procedure E. Synthesis of N6-(2-(4-Phenylpiperazin-1-yl)-
ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-di-
amine (6a). Compound 5a (0.53 g, 1.54 mmol) and pyrrolidine
(0.15 mL, 1.85 mmol) in the presence of catalytic amount of
p-toluenesulfonic acid (0.005 mol ratio) in anhydrous benzene were
heated to reflux in a Dean-Stark apparatus for 1.5 h. Reaction
mixture was then cooled to room temperature and concentrated
under vacuum. The residue was then dissolved in anhydrous
methanol. Sulfur powder (S8) (59 mg, 0.23 mmol) was added at
room temperature, stirred for 20 min, and then cooled to 0 °C.
Cynamide (78 mg, 1.55 mmol) in methanol was added to it, and
the reaction mixture was stirred at room temperature for 12 h.
Methanol was evaporated in vacuo. The residue was dissolved in
ethyl acetate, washed with water and brine, dried over MgSO4,
evaporated. The crude residue was purified by flash chromatography
using solvent system ethyl acetate/methanol (90:10) to yield 0.26 g
of pure compound 6a (43%). 1H NMR (400 MHz, CDCl3): δ
0.87-0.92 (m, 3H), 1.40-1.52 (m, 2H), 1.70-1.77 (m, 1H),
1.98-2.03 (m, 1H), 2.44-2.61 (m, 6H), 2.64-2.75 (m, 8H),
3.02-3.10 (m, 1H), 3.19-3.21 (t, 4H, J ) 4.8 Hz), 4.82 (bs, 2H),
6.83-6.88 (m, 1H), 6.92-6.95 (m, 2H), 7.24-7.28 (m, 2H). The
product was converted into corresponding dioxalate salt, mp
160-163 °C. Anal. (C22H33N5S·2C2H2O4 ·2H2O) C, H, N.
Synthesis of N6-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)eth-
yl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiaxole-2,6-diamine
(6b). Compound 5b (0.36 g, 0.96 mmol) was treated with
pyrrolidine (0.08 mL, 1.01 mmol) in the presence of catalytic
amount of p-toluenesulfonic acid under reflux followed by addition
of sulfur powder (31 mg, 0.12 mmol) and cynamide (41 mg, 1.01
mmol) by following procedure E. The crude residue was purified
by flash chromatography using solvent system ethyl acetate/
methanol (90:10) to yield 0.20 g of pure compound 6b (48%). 1H
NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.6 Hz), 1.43-1.52
(m, 2H), 1.68-1.76 (m, 1H), 1.98-2.04 (m, 1H), 2.45-2.77 (m,
14H), 3.01-3.10 (m, 5H), 3.86 (s, 3H), 4.75 (bs, 2H, -NH2),
6.85-7.02 (m, 4H). The product was converted into corresponding
1
pure 5a (52%). H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J )
7.6 Hz), 1.42-1.51 (m, 2H), 1.69-1.79 (qd, 2H, J1 ) 11.4 Hz, J2
) 4.8 Hz), 2.03-2.07 (m, 2H), 2.30-2.38 (m, 2H), 2.42-2.51
(m, 6H), 2.63-2.69 (m, 6H), 2.95-3.02 (tt, 1H, J1 ) 11.2, J2 )
3.2 Hz, -CH-N), 3.20 (t, 4H, J ) 5.2 Hz, Ph-NCH2), 6.83-6.87
(t, 1H, J ) 7.2 Hz), 6.91-6.94 (d, 2H,J ) 8.4 Hz), 7.24-7.28
(m,2H).
Synthesis of 4-((2-(4-Methoxyphenyl)piperazin-1-yl)ethyl)-
(propyl)amino)cyclohexanone (5b). Compound 4b (0.4 g, 0.96
mmol) dissolved in 5 mL of THF was hydrolyzed in the presence
of 2 N HCl (25 mL) by following procedure D. The residue was
purified by flash chromatography using solvent system ethyl acetate/
methanol (90:10) to yield 0.30 g of pure compound 5b (83%). 1H
NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.2 Hz), 1.42-1.52
(m, 2H), 1.67-1.79 (m, 2H), 2.03-2.07 (m, 2H), 2.30-2.53 (m,
8H), 2.63-2.70 (m, 6H), 2.95-3.02 (tt, 1H, J1 ) 3.2 Hz, J2 )
10.8 Hz), 3.10 (bs, 4H), 3.86 (s, 3H, -OC H3), 6.85-7.02 (m, 4H).
Synthesis of 4-((2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-
ethyl)(propyl)amino)cyclohexanone (5c). Compound 4c (0.59 g,
1.29 mmol) dissolved in 5 mL of THF was hydrolyzed in the
presence of 2 N HCl (25 mL) by following procedure D. The
residue was purified by flash chromatography using solvent system
ethyl acetate/methanol (95:5) to yield 0.31 g of pure compound 5c
1
(58%). H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.6 Hz),
1.45-1.50 (m, 2H), 1.76-1.80 (m, 2H), 2.03-2.30 (m, 2H),
2.32-2.69 (m, 13 H), 2.95-3.07 (m, 5H), 3.67 (t, 1H, J ) 5.6
Hz), 6.94-6.97 (dd, 1H, J1) 6.6 Hz, J2) 3.2 Hz), 7.13-7.15 (m,
2H).
tetrahydrochloride
(C23H35N5OS·4HCl·2H2O) C, H, N.
salt,
mp
105-108
°C.
Anal.
Synthesis of 4-((4-(4-Phenylpiperazin-1-yl)butyl)(propyl)-
amino)cyclohexanone (5d). Compound 4d (0.50 g, 1.2 mmol)
dissolved in 5 mL of THF was hydrolyzed in the presence of 2 N
HCl (25 mL) by following procedure D. The residue was purified
by flash chromatography using solvent system ethyl acetate/
methanol/triethylamine (95:4:0.5) to yield 0.36 g of pure compound
Synthesis of N6-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-
ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiaxole-2,6-di-
amine (6c). Compound 5c (0.315 g, 0.76 mmol) was treated with
pyrrolidine (57.4 mg, 0.07 mL, 0.81 mmol) in the presence of
catalytic amount of p-toluenesulfonic acid under reflux followed
by addition of sulfur powder (24.5 mg, 0.095 mmol) and cynamide
(32.1 mg, 0.76 mmol) by following procedure E. The crude residue
was purified by flash chromatography using solvent system ethyl
acetate/methanol (90:10) to yield 0.20 g of pure compound 6c
1
5d (80%). H NMR (400 MHz, CDCl3): δ 0.88 (t, 3H, J ) 7.2
Hz), 1.43-1.76 (m, 11H), 1.85-2.05 (m, 5H), 2.33-2.50 (m, 5H),
2.61 (t, 4H, J ) 4.4 Hz), 3.21 (t, 4H, J ) 5.2 Hz), 6.84-6.87 (t,
1H, J ) 7.2 Hz), 6.93-6.95 (d, 2H, J ) 8.0 Hz), 7.27 (t, 2H, J )
8.8 Hz).
1
(56%). H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.6 Hz),

Tetrahydronaphthalen-2-ols as Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 3013
1.44-1.50 (m, 2H), 1.66-1.77 (m, 1H), 1.97-2.00 (m, 1H),
2.45-2.73 (m, 14H), 3.01-3.06 (m, 4H), 3.19 (t, 1H, J ) 4.8 Hz),
4.91 (bs, 2H, -NH2), 6.94-6.96 (dd, 1H, J1 ) 6.6 Hz, J2 ) 3.2
Hz), 7.13-7.15 (m, 2H). The product was converted into corre-
sponding dioxalate salt, mp 175-177 °C. Anal. (C22H31-
Cl2N5S·2C2H2O4 ·0.9H2O) C, H, N.
2.80-2.86 (m, 1H, N-CH), 3.20 (t, 4H, J ) 4.8 Hz, Ph-N(CH2)2),
6.86 (t,1H, J ) 7.2 Hz), 6.93 (d, 2H, J ) 8.4 Hz), 7.26 (t, 2H, J
) 8.0 Hz), 8.65 (s, 1H, -CdCH-OH).
