Development of (S)-N6-(2-(4-(isoquinolin-1-yl)piperazin-1-yl) ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: Potent in vivo activity in Parkinson's disease anima

Article abstract of DOI:10.1021/jm901184n

Here we report structure - activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were

Full text of DOI:10.1021/jm901184n

J. Med. Chem. 2010, 53, 1023–1037 1023
DOI: 10.1021/jm901184n
Development of (S)-N6-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,
7-tetrahydrobenzo[d]-thiazole-2,6-diamine and Its Analogue as a D3 Receptor Preferring Agonist:
Potent in Vivo Activity in Parkinson’s Disease Animal Models
Balaram Ghosh,† Tamara Antonio,‡ Juan Zhen,‡ Prashant Kharkar,† Maarten E. A. Reith,‡ and Aloke K. Dutta*,†
†Wayne State University, Department of Pharmaceutical Sciences, Detroit, Michigan 48202 and ‡New York University,
Department of Psychiatry, New York, New York 10016
Received August 9, 2009
Here we report structure-activity relationship study of a novel hybrid series of compounds where structural
alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of
the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells ex-
pressing 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. SAR results identified compound (-)-24c (D-
301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC50 (GTPγS); D3=
0.52 nM; D2/D3 (EC50): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity.
The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson’s disease
(PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future
studies will explore potential use of these compounds in the neuroprotective therapy for PD.
Introduction
used more extensively in the therapy for PD than any other
class of drug molecules besides L-DOPA.15-19 The dopamine
receptor belongs to the class of seven-membered G-protein
coupled receptors and has been divided into two main classes
as D1-like and D2-like. D1-like receptors include D1 and D5
subtypes, whereas D2, D3, and D4 subtype receptors fall in the
D2-like category.20-26 This classification is 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 receptors are
located both pre- and postsynaptically and have a high affinity
for dopamine.27
Because of the high degree of homology between D2 and D3
receptors, especially in the transmembrane domain binding
regions for agonists, it has been challenging to develop agonist
with highly selectivity for D3 receptors.28,29 D3 preferring
agonists have been shown to be neuroprotective in both cell
culture and in vivo experiments.30-33 Some of the most selec-
tive agonist are pramipexole and ropinirole which are used as
therapeutic agents in PD.34,35 However, the neuroprotective
property of pramipexole has been shown to be complex and
mediated by both dopamine- and nondopamine-dependent
pathways.33,36 Recently, another D3 preferring agonist, [(þ)-
trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-
naphth[1,2-b]-1,4-oxazine] (R,R-S32504) has been developed
and shown to possess antiparkinsonian and neuroprotective
effects.37 Interestingly, pramipexole was also shown to be a
potent antidepressant agent in PD patient, speculated to be
due to its interaction with the D3 receptor in the mesolimbic
dopamine pathway which controls behavior and mood.38,39
Parkinson’s Disease (PDa) is a progressive neurodegenera-
tive disorder characterized by degeneration of the nigrostriatal
dopaminergic pathway. It is estimated that PD affects approxi-
mately 1% of people older than 65 years of age. It is primarily
a sporadic disorder, although a rare subset of population
(<10%) acquires this disease due to several genetic defects.1,2
Some of the symptoms associated with PD involve rigidity,
bradykinesia, resting tremor, and postural instability along
with cognitive and psychiatric complications.3-5 The neuro-
pathological hallmark of PD is the presence of Lewy bodies
(LB) in the surviving neurons of the substantia nigra.6,7 The
etiology of PD is not fully understood. Both oxidative stress
and mitochondrial dysfunction have been strongly implicated
in cell death.8-10 Recently, R-synuclein, a presynaptic protein
involved in fibrilization, has been implicated in the pathogen-
esis of PD.7,11 In a rare familial form of PD, a mutation in the R-
synuclein gene has been linked to autosomal dominant PD.12,13
Levo-DOPA (L-DOPA) has proven to be one of the main-
stay therapy for PD. However, prolonged use of L-DOPA gives
rise to motor fluctuations with dyskinesias and the decrease in
duration of response to a given L-DOPA dose.14 Prolong use of
L-DOPA also gives rise to “on” and “off” episodes, resulting in
additional complications. Dopaminergic agents have been
*To whom correspondence should be addressed. Phone: 1-313-577-
1064. Fax: 1-313-577-2033. E-mail: adutta@wayne.edu. Address: De-
partment of Pharmaceutical Sciences, Applebaum College of Pharmacy
& Health Sciences, Room 3128, Detroit, Michigan 48202.
a Abbreviations: GTPγS, guanosine 50-[g-thio]triphosphate; 5-OH-
DPAT, 5-hydroxy-2-(dipropylamino)tetralin; 6-OHDA, 6-hydroxy do-
pamine; CHO, Chinese hamster ovary; HEK, human embryonic kidney;
L-DOPA, (S)-(3,4-dihydroxyphenyl) alanine; DPPH, 1,1-diphenyl-2-
picryl-hydrazyl; PD, Parkinson’s disease.
r
2009 American Chemical Society
Published on Web 12/28/2009
pubs.acs.org/jmc

1024 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
Figure 1. Molecular structure of dopamine D3 receptor preferring agonists and antagonists.
Scheme 1a
a Reagents and conditions: (a) 3-5 mol % PdCl2[P(o-tol)3]2, NaOt-Bu, diglyme, reflux, 48 h; (b) POCl3, reflux, 2 h; (c) piperazine, i-propanol, reflux, 4
h; (d) SnCl2, 2H2O, ethanol, NaBH4, reflux 55 °C, 1.5 h; (e) bis-(2-chloroethyl)amine HCl, diglyme, K2CO3, reflux, 48 h; (f) Boc2O, EtOH; (g) n-BuLi,
trimethyl borate, -78 °C; (h) 4-bromopyridine, Pd(PPh3)4, Na2CO3; (i) TFA/CHCl3.
Such antidepressant effect was found to be beneficial for PD
patients. Besides developing agonists, there is now a growing
interest in developing selective antagonist for the D3 receptor
as therapeutic agents for psychiatric diseases and drugs of
abuse. Consequently, a large number of antagonists have been
developed so far which exhibited varying degree of selectiv-
ities.28,40
It is increasingly evident that for a complex disease such
as PD, a drug targeting only one target site will only parti-
ally address the therapeutic need of the disease. Thus it is
hypothesized that multifunctional drugs having multiple
pharmacological activities will be an effective disease modi-
fying agent in case of PD.41 In our effort to produce such
agent, we have undertaken one of our goals of introducing
antioxidant property in our D2/D3 hybrid agonist temp-
late which we established earlier.42,43 Recently, we have
reported the development of potent D3 preferring agonists,
which exhibited potent in vivo activity in PD animal model
experiments.44,45 It is believed that the neuroprotective
property of pramipexole might originate from its preferen-
tial D3 agonist property coupled with its antioxidant
activity, although some other mechanisms have also been
implicated.46,47 We hypothesize that a combination of
D3 preferential agonist property along with antioxidant
activity in a compound enhances its neuroprotective effect
as it will address an underlying oxidative stress in the
Parkinsonian brain. The current SAR study expands this
line of inquiry by including compounds having bulky
hydrophobic N-aryl substitutions in the piperazine moiety
to explore and map out the binding site interaction fur-
ther. Our earlier report described the development of a
2-aminothiazole based, high-affinity D3 selective agonist 2

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1025
Scheme 2a
a Reagents and conditions: (a) chloroacetonitrile, K2CO3, toluene, reflux, 3 h; (b) Raney nickel, H2, 60 psi, 8 h; (c) 7-methoxy-2-tetralone, NaCNBH3, AcOH,
dichloroethane, RT, overnight; (d) propionyl chloride, Et3N, CH2Cl2, 0 °C to RT, 4 h; (e) LiAlH4, THF, reflux, 4 h; (f) BBr3, CH2Cl2, -40 °C to RT, overnight.
Scheme 3a
a Reagents and conditions: (a) n-propylamine, NaCNBH3, CH3COOH, dichloroethane, RT, overnight; (b) chloroacetyl chloride, TEA, dichlor-
omethane, 0 °C, 30 min; (c) K2CO3, CH3CN, 80 °C, 2 h; (d) LiAlH4, THF, reflux, 2 h; (e) BBr3, -78 °C, CH2Cl2, overnight.
(D-264),44 which is currently undergoing in vivo evaluation
to determine its neuroprotective effect. We introduced
quinolines and isoquinolines in the hybrid structure as
analogues of 2. Future studies will indicate whether these
derivatives will have better pharmacokinetics properties
compared to 2.

1026 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
Scheme 4a
a Reagents and conditions: (a) 2-bromoethanol, K2CO3, AcCN, reflux; (b) oxalyl chloride, DMSO, Et3N, -78 °C; (c) NaCNBH3, AcOH,
1,2-dichloroethane.
Chemistry
amine under reductive amination condition to yield 16a-b.
Enantiomerically pure (-)-16b was obtained from racemic
16b using a synthetic chiral resolving agent following pre-
viously reported procedure.52,45 N-alkylation of 16a-b and
(-)-16b using chloroacetyl chloride in presence of triethyl
amine produced intermediate 17a-b and (-)-17b, which were
coupled with different aryl piperazines 8c-e to yield 18a-d
and (-)-18d in moderate to good yield. Reduction of the
amide group of 18a-d using LiAlH4 followed by demethyla-
tion using boron tribromide at -40 °C yielded the target
compounds 20a-d and (-)-20d.
Scheme 4 depicts the synthesis of (S)-(-)-pramipexole
hybrid analogues 24a-24d. Alkylation of 8c-f with 2-bro-
moethanol produced 21a-d, which were oxidized under
Swern oxidation conditions to the arylpiperazine acetalde-
hydes 22a-d. S-(-)-Pramipexole (23) was further condensed
with 22a-d under reductive amination conditions (NaCN-
BH3 as the reducing agent) to give hybrid analogues 24a-d.
Scheme 1 outlines the syntheses of different aryl piperazines
8a-f used in the following schemes to synthesize the target
compounds. Compound 8a and 8b were synthesized by
palladium(II) catalyzed amination reaction with two corre-
sponding aryl halides 1- or 2-bromonaphthalene with excess
piperazine.48 8c was prepared from commercially available 4-
hydroxyquinoline by chlorination reaction with POCl3 fol-
lowed by reflux in i-propyl alcohol with excess piperazine for 4
h.49 Compound 8d was synthesized from commercially avail-
able 5-nitroquinoline by reduction in presence of SnCl2 in
ethanol under refluxing condition for 1.5 h,50 followed by
reaction of the amino compound 6 with bis-(2-chloroethyl)-
amine HCl in presence of K2CO3 under reflux for 48 h.51 8e
was synthesized from 1-chloroisoquinoline by i-propyl alco-
hol reflux in presence of excess piperazine. Compound 8f was
synthesized by reaction of boronic acid intermediate 7b with
4-bromopyridine in the presence of palladium catalyst.
Scheme 2 depicts the synthesis of two target compounds
14a-b. Aryl piperazine 8a-b were N-alkylated with chloroa-
cetonitrile under reflux in presence of K2CO3 as base to
synthesize intermediate 9a-b, followed by Raney nickel
catalyzed hydrogenation to yield 10a-b, which was subjected
to reductive amination condition in presence of 7-methoxy-2-
tetralone to yield intermediates 11a-b. N-Alkylation of
11a-b with propionyl chloride in presence of triethyl amine
as base yielded 12a-b, which was reduced to the correspond-
ing amines 13a-b using LiAlH4 as reducing agent. The target
compounds 14a-b were obtained by demethylation of 13a-b
using 1 M solution of borontribromide in dichloromethane at
-40 °C to room temperature for overnight.
Discussion
Our earlier SAR studies with hybrid compounds produced
ligands which exhibited potent and selective agonist activity at
D3 receptor. Our two starting piperazine hybrid compounds
based on 7-OH-DPAT and 5-OH-DPAT were 1 (D-315)53
and 4 (D-237) (Figure 1).45 These first generation hybrid
compounds maintained similar affinities and selectivities for
D2/D3 receptors as their parent nonhybrid counterpart.
Further expansion of SAR studies led to the development of
compounds 2 and 3 (D-366),53 which exhibited high and
selective affinity for the D3 receptor.44,53 2 was among the
most potent and selective agonist for the D3 receptor devel-
oped so far. Our SAR studies indicated that the N-piperazinyl
substituent could be modified by introducting biphenyl and
The syntheses of compounds 20a-d are shown in Scheme 3.
5- or 7-Methoxy 2-tetralone was reacted with n-propyl

