Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro- naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors

Article abstract of DOI:10.1016/j.bmc.2013.03.059

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D

Full text of DOI:10.1016/j.bmc.2013.03.059

Bioorganic & Medicinal Chemistry 21 (2013) 3164–3174
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Modification of agonist binding moiety in hybrid derivative
5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-
tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional
activity and selectivity for dopamine D2/D3 receptors
Bhaskar Gopishetty a, Suhong Zhang a, Prashant S. Kharkar a, Tamara Antonio b, Maarten Reith b,c
,
Aloke K. Dutta a,
⇑
a Wayne State University, Department of Pharmaceutical Sciences, 259 Mack Ave, Detroit, MI 48202, United States
b New York University, Department of Psychiatry, New York, NY 10016, United States
c New York University, Department of Biochemistry and Molecular Pharmacology, New York, NY 10016, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The goal of the present study was to explore, in our previously developed hybrid template, the effect of
introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replace-
ment) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the
effect of derivatization of functional groups of the agonist binding moiety in compounds developed by
us earlier from the hybrid template. Binding affinity (Ki) of the new compounds was measured with tri-
tiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional
Received 2 January 2013
Revised 7 March 2013
Accepted 16 March 2013
Available online 1 April 2013
Keywords:
Dopamine receptors
D2 receptor
D3 receptor
Agonist
activity of selected compounds was assessed in the GTPcS binding assay. In the imidazole series, com-
pound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3
affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives
improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionali-
zation of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate
ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from
such derivatization.
Structure activity relationship study
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
striatal regions and also in the thalamus.9 The D2 and D3 receptor
subtypes posses 50% overall structural homology, and 75–80% in
The dopamine (DA) receptor system has been targeted for drug
development for a number of central nervous system (CNS) disor-
ders, including drug abuse, schizophrenia, and Parkinson’s disease
(PD).1,2 DA receptors are found throughout the CNS and periphery.
So far five subtypes of DA receptors have been identified and are
classified as being either D1-like or D2-like.3 These classifications
are based on receptor pharmacology and function.4–7 The D1-like
receptors, which include the D1 and D5 subtypes, activate adenyl-
ate cyclase activity upon receptor activation. The D2-like receptors,
which include the D2, D3, and D4 subtypes, inhibit adenylate cy-
clase activity. The D3 receptor was found to have a distribution
in the brain that is different from that of the D2 receptor.8,9 Recent
study on the brain distribution of D3 receptors indicated highest
density in the nucleus accumbens. In addition D3 receptors are also
expressed at a higher level compared to D2 receptors in the extra-
the agonist binding domains.10,11 It is important to mention that
D3 receptor bound to an antagonist was recently crystallized to
provide a detail molecular structure.12
Many compounds with various selectivities for the D3 versus D2
receptor have been developed.13,14 Due to high homology, develop-
ment of selective agonists for D3 receptor is rather difficult as both
receptors share nearly identical active binding sites for agonist
interaction.15–17 Some of the well known D3 selective agonists in-
clude ropinirole and pramipexole, and these agonists were shown
to exhibit a 4- to 10-fold higher affinity for the D3 than D2 recep-
tor.18 In comparison, the field has faced fewer obstacles in develop-
ing highly selective D3 antagonists. In the majority of these
compounds there is a piperazine ring connected to a suitable benz-
amide-type moiety via a variable-size linker, such as in BP 897
(Fig. 1).13,14,19
Based on our previously developed hybrid molecular template,
we have recently generated highly selective D3 agonists such as D-
264, D-301 and D-440 (see Fig. 1).20–24 Our subsequent structure-
⇑
Corresponding author. Tel.: +1 313 5771064; fax: +1 313 5772033.
E-mail address: adutta@wayne.edu (A.K. Dutta).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.03.059

B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
3165
Figure 1.
activity relationship (SAR) studies explored the effect of replace-
ment of the catechol moiety by different heterocyclic rings and
also the impact of various molecular modifications at the distal
aromatic site connected to the piperazine ring.21–26 In our current
SAR studies, we wanted to explore the effect of introduction of
additional heterocyclic rings mimicking catechol hydroxyl groups
as bioisosteric replacement, on selectivity and affinity for the D3
receptor. In addition, we wanted to explore the effect of substitu-
tions in functional groups of the agonist binding moiety in our hy-
brid template.
10f, respectively.28 Compound 10e was obtained by reaction of
compound 9b with CNBr.29 In another synthesis, compound 9a
on reaction30 with CS2 and KOH gave imidazol-2-thione 10b,
whereas reaction of 9a with 1,10-carbonyldiimidazole resulted31
in imidazol-2-one 10c.
Scheme 2 outlines the synthesis of compounds 13 and 14a–f. In
order to synthesize indole 13, compound 9d was reacted with
bromoacetaldehyde diethyl acetal to give 11. N-Acetylation with
subsequent hydrolysis and cyclization to indole intermediate of
11 was carried out using a mixture of trifluoroacetic acid and triflu-
oroacetic anhydride to yield 12 in moderate yield. Removal of N-
trifluoroacetyl group was performed in refluxing MeOH leading
to the final compound 13.32 In order to make sulfonamides and
amides (14a–f), compound 9d and (+)-9d were reacted with corre-
sponding sulfonyl chlorides and benzoyl/acetyl chlorides in the
presence of pyridine to yield sulfonamides 14a–f and (+)-14f.33
Scheme 3 depicts the synthesis of compounds 16a, 16b, and 18.