Synthesis of N-(2-(4-Phenylpiperazin-1-yl)ethyl)-N-propyl-
4,5,6,7-tetrahydro-1H-indazol-5-amine (8). Compound 7 (0.67 g,
1.80 mmol) was dissolved in 25 mL of ethanol, and a solution of
semicarbazide HCl (0.4 g, 3.60 mmol) and sodium acetate (0.29 g,
3.60 mmol) in 10 mL of water was added dropwise. The mixture
was stirred at 0 °C for 1 h until the TLC showed disappearance of
the starting material. The solvent was evaporated in vacuo. The
reaction mixture was heated under reflux in 15 mL of concentrated
H2SO4/water mixture 1:3 (20 mL) for 15 min. The mixture was
made alkaline with NaOH solution and extracted with CH2Cl2 (3
× 50 mL). The organic layer was washed with brine, dried over
Na2SO4, evaporated under reduced pressure, and purified by flash
chromatography on silica gel using solvent system ethyl acetate/
methanol/triethylamine (85:13:2) to yield 0.46 g of pure compound
8 (69%). 1H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.6 Hz,
N-CH2CH2CH3), 1.44-1.54 (m, 2H), 1.65-1.76 (m, 1H), 2.02-2.08
(m, 1H), 2.44-2.55 (m, 5H), 2.65-2.75 (m, 8H), 2.83-2.99 (m,
2H), 3.20 (t, 4H, J ) 4.8 Hz, Ph-N(CH2)2), 6.85 (t, 1H, J ) 7.2
Hz), 6.92 (d, 2H, J ) 8.0 Hz), 7.24-7.28 (m, 3H, Ph (2H) and
NdCH-C). The product was converted into corresponding tet-
rahydrochloride salt, mp 162-164 °C. Anal. (C22H33N5 · 4HCl ·
0.5H2O) C, H, N.
Synthesis of [2-(4-Phenylpiperazin-1-yl)ethyl]propyl(4,5,6,7-
tetrahydrobenzo[d]isoxazol-5-yl)amine (9b). Into a solution of
compound 7 (0.67 g, 1.80 mmol) in acetic acid (20 mL),
NH2OH·HCl (0.26 g, 3.74 mmol) was added, and the mixture was
heated for 1 h at 80 °C. The reaction mixture was cooled and poured
into ice/water (50 mL). The solution was made alkaline with 2 N
NaOH, and the water layer was extracted with CH2Cl2 (3 × 50
mL). The organic layer was washed with brine, dried over Na2SO4,
and evaporated under reduced pressure. The crude mass was purified
by column chromatography on silica gel by using solvent system
ethyl acetate/methanol/triethylamine (95:4:1) to yield 0.53 g of pure
compound 9b (80%). 1H NMR (400 MHz, CDCl3): δ 0.98 (t, 3H,
J ) 7.2 Hz), 1.43-1.52 (m, 2H), 1.62-1.73 (m, 1H), 2.06-2.10
(m, 1H), 2.42-2.52 (m, 5H), 2.62-2.72 (m, 7H), 2.76-2.81 (m,
1H), 2.90-2.97 (m, 1H), 3.02-3.08 (m, 1H), 3.20 (t, 4H, J ) 4.8
Hz), 6.86 (t, 1H, J ) 7.6 Hz), 6.92 (d, 2H, J ) 8.0 Hz), 7.24-7.28
(m, 2H), 8.09 (s, 1H, -O-NdC H-C). The product was converted
into corresponding trihydrochloride salt, mp 145-148 °C . Anal.
(C22H32N4O·3HCl·0.5H2O) C, H, N.
Synthesis of N6-(4-(4-Phenylpiperazin-1-yl)butyl)-N6-pro-
pyl-4,5,6,7-tetrahydrobenzo[d]thiaxole-2,6-diamine (6d). Com-
pound 5d (0.36 g, 0.96 mmol) was treated with pyrrolidine (0.08
mL, 1.01 mmol) in the presence of catalytic amount of p-
toluenesulfonic acid under reflux followed by addition of sulfur
powder (30.8 mg, 0.12 mmol) and cynamide (40.4 mg, 0.96 mmol)
by following procedure E. The crude residue was purified by flash
chromatography using solvent system ethyl acetate/methanol (95:
5) to yield 0.20 g of pure compound 6d (49%). 1H NMR (400
MHz, CDCl3): δ 0.88 (t, 3H, J ) 7.2 Hz), 1.35-1.57(m, 7H),
1.66-1.75 (m, 1H), 1.96-1.99 (m, 1H), 2.38-2.72 (m, 13H),
2.99-3.10 (m, 1H), 3.21 (t, 4H, J ) 4.8 Hz), 4.77 (bs, 2H, -NH2),
6.85 (t, 1H, J ) 7.2 Hz), 6.92-6.94 (d, 2H, J ) 8.0 Hz), 7.26 (t,
2H, J ) 8.4 Hz). The product was converted into corresponding
tetrahydrochloride salt, mp 210-213 °C. Anal. (C24H37N5S·4HCl)
C, H, N.
Synthesis of N6-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)eth-
yl)-N6-(prop-2-ynyl)-4,5,6,7-tetrahydrobenzo[d]thiaxole-2,6-
diamine (6e). Compound 5e (0.29 g, 0.79 mmol) was treated with
pyrrolidine (0.07 mL, 0.83 mmol) in the presence of catalytic
amount of p-toluenesulfonic acid under reflux followed by addition
of sulfur powder (27 mg, 0.104 mmol) and cynamide (33.2 mg,
0.79 mmol) by following procedure E. The crude residue was
purified by flash chromatography using solvent system ethyl acetate/
1
methanol (95:5) to yield 0.18 g of pure compound 6e (52%). H
NMR (400 MHz, CDCl3): δ 1.69-1.79 (m, 1H), 2.08-2.14 (m,
1H), 2.22 (bs, 1H), 2.56-2.71 (m, 12 H), 3.10 (bs, 5H), 3.57 (d,
2H, J ) 1.6 Hz), 3.86 (s, 3H), 5.07 (bs, 2H), 6.85-7.01 (m, 4H).
The product was converted into corresponding dioxalate salt, mp
150-154 °C. Anal. (C23H31N5OS·2C2H2O4 ·0.8H2O) C, H, N.
Synthesis of N6-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)eth-
yl)-N6-(prop-2-ynyl)-4,5,6,7-tetrahydrobenzo[d]thiaxole-
2,6-diamine (6f). Compound 5f (0.205 g, 0.50 mmol) was treated
with pyrrolidine (0.05 mL, 0.55 mmol) in the presence of catalytic
amount of p-toluenesulfonic acid in benzene under reflux followed
by addition of sulfur powder (16.1 mg, 0.063 mmol) and cynamide
(21.1 mg, 0.50 mmol) by following procedure E. The crude residue
was purified by flash chromatography using solvent system ethyl
acetate/methanol (95:5) to yield 0.10 g of pure compound 6f (43%).
1H NMR (400 MHz, CDCl3): δ 1.69-1.79 (m, 1H), 2.08-2.14
(m, 1H), 2.23-2.27 (m, 1H), 2.57-3.07 (m, 17H), 3.58 (s, 2H),
4.99 (bs, 2H, -N H2), 6.94-6.97 (dd, 1H, J1 ) 6.40 Hz, J2 ) 2.8
Hz), 7.12-7.15 (m, 2H). The product was converted into corre-
sponding dioxalate salt, mp 170-172 °C. Anal. (C22H27Cl2N5S·
2C2H2O4 ·0.2H2O) C, H, N.
Synthesis of 2-Hydroxymethylene-4-{[2-(4-phenylpipera-
zin-1-yl)ethyl]propylamino}cyclohexanone (7). Na metal (2.0 g)
was stirred in excess EtOH (40 mL) under nitrogen atmosphere
for half an hour until evolution of hydrogen gas ceases. The excess
EtOH was removed under reduced pressure. This freshly prepared
NaOEt was dried completely and used for the subsequent reaction.
Compound 5a (1.11 g, 3.22 mmol) in anhydrous benzene and excess
NaOEt (3.5 g, 51.43 mmol) was stirred under nitrogen atmosphere
at 0 °C for 10 min. Ethyl formate (2.1 mL, 2.58 mmol) was added
dropwise, and the reaction mixture was stirred overnight at room
temperature under nitrogen atmosphere.