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1027
indole substituents without compromising affinity for the D3
receptor. It is important to point out here that for develop-
ment of D3 antagonist, one of the frequently used molecular
template consists of amide-piperazine moiety separated via a
linker where bulky aromatic substituents have been intro-
ducedmainly on the amide moiety.28 The compound BP 897 is
one of the prototypical example of a compound developed
from this template.
Table 1. Inhibition Constants for Competing for [3H]Spiperone Bind-
ing to Cloned rat D2L and D3 Receptors Expressed in HEK Cellsa
Ki, (nM), D2L
[3H]spiperone
Ki, (nM), D3
[3H]spiperone
D2L/
D3
compd
7-OH-DPAT
(-)-5-OH-DPAT
202 ( 34
58.8 ( 11.0
26.0 ( 7.5
264 ( 40
2.35 ( 0.29
1.36 ( 0.28
0.825 ( 0.136
0.92 ( 0.23
1.77 ( 0.42
0.570 ( 0.094
0.435 ( 0.13
0.685 ( 0.217
2.65 ( 0.65
1.27 ( 0.52
0.441 ( 0.101
0.40 ( 0.09
0.19 ( 0.03
2.61 ( 0.18
1.21 ( 0.16
2.23 ( 0.60
4.78 ( 0.89
86
43
4b
31.5
253
2 c
1 d
3 d
14a
40.6 ( 3.6
47.5 ( 6.2
13.5 ( 3.0
8.85 ( 1.75
7.08 ( 0.34
5.22 ( 0.71
21.7 ( 4.1
4.89 ( 0.20
3.74 ( 0.70
109 ( 14
22.9
83
In our current SAR study, we wanted to see the influence of
different piperazynyl N-aryl or heteroaryl moieties on interac-
tion with dopamine D2 and D3 receptors. Our previous report
indicated that bulky hydrophobic substituents attached to the
piperazine ring are well tolerated, as 2 and 3 retained affinity
and were selective for D3. Here we wanted to explore this
further with naphthalene and quinoline substituents. Our ini-
tial design to incorporate naphthalalen-1yl and naphthalene-
2yl substituents led to development of compounds 14a and 14b.
Compound 14a showed a 3- to 4-fold increase in binding affinity
for D2/D3 (Ki for D2 = 13.5 nM, Ki for D3 = 0.435 nM),
accompanied by increased selectivity for D3 (D2/D3 =
31.0) compared to 1. Compound 14b exhibited a binding
affinity (Ki for D2=8.85 nM, Ki for D3=0.685 nM) similar
to that of 14a, however, its selectivity (D2/D3=12.9) was re-
duced compared to that of 1and 14a. This result indicated that a
bulkier N-4-substituted group in the piperazine ring is well
tolerated by dopamine D2/D3 receptors. Next, we wanted to
introduce a heteroatom in the naphthalene moiety producing
different quinoline derivatives. Compound 20a with an N-
quinoline-4yl substitution in the piperazine ring displayed no
further increase in binding potency (Ki for D2=7.08 ( 0.34, Ki
for D3=2.65 ( 0.65 nM) compared to 14a or 14b, but its bind-
ing potency was still greater than that of 1although its selectivity
for D3 over D2 was reduced (D2/D3 = 2.67). The other
regioisomer 20b, which is a quinoline-5yl derivative, ex-
hibited comparable low nanomolar binding affinity for D2/D3
receptors (Ki for D2=5.22 nM, Ki for D3=1.27 nM). Both 20a
and 20b were not highly selective for the D3 receptor. Another
compound of this series was 20c, an isomeric isoquinoline-1yl
derivative displaying subnanomolar binding potency at D3
receptors (Ki=0.44 nM) while it was less potent at D2 recep-
tors (Ki=21.7 nM) compared to 20a and 20b. Consequently,
20c exhibited the highest selectivity for D3 receptors (D2/
D3=49.2) in this series of compounds. Subsequently, the posi-
tional effect of an aromatic 5-hydroxyl functionality in the
aminotetraline moiety was evaluated on binding affinity and
selectivity. Thus, compounds 20d and its S(-) enantiomers
(20e) were synthesized. Compound 20d showed increased
binding affinity at both D2 and D3 receptors (Ki for D2 =
4.89 nM, Ki for D3=0.40 nM), although its selectivity for D3
receptors (D2/D3 = 12.22) did not increase appreciably. The
enantiomerically pure compound 20e exhibited increased
potency at both D2 (Ki =3.74 nM) and D3 (Ki =0.19 nM)
receptors compared with its racemic counterpart, with compar-
able selectivity for D3 over D2 receptors (D2/D3=19.68).
In one of our earlier publications, we reported compound 2
as one of the most potent and selective compounds for the D3
receptor; this compound contains a 2-aminothiazolidium
moiety as bioisosteric replacement of the hydroxyl phenyl
moiety in the aminotetraline fragment of the hybrid structure.
In designing the next set of compounds 24a-d, we incorpo-
rated a 2-aminothiazolidinium moiety instead. In addition to
probing the D3 receptor selectivity for these derivatives, we
aimed for improved pharmacokinetic properties by the intro-
duction of the more polar quinoline moiety. Specifically, the
31.0
12.9
2.67
4.11
49.2
12.23
19.68
41.8
47.7
121
14b
20a
20b
20c
20d
(-)-20d
(-)-24a
(-)-24b
(-)-24c
(-)-24d
57.7 ( 3.3
269 ( 16
270 ( 28
56.5
a Results are means ( SEM for 3-5 independent experiments each
performed in triplicate. b See ref 45. c See ref 44. d See ref 53
(-)-isomers of these compounds were made, as we have shown
previously that activity is increased in the (-)-isomers in the
2-aminothiazolidinium series of compounds (Table 1).44
Compound 24a, which is a quinoline-4yl analogue, exhibited
moderate binding affinity for D2 receptors (Ki =109 nM),
while the binding affinity toward D3 (Ki=2.61 nM) receptor
was in the low nanomolar range with selectivity for D3 over
D2 receptors (D2/D3=41.8), higher than that for the corres-
ponding 20a. Compound 24c, an isoquinoline-1yl derivative,
exhibited approximately 2-fold less potency at D2 (Ki=269
nM) and identical affinityatD3 (Ki=2.23nM) receptors com-
pared to 24a. Thus, compound 24c displayed the highest
selectivity (D2/D3=121) for D3 receptor in the current series
of compounds. The other thiazolidinium compound in this
series was quinoline-5yl derivative 24b, which displayed high
binding affinity for both D2 and D3 receptors (Ki for D2 =
57.7nM, Ki for D3 = 1.21nM) withappreciableselectivityfor
D3 over D2 receptors (D2/D3 = 47.7). Next we designed and
synthesized compound 24d, consisting of a linearly fused
4-(pyridine-4-yl)-phenyl moiety. This compound could retain
its binding affinity at D2 and D3 receptors (Ki = 270 nM and
4.78 nM for D2 and D3 receptors, respectively) and was
moderately selective for D3 over D2 receptors (D2/D3 =
56.5). Collectively, the current results are consonant with the
existence of hydrophobic interactions resulting from bulky
substitutions on the piperazine N-atom.
Following binding analysis, selected compounds 24c, 24b,
and 24a were subjected to the [35S]GTPγS functional assay
for D2 and D3 receptors and compared with the full agonist
dopamine. The assays were carried out with the cloned human
D2 and D3 receptors expressed in CHO and AtT cells as
described by us earlier.45 All three compounds exhibited high
potency for the D3 receptor inthe subnanomolar range (EC50;
0.52, 0.52, and 0.49 nM, respectively) (Table 2). Similar to
what was found in the D2 binding assays, isoquinoline
derivative 24c exhibited the lowest potency for D2 receptors
in the functional assays with [35S]GTPγS (EC50; 116 nM); it
was also the most selective for D3 (D2/D3 (EC50 ratio) =
223), and this selectivity was comparable to our previously
developed 2 (D2/D3 (EC50 ratio) = 248). Like compounds
24b and 24c, compound 24a was potent at D3 (EC50: 0.49 nM)

1028 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
Table 2. Stimulation of [35S]GTPγS Binding to Cloned Human D2 Receptor Expressed in CHO Cells and Cloned Human D3 Receptor Expressed in
AtT-20 Cellsa
CHO-D2
EC50 (nM) [35S]GTPγS
AtT-D3
EC50 (nM) [35S]GTPγS
compd
%Emax
%Emax
D2/D3
dopamine
ropinirole
209 (4) ( 29
304 ( 11
100
8.53 ( 0.62
19.2 ( 5.1
0.520 ( 0.16
0.528 ( 0.077
0.493 ( 0.12
1.23 ( 0.53
100
24.5
15.83
223
83.9 ( 0.3
88.4 ( 3.9
104 ( 2
118 ( 4
80.0 ( 4.4
119 ( 6
91.6 ( 0.5
95.1 ( 2.1
101 ( 2
96.8 ( 4.4
91.2 ( 1.0
102 ( 19
24c
24b
116 ( 16
13.5 ( 4.3
77.2 ( 8.3
41.2 ( 6.0
19.9 ( 0.9
25
156
24a
5-OH-DPAT
2
33.49
248
0.085 ( 0.016
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 3-5 independent experimentseach performed in
triplicate.
Figure 2. DPPH radical scavenging activity by 24b, 24c, and
ascorbic acid.
and was less potent at D2 (EC50: 77 nM). Compound 24a was
the second best selective compound for D3 receptor. Com-
pound 24b displayed the highest potency in activating D2
receptors (EC50; 13.5 nM) and was the least selective in
activating D3 receptors. In comparison, the reference com-
pound ropinirole displayed much less selectivity for and
potency at D3 receptors. As demonstrated by plateaus of
activation of 80-119% of maximal stimulation by DA, all
compounds appeared to exert close to full agonism in the
[35S]GTPγS assay (Table 2).
Evaluation of Free Radical Scavenging Activity. Scaven-
ging of DPPH (1,1-diphenyl-2-picryl-hydrazyl) radical by
24c, 24b, and ascorbic acid was carried out based on pub-
lished method and is shown in Figure 2.54 The scavenging
effect is expressedas percentof control. As shown inFigure2,
all three compounds inhibited DPPH radical activity dose
Figure 3. Effects of different drugs (administered sc) upon reser-
dependently. The standard compound ascorbic acid had an
IC50 of 34.6 ( 3.6 μM in this assay procedure, whereas the
IC50 value for 24b was 39.67 ( 6.23 μM and for 24c 45.67 (
6.89 μM (n = 3 for all compounds). It is evident from the
results that the two test compounds are as potent as known
antioxidant ascorbic acid.
Reversal of Reserpine-Induced Hypolocomotion in Rats by
24a, 24b, 24c and Ropinirole. Reserpine induces depletion of
catecholamines in nerve terminals resulting in a cataleptic
condition in rats, which is a well established animal model for
PD.55 Significant reduction of locomotion of the rats was
observed 18 h after the administration of reserpine (5 mg/kg,
sc), which indicated the development of akinesia in rats.
Compounds 24c and 24b were highly efficacious in produ-
cing complete reversal of reserpine induced hypolocomotion.
At a dose of 10 μmol/kg (6.5 mg/kg), sc, 24b not only reversed
the reserpine-induced hypokinetic condition to a level that
was similar or higher than that in control (vehicle treated
pine (5.0 mg/kg, sc, 18 h pretreatment)-induced hypolocomotion in
rats. Each point is the mean ( SEM for six rats. Horizontal activity
was measured as described under materials and methods section.
(A). Representation of horizontal locomotor activity at discrete 30
min intervals after the administration of 24a, 24b, 24c, and ropinir-
ole at the dose of 10 μmol/kg compared to control rats in 18 h
reserpine post treatment. (B) Representation of cumulative hori-
zontal activity data for 6 h period of observation for saline-control,
meaning animals receive saline instead of reserpine, reserpinized
control, and 10 μmol/kg of ropinirole, 24a, 24b, and 24c. One way
ANOVA analysis demonstrates significant effect among treat-
ments: (A) F (6.95) = 13.69 (P < 0.0001). Dunnett’s analysis
following ANOVA showed that the effects of 24b (P < 0.01), 24c
(P < 0.01), and ropinirole (P < 0.05) were significantly different
statistically compared to reserpine control but for 24a was not
statistically significant (P > 0.05).
nonreserpinized rats) rats but also maintained an increased
level of locomotor activity of the reserpinized rats signifi-
cantly throughout the 6 h period (Figure 3A). Subcutaneous

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1029
Figure 4. Effect on turning behavior of (-)-24b and ropinirole in 6-
OHDA unilaterally lesioned rats studied over 10 hours. Each point is
the mean ( SEM for four rats. All drugs were administered sc imme-
diately beforecounting rotational activity. One way ANOVA analysis
demonstrates a significant effect among treatments: F (5.95) = 16.93
(P < 0.0001). Dunnett’s analysis shows that the effect of (-)-24b at
two doses (5 and 10 μmol/kg) and ropinirole at two doses (5 and 10
μmol/kg) are significantly different compared to vehicle (P < 0.01).
Figure 5. Effect on turning behavior of (-)-24c and ropinirole in 6-
OHDA unilaterally lesioned rats studied over seven and a half
hours. Each point is the mean ( SEM for four rats. All drugs were
administered sc immediately before counting rotational activity.
One way ANOVA analysis demonstrates a significant effect among
treatments: F (5.95) = 16.23 (P < 0.0001). Dunnett’s analysis
shows that the effect of (-)-24c at two doses (5 and 10 μmol/kg)
and ropinirole at two doses (5 and 10 μmol/kg) are significantly
different compared to vehicle (P < 0.01).
administration of 10 μmol/kg (6.3 mg/kg) 24c and 10 μmol/
kg (2.96 mg/kg) ropinirole could restore the locomotion to
the normal state. The reference drug ropinirole at a dose of
10 μmol/kg sc exhibited a much shorter duration of action
compared to 24b; the peak of action of ropinirole was
reached within 30 min and the pharmacological action
ceased after 150 min. It is evident that out of the three
compounds, 24b and 24c exhibited the highest CNS loco-
motor activity (Figure 3A). On the other hand, compound
24a (10 μmol/kg) was much less active compared to 24b and
24c. Cumulative horizontal activity data for 6 h period of
observation for saline-control, meaning animals received
saline instead of reserpine, reserpinized control, and 10
μmol/kg of ropinirole. 24a, 24b, and 24c is presented as a
bar graph in Figure 3B.
rotations of 3688 with a long duration of action (>8 h), Figure 5.
The peak activity for 24c was reached at about 7 h. At the
lower dose of 5 μmol/kg (3.16 mg/kg), compound 24c produced
a lower number of rotations (2805) which lasted for 7 h
(Figure 5). It is evident that contrary to stimulating locomotor
activity in reserpinized rats, 24c was more efficacious compared
to 24b in regard to the total number of rotations produced by
respective doses. However, 24b exhibited relatively longer
duration of action. The reference drug ropinirole at 5 and 10
μmol/kg exhibited shorter duration of action and was less
active in producing rotations compared to 24b and 24c at the
same respective doses.
Conclusion
Effect of 24b, 24c, and Ropinirole in 6-OHDA Lesioned
Rats. On the basis of the above locomotor activity results,
compounds 24b and 24c were selected for in vivo evalua-
tion in rats carrying a unilateral lesion in the medial fore-
brain bundle induced by application of the neurotoxin
6-hydroxydopamine (6-OHDA). This results in destruction
of dopamine neurons and development of 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 pos-
sible antiparkinsonian properties.56 Both compounds 24b
and 24c produced potent rotational activity in a dose depen-
dent manner when administered subcutaneously. Thus, 24b
produced dose dependently contralateral rotations, with the
highest dose (10 μmol/kg, 6.5 mg/kg) exhibiting the longest
duration of action (>10 h). At a lower dose (5 μmol/kg, 3.28
mg/kg), 24b reached its peak effect at around 5 h and
produced a number of total rotations of 2295, whereas at a
higher dose (10 umol/kg) the peak effect was reached at
around 7.5 h with 2648 total rotations (Figure 4). It was clear
that 24b was more efficacious in producing rotations at a
higher dose. However, in the first 360 min, the lower dose of 24b
produced significantly higher rotations compared to the higher
dose, indicating possible involvement of stereotype at a higher
dose. In comparison, compound 24c when tested at a dose of 10
μmol/kg (6.3 mg/kg) produced an even higher number of total
The present study describes the development of compounds
with high affinity and selectivity for dopamine D3 receptors.
SAR results have demonstrated that isoquinoline derivatives
have higher selectivity for D3 receptor. In both binding and
functional assays, compound isoquinoline derivative 24c ex-
hibited the highest selectivity for the D3 over D2 receptor.
Lead compounds 24b and 24c also exhibited potent free
radical quenching property, possibly indicating antioxidant
activity. The two lead compounds were tested in two PD
animal models. Compound 24b was the most potent in the
reserpinized animal model, where it exhibited appreciable
locomotor activity, while compound 24c was as active as
ropinirole in this animal model. However, in the 6-OHDA
animal model studies, 24c produced the highest number of
rotations and was the most efficacious among the three com-
pounds. Compound 24b produced a slightly longer duration
of action. Both compounds were more efficacious than ropi-
nirole. Relative contribution of D2 receptor vs D3 receptor in
reversing reserpine effect and to induce rotations by com-
pounds24b and 24c will be assessed infuture. Compounds24b
and 24c will next be studied in the in vitro and in vivo
neuroprotection experiment model to evaluate their potential
as a neuroprotective treatment agent for PD.
Experimental Section
Reagents and solvents were purchased from commercial sup-
pliers and used as received unless otherwise indicated. Dry solvent