Compound 1522 was treated with 4-methyl benzenesulfonyl chlo-
ride and 4-methoxy benzenesulfonyl chloride in the presence of
triethylamine in dichloromethane to afford compounds 16a and
16b, respectively. Finally, compound 18 was achieved by reaction
of known compound 1720 with 4-methoxy benzenesulfonyl
chloride.
2. Chemistry
Scheme 1 describes the synthesis of final targets 10a–f. Tetra-
lone 1 was reacted with N-propylamine under reductive amination
reaction conditions to give 2, which was resolved by chiral 4-(2-
chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane
2-oxide, prepared according to the literature.22 Then, N-alkylation
of ( )-2, (+)-2, and (ꢀ)-2 with ethylbromoacetate in acetonitrile in
the presence of K2CO3 was achieved to produce compounds ( )-3,
(+)-3, and (ꢀ)-3 in quantitative yield. Nitration of these com-
pounds was achieved by using fuming HNO3 to yield 7-nitro deriv-
ative ( )-4, (+)-4, (ꢀ)-4 exclusively. Subsequent reduction of ( )-4
and acetylation of the resulting aniline yielded 5 quantitatively.
Further nitration of 5 with fuming HNO3 resulted in isomeric mix-
ture of 6- and 8-nitro derivatives 7 and 6, respectively and which
were separated from one another by column chromatography.
The acetate esters ( )-4, (+)-4, (ꢀ)-4, 6, and 7 were subjected to
acid hydrolysis followed by coupling with (un)substituted pipera-
zines, thus producing piperazine amides 8a–d, (+)-8d, and (ꢀ)-8d.
Catalytic reduction of the nitro group followed by amide reduction
using borane/THF complex gave intermediates 9a–d, (+)-9d, and
(ꢀ)-9d which were used as the starting materials for preparation
of the final compounds 10a–f. Phenylenediamine 9a was treated27
with formic acid to form imidazole 10a and under similar condi-
tions compounds 9b and 9c gave isomeric imidazoles 10d and
3. Results and discussion
In our goal to explore the effect of addition of an heterocyclic
moiety mimicking catechol hydroxyl groups bioisosterically on a
phenyl ring, compounds 10a–f and 13 were designed and synthe-
sized. In this set, compound 10a exhibited relatively higher affinity
for the D3 receptor with good selectivity (Ki, D3 = 19.7 nM, D2/
D3 = 22.5). Compounds 10f and 10d were moderately potent at
the D3 receptor. These three compounds are imidazole derivatives,
and in the past such derivatives have shown high affinity for the D2
receptor.34 Similar to imidazole containing compounds, indole
derivative 13 displayed similar modest affinity at D3 and weaker

3166
B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
b
a
+
O
NH
NH
NH
1
(-) 2
( ) 2
(+) 2
d
e
c
OEt
OEt
( ) 2, (+) 2 or (-) 2
N
N
O2N
O
O
( ) 3, (+) 3, (-) 3
( ) 4, (+) 4, (-) 4
O2N
AcHN N
f
OEt
OEt
OEt
AcHN
5
N
AcHN
N
O
O
O
NO2
6
7
Z
Z
X
X
Y
g
h
N
N
( ) 4, (+) 4, (-) 4, 6 or 7
N
N
N
N
Y
O
8a X = 6-NO2, Y= 7-NH2, Z =OMe
8b X = 6-NO2, Y= 7-NH2, Z =H
8c X = 7-NH2, Y= 8-NO2, Z=H
( ) 8d X = 7-NO2, Y= H, Z = H
(+) 8d X = 7-NO2, Y= H, Z = H
(-) 8d X = 7-NO2, Y= H, Z = H
9a X = 6-NH2, Y= 7-NH2, Z =OMe
9b X = 6-NH2, Y= 7-NH2, Z =H
9c X = 7-NH2, Y= 8-NH2, Z=H
( ) 9d X = 7-NH2, Y= H, Z = H
(+) 9d X = 7-NH2, Y= H, Z = H
(-) 9d X = 7-NH2, Y= H, Z = H
MeO
MeO
N
H
N
H
N
N
N
X
N
H
i
j or k
N
N
N
9a
N
10b, X = S
10c, X = O
10a
H
N
N
N
N
X
i or l
i
N
N
N
9b
N
9c
N
NH
10d, X = CH
10e, X = CHNH2
10f
Scheme 1. Reagents and conditions: (a) n-Propylamine, NaCNBH3, AcOH, 1,2-dichloroethane; (b) (+) or (ꢀ) chlocyphos, ethanol, recrystallized from isopropanol; (c) BrCH2
CO2 Et, K2 CO3, AcCN; (d) fuming HNO3; (e) (i) 10% Pd/C, H2, EtOH, (ii) AcCI, Et3N, CH2 CI2; (f) fuming HNO3; (g) (i) conc, HCI, (ii) EDCI, HtOH, 1-(2-substituted
phenyl)piperazine, CH2CI2; (h) (i) 10% Pd/C, H2, CH3 OH, (ii) BH3, THF; (i) HCOOH; (j) CS2, KOH, EtOH; (k) 1,10-carbonyldiimidazole, AcCN; (I)CNBr, H2O.
affinity at D2 receptors (Ki; D2 = 127 nM and D3 = 10.7 nM, Table 1).
Benz[e]indole derivatives have been shown in the past to exhibit
potent agonist activity for the dopamine D2 receptor.35 The
remaining compounds in the series were weak to inactive. Collec-
tively, the current results show that introduction of a heterocyclic
moiety in our hybrid molecules are well to modestly tolerated.
We next wanted to evaluate the effect of various substitutions
on the amino and hydroxyl functional groups of 9d, 15 and 17.