Synthesis of [2-(4-Phenylpiperazin-1-yl)ethyl]propyl(4,5,6,7-
tetrahydrobenzo[c]isoxazol-5-yl)amine (9a). Into a solution of
compound 7 (1.84 g, 4.95 mmol) in 30 mL of pyridine,
NH2OH·HCl (0.86 g, 1.24 mmol) in water (3 mL) was added
dropwise. The mixture was then heated under reflux for 6 h, cooled,
and diluted with water. The product was extracted with CH2Cl2 (3
× 50 mL). The organic layer was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The crude product
was purified by column chromatography on silica gel using solvent
system ethyl acetate/methanol/triethylamine (95:5:1) to yield 0.90 g
1
of pure compound 9a (49.3%). H NMR (400 MHz, CDCl3): δ
0.89 (t, 3H, J ) 7.60 Hz), 1.42-1.51 (m, 2H), 1.61-1.72 (m, 1H),
2.05-2.09 (m, 1H), 2.41-2.51 (m, 5H), 2.61-2.78 (m, 8H),
2.89-2.97 (m, 1H), 3.01-3.02 (m, 1H), 3.19 (t, 4H, J ) 4.8 Hz,
Ph-N(C H2)2), 6.85 (t, 1H, J ) 7.6 Hz), 6.92 (d, 2H, J ) 8.0 Hz),
7.24-7.28 (m, 2H), 8.07 (s, 1H, -N-OdCH-C). The product
was converted into corresponding trihydrochloride salt, mp 148-150
°C. Anal. (C22H32N4O·3HCl·0.2H2O) C, H, N.
Benzene layer was extracted with water (two to three times).
The aqueous extract containing sodium salt of 7 was made slightly
acidic with dilute HCl, then buffered with 2 N KHCO3 and extracted
with CH2Cl2 (3 × 100 mL). The organic extract was washed with
brine, dried over Na2SO4, evaporated under reduced pressure to
yield sufficiently pure 1.10 g of compound 7 (92%). 1H NMR (400
MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.2 Hz, N-CH2CH2C H3), 1.45
(m, 2H, CH2C H2CH3), 1.55-1.65 (m, 1H), 1.89-1.92 (m, 1H),
2.24-2.33 (m, 2H), 2.44-2.53 (m, 6H), 2.64-2.71 (m, 6H),
Synthesis of 2-(4-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl-
amino)cyclohexylidene)hydrazinecarboxamide (10). A mixture
of semicarbazide HCl (0.65 g, 5.82 mmol) and sodium acetate (0.48
g, 5.82 mmol) was dissolved in methanol, and the residue formed
was filtered off. Compound 5a (1.0 g, 2.91 mmol) in methanol was
added to the filtrate, and the reaction mixture was heated under
reflux for 4 h. The reaction mixture was concentrated and diluted
with cold water. The aqueous layer was extracted with CH2Cl2 (150
mL). The organic layer was washed with brine, dried over Na2SO4,

3014 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
evaporated and the resulting crude mass was purified by column
chromatography on silica gel column using solvent system ethyl
acetate/methanol/triethylamine (80:15:5) to yield 0.69 g of pure
compound 10 (70%). 1H NMR (400 MHz, CDCl3): δ 0.88 (t, 3H,
J ) 7.6), 1.40-1.57 (m, 4H), 1.68 (bs, 2H), 1.81-1.98 (m, 5H),
2.16-2.24 (m, 1H), 2.42-2.49 (m, 4H), 2.63-2.65 (m, 6H),
2.76-2.81 (m, 1H), 3.2 (t, 4H, J ) 4.8 Hz, Ph-N(CH2)2),
6.84-6.87 (t, 1H, J ) 7.6 Hz), 6.92-6.94 (d, 2H, J ) 8.0 Hz),
7.24-7.84 (t, 2H, J ) 8.0 Hz), 7.79 (s, 1H, -NNHCO).
flash chromatography over a silica gel column using hexane/ethyl
acetate (1:1) as eluant to afford 0.34 g compound 14 (87%). H
NMR (400 MHz, CDCl3): δ 1.36 (t, 3H, J ) 6.8 Hz, -OCH2CH3),
2.46 (t, 2H, J ) 8.0 Hz, OCCH2CH2), 2.75 (t, 2H, J ) 8.0 Hz,
-OCCH2CH2-), 3.86-3.91 (q, 2H, J ) 7.2 Hz, -OCH2CH3), 5.62
(s, 1H, -OCCHCN), 7.19 (s, 1H, -CCHNHN-).
1
Synthesis of 6-Ethoxy-2-(2,4,6-trimethyl-benzenesulfonyl)-
4,5-dihydro-2H-indazole (15). Into a stirred mixture of (0.28 g,
1.7 mmol) of compound 14 and 0.38 mL of 20% sodium hydroxide
solution (1.87 mmol) in 40 mL of CH2Cl2, 2-mesitylene sulfonyl
chloride was added. The reaction mixture was kept in refluxing
condition overnight. The reaction mixture was diluted with CH2Cl2
(50 mL) and washed with water. The water layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo. The crude
mass was purified by flash chromatography over a silica gel column
using hexane/ethyl acetate (9:1) as eluant to yield 0.51 g of title
Synthesis of [2-(4-Phenylpiperazin-1-yl)ethyl]propyl(4,5,6,7-
tetrahydrobenzo[1,2,3]thiadiazol-6-yl)amine (11). Compound 10
(0.45 g, 2.49 mmol) was added to an excess of thionyl chloride
(15 mL) in portionwise manner at -10 °C in stirred conditions
under nitrogen atmosphere. The reaction mixture was allowed to
attain room temperature. Then CH2Cl2 (100 mL) was added and
the diluted reaction mixture was treated with saturated Na2CO3
solution. The organic layer was separated and washed thoroughly
with brine, dried over Na2SO4, and evaporated. The crude reaction
mixture was purified by column chromatography on silica gel
column using solvent system ethyl acetate/methanol/triethylamine
1
compound 15 (86.4%). H NMR (400 MHz, CDCl3): δ 1.33 (t,
3H, J ) 6.8 Hz, -CH2CH3), 2.28 (s, 3H, CH3(Mst)-), 2.43 (t,
2H, J ) 7.6), 2.6 (s, 2H), 2.66 (s, 6H, C H3(Mst)-), 2.74 (t, 2H,
J ) 7.6), 5.56 (s, 1H, -OCCHCN), 6.95 (s, 2H, Ar-H), 7.73 (s,
1H, -CCHN-).
1
(95:4:1) to yield 0.30 g of pure compound 11 (69.3%). H NMR
(400 MHz, CDCl3): δ 0.90 (t, 3H, J ) 7.6 Hz), 1.44-1.53 (m,
2H), 1.74-1.85 (m, 1H), 2.16-2.20 (m, 1H), 2.47-2.85 (m, 11H),
3.00-3.21 (m, 7H), 3.43-3.48 (dd, 1H, J1 ) 16.4 Hz, J2 ) 4 Hz,
-SCCH-), 6.85 (t, 1H, J ) 7.6 Hz), 6.93 (d, 2H, J ) 8.0 Hz),
7.24-7.28 (m, 2H). The product was converted into corresponding
trihydrochloride salt, mp 160-162 °C. Anal. (C21H31N5S ·
3HCl·0.6H2O) C, H, N.
Synthesis of 2-(2,4,6-Trimethylbenzenesulfonyl)-2,4,5,7-
tetrahydroindazol-6-one (16). Into the stirred solution of com-
pound 15 (1.69 g, 4.87 mmol) in 20 mL of THF at 0 °C was added
2.7 mL of 3 N HCl dropwise. After HCl addition, the reaction
mixture was stirred in an ice bath for 30 min. Then it was stirred
at room temperature under nitrogen atmosphere for 16 h. THF was
removed under reduced pressure. Excess saturated NaHCO3 solution
was added. The water layer was extracted three to four times with
EtOAc (3 × 100 mL). The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo to yield
sufficiently pure 1.5 g of compound 16 (96%). 1H NMR (400 MHz,
CDCl3): δ 2.31-2.32 (m, 3H, -Mst-CH3), 2.58-2.62 (m, 2H,
-COCH2CH2), 2.66 (s, 6H, -Mst-CH3), 2.91 (t, 2H, J ) 6.8 Hz,
-COCH2CH2), 3.55 (s, 2H, -COCH2C-), 6.99 (s, 2H, Ar-H),
7.98 (s, 1H, -CCHN-).
Synthesis of [2-(4-Phenylpiperazin-1-yl)ethyl]propyl(4,5,6,7-
tetrahydrobenzo[1,2,3]selenadiazol-6-yl)amine (12). The semicar-
bazone 10 (0.46 g, 2.49 mmol) was dissolved in glacial acetic acid
(20 mL) and warmed gently with stirring to provide a clear solution.