1030 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
was obtained according to the standard procedure. All reactions
were performed under inert atmosphere (N2) unless otherwise
noted. Analytical silica gel 60 F254-coated TLC plates were
obtained from EMD Chemicals, Inc. and were visualized with
UV light or by treatment with phosphomolybdic acid (PMA),
Dragendorff’s reagent, or ninhydrin. Flash column chromato-
graphic purifications were performed using Whatman Purasil 60A
silica gel 230-400 mesh. The proton nuclear magnetic resonance
(1H NMR) spectra were measured on a Varian 400 MHz FT
NMR spectrometer using tetramethylsilane (TMS) as an internal
standard. The NMR solvent used was CDCl3 asindicated. Optical
rotations were recorded on Perkin-Elmer 241 polarimeter. Melt-
ing points were recorded using MEL-TEMP II (Laboratory
Devices Inc., USA) capillary melting point apparatus and were
uncorrected. Elemental analyses were performed by Atlantic
Microlab, Inc. and were within (0.4% of the theoretical value.
Procedure A. Preparation of 1-(Naphthalen-1-yl)piperazine
(8a). Into a solution of 1-bromo naphthalene (3 g, 14.5 mmol)
and piperazine (9.98 g, 115.6 mmol) in 50 mL of diglyme was
added Na-t-butoxide (4.89 g, 43.46 mmol). The reaction mixture
was stirred for few minutes before the addition of palladium
catalyst, dichlorobis(tri-o-tolylphosphine)palladium(II) (0.724
g, 0.724 mmol) and refluxed at 170 °C for 48 h. The reaction
mixture was cooled and the diglyme was evaporated under
reduced pressure. The solid residue was partitioned between
ethyl acetate and water. The aqueous layer was extracted with
ethyl acetate (3 ꢀ 100 mL). The combined organic layer was
dried (Na2SO4), evaporated under educed pressure to get the
crude product, which was purified by column chromatography
(ethylacetate:MeOH 9:1) to yield 1.94 g of pure yellowish oily
compound 8a (63%). 1H NMR (400 MHz, CDCl3): δ ppm
7.68-7.74 (m, 2H), 7.54-7.56 (d, 1H, J = 8 Hz), 7.45-7.48 (t,
1H, J=6 Hz), 7.38-7.42 (m, 1H), 7.26-7.30 (t, 1H, J=8 Hz),
7.08-7.14 (dd, 1H, J=8 Hz), 3.08-3.33 (m, 8H).
1-(Naphthalen-2-yl)piperazine (8b). Compound 8b was syn-
thesized from 2-bromo naphthalene (1.8 g, 8.9 mmol) and
piperazine (6.13 g, 71.17 mmol) according to the procedure A
to afford 1.88 g of oily pure compound 8b (63.55%). 1H NMR
(400 MHz, CDCl3): δ ppm 7.72-7.73 (d, 1H, J=4 Hz), 7.70-
7.71 (d, 1H, J = 4 Hz), 7.68 (s, 1H), 7.37-7.41 (t, 1H, J = 8 Hz),
7.25-7.30 (m, 2H), 7.11-7.12 (d, 1H, J = 4 Hz), 3.09-3.33
(m, 8H).
Procedure B. Preparation of 2-(4-(Naphthalen-1-yl)piperazin-
1-yl)acetonitrile (9a). A suspension of 1-(naphthalene-1-yl)-pi-
perazine (8a) (1.94 g, 9.13 mmol), potassium carbonate (3.77 g,
27.39 mmol), and 2-chloroacetonitrile (1.16 mL, 18.26 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 (Na2-
SO4), concentrated, and purified by column chromatography
(ethyl acetate/hexane = 1:1) to afford the product 9a as a thick
yellow solid (1.95 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm
7.68-7.64 (m,2H), 7.54-7.56 (d, 1H, J = 8 Hz), 7.45-7.48 (t,
1H, J = 6 Hz), 7.38-7.42 (m, 1H), 7.26-7.30 (t, 1H, J = 8 Hz),
7.08-7.14 (dd, 1H, J = 8 Hz), 3.60 (s, 2H), 3.33-3.36 (t, 4H,
J = 6 Hz), 2.81-2.83 (t, 4H, J = 4 Hz).
dried over Na2SO4, evaporated, and purified over a silica gel
column using the solvent system ethyl acetate/methanol/triethy-
lamine (80:15:5) to afford compound 10a as transparent thick
liquid (0.823 g, 94%). 1H NMR (400 MHz, CDCl3) δ ppm
7.68-7.64 (m, 2H), 7.54-7.56 (d, 1H, J = 8 Hz), 7.45-7.48 (t,
1H, J = 6 Hz), 7.38-7.42 (m, 1H), 7.26-7.30 (t, 1H, J = 8 Hz),
7.08-7.14 (dd, 1H, J = 8 Hz), 3.31 (t, 4H, J = 4 Hz), 3.11-3.15
(m, 2H), 2.91-2.96 (m, 2H), 2.71-2.74 (t, 4H, J = 6 Hz).
2-(4-(Naphthalen-2-yl)piperazin-1-yl)ethanamine (10b). Com-
pound 10b was synthesized from compound 9b (1 g, 3.98 mmol)
according to the procedure C to afford 10b as transparent thick
liquid (0.90 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm
7.72-7.73 (d, 1H, J = 4 Hz), 7.70-7.71 (d, 1H, J = 4 Hz),
7.68 (s, 1H), 7.37-7.41 (t, 1H, J = 8 Hz), 7.25-7.30 (m, 2H),
7.11-7.12 (d, 1H, J=4 Hz), 3.30-3.34 (t, 4H, J=6 Hz), 3.13-
3.14 (bs, 2H), 2.90-2.92 (bs, 2H), 2.62-2.73 (m, 4H).
Procedure D. Preparation of 7-Methoxy-N-(2-(4-(naphthalen-
1-yl)piperazin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine
(11a). A mixture of compound 10a (0.823 g, 3.22 mmol), 7-
methoxy-2-tetralone (0.624 g, 3.5 mmol), and glacial acetic acid
(HOAc) (0.19 mL) in 1,2-dichloroethane (50 mL) was stirred at
room temperature under N2 atmosphere for 20 min. Sodium
cyanoborohydride (NaCNBH3) (0.81 g, 12.88 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 evapo-
rated, and saturated NaHCO3/H2O (50 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
1
the product 11a as brown wax (0.84 g, 56%). H NMR (400
MHz, CDCl3) δ ppm 7.68-7.64 (m,2H), 7.54-7.56 (d, 1H, J =
8 Hz), 7.45-7.48 (t, 1H, J = 6 Hz), 7.38-7.42 (m, 1H), 7.26-
7.30 (t, 1H, J = 8 Hz), 7.08-7.14 (dd, 1H, J = 8 Hz), 6.69-7.01
(d, 1H, J = 8 Hz), 6.67-6.70 (d, 1H, J = 12 Hz), 6.62 (s, 1H),
3.76 (s, 3H), 3.27-3.33 (t, 4H, J = 6 Hz), 2.48-2.93 (m, 13H),
1.65-1.68 (m, 2H).
7-Methoxy-N-(2-(4-(Naphthalen-2-yl)piperazin-1-yl)ethyl)-1,2,
3,4-tetrahydronaphthalen-2-amine (11b). Compound 10b (0.90 g,
3.5 mmol) was reacted with 7-methoxy-2-tetralone (0.745 g, 4.23
mmol), NaCNBH3 (0.866 g, 14.99 mmol), and HOAc (0.2 mL)
in 1,2-dichloroethane (50 mL) to yield 11b brown wax (0.855 g,
59%) (procedure D). 1H NMR (400 MHz, CDCl3) δ ppm
7.72-7.73 (d, 1H, J=4 Hz), 7.70-7.71 (d, 1H, J=4 Hz), 7.68
(s, 1H), 7.37-7.41 (t, 1H, J=8 Hz), 7.25-7.30 (m, 2H), 7.11-
7.12 (d, 1H, J = 4 Hz), 6.69-7.01 (d, 1H, J = 8 Hz), 6.67-6.70
(d, 1H, J = 12 Hz), 6.62 (s, 1H), 3.76 (s, 3H), 3.27-3.33 (t, 4H,
J = 6 Hz), 2.48-2.93 (m, 13H), 1.65-1.68 (m, 2H).
Procedure E. Preparation of N-(7-Methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-(2-(4-(naphthalen-1-yl)piperazin-1-yl)ethyl)-
propionamide (12a). Propionyl chloride (0.22 mL, 2.5 mmol) was
added into a solution of compound 11a (0.343 g, 0.83 mmol) and
Et3N (1.0 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 12a as yellow oil (0.318 g, 82%). 1H NMR (400
MHz, CDCl3) δ ppm 7.68-7.64 (m,2H), 7.54-7.56 (d, 1H, J =
8 Hz), 7.45-7.48 (t, 1H, J=6 Hz), 7.38-7.42 (m, 1H), 7.26-
7.30 (t, 1H, J = 8 Hz), 7.08-7.14 (dd, 1H, J = 8 Hz), 6.69-7.01
(d, 1H, J=8 Hz), 6.67-6.70 (d, 1H, J=12 Hz), 6.62 (s, 1H), 3.76
(s, 3H), 3.27-3.33 (t, 4H, J=6 Hz), 2.48-2.93 (m, 13H), 1.95-
1.99 (m, 2H), 1.65-1.68 (m, 2H), 1.15-1.19 (t, 3H, J = 8 Hz).
N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4-
(naphthalen-2-yl)piperazin-1-yl)ethyl)propionamide (12b). Com-
pound 11b (0.855 g, 2.07 mmol) was reacted with propionyl
chloride (0.54 mL, 6.22 mmol) and Et3N (2.0 mL) in CH2Cl2 (20
mL) (procedure E). The crude product was purified by flash
2-(4-(Naphthalen-2-yl)piperazin-1-yl)acetonitrile (9b). Com-
pound 9b was synthesized from 1-(naphthalene-2-yl)-piperazine
(8b) (1.2 g, 5.6 mmol) and 2-chloropropionitrile (1.08 mL, 16.96
mmol) according to the procedure B to afford product 9b as a
thick yellow solid (1.0 g, 83%). 1H NMR (400 MHz, CDCl3) δ
ppm 7.72-7.73 (d, 1H, J = 4 Hz), 7.70-7.71 (d, 1H, J = 4 Hz),
7.68 (s, 1H), 7.37-7.41 (t, 1H, J = 8 Hz), 7.25-7.30 (m, 2H),
7.11-7.12 (d, 1H, J = 4 Hz), 3.33-3.36 (t, 4H, J = 6 Hz),
2.81-2.83 (t, 4H, J = 4 Hz).
Procedure C. Preparation of 2-(4-(Naphthalen-1-yl)piperazin-
1-yl)ethanamine (10a). A solution of compound 9a in methanol
(0.86 g, 3.42 mmol) was hydrogenated in a Parr hydrogenator
apparatus in the presence of Raney nickel catalyst at a pressure
of 60 psi for 8 h. The reaction mixture was passed through celite,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1031
chromatography using solvent system EtOAc/MeOH = 90:10 to
yield pure compound 12b as yellow oil (0.5 g, 51.5%). 1H NMR
(400 MHz, CDCl3) δ ppm 7.72-7.73 (d, 1H, J = 4 Hz), 7.70-7.71
(d, 1H, J = 4 Hz), 7.68 (s, 1H), 7.37-7.41 (t, 1H, J = 8 Hz), 7.25-
7.30 (m, 2H), 7.11-7.12 (d, 1H, J=4 Hz), 6.69-7.01 (d, 1H, J=
8 Hz), 6.67-6.70 (d, 1H, J=12 Hz), 6.62 (s, 1H), 3.76 (s, 3H),
3.27-3.33 (t, 4H, J=6 Hz), 2.48-2.93 (m, 13H), 1.95-1.99 (m,
2H), 1.65-1.68 (m, 2H), 1.15-1.19 (t, 3H, J=8 Hz).
Procedure F. Preparation of 7-Methoxy-N-(2-(4-(Naphthalen-
1-yl)piperazin-1-yl)ethyl)-N-propyl-1,2,3,4-tetrahydronaphtha-
len-2-amine (13a). Compound 12a (0.318 g, 0.68 mmol) in
anhydrous THF (20 mL) was added dropwise into a suspension
of lithium aluminum hydride (LiAlH4) (0.0.154 g, 4.07 mmol) in
anhydrous THF (15 mL) at 0 °C under N2 atmosphere. The
reaction mixture was refluxed for 4 h, cooled to room tempera-
ture, 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
13a as brown wax (0.246 g, 79%). 1H NMR (400 MHz, CDCl3)
δ ppm 7.68-7.64 (m,2H), 7.54-7.56 (d, 1H, J=8 Hz), 7.45-
7.48 (t, 1H, J = 6 Hz), 7.38-7.42 (m, 1H), 7.26-7.30 (t, 1H, J=8
Hz), 7.08-7.14 (dd, 1H, J=8 Hz), 6.69-7.01 (d, 1H, J=8 Hz),
6.67-6.70 (d, 1H, J=12 Hz), 6.62 (s, 1H), 3.76 (s, 3H), 3.27-
3.33 (t, 4H, J = 6 Hz), 2.48-2.93 (m, 15H), 1.95-1.99 (m, 2H),
1.65-1.68 (m, 2H), 0.89-0.92 (t, 3H, J=6 Hz).
(d, 1H, J = 4 Hz), 6.87-6.89 (d, 1H, J = 8 Hz), 6.55-6.58
(d, 1H, J = 12 Hz), 6.46 (s, 1H), 3.27-3.33 (t, 4H, J = 6 Hz),
2.48-2.93 (m, 15H), 1.95-1.99 (m, 2H), 1.65-1.68 (m, 2H),
0.89-0.92 (t, 3H, J = 6 Hz). The product was converted into the
corresponding trihydrochloride salt as white solid, mp 208-211
°C. Anal. calcd for (C29H40Cl3N3O) C, H, N.
4-Chloroquinoline (5).57 This intermediate was made accord-
ing to the reported procedure.49 Commercially available 4-
hydroxyquinoline (1.0 g, 6.9 mmol) was dissolved in POCl3
(3.2 mL, 34.4 mmol) under nitrogen atmosphere and refluxed
for 2 h. It was then cooled and concentrated under vacuo. The
solid concentrate was taken in a beaker with 100 mL water,
neutralized with NaHCO3 powder, and extracted with EtOAc.
The solution was dried over Na2SO4, filtered, and concentrated.
This crude product was then purified by flash chromatography
(EtOAc/hexane = 50:50) to afford compound 5 as off white
solid (0.92 g, 81.6%). 1H NMR (400 MHz, CDCl3) δ ppm
8.74-8.75 (d, 1H, J=4.8 Hz), 8.16-8.18 (d, 1H, J=8 Hz), 8.10-
8.12 (d, 1H, J = 8 Hz), 7.71-7.75 (t, 1H, J = 8 Hz), 7.57-7.61
(t, 1H, J = 8 Hz), 7.43-7.44 (d, 1H, J = 4 Hz).
Procedure H. Preparation of 4-(Piperazin-1-yl)quinoline (8c).
A mixture of 4-chloroquinoline 5 (0.92 g, 5.6 mmol) and
piperazine (4.8 g, 56.2 mmol) in isopropyl alcohol (30 mL)
was refluxed for 4 h. The solvent was evaporated in vacuo,
and the solid obtained was dissolved in dichloromethane (20
mL) and washed with satd NaHCO3 solution followed by water
(2 ꢀ 20 mL). The organic layer was dried (Na2SO4), and the
solvent was evaporated in vacuo to get yellow oily liquid in
quantitative yield. It was used without further purification in the
next step. 1H NMR (400 MHz, CDCl3) δ ppm 8.73-8.74 (d, 1H,
J = 4 Hz), 8.02-8.06 (t, 2H, J = 8 Hz), 7.63-7.67 (t, 1H, J = 8
Hz), 7.46-7.50 (t, 1H, J = 8 Hz), 6.83-6.84 (d, 1H, J = 4 Hz),
3.16-3.18 (m, 8H).
7-Methoxy-N-(2-(4-(naphthalen-2-yl)piperazin-1-yl)ethyl)-N-
propyl-1,2,3,4-tetrahydronaphthalen-2-amine (13b). Compound
12b (0.50 g, 1.07 mmol) was reacted with LiAlH4 (0.243 g, 6.4
mmol) in THF (20 mL) by following the procedure F. The crude
product was purified by flash chromatography using solvent
system EtOAc/MeOH/Et3N = 95:4:1 to yield compound 13b as
1
brown wax (0.393 g, 80.7%). H NMR (400 MHz, CDCl3) δ
ppm 7.72-7.73 (d, 1H, J = 4 Hz), 7.70-7.71 (d, 1H, J = 4 Hz),
7.68 (s, 1H), 7.37-7.41 (t, 1H, J = 8 Hz), 7.25-7.30 (m, 2H),
7.11-7.12 (d, 1H, J = 4 Hz), 6.69-7.01 (d, 1H, J = 8 Hz), 6.67-
6.70 (d, 1H, J = 12 Hz), 6.62 (s, 1H), 3.76 (s, 3H), 3.27-3.33 (t,
4H, J=6 Hz), 2.48-2.93 (m, 15H), 1.95-1.99 (m, 2H), 1.65-
1.68 (m, 2H), 0.89-0.92 (t, 3H, J=6 Hz).
Quinolin-5-amine (6). Into the solution of 5-nitroquinoline
(1.5 g, 8.6 mmol) in absolute ethanol was added stannous
chloride dihydrate (10.92 g, 43.06 mmol). The mixture was
refluxed at 60 °C for 1 h. NaBH4 (0.022 g, 4.3 mmol) was added
to it and refluxed for another 30 min. The reaction mixture was
cooled, ethanol was evaporated, and the concentrate was dis-
solved in water. The reaction mixture was made alkaline with
40% aq NaOH and extracted with ethyl acetate (3 ꢀ 100 mL).
The organic layer was evaporated under reduced pressure and
dried (Na2SO4) to get a yellow liquid of almost quantitative
yield. It was used in the next step without further purification.
1H NMR (400 MHz, CDCl3) δ ppm 8.89-8.90 (d, 1H, J=4 Hz),
8.17-8.19 (d, 1H, J=8 Hz), 7.57-7.59 (d, 1H, J=8 Hz), 7.49-
7.53 (t, 1H, J=8 Hz), 7.34-7.37 (dd, 1H, J=4 Hz), 6.82-6.84 (d,
1H, J = 8 Hz).
5-(Piperazin-1-yl)quinoline (8d). 5-Aminoquinoline 6 (2.2 g,
15.3 mmol) and bis(2-chloroethyl)amine HCl (3.27 g, 18.3
mmol, 1.2 equiv) were refluxed in diglyme for 2 days. The
reaction mixture was cooled and diglyme was evaporated in
vacuo. To the solid residue water and ethyl acetate were added
and extracted with (3 ꢀ 100 mL) ethyl acetate. The combined or-
ganic layers were washed with water, dried (Na2SO4), and the
solvent was evaporated to get the crude product which was puri-
fied by column chromatography (dichloromethane/MeOH =
4:1) to afford a resinous pure mass. Yield: 56%. 1H NMR (400
MHz, CDCl3) δ ppm 8.85-8.86 (d, 1H, J = 4 Hz), 8.70-8.71 (d,
1H, J=4 Hz), 7.80-7.82 (d, 1H, J = 8 Hz), 7.72-7.76 (t, 1H,
J=8 Hz), 7.57-7.60 (dd, 1H, J = 4 Hz), 7.34-7.36 (d, 1H, J=
8 Hz), 3.51-3.54 (t, 4H, J = 6 Hz), 3.30-3.34 (m, 4H).
1-(Piperazin-1-yl)isoquinoline (8e). It was synthesized follow-
ing the procedure H to furnish 8e using 1-chloroisoquinoline 7
(0.95 g, 5.8 mmol) and piperazine (2.5 g, 29 mmol) in isopropyl
alcohol (50 mL) with quantitative yield of 8e as a yellow
semisolid. It was used without further purification in the next
step. 1H NMR (400 MHz, CDCl3) δ ppm 8.14-8.16 (d, 1H, J =
8 Hz), 8.08-8.10 (d, 1H, J = 8 Hz), 7.72-7.74 (d, 1H, J =
8 Hz), 7.57-7.61 (t, 1H, J=8 Hz), 7.48-7.52 (t, 1H, J=8 Hz),
Procedure G. Preparation of 7-((2-(4-(Naphthalen-1-yl)-
piperazin-1-yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphtha-
len-2-ol (14a, Hhydrochloride Salt). Boron tribromide (1 M
solution in dichloromethane) (1.62 mL, 1.62 mmol) was added
into a solution of 13a (0.246 g, 0.54 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 = 95:5) to afford compound
14a as yellowish thick oily (0.075 g, 32%). 1H NMR (400 MHz,
CDCl3) δ ppm 7.68-7.64 (m,2H), 7.54-7.56 (d, 1H, J = 8 Hz),
7.45-7.48 (t, 1H, J = 6 Hz), 7.38-7.42 (m, 1H), 7.26-7.30 (t,
1H, J = 8 Hz), 7.08-7.14 (dd, 1H, J = 8 Hz), 6.87-6.89 (d, 1H,
J = 8 Hz), 6.55-6.58 (d, 1H, J = 12 Hz), 6.46 (s, 1H), 3.27-3.33
(t, 4H, J = 6 Hz), 2.48-2.93 (m, 15H), 1.95-1.99 (m, 2H),
1.65-1.68 (m, 2H), 0.89-0.92 (t, 3H, J = 6 Hz). The product
was converted into the corresponding trihydrochloride salt as
white solid, mp 202-205 °C. Anal. calcd for (C29H40N3Cl3O,
2H2O) C, H, N.
7-((2-(4-(Naphthalen-2-yl)piperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-2-ol (14b, Hydrochloride Salt).
Compound 13b (0.393 g, 0.86 mmol) was reacted with 1 M
BBr3/CH2Cl2 (2.6 mL, 2.6 mmol) in CH2Cl2 (20 mL) by
following the procedure G to furnish 14b as yellow wax (0.227
1
g, 59.4%). H NMR (400 MHz, CDCl3) δ ppm 7.72-7.73 (d,
1H, J = 4 Hz), 7.70-7.71 (d, 1H, J = 4 Hz), 7.68 (s, 1H),
7.37-7.41 (t, 1H, J = 8 Hz), 7.25-7.30 (m, 2H), 7.11-7.12