We previously characterized these molecules as potent and selec-
tive agonists for D3 receptors.22,25 Compounds 14a–f were de-
signed to explore the effect of different electron withdrawing and
donating groups on affinity and selectivity for the D3 receptor. In
this effort, compound 9d was converted into 14a–f by derivatiza-
tion of the amino group to various sulfonamides and amides. The
sulfonamides 14e and 14f containing electron donating groups
exhibited the highest affinity for D3 receptor (Ki, D3 = 3.69 and
2.22 nM for 14e and 14f, respectively, Table 1) in this series. In this
regard, 14f was relatively more selective for D3 receptors com-
pared to p-toluene sulfonamide derivative 14e (D2/D3, 29.2 vs
10.6 for 14f and 14e, respectively). Enantiomerically pure (+)-14f
exhibited higher selectivity (D2/D3 = 43.5). Similarly, sulfonamides
14a–b showed an interesting trend of activity. Thus, 14a and 14b
containing electronegative 4-Cl and 4-CF3 substitutions exhibited
high affinity (Ki; D3 = 4.13 and 8.64 nM for 14a and 14b, respec-
tively) although they were less potent compared to 14e and 14f.
Interestingly, benzamide and acetamide compounds 14c–d were
much weaker at D3 (Ki; D3 = 109 and 174 nM for 14c and 14d,
respectively, Table 1).
Next in our effort to evaluate the effect on modification of func-
tional OH group in D3 preferring potent agonists 1522 and D3 pre-
ferring compound 17, compounds 16a–b and 18 were designed.
Previously, compound 15 was shown to exhibit potent agonist
activity in vitro and in vivo experiments.22 Conversion of the hy-
droxyl group in this compound to sulfonate ester provided 16a,

B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
3167
N
N
a
N
EtO
N
N
H2N
N
N
H
OEt
( ) 9d, (+) 9d
11
b
d
N
N
N
N
N
O
CF3
X
N
N
Y
N
H
12
c
14a X = SO2, Y = 4-ClPh
14b X = SO2, Y = 4-CF3Ph
14c X = CO, Y = Ph
N
N
N
H
N
14d X = CO, Y = Me
14e X = SO2, Y = 4-CH3Ph
( ) 14f X = SO2, Y = 4-CH3OPh
(+) 14f X = SO2, Y = 4-CH3OPh
13
Scheme 2. Reagent and conditions: (a) Bromoacetaldehyde diethyl acetal, Na2CO3, EtOH, reflux; (b) (CF3CO)2/CF3 COOH, reflux; (c) MeOH, reflux; (d) YXCI, pyridine (for 14a,
4-CIC6H4SO2CI; for 14b, 4-CF3C6H4SO2Cl); for 14c, PhCOCI; for 14d, AcCI; for 14e, 4-CH3C6h4SO2Cl; for ( )14f and (+)14f, 4-CH3OC6h4SO2Cl).
X Y
OH
O
N
a
N
N
N
N
N
15
16a X = SO2, Y = 4-CH3C6H4
16b X = SO2, Y = 4-CH3OC6H4
a
N
N
N
N
N
N
HO
O
X
Y
17
18 X = SO2, Y = 4-CH3OC6H4
Scheme 3. Reagents and conditions: (a) YXCI, Et3N, DCM, over night (For 16a, 4-CH3C6H4SO2Cl; for 16b and 18, 4-CH3OC6H4SO2Cl).
16b and 18. Compound 16b, containing the 4-methoxy substituent,
exhibited comparable activity to 4-methyl substituted 16a (Ki,
D3 = 17.6 vs 32.0 nM for 16b and 16a, respectively). Overall, sulfon-
amide derivatives produced from 9d showed higher affinity for D2/
D3 compared to sulfone ester derived from (ꢀ)-15 and (+)-17 (see
Table 1).
Our recent work points to hydroxyl group functionality playing
a critical role in agonist activity of hybrid compounds.36 Thus, com-
pound 15 (D-237), a potent agonist for D2/D3 receptors, was shown
to exhibit much lower affinity for the D3 receptor mutant S192A,
indicating a critical role of the hydroxyl group in interacting with
serine-192 in the agonist binding cavity of the receptor.36 In this
regard, it has been demonstrated that serine-192 plays a critical
role via H-bond formation in agonist activity at the D3 receptor.
Thus, we wanted to evaluate whether functionalization of this
hydroxyl group in 15 will lead to any changes in agonist activity.