Selenium dioxide (0.33 g, 2.99 mmol) was added in a portionwise
manner into the solution. The reaction mixture was stirred for 30
min. The deposited selenium was removed by filtration. The filtrate
was diluted with cold water (50 mL) and washed with saturated
NaHCO3 solution. The aqueous layer was extracted with CH2Cl2
(150 mL). The organic layer was washed with brine, dried over
Na2SO4, evaporated under reduced pressure. The crude mass was
purified by column chromatography on silica gel column using
solvent system ethyl acetate/methanol/triethylamine (95:4:1) to yield
0.36 g of pure compound 11 (73%). 1H NMR (400 MHz, CDCl3):
δ 0.89 (t, 3H, J ) 7.6 Hz), 1.42-1.51 (m, 2H), 1.74-1.84 (m,
1H), 2.12-2.20 (m, 1H), 2.48-2.83 (m, 11H), 3.15-3.29 (m, 7H),
3.53-3.56 (dd, 1H, J1 ) 16.2 Hz, J2 ) 4 Hz, -SeCCH-), 6.85 (t,
1H, J ) 7.6 Hz), 6.92 (d, 2H, J ) 8.0 Hz), 7.24-7.28 (m, 2H).
The product was converted into corresponding trihydrochloride salt,
mp 210-212 °C. Anal. (C21H31N5Se·3HCl·0.7H2O) C, H, N.
Synthesis of 3-Ethoxy-6-hydroxymethylenecyclohex-2-
enone (13). Into a stirred solution of 3-ethoxy-2 cyclohexen-1-one
(3.50 g, 25 mmol) and freshly prepared sodium ethoxide (obtained
from 7.0 g (30.0 mmol) of sodium metal) in benzene (100 mL) at
0 °C was added ethyl formate (7.4 g, 100 mmol) dropwise under
nitrogen atmosphere. The mixture was stirred overnight at room
temperature. Benzene layer was extracted with water (two to three
times). The aqueous extract containing sodium salt of 13 was made
slightly acidic with dilute HCl, then buffered with 2 N KHCO3
and extracted with 3 × 100 mL of CH2Cl2. The combined organic
layer was washed with brine, dried over Na2SO4, and evaporated
under reduced pressure. The crude mass was purified by flash
chromatography over a silica gel column using hexane/ethyl acetate
(1:1) as eluant to yield 3.04 g of title compound 13 (72%). 1H
NMR (400 MHz, CDCl3): δ 1.36 (t, 3H, J ) 6.8 Hz, -OCH2CH3),
2.39-2.44 (m, 4H, -OCCH2CH2C), 3.89-3.95 (q, 2H, J ) 7.2
Hz, -OCH2CH3), 5.31 (s, -OCCHCO), 7.17 (d, 1H, J ) 9.2 Hz,
-CCHOH).
Synthesis of [2-(4-Phenylpiperazin-1-yl)ethyl][2-(2,4,6-tri-
methylbenzenesulfonyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]-
amine (17). A mixture of amine 1a (0.3976 g, 1.94 mmol),
compound 16 (1.29 mmol), and acetic acid in dichloroethane (20
mL) was stirred at room temperature under nitrogen atmosphere
for 15-20 min. NaCNBH3(0.33 g, 5.17 mmol) dissolved in 2 mL
of methanol was added dropwise. The reaction mixture was stirred
for 4 h at room temperature. Water was added followed by dilute
HCl. Excess HCl was then neutralized with saturated NaHCO3
solution. The water layer was extracted with CH2Cl2 (3 × 100 mL).
The combined organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The crude mass was purified by
flash chromatography over a silica gel column using ethyl acetate/
methanol/triethylamine (95:4:1) as eluant to yield 0.47 g of title
1
compound 17 (48%). H NMR (400 MHz, CDCl3): δ 1.56-1.66
(m, 1H, -NHCHCH2-), 1.95-2.00 (m, 1H), 1.78 (broad s, 1H,
-NH-), 2.29-2.30 (m, 3H, Mst-C H3), 2.39-2.46 (m, 1H),
2.53-2.65 (m, 14H), 2.69-2.86 (m, 2H), 2.92-3.03 (m, 1H),
3.16-3.21 (m, 4H, N(CH2)2), 3.36-3.41 (m, 1H, -NHCH(CH2)2),
6.83-6.96 (m, 5H, Ar-H), 7.24-7.29 (m, 2H, Ar-H), 7.83 (s,1H,
-CCHN-).
Synthesis of N-[2-(4-Phenylpiperazin-1-yl)ethyl][2-(2,4,6-tri-
methyl-benzenesulfonyl)-4,5,6,7-tetrahydro-2H-indazol-6-yl]pro-
pionamide (18). Into a stirred solution of compound 17 (0.4729 g,
0.93 mmol) and 1 mL of Et3N in anhydrous CH2Cl2 (20 mL) under
nitrogen atmosphere at 0 °C was added propionyl chloride (0.20
mL, 2.33 mmol). The reaction mixture was stirred for 2 h. The
reaction mixture was diluted with CH2Cl2 (20 mL) and washed
with water and brine. The organic layer was dried over Na2SO4
and evaporated in vacuo. The crude mass was purified by flash
chromatography over a silica gel column using ethyl acetate/
methanol/triethylamine (95:4:1) as eluant to yield 0.44 g of title
Synthesis of 6-Ethoxy-4,5-dihydro-2H-indazole (14). Into the
solution of compound 13 (0.4 g, 2.37 mmol) in 20 mL of ethanol
was added hydrazine (0.15 mL, 4.76 mmol) under nitrogen
atmosphere. The reaction mixture was refluxed for 6 h. The solvent
was evaporated in vacuo and the crude product was purified by
1
compound 18 (84%). H NMR (400 MHz, CDCl3): δ 1.12-1.21
(m, 3H), 1.74 (s, 1H), 1.88-1.99 (m, 2H), 2.31-2.32 (m, 3H,

Tetrahydronaphthalen-2-ols as Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 3015
Mst-CH3), 2.35-2.46 (m, 2H), 2.57-2.74 (m, 14H, Mst-CH3),
2.81-2.85 (m, 1H), 3.16-3.20 (m, 4H, N(CH2)2), 3.29-3.36 (m,
1H), 3.38-3.49 (m, 2H), 6.83-6.99 (m, 5H, Ar-H), 7.24-7.29
(m, 2H, Ar-H), 7.83-7.89 (d, 1H, J ) 23.6, 1H, -CCHN-).
Synthesis of [2-(4-Phenylpiperazin-1-yl)ethyl]propyl(4,5,6,7-
tetrahydro-2H-indazol-6-yl]amine (19). Compound 18 (0.44 g, 0.78
mmol) in anhydrous THF was added dropwise into the suspension
of LiAlH4 (0.18 g, 4.68 mmol) in anhydrous THF at 0 °C under
nitrogen atmosphere. The reaction mixture was refluxed for 8 h
and cooled to room temperature. The reaction mixture was diluted
with EtOAc, and saturated NaOH/H2O (4 mL) was added dropwise.
The mixture was stirred for 15-20 min. Then it was filtered, and
the organic layer was dried over Na2SO4 and evaporated in vacuo.
The crude mass was purified by flash chromatography over a silica
gel column using ethyl acetate/methanol/triethylamine (95: 4:1) as
eluant to yield 0.22 g of title compound 19 (78%). The product
was converted into corresponding tetrahydrochloride salt, mp
1.92-1.99 (m, 2H), 2.11-2.15 (m, 2H), 2.31 (s, 3H), 2.40-2.43
(q, 4H, J ) 4.0 Hz), 2.63 (s, 6H), 3.05-3.09 (m, 2H,
-NCH2CH2CH3), 4.06-4.12 (tt, 1H, J1 ) 12.0 Hz, J2 ) 3.2 Hz,
-CH2CHN-), 6.96 (bs, 2H, -Ar-H).
Synthesis of N-(2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-
6-yl)-2,4,6-trimethyl-N-propylbenzenesulfonamide (23). Com-
pound 22 (1.21 g, 3.59 mmol) was treated with pyrolidine (0.36
mL, 4.30 mmol) in the presence of catalytic amount of p-
toluenesulfonic acid (3.4 mg, 0.0179 mmol) under reflux followed
by the addition of sulfur powder (0.14 g, 0.54 mmol) and cynamide
(0.18 g, 4.30 mmol) by following procedure E. The crude residue
was purified by flash chromatography using solvent system hexane/
ethyl acetate (20:80) to yield 0.80 g of pure compound 23. (58%).
1H NMR (400 MHz, CDCl3): δ 0.79 (t, 3H, J ) 8.0 Hz, CH2CH3),
1.44-1.58 (m, 2H), 1.90-1.94 (m, 1H), 2.03-2.05 (m, 1H), 2.30
(s, 3H), 2.53-2.62 (m, 7H), 2.67-2.71 (m, 2H), 2.76-2.83 (m,
1H), 3.11-3.22 (m, 2H), 3.90-3.98 (m, 1H), 4.8 (bs, 2H, -NH2),
6.94 (s, 2H).