1032 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
7.23-7.24 (d, 1H, J = 4 Hz), 3.39-3.41 (t, 4H, J = 4 Hz),
3.15-3.18 (t, 4H, J = 6 Hz),), 2.72 (brs, 1H).
2-Chloro-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
N-propyl-acetamide (17b). This compound was prepared from
16b by following the procedure J (93%). 1H NMR (400 MHz,
CDCl3) 6.96-7.04 (m, 1H), 6.61-6.68 (m, 2H), 4.00 (s, 3H),
3.19-3.27 (m, 2H), 1.64-1.72 (m, 2H), 0.90-0.98 (m, 3H).
(-)-2-Chloro-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-propylacetamide (-)-17b. Compound (-)-16b (1.20 g,
5.47 mmol) was reacted under similar conditions as reported
above (procedure J) to afford the optically pure (-)-17b as
transparent liquid (1.58 g, 97%). 1H NMR (400 MHz, CDCl3) δ
7.07-7.15 (m, 1H), 6.65-6.71 (m, 2H), 4.08-4.12 (m, 2H),
3.95-4.03 (m, 1H), 3.80-3.82 (d, 3H, -OCH3), 3.15-3.26 (m,
2H), 3.00-3.10 (m, 2H), 2.84-2.89 (dd, 1H, J1 = 16.0 Hz, J2 =
4.8 Hz), 1.83-2.12 (m, 2H), 2.58-2.70 (m, 1H), 1.61-1.73 (m,
2H), 0.90-0.97 (m, 3H, CH2CH3),
Procedure K. Preparation of N-(7-Methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-propyl-2-(4-(quinolin-4-yl)piperazin-1-yl)-
acetamide (18a). Compound 17a (0.70 g, 2.4 mmol) and 8c
(0.614 g, 2.84 mmol) were refluxed in CH3CN (100 mL) in
presence of K2CO3 (1.635 g, 11.83 mmol) for 2 h. The solution
was cooled, filtered, and concentrated. The crude material was
then partitioned between EtOAc and H2O, and the organic layer
was separated, dried (Na2SO4), and concentrated. The crude
mixture was purified by column chromatography (EtOAc:
MeOH; 4:1) to give 0.45 g (41%) of 18a as yellow sticky mass.
1H NMR (400 MHz, CDCl3) δ ppm 8.73-8.74 (d, 1H, J=4 Hz),
8.04-8.06 (d, 1H, J=8 Hz), 7.99-8.02 (d, 1H, J=12 Hz), 7.64-
7.68 (t, 1H, J = 8 Hz), 7.46-7.50 (t, 1H, J = 8 Hz), 7.01-7.03
(d, 1H, J = 8 Hz), 6.83-6.84 (d, 1H, J = 4 Hz), 6.62-6.64 (d,
1H, J = 8 Hz), 6.66 (s, 1H), 3.76 (s, 3H), 3.49 (s, 2H), 2.82-3.30
(m, 13H), 2.55 (brs, 2H), 1.85-2.07 (m, 2H), 1.63 (brs, 2H),
0.88-0.91 (t, 3H, J = 6 Hz).
Procedure I. Preparation of (7-Methoxy-1,2,3,4-tetrahydro-
naphthalen-2-yl)-propyl-amine (16a).45 7-Methoxy-2-tetralone
(10 g, 56.75 mmol) and acetic acid (13.5 mL, 226.9 mmol) were
dissolved in dichloroethane (150 mL) and cooled to 0 °C. Propyl
amine (11.7 mL, 141.87 mmol) was added, and the mixture was
stirred under a N2 atmosphere for 30 min. NaCNBH3 (8.915 g,
141.87 mmol) in anhydrous MeOH (15 mL) was then added to
the mixture and allowed to stir overnight at ambient tempera-
ture. The volatiles were then evaporated, and saturated NaH-
CO3 solution was added into the mixture. The compound was
then extracted into dichloromethane, dried over Na2SO4, fil-
tered, and concentrated. The crude residue was dissolved in
EtOAc, and ethereal HCl was added. The crude salt was filtered
and dried in a vacuum oven. The crude salt was then recrystal-
lized from ethanol. The white salt was collected via filtration and
dried to yield 9.5 g (65%) and used in the subsequent transfor-
mations. 1H NMR (free base) (400 MHz, CDCl3) 6.95-6.98 (d,
1H, J=8.8 Hz), 6.65-6.78 (m, 1H), 6.60-6.61 (dd, 1H, J=1.6
Hz), 3.81 (s, 3H), 2.97-3.04 (m, 1H), 2.88-2.92 (m, 2H), 2.67-
2.71 (t, 3H, J=7.6 Hz), 2.54-2.62 (m, 2H), 2.04-2.09 (m, 1H),
1.38 (bs, 1H), 1.48-1.60 (m, 3H), 0.91-0.95 (t, 3H, J = 7.6 Hz),
(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine
(16b). Compound 16b was prepared by following the procedure
I from 5-methoxy 2-tetralone (64%). 1H NMR (free base) (400
MHz, CDCl3) 7.07-7.11 (t, 1H, J=7.2 Hz), 6.96-6.71 (d, 1H,
J=8 Hz), 6.65-6.67 (d, 1H, J=8 Hz), 3.81 (s, 3H), 2.98-3.03
(m, 1H), 2.87-2.94 (m, 2H), 2.66-2.70 (t, 3H, J=7.6 Hz), 2.53-
2.62 (m, 2H), 2.05-2.10 (m, 1H), 1.49-1.61 (m, 3H), 1.39 (bs,
1H), 0.92-0.964 (t, 3H, J=7.6 Hz).
Resolution of 5-Methoxy-N-propyl-1,2,3,4-tetrahydronaph-
thalen-2-amine (-)-16b. Racemic compound 16b was resolved
into its (-) isomer by using the (þ) isomer of a synthetic resolv-
ing agent 4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-di-
oxaphosphorinane 2-oxide. The (þ) and the (-) resolving
agents were prepared according to the method of Ten Hoeve
and Wynberg. 16b (free base 14.77 g, 67.36 mmol) and (þ)-4-(2-
chlorophenyl)-5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphorinane
2-oxide (20.5 g, 74.1 mmol) were dissolved by warming in
100 mL of ethanol. The solution was cooled to room temperature
and then at 0 °C. The precipitated crystals were filtered off and
N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-
2-(4-(quinolin-5-yl)piperazin-1-yl)acetamide (18b). Compound
17a (0.472 g, 1.6 mmol) was reacted with 8d (0.23 g, 1.1 mmol)
in CH3CN (50 mL) by following the procedure K to furnish 18b
1
as a yellow sticky mass (0.240 g, 23%). H NMR (400 MHz,
CDCl3) δ ppm 8.89-8.90 (d, 1H, J = 4 Hz), 8.48-8.54 (t, 1H,
J = 12 Hz), 7.80-7.82 (d, 1H, J = 8 Hz), 7.61-7.65 (t, 1H, J =
8 Hz), 7.37-7.40 (dd, 1H, J = 4 Hz), 7.11-7.13 (d, 1H, J = 8
Hz), 6.99-7.00 (dd, 1H, J = 4 Hz), 6.65-6.75 (m, 1H), 6.60 (s,
1H), 3.76 (s, 3H), 2.80-3.45 (m, 15H), 2.55 (brs, 2H), 1.85-2.07
(m, 2H), 1.63 (brs, 2H), 0.88-0.91 (t, 3H, J = 6 Hz).
washed with cold ether to yield 17.4 g of the salt ([R]
=
D
2-(4-(Isoquinolin-1-yl)piperazin-1-yl)-N-(7-methoxy-1,2,3,4-
tetrahydronaphthalen-2-yl)-N-propylacetamide (18c). Com-
pound 17a (1.56 g, 5.27 mmol) was reacted with 8e (0.760 g,
3.5 mmol) in CH3CN (100 mL) by following the procedure K to
furnish 18c as a yellow sticky mass (1.45 g, 87%). 1H NMR (400
MHz, CDCl3) δ ppm 8.14-8.16 (d, 1H, J = 8 Hz), 8.08-8.10 (d,
1H, J = 8 Hz), 7.72-7.74 (d, 1H, J = 8 Hz), 7.57-7.61 (t, 1H,
J = 8 Hz), 7.48-7.52 (t, 1H, J = 8 Hz), 7.23-7.24 (d, 1H, J = 4
Hz), 6.98-7.02 (t, 1H, 8 Hz), 6.64-6.77 (m, 1H), 6.63 (s, 1H),
3.78 (s, 3H), 2.78-3.84 (m, 16H), 1.63-2.04(m, 5H), 0.90-0.98
(m, 3H).
(-)1.2°, c = 1 in methanol). Further recrystallization (2 times)
from hot ethanol yielded the salt (12.9 g, [R] D = (-)14.1°, c =
1 in methanol). Further crystallization of the salt from hot
ethanol did not change the optical rotation to a signifi-
cant extent. The salt was then neutralized in presence of 20%
NaOH solution in water under stirred condition for 2 h at room
temperature. The aqueous layer was extracted with dichloro-
methane (3 ꢀ 100 mL), dried over Na2SO4, and evaporated to
dryness to yield (-)-16b as transparent liquid (5.8 g, [R] D of the
white solid, HCl salt of (-)-16b = (-)71.5°, (c = 1 in methanol).
Yield 78.5%.
Procedure J. Preparation of 2-Chloro-N-(7-methoxy-1,2,3,4-
tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (17a). Com-
pound 16a (HCl salt, 3.117 g, 12.18 mmol) and Et3N (8.4 mL,
60.9 mmol) was stirred at 0 °C in CH2Cl2 (75 mL) for 30 min.
Chloroacetyl chloride (1.94 mL, 24.37 mmol) was added drop-
wise, and the resulting solution was stirred at room temperature
for 20 min, at which time the reaction mixture was poured onto a
1 M solution of NaOH (50 mL) and the product was extracted
with dichloromethane, dried (Na2SO4), filtered, and concen-
trated. The crude material was purified by column chromatog-
raphy (Hex:EtOAc, 3:1) to give 3.42 g (95%) of 17a as a
transparent liquid. 1H NMR (400 MHz, CDCl3)) 0.90-0.98
(m, 3H), 1.64-1.72 (m, 2H), 3.19-3.27 (m, 2H), 4.00 (s, 3H),
6.61-6.62 (dd, 1H, J=1.6 Hz), 6.64-6.77 (m, 1H), 6.96-6.99
(d, 1H, J = 8.8 Hz).
N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-
2-(4-(quinolin-4-yl)piperazin-1-yl)acetamide (18d). Compound
17b (1.1 g, 3.7 mmol) was reacted with 8c (0.855 g, 4.1 mmol)
in CH3CN (100 mL) by following the procedure K to furnish 18d
1
as a yellow sticky mass (1.63 g, 92.7%). H NMR (400 MHz,
CDCl3) δ ppm 8.73-8.74 (d, 1H, J = 4 Hz), 7.99-8.06 (m, 2H
Hz), 7.63-7.67 (t, 1H, J=8 Hz), 7.46-7.50 (t, 1H, J=8 Hz),
7.07-7.16 (m, 1H), 6.83-6.87 (m, 1H), 6.65-6.73 (m, 2H), 3.83
(s, 3H), 2.80-3.45 (m, 15H), 2.63 (brs, 1H), 2.05 (m, 2H),
1.65-1.71 (m, 2H), 1.24-1.28 (t, 1H, J = 4 Hz), 0.90-0.98
(m, 3H).
(S)-N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-pro-
pyl-2-(4-(quinolin-4-yl)piperazin-1-yl)acetamide (-)-18d. Com-
pound (-)-17b (0.67 g, 2.25 mmol) was reacted with 8c (0.539 g,
2.5 mmol) in CH3CN (100 mL) by following procedure K
to furnish (-)-18d as a yellow sticky mass (0.854 g, 79.8%).