Indeed, compound (ꢀ)-16b which is derived from agonist (ꢀ)-15
(D-237), failed to show any agonist activity in the GTPcS binding
assay (Table 2). Similarly, (+)-14f, derived from partial agonist
(+)-9d, displays high affinity and selectivity for D3 selective mole-
cule but was inactive in the functional assay (Table 2). These re-
sults reinforce the critical requirement of the hydroxyl and
amino groups for interaction with the agonist binding domains
e.g. S192A, in the D3 binding pocket, in order for the receptor to
become activated. Finally, recently a crystal structure of human
D3 receptor complexed with D2/D3 antagonist eticlopride was iden-
tified.12 Further docking of another D3 antagonist in D3 molecular
structure identified a second binding pocket unique to D3 receptor,

3168
B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
Table 1
Affinity for cloned rat D2L and D3 receptors expressed in HEK293 cells measured by inhibition of [3H]spiperone binding
Compound
Ki (nM), rD2L [3H]spiperone
Ki (nM), rD3 [3H]spiperone
D2L/D3
(ꢀ)-5-OH-DPAT
Ropinirole
58.8 11.0
2,674 305
40.6 3.6
26.0 7.5
264 40
269 16
1,073 92
638 40
601 98
2,707 178
443 57
230 25
417 93
1.36 0.28
29.3 4.2
1.77 0.42
0.825 0.136
0.92 0.23
2.23 0.60
1.84 0.51
22.2 3.8
20.2 2.1
45.5 8.8
19.7 1.3
112 41
43.2
91.3
22.9
31.5
253
(+)-17 D-315c
(ꢀ)-15 D-237a
D-264b
D-301
D-440
9d
121
583
28.7
29.8
59.6
22.5
2.05
2.14
9.61
21.3
8.89
11.9
17.5
10.6
5.72
7.44
10.6
29.2
43.5
28.2
19.8
40.0
(+)-9d (D-515)
(ꢀ)-9d (D-516)
10a (D-261)
10b (D-262)
10c (D-263)
10f (D-311)
10d (D-312)
10e (D-314)
13 (D-355)
14a (D-357)
14b (D-358)
14c (D-359)
14d (D-360)
14e (D-397)
14f (D-401)
(+)-14f (D-532)
(ꢀ)-16b (D-399)
16a (D-400)
18 (D-398)
195 62
520 22
1,280 218
15,922 3,820
54.1 12.8
60.0 12.9
1,790 215
10.7 2.32
4.13 0.90
8.64 2.10
109 37
127
2
72.4 7.3
91.2 6.1
624 54
1,296 322
39.2 6.1
64.9 12.0
101 10
497 214
632 264
1,076 375
174 28
3.69 0.61
2.22 0.22
2.32 0.35
17.6 3.1
32.0 12.6
26.9 4.77
Results are the mean SEM for three to eight experiments, each performed in triplicate.
a
From our previous work (Ref. 22).
From our previous work (Ref. 21).
From our previous work (Ref. 25).
b
c
replacement of hydroxyl group. Imidazole derivative 10a and the in-
dole derivative 13 produced comparable affinity for D3 receptor,
however, 13 exhibited higher affinity for D2 compared to 10a. Inter-
estingly, the effect of substitutions on amino functionality in com-
pound 9d was different compared to the effect of substitutions on
the hydroxyl group of 15 and 17. Sulfonamide derivative (+)-14f de-
rived from (+)-9d produced significant gain in affinity for both D2
and D3 receptors compared to the parent molecule but lost func-
tional agonist activity.
Table 2
Stimulation of [35S]GTP
CHO cells
cS binding to cloned human D2 and D3 receptors expressed in
D-compound
hCHO-D2
EC50 (nM)
hCHO-D3
EC50 (nM)
Emax (%)
Emax (%)
D2/D3
Dopamine
D-301a
227 11a
116 16
114 12
100
7.64 0.56 100
26.6
141
438
88.4 3.9 0.82 0.20 102
101 0.26 0.07 103 10
2
D-440c
5
(ꢀ)-15 D-237b
2.22 0.27 63.4 3.5
(ꢀ)-16b D-399 Not active
Not active
36.8 8.7 30.3 6.4
Not active
5. Experimental section
(+)-9d D-515
(+)-14f D-532
179 47
Not active
58.6 4.8
Reagents and solvents were purchased from commercial suppli-
ers and used as received unless otherwise noted. Dry solvents were
obtained following the standard procedure. All reactions were per-
formed under N2 atmosphere unless otherwise indicated. Analyti-
cal silica gel 60 F254-coated TLC plates were purchased from EMD
Chemicals, Inc. and were visualized with UV light or by treatment
with phosphomolybdic acid (PMA), Dragendorff’s reagent or nin-
hydrin. Whatman PurasilÒ 60A silica gel 230–400 mesh was used
for flash column chromatographic purifications. The proton nucle-
ar magnetic resonance (1H NMR) spectra were measured on Varian
400 MHz FT NMR spectrometer using tetramethylsilane (TMS) as
an internal standard. The NMR solvent used was CDCl3 unless
otherwise indicated. Mass spectra were recorded on Micromass
QuattroLC triple quadrupole mass spectrometer. Melting 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 with-
in 0.4% of the theoretical value.
EC50, the concentration producing half-maximal stimulation, is shown as the
mean SEM for three to four experiments, each performed in triplicate.
a
From our previous work.23
From our previous work.22
b
c
From our previous work.24
indicating the reason for selectivity for D3.12 This information
should be useful for development of selective antagonist. In the
current context of our work, which focuses on development of ago-
nist, it would be interesting to see whether the D3 molecular struc-
ture could potentially be used to develop selective D3 agonist even
though the agonist binding domains for both D2 and D3 receptors
are very similar. Although, identification of involvement of any
accessory binding sites for agonists unique to D3 receptor should
provide selectivity for D3 preferring agonists.
4. Conclusion
The results from our current SAR studies have provided addi-
tional insight on molecular structural requirements for introduction
of an heterocyclic ring onto the phenyl ring of the hybrid template.