1
230-233 °C. Anal. (C22H33N5 ·4HCl·0.5H2O) C, H, N. H NMR
(400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.2 Hz, CH2C H3), 1.44-1.53
(m, 2H, CH2CH3), 1.56-1.66 (m, 1H), 1.99-2.02 (m, 1H),
2.49-2.59 (m, 6H), 2.62-2.68 (m, 5H), 2.71-2.75 (m, 3H),
2.84-2.89 (dd, 2H, J1 ) 15.6, J2 ) 4.4, -NCHCH2CN-),
2.99-3.06 (m, 1H), 3.19 (t, 4H, J ) 8.0 Hz), 6.85 (t, 1H, J ) 7.2
Hz, Ar-H), 6.90-6.93 (d, 2H, J ) 8.4, Ar-H), 7.23-7.27 (m,
3H, 2Ar-H, -CCHNH-).
Synthesis of (()-N6-Propyl-4,5,6,7-tetrahydrobenzo[d]thia-
zole-2,6-diamine. ((()-24). Into a suspension of compound 23
(16.73 g, 42.51 mmol) and phenol (40 g, 435.08 mmol) in 200 mL
of ethyl acetate at 0 °C was added 200 mL of 33% HBr in acetic
acid drop by drop under nitrogen atmosphere. The reaction mixture
was stirred at room temperature for 12 h. The reaction mixture
was evaporated to dryness. The solid HBr salt of the compound
was triturated with ethyl acetate, filtered, and crystallized using
solvent system ethanol/methanol. The white crystals of the HBr
salt were filtered and dried under vacuum. The salt was dissolved
in water. The water layer was made saturated with powdered
K2CO3. The aqueous layer was extracted with ethyl acetate (3 ×
200 mL). The combined organic layer was dried over Na2SO4 and
evaporated in vacuo to yield 6.88 g of pure title compound (()-24
Synthesis of N-Propyl-1,4-dioxaspiro[4.5]decan-8-amine
(20). 1,4-Cyclohexanedione monoethylene ketal (10 g, 64.03 mmol)
was reacted with n-propylamine (10.5 mL, 128.06 mmol) in the
presence of NaCNBH3 (10.06 g, 160.07 mmol) and HOAc (7.6
mL) in 1,2-dichloroethane (100 mL) by following procedure A.
The crude reaction mixture was purified by column chromatography
on silica gel column using solvent system dichloromethane/methanol
(100:1) to yield 12.04 g of pure compound 20 (94%). Compound
20 was also purified in some batches by dissolving the crude mixture
in ethanol/ether and passing HCl gas through the solution for 15
min till the solution is acidic to litmus paper. The precipitated HCl
salt was collected by filtration, which was used directly in next
1
(77%). H NMR (400 MHz, CDCl3): δ 0.93 (t, 3H, J ) 7.6 Hz),
1.49-1.57 (m, 2H), 1.64-1.70 (m, 1H), 2.0-2.05 (m, 1H),
2.36-2.42 (m, 1H), 2.52-2.66 (m, 4H), 2.83-2.95 (dd, 1H, J1 )
15.2 Hz, J2 ) 4.4 Hz), 2.96-3.00 (m, 1H), 5.13 (bs, 2H).
Resolution of (()-Pramipexole (24) via Its Monohydro-
chloride Tartrate (U.S. Patent 6,727,367). Into a warm solution
of (()-24 (10.57 g, 50 mmol) in CH3OH (100 mL), concentrated
HCl (4.13 mL, 50 mmol) was added dropwise, and the solid that
formed was dissolved by further heating. L-(+)-tartaric acid (7.50
g, 50 mmol) was added and the solution mixed until white crystals
precipitated. After cooling, the crystals were collected and washed
with cold CH3OH before recrystallizing from CH3OH.
The free base was liberated using saturated K2CO3 and extracting
with EtOAc (4×). This gave the (S)-enantiomer as a white solid
with a maximum optical rotation of [R]D -94° (c 0.5, CH3OH). (If
the maximum rotation had not been reached, the procedure was
repeated for a second time.)
1
step without converting the salt back to free base. H NMR (400
MHz, CDCl3): δ 0.91 (t, 3H, J ) 7.2 Hz), 1.36-1.59 (m, 6H),
1.74-1.79 (m, 2H), 1.84-1.89 (m, 2H), 2.49-2.60 (m, 3H), 3.94
(s, 4H, -O(CH2)2O-).
Synthesis of 2,4,6-Trimethyl-N-propyl-N-(1,4-dioxaspiro-
[4.5]decan-8-yl)benzenesulfonamide (21). Into a stirred mixture
of compound 20 (2.17 g, 10.89 mmol) and 2.4 mL of 20% w/v
NaOH solution (11.98 mmol) in 20 mL of dichloromethane was
added 2-mesitylenesulfonyl chloride (2.62 g, 11.98 mmol). The
reaction mixture was refluxed for 12 h. The reaction mixture was
diluted with CH2Cl2 (25 mL) and washed with water. The water
layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The crude mass was purified by flash
chromatography over a silica gel column using hexane/ethyl acetate
(9:1) as eluant to yield 2.90 g of title compound 21 (70%). 1H
NMR (400 MHz, CDCl3): δ 0.75 (t, 3H, J ) 7.6 Hz,
-CH2CH2CH3), 1.36-1.43 (m, 2H, -CH2CH2CH3), 1.94-2.01 (m,
2H), 2.11-2.16 (m, 2H), 2.31 (s, 3H), 2.40-2.43 (q, 4H, J ) 4.0
Hz), 2.63 (s, 6H), 3.05-3.10 (m, 2H, -NCH2CH2CH3), 3.90 (s,
4H, -O(CH2)2O-), 4.06-4.12 (tt, 1H, J1 ) 12.0 Hz, J2 ) 3.2 Hz,
-CH2CHN-), 6.96 (bs, 2H, -Ar-H).
Synthesis of 2,4,6-Trimethyl-N-(4-oxocyclohexyl)-N-propyl-
benzenesulfonamide (22). Into a stirred solution of compound 21
(38.5 g, 0.10 mol) in 100 mL of THF was added 400 mL of 1 N
HCl. The reaction mixture was stirred at 80 °C for 6 h. THF was
evaporated. The reaction mixture was neutralized by using saturated
NaHCO3 solution. The aqueous layer was extracted using ethyl
acetate (3 × 200 mL). The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo. The crude
mass was purified by flash chromatography over a silica gel column
using hexane/ethyl acetate (8:2) as eluant to yield 31.0 g of title
compound 22 (91%). 1H NMR (400 MHz, CDCl3): δ 0.74 (t, 3H,
J ) 7.2 Hz, -CH2CH2CH3), 1.36-1.42 (m, 2H, -CH2CH2CH3),
The different filtrates were concentrated and converted to the
free base. The samples that had a positive optical rotation were
further separated using D-(-)-tartaric acid to give the pure (R)-
enantiomer.
Procedure F. Synthesis of 2-Chloro-1-(4-phenylpiperazin-
1-yl)ethanone (26a). Into the solution of 1-phenylpiperazine (5.6
mL, 36.98 mmol) and triethylamine (10 mL) in anhydrous dichlo-
romethane (50 mL) was added chloroacetyl chloride (3.2 mL, 40.68
mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was
stirred for half an hour and diluted with dichloromethane. The
organic layer was washed with water, dried over Na2SO4, and
evaporated in vacuo. The crude residue was purified by flash
chromatography on silica gel column using solvent system hexane/
ethyl acetate (75:25) to yield 6.05 g of pure compound 26a (69%).
1H NMR (400 MHz, CDCl3): δ 3.19 (t, 2H, J ) 4.8 Hz), 3.24 (t,
2H, J ) 5.2 Hz), 3.69 (t, 2H, J ) 5.2 Hz), 3.80 (t, 2H, J ) 5.6
Hz), 4.12 (s, 2H), 6.91-6.95 (m, 3H), 7.26-7.32 (m, 2H).
Synthesis of 2-Chloro-1-(4-(2-methoxyphenyl)piperazin-
1-yl)ethanone (26b). 1-(2-Methoxyphenyl)piperazine HCl (5.89 g,
25.0 mmol) was treated with chloroacetyl chloride (2.2 mL, 27.0
mmol) in the presence of triethylamine (8.7 mL) in 100 mL of
anhydrous CH2Cl2 by following procedure F. Reaction mixture was

3016 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
purified by flash chromatography using solvent system hexane/ethyl
acetate (50:50) to yield 6.10 g of pure compound 26b (91%). H
mmol) and a catalytic amount of KI by following procedure G.