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1033
1H NMR (400 MHz, CDCl3) δ ppm 8.73-8.74 (d, 1H, J = 4 Hz),
7.99-8.06 (m, 2H Hz), 7.63-7.67 (t, 1H, J = 8 Hz), 7.46-7.50
(t, 1H, J = 8 Hz), 7.07-7.16 (m, 1H), 6.83-6.87 (m, 1H), 6.65-
6.73 (m, 2H), 3.83 (s, 3H), 2.80-3.45 (m, 15H), 2.63 (brs, 1H),
2.05 (m, 2H), 1.65-1.71 (m, 2H), 1.24-1.28 (t, 1H, J = 4 Hz),
0.90-0.98 (m, 3H).
7-Methoxy-N-propyl-N-(2-(4-(quinolin-4-yl)piperazin-1-yl)ethyl)-
1,2,3,4-tetrahydronaphthalen-2-amine (19a). Compound 18a
(0.45 g, 0.95 mmol) was reacted with LiAlH4 (0.18 g, 4.76 mmol)
in THF (20 mL) by following procedure F to furnish 19a as a
yellow thick liquid (0.14 g, 35%). 1H NMR (400 MHz, CDCl3) δ
ppm 8.72-8.73 (d, 1H, J = 4 Hz), 8.04-8.06 (d, 1H, J = 8 Hz),
8.01-8.03 (d, 1H, J = 8 Hz), 7.63-7.67 (t, 1H, J = 8 Hz), 7.45-
7.49 (t, 1H, J = 8 Hz), 6.98-7.00 (d, 1H, J = 8 Hz), 6.83-6.84
(d, 1H, J = 4 Hz), 6.67-6.70 (d, 1H, J = 12 Hz), 6.64 (s, 1H),
3.77 (s, 3H), 3.26 (brs, 4H), 2.99-3.02 (m, 1H), 2.73-2.88 (m,
10H), 2.54-2.64 (m, 4H), 2.05 (brs, 1H), 1.49-1.66 (m, 3H),
0.90-0.94 (t, 3H, J = 8 Hz).
1H, J =4 Hz), 6.84-6.85 (d, 1H, J = 4 Hz), 6.63-6.65 (d, 1H,
J = 8 Hz), 6.58 (s, 1H), 3.26 (brs, 4H), 2.99-3.02 (m, 1H),
2.73-2.88 (m, 10H), 2.54-2.64 (m, 4H), 2.05 (brs, 1H), 1.49-
1.66 (m, 3H), 0.90-0.94 (t, 3H, J = 8 Hz).
The product was converted into the corresponding hydro-
chloride salt as white solid, mp 225-228 °C. Anal. calcd for
(C28H40Cl4N4O, 2.6H2O) C, H, N
7-(Propyl(2-(4-(quinolin-5-yl)piperazin-1-yl)ethyl)amino)-5,6,
7,8-tetrahydronaphthalen-2-ol (20b, Oxalate Salt). Compound
19b (0.20 g, 0.44 mmol) was reacted with 1 M BBr3/CH2Cl2 (1.74
mL, 1.74 mmol) in CH2Cl2 (20 mL) by following procedure G to
1
furnish 20b as a white wax (0.123 g, 63.4%). H NMR (400
MHz, CDCl3) δ ppm 8.87-8.89 (d, 1H, J = 8 Hz), 8.50-8.52 (d,
1H, J = 8 Hz), 7.79-7.81 (d, 1H, J = 8 Hz), 7.60-7.64 (t, 1H,
J = 8 Hz), 7.36-7.39 (dd, 1H, J = 4 Hz), 7.12-7.14 (d, 1H, J=8
Hz), 6.88-6.90 (d, 1H, J = 8 Hz), 6.62-6.64 (m, 1H), 6.55 (s,
1H), 2.80-3.45 (m, 15H), 2.04 (brs, 2H), 1.47-1.1.68 (m, 4H),
1.63 (brs, 2H), 0.88-0.91 (t, 3H, J = 6 Hz).
The product was converted into the corresponding oxalate
salt as a light yellowish solid, mp 155-158 °C. Anal. calcd for
(C34H42N4O13, 1.5H2O) C, H, N
7-Methoxy-N-propyl-N-(2-(4-(quinolin-5-yl)piperazin-1-yl)
ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (19b). Compound
18b (0.24 g, 0.51 mmol) was reacted with LiAlH4 (0.097, 2.5
mmol) in THF (20 mL) by following procedure F to furnish 19b
as a yellow thick liquid (0.200 g, 85.9%). 1H NMR (400 MHz,
CDCl3) δ ppm 8.87-8.89 (d, 1H, J = 8 Hz), 8.50-8.52 (d, 1H,
J = 8 Hz), 7.79-7.81 (d, 1H, J = 8 Hz), 7.60-7.64 (t, 1H, J = 8
Hz), 7.36-7.39 (dd, 1H, J = 4 Hz), 7.12-7.14 (d, 1H, J = 8 Hz),
6.97-7.00 (dd, 1H, J = 4 Hz), 6.65-6.75 (m, 1H), 6.60 (s, 1H),
3.76 (s, 3H), 2.80-3.45 (m, 15H), 2.04 (brs, 2H), 1.47-1.1.68 (m,
4H), 1.63 (brs, 2H), 0.88-0.91 (t, 3H, J = 6 Hz).
N-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-7-methoxy-N-
propyl-1,2,3,4-tetrahydronaphthalen-2-amine (19c). Compound
18c (1.42 g, 3.0 mmol) was reacted with LiAlH4 (0.570 g, 15.02
mmol) in THF (30 mL) by following procedure F to furnish 19c
as a yellow thick liquid (1.2 g, 87%). 1H NMR (400 MHz,
CDCl3) δ ppm 8.14-8.16 (d, 1H, J = 8 Hz), 8.08-8.10 (d, 1H,
J = 8 Hz), 7.72-7.74 (d, 1H, J = 8 Hz), 7.57-7.61 (t, 1H, J = 8
Hz), 7.48-7.52 (t, 1H, J = 8 Hz), 7.23-7.24 (d, 1H, J = 4 Hz),
6.98-7.02 (t, 1H, 8 Hz), 6.64-6.77 (m, 1H), 6.63 (s, 1H), 3.77 (s,
3H), 3.45 (brs, 4H), 2.78-3.00 (m, 11H), 2.57 (m, 5H), 2.05 (S,
1H), 1.51 (m, 2H), 0.90-0.93 (t, 3H, 6 Hz).
7-((2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-2-ol (20c, Hydrochloride Salt). Com-
pound 19c (1.0 g, 2.18 mmol) was reacted with 1 M BBr3/CH2Cl2
(8.7 mL, 8.7 mmol) in CH2Cl2 (50 mL) by following procedure G
to furnish 20c as white wax (0.600 g, 62%). 1H NMR (400 MHz,
CDCl3) δ ppm 8.10-8.12 (d, 1H, J = 8 Hz), 8.05-8.07 (d, 1H,
J = 8 Hz), 7.72-7.74 (d, 1H, J = 8 Hz), 7.59-7.63 (t, 1H, J=
8 Hz), 7.49-7.53 (t, 1H, J = 8 Hz), 7.24-7.26 (d, 1H, J = 8 Hz),
6.84-6.86 (d, 1H, 8Hz), 6.64-6.66 (d, 1H, J=8Hz), 6.57 (s, 1H),
3.47 (brs, 4H), 3.28 (brs, 1H), 3.04-2.66 (m, 14H), 2.21 (m, 1H),
2.04 (s, 1H), 1.69 (brs, 2H), 0.90-0.93 (t, 3H, 6 Hz).
The product was converted into the corresponding trihy-
drochloride salt as white solid, mp 140-142 °C. Anal. calcd
for (C28H39Cl3N4O, 1.4H2O) C, H, N
6-(Propyl(2-(4-(quinolin-4-yl)piperazin-1-yl)ethyl)amino)-5,6,
7,8-tetrahydronaphthalen-1-ol (20d, Hydrochloride Salt). Com-
pound 19d (0.30 g, 0.65 mmol) was reacted with 1 M BBr3/
CH2Cl2 (3.3 mL, 3.3 mmol) in CH2Cl2 (20 mL) by following
1
procedure G to furnish 20d as white wax (0.175 g, 45%). H
NMR (400 MHz, CDCl3) δ ppm 8.70-8.71 (d, 1H, J=4 Hz),
8.05-8.07 (d, 1H, J=8 Hz), 7.99-8.01(d, 1H, J = 8 Hz), 7.63-
7.67 (t, 1H, J = 8 Hz), 7.46-7.50 (t, 2H, J = 8 Hz), 6.93-6.97
(t, 1H, J=8 Hz), 6.83-6.84 (d, 1H, J=4 Hz), 6.70-6.72 (m, 1H),
6.59-6.60 (d, 1H, J = 4 Hz), 2.80-3.45 (m, 17H), 2.63 (brs, 1H),
2.05 (m, 2H), 1.65-1.71 (m, 2H), 1.24-1.28 (t, 1H, J = 4 Hz),
0.94-0.97 (t, 3H, J = 6 Hz).
The product was converted into the corresponding hydro-
chloride salt as white solid, mp 223-225 °C. Anal. calcd for
(C28H40Cl4N4O, C2H5OH) C, H, N.
(S)-6-(Propyl(2-(4-(quinolin-4-yl)piperazin-1-yl)ethyl)amino)-
5,6,7,8-tetrahydronaphthalen-1-ol.[(-)-20d (HydrochlorideSalt)].
Compound (-)-19d (0.193 g, 0.42 mmol) was reacted with 1 M
BBr3/CH2Cl2 (2.1 mL, 2.1mmol) inCH2Cl2 (20mL) by following
procedure G to furnish (-)-20d as white wax (0.83 g, 45%). 1H
NMR (400 MHz, CDCl3) δ ppm 8.70-8.71 (d, 1H, J = 4 Hz),
8.05-8.07 (d, 1H, J = 8 Hz), 7.99-8.01(d, 1H, J = 8 Hz), 7.63-
7.67 (t, 1H, J = 8 Hz), 7.46-7.50 (t, 2H, J = 8 Hz), 6.93-6.97 (t,
1H, J = 8 Hz), 6.83-6.84 (d, 1H, J = 4 Hz), 6.70-6.72 (m, 1H),
6.59-6.60 (d, 1H, J = 4 Hz), 2.80-3.45 (m, 17H), 2.63 (brs, 1H),
2.05 (m, 2H), 1.65-1.71 (m, 2H), 1.24-1.28 (t, 1H, J = 4 Hz),
0.94-0.97 (t, 3H, J = 6 Hz). [R]25D= -36° (c = 1, CH3OH). The
product was converted into the corresponding hydrochloride salt
as white solid, mp 219-222 °C. Anal. Calcd for C28H40Cl4N4O,
C2H5OH) C, H, N.
5-Methoxy-N-propyl-N-(2-(4-(quinolin-4-yl)piperazin-1-yl)
ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (19d). Compound
18d (1.63 g, 3.45 mmol) was reacted with LiAlH4 (0.654 g,
17.24 mmol) in THF (30 mL) by following procedure F to
1
furnish 19d as a yellow thick liquid (0.325 g, 21%). H NMR
(400 MHz, CDCl3) δ ppm 8.73-8.74 (d, 1H, J = 4 Hz), 7.99-
8.06 (m, 2H), 7.63-7.67 (t, 1H, J = 8 Hz), 7.46-7.50 (t, 1H, J=8
Hz), 7.08-7.12 (m, 2H), 6.83-6.84 (d, 1H, J = 4 Hz), 6.71-
6.73 (d, 1H, J=8 Hz), 3.83 (s, 3H), 2.80-3.45 (m, 17H), 2.63
(brs, 1H), 2.05 (m, 2H), 1.65-1.71 (m, 2H), 1.24-1.28 (t, 1H,
J=4 Hz), 0.90-0.98 (m, 3H).
(S)-5-Methoxy-N-propyl-N-(2-(4-(quinolin-4-yl)piperazin-1-yl)-
ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (-)-19d. Com-
pound (-)-18d (0.83 g, 1.76 mmol) was reacted with LiAlH4
(0.333 g, 8.8 mmol) in THF (20 mL) by following procedure F to
furnish (-)-19d as a yellow thick liquid (0.20 g, 24%). 1H NMR
(400 MHz, CDCl3) δ ppm 8.73-8.74 (d, 1H, J = 4 Hz), 7.99-
8.06 (m, 2H), 7.63-7.67 (t, 1H, J = 8 Hz), 7.46-7.50 (t, 1H, J=8
Hz), 7.08-7.12 (m, 2H), 6.83-6.84 (d, 1H, J = 4 Hz), 6.71-
6.73 (d, 1H, J=8 Hz), 3.83 (s, 3H), 2.80-3.45 (m, 17H), 2.63
(brs, 1H), 2.05 (m, 2H), 1.65-1.71 (m, 2H), 1.24-1.28 (t, 1H,
J=4 Hz), 0.90-0.98 (m, 3H).
7-(Propyl(2-(4-(quinolin-4-yl)piperazin-1-yl)ethyl)amino)-5,6,
7,8-tetrahydronaphthalen-2-ol (20a, Hydrochloride Salt). Com-
pound 19a (0.14 g, 0.31 mmol) was reacted with 1 M BBr3/
CH2Cl2 (1.22 mL, 1.22 mmol) in CH2Cl2 (20 mL) by following
procedure G to furnish 20a as a white wax (0.030 g, 31%). 1H
NMR (400 MHz, CDCl3) δ ppm 8.72-8.73 (d, 1H, J=4 Hz),
8.04-8.06 (d, 1H, J=8 Hz), 8.01-8.03 (d, 1H, J=8 Hz), 7.63-
7.67 (t, 1H, J=8 Hz), 7.45-7.49 (t, 1H, J=8 Hz), 6.89-6.91 (d,
4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)phenylboronic Acid
(7b). 1-(4-Iodophenyl)-piperazine HCl (0.5 g, 1.54 mmol) was
suspended in dichloromethane (15 mL) when Et3N (1 equiv)
was added dropwise. The clear solution was washed with
water, dried (Na2SO4), and the solvent evaporated to obtain