Appropriate location of N-atoms in these heterocyclic ring can
potentially provide H-bonding thereby acting as a bioisosteric
5.1. N-Propyl-1,2,3,4-tetrahydronaphthalen-2-amine (( )-2)
A
mixture 2-tetralone
1 (5 g, 35.7 mmol), n-propylamine
(4.22 g, 71.3 mmol) and glacial acetic acid (3 mL) in 1,2-dichloro-

B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
3169
ethane (100 mL) was stirred at room temperature for 20 min. NaC-
NBH3 (6.72 g, 107 mmol) dissolved in methanol (15 mL) was added
to the above reaction mixture. The reaction mixture was stirred at
room temperature overnight. The solvent was evaporated and sat-
urated NaHCO3 solution (30 mL) was added to the mixture, which
was then extracted with ethyl acetate (3 ꢁ 100 mL). The combined
organic layers were dried (Na2SO4) and the solvent evaporated in
vacuo to afford the crude product, which was further purified by
column chromatography (EtOAc/MeOH/Et3N 95:4:1) to give the
product ( )-2 (6.14 g, 91%) as a brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.94 (t, J = 7.6 Hz, 3H), 1.28 (br s, 1H),
1.49–1.64 (m, 3H), 2.02–2.08 (m, 1H), 2.56–2.62 (m, 1H), 2.68 (t,
J = 7.2 Hz, 2H), 2.81–2.87 (m, 2H), 2.89–2.92 (m, 1H), 3.02 (dd,
J = 15.2, 4.8 Hz, 1H), 7.05–7.11 (m, 4H).
(0.84 mL, 7.61 mmol), and anhydrous K2CO3 (2.63 g, 19.02 mmol)
were used to afford compound (+)-3 (1.58 g, 90%) as a brown vis-
cous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.86 (t, J = 7.2 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.47–1.65 (m, 3H), 2.04–2.11 (m, 1H),
2.64–2.69 (m, 2H), 2.69–2.97 (m, 4H), 3.06–3.13 (m, 1H), 3.40 (s,
2H), 4.17 (q, J = 7.2 Hz, 2H), 7.05–7.11 (m, 4H).
5.5. (S)-Ethyl 2-(propyl(1,2,3,4-tetrahydronaphthalen-2-yl)
amino)acetate ((ꢀ)-3)
This compound was prepared following procedure A in which
compound (ꢀ)-2 (0.6 g, 3.17 mmol), ethyl 2-bromoacetate
(0.42 mL, 3.80 mmol), and anhydrous K2CO3 (1.31 g, 9.51 mmol)
were used to afford compound (ꢀ)-3 (0.72 g, 88%) as a brown vis-
cous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.86 (t, J = 7.2 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.47–1.65 (m, 3H), 2.04–2.11 (m, 1H),
2.64–2.69 (m, 2H), 2.69–2.97 (m, 4H), 3.06–3.13 (m, 1H), 3.40 (s,
2H), 4.17 (q, J = 7.2 Hz, 2H), 7.05–7.11 (m, 4H).
5.2. Resolution of N-propyl-1,2,3,4-tetrahydronaphthalen-2-
amine (( )-2)
Racemic ( )-2 was resolved into its (+)- and (ꢀ)-isomers by
using both (ꢀ)- and (+)-isomers of the synthetic resolving agent
4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphor-
inane 2-oxide. This optically active resolving agent was prepared
according to the published procedure. Compound ( )-2 (7.5 g,
39.62 mmol) and (+)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-
1,3,2-dioxaphosphorinane 2-oxide (10.85 g, 39.22 mmol) were dis-
solved by warming in 40 mL of ethanol. The solution was cooled to
room temperature and then to 0 °C. The precipitated crystals were
5.6. Procedure B: Ethyl 2-((7-nitro-1,2,3,4-tetra-
hydronaphthalen-2-yl)(propyl)amino)acetate (( )-4)
Fuming HNO3 (90%, 90 mL) was transferred through cannula
into a 250-mL round bottom flask cooled to ꢀ50 °C containing
compound ( )-3 (11.0 g, 39.97 mmol). The mixture was stirred at
ꢀ20 °C for 30 min and poured onto ice. It was neutralized by 20%
NaOH solution at 0 °C and extracted by ethyl acetate
(3 ꢁ 150 mL). The combined organic layers were dried (Na2SO4)
and the solvent evaporated to obtain the crude product, which
was purified by column chromatography (hexanes/EtOAc 1:4) to
afford ( )-4 (11.0 g, 86%) as a brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz,
3H), 1.45–1.54 (m, 2H), 1.58–1.72 (m, 1H), 2.11–2.15 (m, 1H),
2.66 (t, J = 7.6 Hz, 2H), 2.76–2.92 (m, 2H), 2.98–3.07 (m, 2H),
3.12–3.20 (m, 1H), 3.42 (s, 2H), 4.17 (q, J = 6.8 Hz, 2H), 7.19–7.23
(m, 1H), 7.92–7.96 (m, 2H).
filtered off, washed with cold ether to yield 7.5 g of the salt (½a D25
ꢂ
=
ꢀ4.6° (c 1, MeOH). Further recrystallization (two times) from hot
isopropanol yielded the salt, 6.8 g (½a D25
= ꢀ11.7° (c 1, MeOH). Fur-
ꢂ
ther crystallization of the salt from hot isopropanol did not change
the optical rotation any further. The salt was then hydrolyzed in the
presence of 20% NaOH solution in water under stirring conditions
for 2 h at room temperature. The aqueous layer was extracted with
dichloromethane (3 ꢁ 150 mL), dried over Na2SO4, and evaporated
to dryness to yield (ꢀ)-2 (2.6 g, 35%). (½a D25
= ꢀ84.6° (c 1, MeOH).
ꢂ
( )-2 (4.4 g, 23.24 mmol) was similarly treated by using (ꢀ)-4-
(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphor-
inane 2-oxide (6.36 g, 23.01 mmol). Recrystallization from hot iso-
5.7. (R)-Ethyl 2-((7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)acetate ((+)-4)
propanol yielded the salt, 3.8 g (½a D25
ꢂ
= +11.6° (c 1, MeOH). Further
crystallization of the salt from hot isopropanol did not change the
optical rotation to a significant extent. Hydrolysis of the salt fol-
lowing the above-mentioned procedure yielded (+)-2 (1.4 g, 32%).