The reaction mixture was purified by flash chromatography on silica
gel column using solvent system ethyl acetate/methanol (90:10) to
yield 0.15 g of pure compound (-)-27 (36%). 1H NMR (400 MHz,
CDCl3): δ 0.89 (t, J ) 7.2 Hz, 3H), 1.49 (h, J ) 7.2 Hz, 2H),
1.81-1.68 (m, 1H), 2.06-1.96 (m, 1H), 2.65-2.45 (m, 4H),
2.76-2.65 (m, 2H), 3.26-3.04 (m, 5H), 3.50-3.38 (m, 2H),
3.90-3.66 (m, 4H), 4.94 (bs, 2H), 6.97-6.86 (m, 3H), 7.32-7.25
(m, 2H).
1
NMR (400 MHz, CDCl3): δ 3.06 (t, 2H, J ) 5.2 Hz), 3.12 (t, 2H,
J ) 5.2 Hz), 3.71 (t, 2H, J ) 5.2 Hz), 3.82 (t, 2H, J ) 5.2 Hz),
3.89 (s, 3H), 4.12 (s, 2H), 6.87-6.97 (m, 3H), 7.02-7.08 (m, 1H).
Synthesis of 2-Chloro-1-(4-(2,3-dichlorophenyl)piperazin-
1-yl)ethanone (26c). 1-(2,3-Dichlorophenyl)piperazine HCl (6.0 g,
22.42 mmol) was treated with chloroacetyl chloride (1.96 mL, 24.66
mmol) in the presence of triethylamine (5 mL) in 75 mL of
anhydrous CH2Cl2 by following procedure F. Reaction mixture was
purified by flash chromatography using solvent system hexane/ethyl
Synthesis of (+)-2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propylamino)-1-(4-(2-methoxyphenyl)piperazin-
1-yl)ethanone ((+)-28). Compound (+)-24 (0.3 g, 1.42 mmol) was
treated with 26b (0.57 g, 2.13 mmol) in the presence of base K2CO3
(0.39 g, 2.84 mmol) and a catalytic amount of KI by following
procedure G. The reaction mixture was purified by flash chroma-
tography on silica gel column using solvent system diethyl ether/
methanol (92:8) to yield 0.24 g of pure compound (+)-28 (38%).
1H NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.6 Hz), 1.43-1.52
(m, 2H), 1.71-1.80 (m, 1H), 2.00-2.04 (m, 1H), 2.47-2.63 (m,
4H), 2.69-2.73 (m, 2H), 2.97-3.13 (m, 5H), 3.40-3.50 (q, 2H, J
) 13.6 Hz), 3.72-3.89 (m, 7H), 4.71 (bs, 2H), 6.88-6.94 (m, 3H),
7.02-7.06 (m, 1H).
Synthesis of (-)-2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propylamino)-1-(4-(2-methoxyphenyl)piperazin-
1-yl)ethanone ((-)-28). Compound (-)-24 (0.21 g, 1.0 mmol) was
treated with 26b (0.34 g, 1.25 mmol) in the presence of base K2CO3
(0.21 g, 1.5 mmol) and a catalytic amount of KI following procedure
G. The reaction mixture was purified by flash chromatography on
silica gel column using solvent system ethyl acetate/methanol (90:
10) to yield 0.15 g of pure compound (-)-28 (34%). 1H NMR
(400 MHz, CDCl3): δ 0.89 (t, 3H, J ) 7.6 Hz), 1.43-1.56 (m,
2H), 1.68-1.82 (m, 1H), 2.00-2.05 (m, 1H), 2.47-2.65 (m, 4H),
2.65-2.76 (m, 2H), 2.96-3.16 (m, 5H), 3.40-3.52 (q, 2H, J )
13.6 Hz), 3.70-3.92 (m, 7H), 4.88 (bs, 2H), 6.86-6.97 (m, 3H),
7.00-7.08 (m, 1H).
Synthesis of (+)-2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propylamino)-1-(4-(2,3-dichlorophenyl)piperazin-
1-yl)ethanone ((+)-29). Compound (+)-24 (0.3 g, 1.42 mmol) was
treated with 26c (0.65 g, 2.13 mmol) in the presence of base K2CO3
(0.39 g, 2.84 mmol) and catalytic amount of KI by following
procedure G. The reaction mixture was purified by flash chroma-
tography on silica gel column using solvent system ethyl acetate/
methanol (95:5) to yield 0.31 g of pure compound (+)-29 (45%).
1H NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J ) 7.2 Hz), 1.43-1.52
(m, 2H), 1.71-1.81 (m, 1H), 2.00-2.05 (m, 1H), 2.48-2.63 (m,
4H), 2.70-2.75 (m, 2H), 2.98-3.13 (m, 5H), 3.40-3.50 (q, 2H, J
) 13.6 Hz), 3.76-3.91 (m, 4H), 4.71 (bs, 2H), 6.91-6.94 (dd,
1H, J1 ) 7.6 Hz, J2 ) 1.6 Hz), 7.14-7.22 (m, 2H).
Synthesis of (-)-2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propylamino)-1-(4-(2,3-dichlorophenyl)pipera-
zin-1-yl)ethanone ((-)-29). Compound (-)-24 (0.21 g, 1.0 mmol)
was treated with 26c (0.34 g, 1.1 mmol) in the presence of base
K2CO3 (0.17 g, 1.25 mmol) and a catalytic amount of KI following
procedure G. The reaction mixture was purified by flash chroma-
tography on silica gel column using solvent system ethyl acetate/
methanol (90:10) to yield 0.21 g of pure compound (-)-29 (44%).
1H NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J ) 7.2 Hz), 1.43-1.55
(m, 2H), 1.69-1.82 (m, 1H), 1.97-2.06 (m, 1H), 2.46-2.65 (m,
4H), 2.65-2.75 (m, 2H), 2.95-3.15 (m, 5H), 3.40-3.50 (q, 2H, J
) 13.6 Hz), 3.68-3.95 (m, 4H), 4.81 (bs, 2H), 6.91-6.94 (dd,
1H, J1 ) 7.6 Hz, J2 ) 1.6 Hz), 7.13-7.22 (m, 2H).
1
acetate (70:30) to yield 5.0 g of pure compound 26c (62%). H
NMR (400 MHz, CDCl3): δ 3.05 (t, 2H, J ) 4.8 Hz), 3.10 (t, 2H,
J ) 4.4 Hz), 3.72 (t, 2H, J ) 5.2 Hz), 3.82 (t, 2H, J ) 4.8 Hz),
4.12 (s, 2H), 6.93-6.95 (dd, 1H, J1 ) 8.0 Hz, J2 ) 2.0 Hz),
7.15-7.23 (m, 2H).
Synthesis of 1-(4-Biphenylyl)piperazine Trifluoroacetate
(25d). Into the suspension of tert-butyl piperazine-1-carboxylate
(0.44 g, 2.36 mmol), sodium tert-butoxide (0.413 g, 4.29 mmol),
and the catalyst dichlorobis(tri-o-tolylphosphine)palladium(II) (50
mg, 0.0644 mmol, 3 mol %) in anhydrous toluene was added
4-bromobiphenyl (0.5 g, 2.15 mmol). Reaction mixture was refluxed
for 3 h. The crude reaction mixture was filtered through Celite,
washed with ethyl acetate, evaporated in vacuo, and purified by
flash chromatography on silica gel column using solvent system
hexane/ethyl acetate (90:10) to yield 0.60 g of pure compound tert-
butyl 4-(biphenyl-4-yl)piperazine-1-carboxylate (80%). This com-
pound was deprotected to afford 1-(4-biphenyl)piperazine. Depro-
tection of tert-butyl 4-(biphenyl-4-yl)piperazine-1-carboxylate was
done as follows.
Into the solution of tert-butyl 4-(biphenyl-4-yl)piperazine-1-
carboxylate (3.6 g, 10.64 mmol) in 25 mL of dry CH2Cl2 was added
trifluoroacetic acid (25 mL) dropwise at room temperature. Reaction
mixture was stirred at room temperature for 6 h. The reaction
mixture was concentrated under reduced pressure. The salt of the
product was recrystallized from solvent system dichloromethane/
hexane to yield 2.81 g of the desired compound 1-(4-biphenyl)pip-
erazine as trifluoroacetate salt form (75%) 25d. 1H NMR (400 MHz,
CDCl3): δ 1.63 (bs, 1H, -NH), 3.05 (t, 4H, J ) 4.4 Hz), 3.20 (t,
4H, J ) 5.2 Hz), 6.99-7.01 (d, 2H, J ) 8.8 Hz), 7.26-7.30 (m,
1H), 7.40 (t, 2H, J ) 7.6 Hz), 7.51-7.57 (m, 4H).