1034 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
pale-brown semisolid, which was dissolved in absolute EtOH.
Di-tert-butyl dicarbonate (0.34 g, 1.54 mmol) was added
to the above ethanolic solution and the reaction mixture
stirred for 30 min. The solvent was evaporated and the residue
taken in dichloromethane, washed with water, and dried
(Na2SO4) with subsequent removal of the solvent to yield
tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (0.56 g,
93%), which was used without further purification in the
next step.
To a solution of tert-butyl 4-(4-iodophenyl)piperazine-1-car-
boxylate (0.5 g, 2.601 mmol) in dry THF was added dropwise 2.5
M nBuLi in hexane solution (1.36 mL, 3.381 mmol, 1.3 equiv) at
-78 °C and the mixture stirred at the same temperature for 30
min. Trimethyl borate (0.38 mL, 3.381 mmol, 1.3 equiv) was
added dropwise over 15 min period. The mixture was stirred at
-78 °C for 1 h and then gradually warmed to RT when it was
quenched with 1.2 M HCl solution (pH 5-7) and then extracted
with diethyl ether (3 ꢀ 20 mL). The combined organic layers
were washed with brine, dried (Na2SO4), and the solvent
evaporated to get the boronic acid 7b (0.23 g, 58%). 1H NMR
(400 MHz, CDCl3) δ ppm 8.11-8.13 (d, 2H, J = 8 Hz),
6.98-7.0 (d, 2H, J = 8 Hz), 3.61-3.63 (t, 4H, J = 4 Hz), 3.31-
3.33 (t, 4H, J = 4 Hz), 1.50 (s, 9H).
1-(4-(Pyridin-4-yl)phenyl)piperazine (8f). A mixture of Pd-
(PPh3)4 (31.5 mg, 5 mol %) and 4-bromopyridine HCl (0.106
g, 0.544 mmol) in DME was stirred at RT for 30 min. The
suspension of boronic acid 7b (0.2 g, 0.653 mmol, 1.2 equiv) in
DME was added to the above solution followed by addition of 2
M Na2CO3 solution (0.55 mL, 2 equiv). The reaction mixture
was refluxed overnight, cooled to RT, and the solids filtered. To
the filtrate was added satd aq NH4Cl solution with subsequent
extraction by dichloromethane (3 ꢀ 20 mL). The combined
organic layers were dried (Na2SO4) and the solvent evaporated
in vacuo to get tert-butyl 4-(4-(pyridin-4-yl)phenyl)piperazine-
1-carboxylate (0.15 g, 68%).
2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethanol (21c). Yield: 64%,
oil, starting with 1.3 g (6.1 mmol) of 1-(piperazin-1-yl)isoquino-
line 8e. 1H NMR (400 MHz, CDCl3) ppm 8.13-8.14 (d, 1H, J=
4 Hz), 8.07-8.09 (d, 1H, J=8 Hz), 7.73-7.75 (d, 1H, J=8 Hz),
7.58-7.62 (t, 1H, J = 8 Hz), 7.48-7.52 (t, 1H, J = 8 Hz), 7.24-
7.25 (d, 1H, J=4 Hz), 3.68-3.7 (t, 2H, J = 4 Hz), 3.46 (brs, 4H),
2.80-2.82 (t, 4H, J=4 Hz), 2.67-2.70 (t, 2H, J=6 Hz), 2.56 (brs,
1H).
2-(4-(4-(Pyridin-4-yl)phenyl)piperazin-1-yl)ethanol (21d). Yield:
64%, sticky oil, starting with 0.1 g (0.43 mmol) of 1-(4-(pyridin-4-
yl)phenyl)piperazine 8f. 1H NMR (400 MHz, CDCl3) δ ppm
8.51-8.52 (d, 2H, J = 4 Hz), 7.50-7.52 (d, 2H, J = 8 Hz), 7.39-
7.40 (d, 2H, J = 4 Hz), 6.91-6.93 (d, 2H, J = 8 Hz), 3.61-3.64 (t,
2H, J = 6 Hz), 3.23-3.25 (t, 4H, J = 4 Hz), 3.0 (brs, 1H),
2.63-2.66 (t, 4H, J = 6 Hz), 2.56-2.58 (t, 2H, J = 4 Hz).
General Procedure for the Preparation of 2-(4-Arylpiperazin-
1-yl)acetaldehydes 22a-22d. To a solution of oxalyl chloride
(2 equiv) in dichloromethane (20 mL) at -78 °C was added
dimethyl sulfoxide (4 equiv). The mixture was stirred, and a
solution of 2-(4-arylpiperazin-1-yl)ethanol 21 in dichloro-
methane (10 mL) was added dropwise within 5 min. The stirring
was continued for 15-20 min at -78 °C. After the addition of
Et3N (6 equiv), the mixture was allowed to reach to RT and then
poured into water (25 mL). The aqueous phase was further
extracted with dichloromethane (2 ꢀ 20 mL). The combined
organic phases were concentrated in vacuo, and the residue
obtained was stirred with ether (20 mL). The ether solution was
dried (Na2SO4) and concentrated in vacuo to yield 2-(4-arylpi-
perazin-1-yl)acetaldehyde, which was used without further pur-
ification in the next step.
2-(4-(Quinolin-4-yl)piperazin-1-yl)acetaldehyde (22a). Yield:
73%, starting with 0.6 g (2.33 mmol) of 2-(4-(quinolin-4-
yl)piperazin-1-yl)ethanol 21a. This compound was found highly
unstable on exposure to air and was used in the next step without
further purification.
The deprotection of the N-Boc group was done by stirring
tert-butyl 4-(4-(pyridin-4-yl)phenyl)-piperazine-1-carboxylate
(0.15 g) in trifluoroacetic acid (2 mL) and chloroform (2 mL).
The trifluoro-acetate salt (obtained after the removal of the
solvent in vacuo) was converted to the free base using 1 M
2-(4-(Quinolin-5-yl)piperazin-1-yl)acetaldehyde (22b). Yield:
65%, starting with 0.8 g (3.1 mmol) of 2-(4-(quinolin-5-yl)-
piperazin-1-yl)ethanol 21b. 1H NMR (400 MHz, CDCl3) δ
ppm 9.69 (s, 1H), 8.80-8.81 (d, 1H, J=4 Hz), 8.40-8.42 (d,
1H, J = 8 Hz), 7.74-7.76 (d, 1H, J = 8 Hz), 7.53-7.57 (t, 1H,
J = 6 Hz), 7.28-7.31 (dd, 1H, J1 = 4 Hz, J2 = 8 Hz), 7.05-7.07
(d, 1H, J = 8 Hz), 3.24 (s, 2H), 3.0-3.1 (t, 4H, J = 20 Hz),
2.74-2.77 (t, 4H, J = 6 Hz).
2-(4-(Isoquinolin-1-yl)piperazin-1-yl)acetaldehyde (22c). Yield:
52%, starting with 0.8 g (3.1 mmol) of 2-(4-(isoquinolin-1-yl)
piperazin-1-yl)ethanol 21c. 1H NMR (400 MHz, CDCl3) δ ppm
9.72 (s, 1H), 8.07-8.09 (d, 1H, J = 8 Hz), 7.99-8.01 (d, 1H, J=
4 Hz), 7.67-7.69 (d, 1H, J = 8 Hz), 7.52-7.54 (t, 1H, J=4 Hz),
7.43-7.46 (t, 1H, J = 6 Hz), 7.18-7.20 (d, 1H, J = 8 Hz), 3.38-
3.44 (t, 4H, J=12 Hz), 3.23 (s, 2H), 2.75-2.77 (t, 4H, J=4 Hz).
2-(4-(4-(Pyridin-4-yl)phenyl)piperazin-1-yl)acetaldehyde (22d).
Yield: 70%, starting with 0.6 g (2.12 mmol) of 2-(4-(4-(pyridin-
4-yl)phenyl)piperazin-1-yl)ethanol 21d. 1H NMR (400 MHz,
CDCl3) δ ppm 9.67 (s, 1H), 8.50-8.52 (d, 2H, J = 8 Hz), 7.50-
7.52 (d, 2H, J = 8 Hz), 7.38-7.40 (d, 2H, J = 8 Hz), 6.91-6.93
(d, 2H, J = 8 Hz), 3.25-3.28 (t, 4H, J=6 Hz), 3.19 (s, 2H),
2.62-2.65 (t, 4H, J=6 Hz).
1
NaOH aq solution to yield 8f (0.1 g) as an oil. H NMR (400
MHz, CDCl3) δ ppm 8.51-8.52 (d, 2H, J = 4 Hz), 7.50-7.53 (d,
2H, J = 12 Hz), 7.39-7.40 (d, 2H, J = 4 Hz), 6.92-6.94 (d, 2H,
J=8 Hz), 3.16-3.18 (t, 4H, J=4 Hz), 2.98-3.0 (t, 4H, J=4 Hz),
1.89 (brs, 1H).
General Procedure for the Preparation of 2-(4-Arylpiperazin-
1-yl)ethanols 21a-21d. Into a stirring suspension of 1-arylpiper-
azine 8c-f and anhydrous K2CO3 (2 equiv) in acetonitrile,
bromoethanol (1.2 equiv) and KI (catalytic amt) were added.
The mixture was refluxed overnight and cooled to RT. The
solvent was evaporated in vacuo, and the residue was partitioned
between ethyl acetate and water. The aqueous layer was further
extracted with ethyl acetate (2 ꢀ 20 mL). The combined organic
layers were dried (MgSO4) and the solvent evaporated in vacuo to
yield oily liquid which was purified by column chromatography
(dichloromethane:MeOH 95:5) to obtain pure 21a-d.
2-(4-(Quinolin-4-yl)piperazin-1-yl)ethanol (21a). Yield: 71%,
yellow oil, starting with 0.7 g (3.28 mmol) of 4-(piperazin-1-
yl)quinoline 8c. 1H NMR (400 MHz, CDCl3) δ ppm 8.73-8.74
(d, 1H, J=4 Hz), 8.06-8.08 (d, 1H, J=8 Hz), 8.01-8.03 (d, 1H,
J = 8 Hz), 7.65-7.69 (m, 1H), 7.47-7.51 (m, 1H), 6.85-6.87 (d,
1H, J=8 Hz), 3.70-3.73 (t, 2H, J = 6 Hz), 3.30 (brs, 4H), 3.01
(brs, 1H), 2.84 (brs, 2H), 2.70-2.73 (t, 2H, J = 6 Hz).
2-(4-(Quinolin-5-yl)piperazin-1-yl)ethanol (21b). Yield: 67%,
starting with 1.0 g (4.69 mmol) of 5-(piperazin-1-yl)quinoline 8d.
1H NMR (400 MHz, CDCl3) δ ppm 8.92-8.96 (m, 1H),
8.53-8.59 (m, 1H), 7.87-7.92 (t, 1H, J = 10 Hz), 7.64-7.71
(m, 1H), 7.40-7.47 (m, 1H), 7.12-7.19 (m, 1H), 4.09 (s, 1H),
3.80-3.84 (t, 2H, J = 8 Hz), 3.13 (brs, 4H), 2.83 (brs, 4H),
2.72-2.78 (t, 2H, J = 12 Hz).
General Procedure for the Preparation of (S)-N6-Propyl-
N6-(2-(4-arylpiperazin-1-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thi-
azole-2,6-diamine 24a-24d. To a solution of 2-(4-arylpiperazin-
1-yl)acetaldehyde 22 (1.5 equiv) in dichloroethane, (S)-(-)-pra-
mipexole 23 {[R]D=-94° (c=0.5, CH3OH)} was added followed
by acetic acid (1 equiv). (S)-(-) pramipexole was made accord-
ing o the reported procedure.44 The mixture was stirred for 1 h at
RT. NaCNBH3 (3 equiv) was added to the reaction mixture
under vigorous stirring. The contents of the flask were stirred
overnight. Saturated NaHCO3 was added and the layers sepa-
rated. Aqueous layer was extracted with dichloromethane (2 ꢀ
20 mL). The combined organic layers were dried (Na2SO4) and