This compound was prepared following procedure B in which
compound (+)-3 (0.6 g, 2.18 mmol) and Fuming HNO3 (90%,
6 mL) were used to afford compound (+)-4 (0.61 g, 87%) as a brown
viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.45–1.54 (m, 2H), 1.58–1.72 (m, 1H),
2.11–2.15 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.76–2.92 (m, 2H),
2.98–3.07 (m, 2H), 3.12–3.20 (m, 1H), 3.42 (s, 2H), 4.17 (q,
J = 6.8 Hz, 2H), 7.19–7.23 (m, 1H), 7.92–7.96 (m, 2H).
(½a 2D5
ꢂ
= +82. 8° (c 1, MeOH).
5.3. Procedure A: ethyl 2-(propyl(1,2,3,4-tetrahydronaphthalen-
2-yl)amino)acetate (( )-3)
Into the stirred suspension of compound ( )-2 (9.0 g,
47.54 mmol), anhydrous K2CO3 (19.71 g, 143 mmol) in acetonitrile
(200 mL) was added ethyl 2-bromoacetate (9.53 g, 57.05 mmol).
The reaction mixture was refluxed overnight, cooled to room tem-
perature and filtered. The residue was washed with ethyl acetate
and the combined filtrate was evaporated to obtain the crude prod-
uct, which was purified by column chromatography (hexanes/
EtOAc 1:4) to afford ( )-3 (12.3 g, 94%) as a brown viscous liquid.
1H NMR (400 MHz, CDCl3) d ppm 0.86 (t, J = 7.2 Hz, 3H), 1.27 (t,
J = 7.2 Hz, 3H), 1.47–1.65 (m, 3H), 2.04–2.11 (m, 1H), 2.64–2.69
(m, 2H), 2.69–2.97 (m, 4H), 3.06–3.13 (m, 1H), 3.40 (s, 2H), 4.17
(q, J = 7.2 Hz, 2H), 7.05–7.11 (m, 4H).
5.8. (S)-Ethyl 2-((7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)acetate ((ꢀ)-4)
This compound was prepared following procedure B in which
compound (ꢀ)-3 (0.2 g, 0.73 mmol) and Fuming HNO3 (90%,
2 mL) were used to afford compound (ꢀ)-4 (0.2 g, 87%) as a brown
viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.45–1.54 (m, 2H), 1.58–1.72 (m, 1H),
2.11–2.15 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.76–2.92 (m, 2H),
2.98–3.07 (m, 2H), 3.12–3.20 (m, 1H), 3.42 (s, 2H), 4.17 (q,
J = 6.8 Hz, 2H), 7.19–7.23 (m, 1H), 7.92–7.96 (m, 2H).
5.4. (R)-Ethyl 2-(propyl(1,2,3,4-tetrahydronaphthalen-2-
yl)amino)acetate ((+)-3)
5.9. Ethyl 2-((7-acetamido-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)acetate (5)
This compound was prepared following procedure A in which
To the stirred solution of ( )-4 (11.0 g, 34.36 mmol) in dry EtOH
compound (+)-2 (1.2 g, 6.34 mmol), ethyl 2-bromoacetate
(100 mL) was added 10% Pd/C (1.10 g). The reaction was continued

3170
B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
under 50 psi H2 for 3 h and the reaction mixture was filtered through
celite. Solvent was evaporated to afford crude compound (9.8 g,
98%). Acetyl chloride (2.94 mL, 41.32 mmol) was added into a solu-
tion of the crude compound (9.8 g, 33.75 mmol) and Et3N (14.4 mL)
in anhydrous CH2Cl2 at 0 °C and then stirred at room temperature for
4 h. The reaction mixture was diluted with CH2Cl2, washed with
brine and the organic layer was dried (Na2SO4), evaporated in vacuo
and the residue was purified by column chromatography (EtOAc/
hexanes 1:1) to afford compound 5 (11.0 g, 98%) as a brown viscous
liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.89 (t, J = 7.2 Hz, 3H), 1.27
(t, J = 7.2 Hz, 3H), 1.44–1.52 (m, 2H), 1.54–1.60 (m, 1H), 2.04–2.10
(m, 1H), 2.15 (s, 3H), 2.64 (t, J = 7.2 Hz, 2H), 2.72–2.92 (m, 4H),
3.05–3.09 (m, 1H), 3.39 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 6.99–7.01
(m, 1H), 7.16–7.08 (m, 1H), 7.26–7.27 (m, 1H).
5.12. 2-((7-Amino-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)-1-(4-phenylpiperazin-1-yl)ethanone (8b)
This compound was prepared following procedure
C in
which compound 7 (1.5 g, 3.97 mmol) and 1-phenylpiperazine
(1.32 g, 7.95 mmol) were used to afford compound 8b (0.92 g,
55%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3) d
ppm 0.90 (t, J = 7.2 Hz, 3H), 1.45–1.55 (m, 2H), 1.59–1.66 (m,
1H), 2.01 (br s, 1H), 2.51–2.55 (m, 2H), 2.69–2.75 (m, 2H),
2.78–2.87 (m, 2H), 3.00–3.04 (m, 1H), 3.13–3.19 (m, 4H),
3.45–3.46 (m, 2H), 3.69–3.83 (m, 4H), 5.83 (br s, 2H), 6.51–
6.52 (m,1H), 6.90–6.95 (m, 3H), 7.29–7.31 (m, 2H), 7.84–7.86
(m,1H).