Synthesis of 1-(4-(Biphenyl-4-yl)piperazin-1-yl)-2-chloro-
ethanone (26d). 1-(4-Biphenylyl)piperazine trifluoroacetate 25d
(2.81 g, 7.98 mmol) was treated with chloroacetyl chloride (0.70
mL, 8.78 mmol) in the presence of triethylamine (5 mL) in
anhydrous CH2Cl2 (50 mL) by following procedure F. Reaction
mixture was purified by flash chromatography using solvent system
ethyl acetate/methanol/triethylamine (90:10:1) to yield 2.0 g of pure
compound 26d (80%). 1H NMR (400 MHz, CDCl3): δ 3.23-3.30
(tt, 4H, J1 ) 19.6 Hz, J2 ) 4.8 Hz), 3.69-3.71 (t, 2H, J ) 5.6
Hz), 3.80-3.82 (t, 2H, J ) 5.2 Hz), 4.12 (s, 2H), 6.99-7.01 (d,
2H, J ) 8.8 Hz), 7.28-7.32 (m, 1H), 7.40-7.43 (t, 2H, J ) 8.0
Hz), 7.53-7.57 (t, 4H, J ) 8.8 Hz).
Procedure G. Synthesis of (+)-2-((2-Amino-4,5,6,7-tetra-
hydrobenzo[d]thiazol-6-yl)(propylamino)-1-(4-phenylpipera-
zin-1-yl)ethanone ((+)-27). Into a suspension of (+)-24 (0.20 g,
0.95 mmol), K2CO3 (0.39 g, 2.84 mmol), and a catalytic amount
of KI in acetonitrile (25 mL) was added 26a (0.34 g, 1.42 mmol).
Reaction mixture was refluxed for 3 h. The crude reaction mixture
was filtered, washed with ethyl acetate, evaporated in vacuo, and
purified by flash chromatography on silica gel column using solvent
system ethyl acetate/methanol (95:5) to yield 0.15 g of pure
compound (+)-27 (38%). 1H NMR (400 MHz, CDCl3): δ 0.87-0.90
(m, 3H), 1.47-1.52 (m, 2H), 1.73-1.78 (m, 1H), 1.98-2.05 (m,
1H), 2.51-2.73 (m, 6H), 3.06-3.26 (m, 5H), 3.40-3.50 (q, 2H, J
) 13.6 Hz), 3.74-3.86 (m, 4H), 4.69 (bs, 2H), 6.89-6.96 (m, 3H),
7.26-7.31 (m, 2H).
Synthesis of (-)-2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propylamino)-1-(4-(biphenyl-4-yl)piperazin-1-yl)-
ethanone ((-)-30). Compound (-)-24 (0.3 g, 1.42 mmol) was
treated with 26d (0.67 g, 2.13 mmol) in the presence of base K2CO3
(0.39 g, 2.84 mmol) and a catalytic amount of KI following
procedure G. The reaction mixture was purified by flash chroma-
tography on silica gel column using solvent system ethyl acetate/
methanol (95:5) to yield 0.25 g of pure compound (-)-30 (36%).
1H NMR (400 MHz, CDCl3): δ 0.89-0.92 (t, 3H, J ) 7.2 Hz),
Synthesis of (-)-2-((2-Amino-4,5,6,7-tetrahydrobenzo[d]-
thiazol-6-yl)(propylamino)-1-(4-phenylpiperazin-1-yl)ethanone ((-)-
27). Compound (-)-24 (0.21 g, 1.0 mmol) was treated with 26a
(0.36 g, 1.5 mmol) in the presence of base K2CO3 (0.28 g, 2.0

Tetrahydronaphthalen-2-ols as Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10 3017
1.44-1.53 (m, 2H), 1.75-1.79 (m, 1H), 2.02-2.05 (m, 1H),
2.52-2.75 (m, 6H), 3.06-3.26 (m, 5H), 3.42-3.51 (q, 2H, J )
13.6 Hz), 3.77-3.89 (m, 4H), 4.70 (bs, 2H), 7.00-7.02 (d, 2H, J
) 8.0 Hz), 7.30-7.32 (m, 1H), 7.40-7.44 (t, 2H, J ) 8.0 Hz),
7.53-7.58 (t, 4H, J ) 9.2 Hz).
Synthesis of (+)-N6-(2-(4-(2,3-Dichlorophenyl)piperazin-1-
yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ((+)-33). Compound (+)-29 (0.31 g, 0.64 mmol) in 5 mL
of anhydrous THF was treated with borane-THF complex (3.9
mL) by following procedure H. Crude reaction mixture was purified
by flash chromatography on silica gel column using solvent system
ethyl acetate/methanol (90:10) to afford 0.14 g of compound (+)-
33 (47%). [R]D +36.4° (c 1, dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 0.89 (t, 3H, J ) 7.2 Hz), 1.43-1.52 (m, 2H), 1.67-1.77
(m, 1H), 1.98-2.04 (m, 1H), 2.44-2.60 (m, 6H), 2.66-2.77 (m,
8H), 3.01-3.09 (m, 5H), 4.99 (bs, 2H, -NH2), 6.94-6.98 (m, 1H),
7.12-7.17 (m, 2H). The product was converted into corresponding
trihydrochloride salt, mp 175-178 °C. Anal. (C22H31Cl2-
N5S·3HCl·1.8H2O) C, H, N.
Procedure H. Synthesis of (+)-N6-(2-(4-Phenylpiperazin-
1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ((+)-31). Into the solution of (+)-27 (0.26 g, 0.63 mmol)
in dry THF (5 mL) at 0 °C was added (3.8 mL, 3.8 mmol) solution
of borane-THF complex (1 M solution) with stirring under nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 36 h 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 room temperature. Methanol was evaporated
under vacuo. 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
vacuo, and purified by flash chromatography on silica gel column
using solvent system ethyl acetate/methanol (90:10) to afford 0.14 g
of compound (+)-31 (56%). [R]D +40.6° (c 1, dichloromethane).
1H NMR (400 MHz, CDCl3): δ 0.87-0.92 (m, 3H), 1.43-1.52
(m, 2H), 1.68-1.77 (m, 1H), 1.98-2.01 (m, 1H), 2.44-2.60 (m,
6H), 2.64-2.75 (m, 8H), 3.02-3.08 (m, 1H), 3.19-3.21 (t, 4H, J
) 4.8 Hz), 4.81 (bs, 2H), 6.83-6.87 (m, 1H), 6.92-6.94 (m, 2H),
7.24-7.28 (m, 2H). The product was converted into corresponding
tetrahydrochloride salt, mp 230-233 °C. Anal. (C22H33N5S·4HCl)
C, H, N.
Synthesis of (-)-N6-(2-(4-(2,3-Dichlorophenyl)piperazin-1-
yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ((-)-33). Compound (-)-29 (0.21 g, 0.44 mmol) in 25
mL of anhydrous THF was treated with borane-THF complex (2.2
mL) following procedure H. Crude reaction mixture was purified
by flash chromatography on silica gel column using solvent system
ethyl acetate/methanol (80:20) to afford compound (-)-33. [R]D
1
-35.9° (c 1.0, dichloromethane). H NMR (400 MHz, CDCl3): δ
0.90 (t, 3H, J ) 7.2 Hz), 1.45-1.55 (m, 2H), 1.66-1.77 (m, 1H),
1.97-2.05 (m, 1H), 2.46-2.64 (m, 6H), 2.64-2.82 (m, 8H),
3.00-3.14 (m, 5H), 5.28 (bs, 2H, -NH2), 6.94-6.97 (m, 1H),
7.11-7.17 (m, 2H). The product was converted into corresponding
trihydrochloride salt (0.12 g), mp ∼210 °C (dec). Anal.
(C22H31N5S·3HCl·0.8H2O) C, H, N.