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1035
the solvent evaporated in vacuo to yield the crude product,
which was purified by column chromatography.
vigorously at 30 °C for 20 min. Control wells received 40 μL of
methanol and 200 μL of methanolic DPPH solution. Wells
containing only 240 μL of methanol served as background for
baseline correction. The changes in the absorbance of all the
samples and standard (ascorbic acid) were measured at 517 nm.
the radical scavenging activity was expressed as the inhibition
percentage and was calculated using the following formula: %
scavenging activity = [(absorbance of control - absorbance of
sample)/absorbance of control] ꢀ 100.54
(S)-N6-Propyl-N6-(2-(4-(quinolin-4-yl)piperazin-1-yl)ethyl)-4,
5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (24a). Yield: 35
mg, starting with 100 mg of (S)-(-)-pramipexole 23. Mobile
phase used for column chromatographic purification was di-
1
chloromethane:MeOH (95:5). H NMR (400 MHz, CDCl3) δ
ppm 8.65-8.66 (d, 1H, J = 4 Hz), 7.94-7.99 (m, 2H), 7.57-7.60
(t, 1H, J = 6 Hz), 7.39-7.43 (t, 1H, J = 8 Hz), 6.77-6.78 (d, 1H,
J = 4 Hz), 4.89 (brs, 2H), 3.20 (brs, 4H), 3.01 (brs, 1H), 2.62-
2.73 (m, 9H), 2.40-2.55 (m, 5H), 1.94-1.96 (brm, 1H), 1.65-
1.71 (m, 1H), 1.39-1.46 (m, 2H), 0.82-0.86 (t, 3H, J = 8 Hz).
[R]25D=-26.0° (c=1.0, CHCl3). The free base was converted to
HCl salt as white solid, mp = 212-214 °C. Analysis calcd for
Animal Experiment. Drugs and Chemicals. The following
commercially available drugs were used in the experiment:
reserpine hydrochloride (Alfa Aesar) and Ropinirole (Sigma
Aldrich). The hydrochloride salts of compounds 24a, 24b, 24c,
and ropinirole were dissolved in water for both locomotor and
6-OHDA rotational experiments. Reserpine was dissolved in
10-25 μL of glacial acetic acid and further diluted with 5.5%
glucose solution. All compounds for this study were adminis-
tered sc in a volume of 0.1 to 0.2 mL into each rat.
(C25H39Cl5N6S 0.5C2H5OC2H5) C, H, N.
3
(S)-N6-Propyl-N6-(2-(4-(quinolin-5-yl)piperazin-1-yl)ethyl)-4,
5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (24b). Yield: 24 mg,
starting with50mg of(S)-(-)-pramipexole23. Mobile phase used
for column chromatographic purification was dichloromethane:
Animals. In rodent studies, animals were male Sprague-
Dawley rats from Harlan (Indianapolis, IN) weighing 220-
225 g unless otherwise specified. The lesioned rats (290-320 g)
were purchased from Taconic Biotechnology (Rensselaer, NY),
and their unilateral lesion was checked twice by apomorphine
challenge following the surgery. Animals were maintained in
sawdust-lined cages in a temperature and humidity controlled
environment at 22 ( 1 °C and 60 ( 5%, respectively, with a 12 h
light/dark cycle, with lights on from 6:00 a.m. to 6:00 p.m. They
were group housed with unrestricted access to food and water.
All experiments were performed during the light component. All
animal use procedures were in compliance with the Wayne State
University Animal Investigation Committee consistent with
AALAC guidelines.
Reversal of Reserpine-Induced Hypolocomotion in Rats. Ad-
ministration of reserpine induces catalepsy in rodents primarily
by blocking the vesicular monoamine trasporter (VMAT),
which helps in the internalization of monoamines into vesicles,
resulting in metabolism of unprotected monoamines in the
cytosol that ultimately causes depletion of monoamines in
the synapse of the peripheral sympathetic nerve terminals.55,58
The ability of the compounds (24a, 24b, and 24c) to reverse the
reserpine induced hypolocomotion was investigated.59 Ropinir-
ole was used as standard reference compound in this study.
Reserpine (5.0 mg/kg, sc) or saline (sc) were administered 18 h
before the injection of drug or vehicle (sc). The rats were placed
individually in chambers for 1 h for acclimatization purpose
before the administration of the test drug, standard drug, or
vehicle. Immediately after administration of drug or vehicle,
animals were individually placed in versamax animal activity
monitor chamber (45 cm ꢀ 30 cm ꢀ 20 cm) (AccuScan Instru-
ments, Inc., Columbus, OH) to start measuring locomotor
activity. Locomotion was monitored for 6 h. Consecutive inter-
ruption of two infrared beams situated 24 cm apart and 4 cm
above the cage floor in the monitor chamber recorded move-
ment. The data were presented as horizontal counts (HACTV).
The effect of the individual doses of drugs on locomotor activity
was compared with respect to saline treated controls (mean (
SEM). The data were analyzed by one-way analysis of variance
(ANOVA) followed by Dunnett’s post hoc test. The effect was
considered significant if the difference from control group was
observed at p < 0.05.
1
MeOH (95:5). H NMR (400 MHz, CDCl3) δ ppm 8.87-8.89
(dd, 1H, J1=1.6 Hz, J2 = 4 Hz), 8.48-8.51 (d, 1H, J=12 Hz),
7.79-7.81 (d, 1H, J=8 Hz), 7.60-7.64 (t, 1H, J=8 Hz), 7.36-
7.39 (dd, 1H, J1 = 4 Hz, J2 = 8.4 Hz), 7.12-7.14 (d, 1H, J=
8 Hz), 4.84 (brs, 2H), 3.14 (brs, 5H), 2.59-2.81 (m, 14H), 2.04-
2.07 (brm, 1H), 1.73-1.82 (m, 1H), 1.54-1.56 (m, 2H), 0.9-0.94
(t, 3H, J=8 Hz). [R]25D= -23.85° (c=0.9, CHCl3). The free base
was converted to HCl salt as yellow solid, mp=112-114 °C.
Analysis calcd for (C25H38Cl4N6S) C, H, N.
(S)-N6-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-
4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine (24c). Yield: 48 mg,
starting with 50 mg of (S)-(-)-pramipexole 23. Mobile phase used
for column chromatographic purification was dichloromethane:
MeOH (95:5). 1H NMR (400 MHz, CDCl3) δ ppm 8.06-8.07 (d,
1H, J=4 Hz), 8.0-8.02 (d, 1H, J=8 Hz), 7.66-7.68 (d, 1H, J =
8 Hz), 7.51-7.55 (t, 1H, J=8 Hz), 7.41-7.45 (t, 1H, J=8 Hz),
7.16-7.18 (d, 1H, J = 8 Hz), 4.79 (brs, 2H), 3.40 (brs, 4H), 3.04
(brm, 1H), 2.62-2.74 (m, 9H), 2.43-2.58 (m, 5H), 1.95-1.97
(brm, 1H), 1.64-1.73 (m, 1H), 1.40-1.50 (m, 2H), 0.82-0.86 (t,
3H, J=8 Hz). [R]25D=-30.56° (c = 0.82, CHCl3). The free base
was converted to oxalate salt as white solid, mp = 100-102 °C.
Analysis calcd for (C35H44N6O20S H2O) C, H, N.
3
(S)-N6-Propyl-N6-(2-(4-(4-(pyridin-4-yl)phenyl)piperazin-1-yl)-
ethyl)-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine (24d). Yield:
20 mg, starting with 35 mg of (S)-(-)-pramipexole 23. Mobile
phase used for column chromatographic purification was dichlor-
1
omethane:MeOH (95:5). H NMR (400 MHz, CDCl3) δ ppm
8.51-8.52 (d, 2H, J=8 Hz), 7.50-7.52 (d, 2H, J=8 Hz), 7.39-
7.40 (d, 2H, J = 4 Hz), 6.91-6.93 (d, 2H, J = 8 Hz), 4.65 (brs,
2H), 3.21-3.23 (t, 4H, J = 4 Hz), 3.0 (brs, 1H), 2.44-2.66 (m,
14H), 1.92-1.99 (brm, 1H), 1.61-1.72 (m, 1H), 1.39-1.45 (m,
2H), 0.81-0.85 (t, 3H, J = 8 Hz). [a]25D= -22.08° (c = 0.56,
CHCl3). The free base was converted to HCl salt, off white solid,
mp = 206-210 °C. Analysis calcd for (C27H41Cl5N6S 0.8H2O
0.5C2H5OC2H5) C, H, N.
3
3
Evaluation of Potency in Binding to and Activating Dopamine
D2 and D3 Receptors. Binding potency was monitored by
inhibition of [3H]spiperone (15.0 Ci/mmole, Perkin-Elmer) bin-
ding to dopamine rD2 and rD3 receptors expressed in HEK-293
cells in a buffer containing 0.9% NaCl as described by us
previously.44 Functional activity of test compounds in activat-
ing dopamine hD2 and hD3 receptors expressed in CHO and
AtT cells, respectively, was measured by stimulation of [35S]-
GTPγS (1250 Ci/mmole, Perkin-Elmer) binding in comparison
to stimulation by the full agonist dopamine as described by us
previously.44
Evaluation of Antioxidant Activity. DPPH Radical Scaven-
ging Assay. To a 96 well plate, 40 μL of different concentra-
tions of methanolic drug solutions ranging from 20 to 250 μM
were added. Then 200 μL of 100 μM methanolic solution of
DPPH (1,1-diphenyl-2-picryl-hydrazyl) was added and shaken
In Vivo Rotational Experiment with 6-OHDA Lesioned Rats.
The first 14 days post lesion challenge with apomorphine was
done with lesioned animals to observe a complete rotation
session post administration. In the second challenge with apo-
morphine (0.05 mg/kg) 21 days post lesion, contralateral rota-
tions 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 of the medial forebrain bundle in the brain and
the coordinates used from Bregma are: AP-4.3, ML þ1.2, DV