5.13. 2-((7-Amino-8-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)-1-(4-phenylpiperazin-1-yl)ethanone (8c)
5.10. Ethyl 2-((7-acetamido-8-nitro-1,2,3,4-
tetrahydronaphthalen-2-yl)(propyl)amino)acetate (6) and ethyl
2-((7-acetamido-6-nitro-1,2,3,4-tetrahydronaphthalen-2-
yl)(propyl)amino)acetate (7)
This compound was prepared following procedure
C in
which compound 6 (2.35 g, 6.23 mmol) and 1-phenylpiperazine
(2.07 g, 12.45 mmol) were used to afford compound 8c (1.50 g,
53%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3) d
ppm 0.89 (t, J = 7.2 Hz, 3H), 1.46–1.56 (m, 2H), 1.59–1.64 (m,
1H), 2.01–2.05 (m, 1H), 2.53–2.58 (m, 2H), 2.69–3.04 (m, 4H),
3.13–3.18 (m, 4H), 3.39–3.52 (m, 2H), 3.70–3.83 (m, 4H),
4.84–4.87 (m, 2H), 6.59–6.61 (m,1H), 6.88–7.00 (m, 4H), 7.27–
7.31 (m, 2H).
Compound 5 (6.5 g, 19.55 mmol) was placed in 250-mL flask
and cooled down to ꢀ50 °C, 70 mL of 90% HNO3 was transferred
dropwise through cannula into the flask. The mixture was stirred
at ꢀ20 °C for 30 min and poured onto ice. The mixture was neutral-
ized by 20% NaOH solution at 0 °C and extracted by EtOAc
(3 ꢁ 100 mL). The combined organic layers were dried (Na2SO4)
and the solvent evaporated to obtain the crude product which
was purified by column chromatography (hexanes/EtOAc
1:1).The first eluent afforded 7 (4.0 g, 54%) as a brown viscous li-
quid. 1H NMR (400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz, 3H),
1.28 (t, J = 7.2 Hz, 3H), 1.45–1.57 (m, 2H), 1.59–1.69 (m, 1H),
2.10–2.12 (m, 1H), 2.27 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 2.72–2.87
(m, 2H), 2.89–3.16 (m, 2H), 3.10–3.06 (m, 1H), 3.41 (s, 2H), 4.18
(q, J = 7.2 Hz, 2H), 7.90 (d, J = 6.0 Hz,1H), 8.45 (d, J = 5.2 Hz,1H),
10.21 (s, 1H). MS (ESI): 378.40 (C19H28N3O5, [M+H]+). The second
eluent provided 6 (2.4 g, 33%) as a brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz,
3H), 1.42–1.55 (m, 2H), 1.57–1.67 (m, 1H), 2.06–2.10 (m, 1H),
2.16 (s, 3H), 2.62 (t, J = 7.2 Hz, 2H), 2.72–2.86 (m, 3H), 2.86–3.00
(m, 1H), 3.02–3.12 (m, 1H), 3.41 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H),
7.19–7.22 (m, 1H), 7.79–7.83 (m, 1H), 8.23–8.25 (m, 1H). MS
(ESI): 378.30 (C19H28N3O5, [M+H]+).
5.14. 2-((7-Nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)-1-(4-phenylpiperazin-1-yl)ethanone (( )8d)
This compound was prepared following procedure C in which
compound ( )-4 (8.56 g, 26.73 mmol) and 1-phenylpiperazine
(8.89 g, 53.47 mmol) were used to afford compound
( )-8d (8.17 g, 70%) as a brown viscous liquid. 1H NMR (400 MHz,
CDCl3)
d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.47–1.56 (m, 2H),
1.65–1.75 (m, 1H), 2.09–2.13 (m, 1H), 2.55–2.59 (m, 2H), 2.83–
2.90 (m, 2H,), 2.97–3.02 (m, 2H), 3.10–3.18 (m, 5H), 3.49 (s, 2H),
3.70–3.82 (m, 4H), 6.88–6.94 (m, 3H), 7.17–7.33 (m, 3H), 7.90–
7.95 (m, 2H).
5.15. (R)-2-((7-Nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)-1-(4-phenylpiperazin-1-yl)ethanone ((+)-8d)
5.11. Procedure C: 2-((7-amino-6-nitro-1,2,3,4-
tetrahydronaphthalen-2-yl)(propyl)amino)-1-(4-(2-
methoxyphenyl)-piperazin-1-yl)ethanone (8a)
This compound was prepared following procedure C in which
compound (+)-4 (0.61 g, 1.90 mmol) and 1-phenylpiperazine
(0.58 mL, 3.80 mmol) were used to afford compound (+)-8d
(0.6 g, 72%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3)
d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.47–1.56 (m, 2H), 1.65–1.75 (m,
1H), 2.09–2.13 (m, 1H), 2.55–2.59 (m, 2H), 2.83–2.90 (m, 2H,),
2.97–3.02 (m, 2H), 3.10–3.18 (m, 5H), 3.49 (s, 2H), 3.70–3.82
(m, 4H), 6.88–6.94 (m, 3H), 7.17–7.33 (m, 3H), 7.90–7.95 (m,
2H).