Synthesis of (-)-N6-(2-(4-Phenylpiperazin-1-yl)ethyl)-N6-
propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine ((-)-
31). Compound (-)-27 (0.15 g, 0.36 mmol) in 25 mL of anhydrous
THF was treated with borane-THF complex (1.8 mL) by following
procedure H. Crude reaction mixture was purified by flash chro-
matography on silica gel column using solvent system ethyl acetate/
methanol (80:20) to afford compound (-)-31. [R]D -38.4° (c 1.0,
dichloromethane). 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J ) 8.0
Hz, 2H), 6.93 (d, J ) 8.0 Hz, 2H), 6.85 (t, J ) 7.2 Hz, 1H), 4.83
(bs, 2H), 3.24-3.16 (m, 4H), 3.11-3.01 (m, 1H), 2.78-2.63 (m,
7H), 2.63-2.45 (m, 6H), 2.04-1.96 (m, 1H), 1.79-1.66 (m, 1H),
1.48 (h, J ) 7.2 Hz, 2H), 0.89 (t, J ) 7.2 Hz, 3H). The product
was converted into corresponding tetrahydrochloride salt (0.09 g),
mp ∼210 °C (dec). Anal. (C22H33N5S·4HCl·0.3Et2O) C, H, N.
Synthesis of (-)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-
ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ((-)-34). Compound (+)-30 (0.23 g, 0.47 mmol) in 5 mL
of anhydrous THF was treated with borane-THF complex (4.0
mL) by following procedure H. Crude reaction mixture was purified
by flash chromatography on silica gel column using solvent system
ethyl acetate/methanol (90:10) to afford 0.12 g of compound (-)-
34 (54%). [R]D -34.4° (c 1, dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 0.88-0.91 (t, 3H, J ) 7.2 Hz), 1.45-1.51 (q, 2H, J )
7.2 Hz), 1.68-1.78 (m, 1H), 1.97-2.04 (m, 1H), 2.44-2.75 (m,
14H), 3.03-3.08 (m, 1H), 3.24-3.27 (m, 4H), 4.76 (bs, 2H),
6.98-7.01 (m, 2H), 7.28-7.31 (m, 1H), 7.38-7.43 (m, 2H),
7.50-7.59 (m, 4H). The product was converted into corresponding
trioxalate salt., mp 198-200 °C. Anal. (C28H37N5S·2C2H2O4 ·H2O)
C, H, N.
Measurement of Binding Potencies at Dopamine D2 and
D3 Receptors. [3H]Spiperone Binding. Binding affinities were
assessed according to the general procedure described in our
previous study (Table 1).39 Human embryonic kidney (HEK) 293
cells, newly transfected with rat D2L and D3 receptors, were
generously donated by Dr. Kim A. Neve (Oregon Health Sciences
University). As described previously, membranes preparations from
these cells were incubated with each test compound and [3H]spip-
erone (0.4 nM, 15 Ci/mmol, Perkin-Elmer) was incubated 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. (+)-Butaclamol (2 µM) was
used to define nonspecific binding. Assays were terminated by
addition of ice-cold buffer and filtration in a 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.50 In this conversion,
the Kd values for [3H]spiperone binding were 0.057 nM for D2
receptors and 0.125 nM for D3 receptors.
Synthesis of (+)-N6-(2-(4-(2-Methoxyphenyl)piperazin-1-
yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ((+)-32). Compound (+)-28 (0.24 g, 0.54 mmol) in 5 mL
of anhydrous THF was treated with borane-THF complex (3.3
mL) by following procedure H. Crude reaction mixture was purified
by flash chromatography on silica gel column using solvent system
ethyl acetate/methanol (90:10) to afford 0.15 g of compound (+)-
1
32 (64%). [R]D (+36.2° (c 1 , dichloromethane). H NMR (400
MHz, CDCl3): δ 0.87-0.92 (m, 3H), 1.42-1.51 (m, 2H), 1.70-1.74
(m, 1H), 1.98-2.02 (m, 1H), 2.46-2.60 (m, 6H), 2.65-2.74 (m,
8H), 3.01-3.09 (m, 5H), 3.86 (s, 3H, -OCH3), 4.74 (bs, 2H,
-NH2), 6.84-7.01 (m, 4H). The product was converted into
corresponding dioxalate salt, mp 170-173 °C. Anal. (C23H35-
N5OS·2C2H2O4 ·1.7H2O) C, H, N.
Synthesis of (-)-N6-(2-(4-(2-Methoxyphenyl)piperazin-1-
yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ((-)-32). Compound (-)-28 (0.15 g, 0.34 mmol) in 25
mL of anhydrous THF was treated with borane-THF complex (1.8
mL) by following procedure H. Crude reaction mixture was purified
by flash chromatography on silica gel column using solvent system
ethyl acetate/methanol (80:20) to afford compound (-)-32. [R]D
Measurement of Stimulation of Dopamine D2 and D3
receptors. [35S]GTPγS Binding. All procedures were as described
in our recent work.39 The general procedures used for measuring
[35S]GTPγS binding are modified from protocols described for DA
receptors51 and other G-protein-coupled receptors.52,53 Chinese
hamster ovary (CHO) cells expressing human D2L receptors and
ATt-20 cells expressing human D3 receptors served as the source
for membrane fractions that were washed and resuspended with
assay buffer containing Mg2+, Na+, EGTA, and bovine serum
1
-40.2° (c 1.0, dichloromethane). H NMR (400 MHz, CDCl3) δ
7.03-6.82 (m, 4H), 4.84 (bs, 2H), 3.86 (s, 3H), 3.20-3.00 (m,
5H), 2.84-2.64 (m, 8H), 2.64-2.45 (m, 6H), 2.06-1.96 (m, 1H),
1.80-1.67 (m, 1H), 1.49 (h, J ) 7.2 Hz, 2H), 0.89 (t, J ) 7.2 Hz,
3H). The product was converted into corresponding tetrahydro-
chloride salt (0.10 g), mp ∼210 °C (dec). Anal. (C23H35-
N5OS·4HCl·0.6H2O) C, H, N.

3018 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 10
Biswas et al.
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albumin. The GTPγS binding assays were performed in triplicate
in a final volume of 1 mL containing test drug, DA (1 mM for D2
cells and 100 µM for D3 cells) as indicator of binding plateau,
[35S]GTPγS (1.72 nM, 1,250 Ci/mmol, Perkin-Elmer), and cell
suspension (cells suspended in assay buffer and GDP for final
concentration of 3 µM in assay). After incubation at room
temperature in a shaking water bath for 60 min, cells were harvested
on Brandel GF/B filter mats with a 24-pin Brandel harvester
(Biomedical Research & Development Laboratories, Inc., Gaith-
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to determine 35S radioactivity at 70% efficiency. Nonspecific
binding of [35S]GTPγS measured in the presence of 10 µM GTPγS
was a very small fraction (5% or less) of basal binding in the
absence of drug and did not impact 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).
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. Animals were housed
in a temperature and humidity controlled room with a 12 h light/
dark cycle. Food and water were accessible to animals freely
throughout the duration of study. All testing occurred during the
light component. All animal procedures were reviewed and ap-
proved by Wayne State University animal investigation committee
consistent with AALAC guidelines.
The first 14 days postlesion challenge with apomorphine was
done to observe a complete rotation session postadministration. In
the second challenge with apomorphine (0.05 mg/kg) 21 days
postlesion, contralateral rotations were recorded for 30 min;
apomorphine produced rotations in all four rats (average rotation
of >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 this study, apomorphine
was also used as a reference compound. The test drugs were
dissolved in 5% ꢀ-hydroxycyclodextrin solution and were admin-
istered. The number of rotations was measured over 10 h. For
control, vehicle was administered alone. Rotations were measured
in the Rotomax rotometry system (AccuScan Instruments, Inc.,
Columbus, OH) equipped with Rotomax analyzer, high resolution
sensor, and animal chambers with harnesses. Data were analyzed
with Rotomax Window software program. Test drugs (-)-33 (2.5
and 5 µmol/kg) and (-)-34 (2.5 and 5 µmol/kg) dissolved in 5%
ꢀ-hydroxycyclodextrin solution were administered sc. The rotations
were measured in a rotational chamber immediately after admin-
istration of drugs. The data were collected at every 30 min. Data
were analyzed by the Graph Pad (version 4, San Diego, CA)
program. Compounds (-)-33 and (-)-34 produced contralateral
rotations in all lesioned rats which lasted over 8-10 h.
Acknowledgment. This work was supported by National
Institute of Neurological Disorders and Stroke, National Insti-
tutes of Health (Grant NS047198, A.K.D.). We are grateful to
Prof. J. Shine, Garvan Institute for Medical Research, Sydney,
Australia, for D2L expressing CHO cells and to Dr. K. Neve,
Oregon Health and Science University, Portland, OR, for D2L
and D3 expressing HEK cells.
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Supporting Information Available: Elemental analysis data for
all final targets. This material is available free of charge via the
Internet at http://pubs.acs.org.
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