1036 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3
Ghosh et al.
-8.3. The rotations produced upon agonist challenge occurring
clockwise. In this study, apomorphine was also used as a
reference compound. The test drugs including ropinirole were
dissolved in saline and were administered sc. The rats were
brought to the test room 1 h before the administration of the test
drug, standard drug, or vehicle for acclimatization purpose. The
rotations were measured over 7-10 h. For control, vehicle was
administered alone. Rotations were measured in the Rotomax
rotometry system (AccuScan Instruments, Inc., Columbus,
Ohio) equipped with Rotomax analyzer, high resolution sensor,
and animal chambers with harnesses. Data were analyzed with
Rotomax Windows software program. Test drugs 24c (5 and 10
μmol/kg), 24b (5 and 10 μmol/kg), and ropinirole (5 and 10
μmol/kg) dissolved in saline were administered sc. The rotations
were measured in a rotational chamber immediately after
administration of drugs. The data were collected at every 30
min. Data were analyzed by Graph Pad (Version 4, San Diego)
program. All drugs produced contralateral rotations in all
lesioned rats, which lasted over 3-10 h.
(14) Marsden, C. D.; Parkes, J. D. “On-off” effects in patients with
Parkinson’s disease on chronic levodopa therapy. Lancet 1976, 1,
292–296.
(15) Foley, P.; Gerlach, M.; Double, K. L.; Riederer, P. Dopamine
receptor agonists in the therapy of Parkinson’s disease. J. Neural
Transm. 2004, 111, 1375–1446.
(16) Schapira, A. H.; Olanow, C. W. Rationale for the use of dopamine
agonists as neuroprotective agents in Parkinson’s disease. Ann.
Neurol. 2003, 53 Suppl 3, S149-S57; discussion S157-S159.
(17) Clarke, C. E.; Guttman, M. Dopamine agonist monotherapy in
Parkinson’s disease. Lancet 2002, 360, 1767–1769.
(18) Lledo, A. Dopamine agonists: the treatment for Parkinson’s dis-
ease in the XXI century? Parkinson Relat. Disord. 2001, 7, 51–58.
(19) Dutta, A. K.; L., W. Existing Dopaminergic Therapies for Parkin-
son’s Disease. Expert Opin. Ther. Patents 2006, 16, 1613–1625.
(20) Kebabian, J. W.; Calne, D. B. Multiple receptors for dopamine.
Nature 1979, 277, 93–96.
(21) Giros, B.; Martres, M. P.; Sokoloff, P.; Schwartz, J. C. Gene
cloning of human dopaminergic D3 receptor and identification of
its chromosome. C. R. Acad. Sci. III 1990, 311, 501–508.
(22) Sokoloff, P.; Giros, B.; Martres, M. P.; Bouthenet, M. L.;
Schwartz, J. C. Molecular cloning and characterization of a novel
dopamine receptor (D3) as a target for neuroleptics. Nature 1990,
347, 146–151.
(23) Van Tol, H. H.; Bunzow, J. R.; Guan, H. C.; Sunahara, R. K.;
Seeman, P.; Niznik, H. B.; Civelli, O. Cloning of the gene for a
human dopamine D4 receptor with high affinity for the antipsy-
chotic clozapine. Nature 1991, 350, 610–614.
(24) Sunahara, R. K.; Guan, H. C.; O’Dowd, B. F.; Seeman, P.; Laurier,
L. G.; Ng, G.; George, S. R.; Torchia, J.; Van Tol, H. H.; Niznik,
H. B. Cloning of the gene for a human dopamine D5 receptor
with higher affinity for dopamine than D1. Nature 1991, 350,
614–619.
Acknowledgment. This work is supported by National
Institute of Neurological Disorders and Stroke/National In-
stitutes of Health (NS047198, A.K.D.). We are grateful to Dr.
K. Neve, Oregon Health and Science University, Portland,
OR, for D2L and D3 expressing HEK cells. We are also
grateful to Dr. J. Shine, Garvan Institute for Medical Re-
search, Sydney, Australia, for D2L expressing CHO cells and
Dr. Eldo Kuzhikandathil of UMDNJ-New Jersey Medical
School, Newark for AtT-D3 cells.
(25) Strange, P. G. New insights into dopamine receptors in the central
nervous system. Neurochem. Int. 1993, 22, 223–236.
(26) Civelli, O.; Bunzow, J. R.; Grandy, D. K. Molecular diversity of the
dopamine receptors. Annu. Rev. Pharmacol. Toxicol. 1993, 33, 281–307.
(27) Emilien, G.; Maloteaux, J. M.; Geurts, M.; Hoogenberg, K.;
Cragg, S. Dopamine receptors;physiological understanding to
therapeutic intervention potential. Pharmacol. Ther. 1999, 84, 133–
156.
Supporting Information Available: Elemental analysis data
for all final targets is available. This material is available free of
charge via the Internet at http://pubs.acs.org.
(28) Boeckler, F.; Gmeiner, P. The structural evolution of dopamine D3
receptor ligands: structure-activity relationships and selected
neuropharmacological aspects. Pharmacol. Ther. 2006, 112, 281–
333.
(29) Park, B. H.; Fishburn, C. S.; Carmon, S.; Accili, D.; Fuchs, S.
Structural organization of the murine D3 dopamine receptor gene.
J. Neurochem. 1995, 64, 482–486.
(30) Chen, S.; Zhang, X.; Yang, D.; Du, Y.; Li, L.; Li, X.; Ming, M.; Le,
W. D2/D3 receptor agonist ropinirole protects dopaminergic cell
line against rotenone-induced apoptosis through inhibition of
caspase- and JNK-dependent pathways. FEBS Lett. 2008, 582,
603–610.
(31) Bellucci, A.; Collo, G.; Sarnico, I.; Battistin, L.; Missale, C.; Spano,
P. Alpha-synuclein aggregation and cell death triggered by energy
deprivation and dopamine overload are counteracted by D2/D3
receptor activation. J. Neurochem. 2008, 106, 560–577.
(32) Joyce, J. N.; Millan, M. J. Dopamine D3 receptor agonists for
protection and repair in Parkinson’s disease. Curr. Opin. Pharma-
col. 2007, 7, 100–105.
(33) Ramirez, A. D.; Wong, S. K.; Menniti, F. S. Pramipexole inhibits
MPTP toxicity in mice by dopamine D3 receptor dependent and
independent mechanisms. Eur. J. Pharmacol. 2003, 475, 29–35.
(34) Gallagher, D. A.; Schrag, A. Impact of newer pharmacological
treatments on quality of life in patients with Parkinson’s disease.
CNS Drugs 2008, 22, 563–586.
(35) Yamamoto, M.; Schapira, A. H. Dopamine agonists in Parkinson’s
disease. Expert. Rev. Neurother. 2008, 8, 671–677.
(36) Gu, M.; Iravani, M. M.; Cooper, J. M.; King, D.; Jenner, P.;
Schapira, A. H. Pramipexole protects against apoptotic cell death
by non-dopaminergic mechanisms. J. Neurochem. 2004, 91, 1075–
1081.
References
(1) Mouradian, M. M. Recent advances in the genetics and pathogen-
esis of Parkinson disease. Neurology 2002, 58, 179–185.
(2) Moore, D. J.; West, A. B.; Dawson, V. L.; Dawson, T. M.
Molecular pathophysiology of Parkinson’s disease. Annu. Rev.
Neurosci. 2005, 28, 57–87.
(3) Paulus, W.; Jellinger, K. The neuropathologic basis of different
clinical subgroups of Parkinson’s disease. J. Neuropathol. Exp.
Neurol. 1991, 50, 743–755.
(4) Sherer, T. B.; Betarbet, R.; Greenamyre, J. T. Pathogenesis of
Parkinson’s disease. Curr. Opin. Investig. Drugs 2001, 2, 657–662.
(5) Wooten, G. F. Movement Disorders. Neurologic Principles and
Practice; McGraw-Hill: New York, NY, 1997; pp 153-160.
(6) Forno, L. S. Neuropathology of Parkinson’s disease. J. Neuro-
pathol. Exp. Neurol. 1996, 55, 259–272.
(7) Spillantini, M. G.; Schmidt, M. L.; Lee, V. M.; Trojanowski, J. Q.;
Jakes, R.; Goedert, M. Alpha-synuclein in Lewy bodies. Nature
1997, 388, 839–840.
(8) Jenner, P. Oxidative stress in Parkinson’s disease. Ann. Neurol.
2003, 53 Suppl 3, S26-S36; discussion S36-S38.
(9) Dawson, T. M.; Dawson, V. L. Molecular pathways of neurode-
generation in Parkinson’s disease. Science 2003, 302, 819–822.
(10) Betarbet, R.; Sherer, T. B.; MacKenzie, G.; Garcia-Osuna, M.;
Panov, A. V.; Greenamyre, J. T. Chronic systemic pesticide
exposure reproduces features of Parkinson’s disease. Nat. Neuros-
ci. 2000, 3, 1301–1306.
(11) Olanow, C. W.; Tatton, W. G. Etiology and pathogenesis of
Parkinson’s disease. Annu. Rev. Neurosci. 1999, 22, 123–144.
(12) Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.;
Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer,
R.; Stenroos, E. S.; Chandrasekharappa, S.; Athanassiadou, A.;
Papapetropoulos, T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin,
R. C.; Di Iorio, G.; Golbe, L. I.; Nussbaum, R. L. Mutation in the
alpha-synuclein gene identified in families with Parkinson’s dis-
ease. Science 1997, 276, 2045–2047.
(13) Kruger, R.; Kuhn, W.; Muller, T.; Woitalla, D.; Graeber, M.;
Kosel, S.; Przuntek, H.; Epplen, J. T.; Schols, L.; Riess, O.
Ala30Pro mutation in the gene encoding alpha-synuclein in
Parkinson’s disease. Nat. Genet. 1998, 18, 106–108.
(37) Joyce, J. N.; Presgraves, S.; Renish, L.; Borwege, S.; Osredkar, T.;
Hagner, D.; Replogle, M.; PazSoldan, M.; Millan, M. J. Neuro-
protective effects of the novel D3/D2 receptor agonist and anti-
parkinson agent, S32504, in vitro against 1-methyl-4-phenylpyri-
dinium (MPPþ) and in vivo against 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP): a comparison to ropinirole. Exp.
Neurol. 2003, 184, 393–407.
(38) Willner, P. The mesolimbic dopamine system as a target for
rapid antidepressant action. Int. Clin. Psychopharmacol. 1997,
12 (Suppl 3), S7–S14.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 3 1037
(39) Corrigan, M. H.;Denahan, A. Q.;Wright, C. E.;Ragual, R. J.;Evans,
D. L. Comparison of pramipexole, fluoxetine, and placebo in patients
with major depression. Depression Anxiety 2000, 11, 58–65.
(40) Newman, A. H.; Grundt, P.; Cyriac, G.; Deschamps, J. R.; Taylor,
M.; Kumar, R.; Ho, D.; Luedtke, R. R. N-(4-(4-(2,3-Dichloro- or
2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides
with functionalized linking chains as high affinity and enantiose-
lective D3 receptor antagonists. J. Med. Chem. 2009, 52, 2559–
2570.
(41) Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti,
V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands
to combat neurodegenerative diseases. J. Med. Chem. 2008, 51,
347–372.
(49) Madrid, P. B.; Sherrill, J.; Liou, A. P.; Weisman, J. L.; Derisi, J. L.;
Guy, R. K. Synthesis of ring-substituted 4-aminoquinolines and
evaluation of their antimalarial activities. Bioorg. Med. Chem. Lett.
2005, 15, 10151–10158.
(50) Dionne, G.;Humber, L. G.;Asselin, A.;McQuillan, J.; Treasurywala,
A. M. Ligand-receptor interactions via hydrogen-bond formation.
Synthesis and pharmacological evaluation of pyrrolo and pyrido
analogues of the cardiotonic agent 7-hydroxycyclindole. J. Med.
Chem. 1986, 29, 1452–1457.
(51) Orus, L.; Perez-Silanes, S.; Oficialdegui, A. M.; Martinez-Esparza,
J.; Del Castillo, J. C.; Mourelle, M.; Langer, T.; Guccione,
S.; Donzella, G.; Krovat, E. M.; Poptodorov, K.; Lasheras, B.;
Ballaz, S.; Hervias, I.; Tordera, R.; Del Rio, J.; Monge, A. Syn-
thesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-
1-yl]-1-propane derivatives with high affinity at the serotonin
transporter and at 5-HT(1A) receptors. J. Med. Chem. 2002, 45,
4128–4139.
(42) Dutta, A. K.; Fei, X. S.; Reith, M. E. A novel series of hybrid
compounds derived by combining 2-aminotetralin and piperazine
fragments: binding activity at D2 and D3 receptors. Bioorg. Med.
Chem. Lett. 2002, 12, 619–622.
(52) Ten Hoeve, W.; Wynberg, H. The design of resolving agents. Chiral
cyclic phosphoric acids. J. Org. Chem. 2002, 50, 4508–4514.
(53) Brown, D. A.; Mishra, M.; Zhang, S.; Biswas, S.; Parrington, I.;
Antonio, T.; Reith, M. E.; Dutta, A. K. Investigation of various N-
heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-pi-
perazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-na phtha-
len-2-ol: effect on affinity and selectivity for dopamine D3
receptor. Bioorg. Med. Chem. 2009, 17, 3923–3933.
(54) Girennavar, B.; Jayaprakasha, G. K.; Jadegoud, Y.; Nagana
Gowda, G. A.; Patil, B. S. Radical scavenging and cytochrome
P450 3A4 inhibitory activity of bergaptol and geranylcoumarin
from grapefruit. Bioorg. Med. Chem. 2007, 15, 3684–3691.
(55) Carlsson, A.; Lindqvist, M.; Magnusson, T. 3,4-Dihydroxypheny-
lalanine and 5-hydroxytryptophan as reserpine antagonists. Nature
1957, 180, 1200.
(43) Dutta, A. K.; Venkataraman, S. K.; Fei, X. S.; Kolhatkar, R.;
Zhang, S.; Reith, M. E. Synthesis and biological characterization
of novel hybrid 7-[[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-
amino]-5,6,7,8-tetrahydro-naphthalen-2-ol and their heterocyclic
bioisosteric analogues for dopamine D2 and D3 receptors. Bioorg.
Med. Chem. 2004, 12, 4361–4373.
(44) Biswas, S.; Hazeldine, S.; Ghosh, B.; Parrington, I.; Kuzhikandathil,
E.; Reith, M. E.; Dutta, A. K. Bioisosteric heterocyclic versions of
7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetra-
hydronaphth alen-2-ol: identification of highly potent and selec-
tive agonists for dopamine D3 receptor with potent in vivo
activity. J. Med. Chem. 2008, 51, 3005–3019.
(45) Biswas, S.; Zhang, S.; Fernandez, F.; Ghosh, B.; Zhen, J.; Kuzhi-
kandathil, E.; Reith, M. E.; Dutta, A. K. Further structure-activ-
ity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-
yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphtha len-2-ol analo-
gues: identification of a high-affinity D3-preferring agonist with
potent in vivo activity with long duration of action. J. Med. Chem.
2008, 51, 101–117.
(56) Ungerstedt, U. 6-Hydroxy-dopamine induced degeneration of
central monoamine neurons. Eur. J. Pharmacol. 1968, 5, 107–110.
(57) Schonafinger, K. Y.; Christine, M.; Vollman, Anne; Ong, Helen H.
Synthesis
of
7,8,9,10-tetrahydropyrido[30,40:4,5]pyrrolo[3,2-
(46) Ling, Z. D.; Robie, H. C.; Tong, C. W.; Carvey, P. M. Both the
antioxidant and D3 agonist actions of pramipexole mediate its
neuroprotective actions in mesencephalic cultures. J. Pharmacol.
Exp. Ther. 1999, 289, 202–210.
(47) Zou, L.; Xu, J.; Jankovic, J.; He, Y.; Appel, S. H.; Le, W.
Pramipexole inhibits lipid peroxidation and reduces injury in the
substantia nigra induced by the dopaminergic neurotoxin 1-meth-
yl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice. Neurosci.
Lett. 2000, 281, 167–170.
c]quinolines. J. Heterocycl. Chem. 1988, 25, 535–537.
(58) Millan, M. J.; Di Cara, B.; Hill, M.; Jackson, M.; Joyce, J. N.;
Brotchie, J.; McGuire, S.; Crossman, A.; Smith, L.; Jenner, P.;
Gobert, A.; Peglion, J. L.; Brocco, M. S32504, a novel naphtox-
azine agonist at dopamine D3/D2 receptors: II. Actions in rodent,
primate, and cellular models of antiparkinsonian activity in com-
parison to ropinirole. J. Pharmacol. Exp. Ther. 2004, 309, 921–935.
(59) McCall, R. B.; Lookingland, K. J.; Bedard, P. J.; Huff, R. M.
Sumanirole, a highly dopamine D2-selective receptor agonist: in
vitro and in vivo pharmacological characterization and efficacy in
animal models of Parkinson’s disease. J. Pharmacol. Exp. Ther.
2005, 314, 1248–1256.
(48) Wang, T.; Magnin, D. R.; Hamann, L. G. Palladium-catalyzed
microwave-assisted amination of 1-bromonaphthalenes and 5- and
8-bromoquinolines. Org. Lett. 2003, 5, 897–900.