Compound 7 (280 mg, 0.742 mmol) was refluxed in 12 N HCl
overnight. The mixture was evaporated to dryness followed by
overnight drying under vacuum at 70 °C. The yellow solid was
dissolved in CH2Cl2 (40 mL). EDCI (242 mg, 1.26 mmol), HOBT
(150 mg, 1.11 mmol) and Et3N (1.48 mL, 14.84 mmol) were added
and stirred at room temperature for 1 h. Then, 1-(2-methoxylphe-
nyl)-piperazine (339 mg, 1.48 mmol) was added into the reaction
mixture and stirred for 24 h. The reaction mixture was diluted
with CH2Cl2, washed with water, brine, the organic layer was
dried (Na2SO4), and evaporated in vacuo. The residue was purified
5.16. (S)-2-((7-Nitro-1,2,3,4-tetrahydronaphthalen-2-yl)
(propyl)amino)-1-(4-phenylpiperazin-1-yl)ethanone ((ꢀ)-8d)
This compound was prepared following procedure C in which
compound (ꢀ)-4 (0.35 g, 1.09 mmol) and 1-phenylpiperazine
(0.33 mL, 2.18 mmol) were used to afford compound (ꢀ)-8d
(0.31 g, 65%) as a brown viscous liquid. 1H NMR (400 MHz,
CDCl3) d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.47–1.56 (m, 2H), 1.65–
1.75 (m, 1H), 2.09–2.13 (m, 1H), 2.55–2.59 (m, 2H), 2.83–2.90
(m, 2H,), 2.97–3.02 (m, 2H), 3.10–3.18 (m, 5H), 3.49 (s, 2H),
3.70–3.82 (m, 4H), 6.88–6.94 (m, 3H), 7.17–7.33 (m, 3H), 7.90–
7.95 (m, 2H).
by
column
chromatography
(hexanes/EtOAc/MeOH/Et3N
40:52:4:4) to afford 8a (300 mg, 84%) as a brown viscous liquid.
1H NMR (400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz, 3H), 1.46–
1.55 (m, 2H), 1.57–1.68 (m, 1H), 2.01–2.04 (m, 1H), 2.52–
2.57(m, 2H), 2.65–2.76 (m, 2H), 2.83–2.87 (m, 2H), 2.95–3.05
(m, 5H), 3.47 (s, 2H), 3.70–3.84 (m, 4H), 3.88 (s, 3H), 6.09 (br s,
2H), 6.52–6.54 (m, 1H), 6.88–6.95 (m, 3H), 7.01–7.05 (m, 1H),
7.77–8.00 (m,1H).

B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
3171
5.17. Procedure D: N6-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethyl)-N6-propyl-5,6,7,8-tetrahydronaphthalene-2,3,6-triamine
(9a)
1H NMR (400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz, 3H), 1.46–1.54
(m, 2H), 1.55–1.64 (m, 1H), 1.99 (br s, 1H), 2.50–2.59 (m, 4H),
2.64–2.67 (m, 4H), 2.70–2.81 (m, 4H), 3.19–3.22 (m, 4H), 3.51–
3.60 (m, 3H), 6.44–6.57 (m, 2H), 6.83–6.98 (m, 4H), 7.21–7.28
(m, 2H). The free base was converted into HCl salt, mp: 202–
204 °C Anal. [C25H36N4ꢃ4HClꢃH2O] C, H, N.
To a solution of 8a (290 mg, 0.603 mmol) in dry MeOH (20 mL)
was added 10% Pd/C (58 mg). The reaction was continued under 70
psi H2 for 36 h and the reaction mixture filtered through celite. Sol-
vent was evaporated to afford crude compound 250 mg (92%). Into
the solution of this crude product (220 mg, 0.487 mmol) in dry THF
was added 2.4 mL solution of BH3–THF complex (1 M). The reac-
tion mixture was refluxed overnight, cooled to room temperature
and then quenched with MeOH at 0 °C. The solvent was evaporated
and the solid complex was suspended in 6 N HCl in methanol. After
refluxing for 5 h, MeOH was evaporated in vacuo. Reaction mixture
was made alkaline using saturated K2CO3 solution. The aqueous
layer was extracted with EtOAc (3 ꢁ 20 mL), the combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by column chromatography (Hex/EtOAc/
MeOH/Et3N 40:52:4:4) to yield pure compound 9a (138 mg, 65%)
as a brown viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.91
(t, J = 7.2 Hz, 3H), 1.49–1.57 (m, 2H), 1.64–1.74 (m, 1H), 2.07–
2.11 (m, 1H), 2.56–2.64 (m, 6H), 2.73–2.83 (m, 6H), 2.87–3.0 (m,
7H), 3.83 (s, 3H), 6.84–6.86 (m, 1H), 6.89–6.96 (m, 2H), 6.97–
7.02 (m, 1H), 7.21 (br s, 2H).
5.22. (S)-N2-(2-(4-Phenylpiperazin-1-yl)ethyl)-N2-propyl-
1,2,3,4-tetrahydronaphthalene-2,7-diamine ((ꢀ)-9d)
This compound was prepared from compound (ꢀ)-8d (0.3 g,
0.69 mmol) following procedure D to give compound (ꢀ)-9d
(0.17 g, 63%) as a brown viscous liquid. ½a D25
= ꢀ39.6 (c 0.5, MeOH).
ꢂ
1H NMR (400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz, 3H), 1.46–1.54
(m, 2H), 1.55–1.64 (m, 1H), 1.99 (br s, 1H), 2.50–2.59 (m, 4H),
2.64–2.67 (m, 4H), 2.70–2.81 (m, 4H), 3.19–3.22 (m, 4H), 3.51–
3.60 (m, 3H), 6.44–6.57 (m, 2H), 6.83–6.98 (m, 4H), 7.21–7.28
(m, 2H). The free base was converted into HCl salt, mp: 200–
202 °C Anal. [C25H36N4ꢃ4HCl] C, H, N.
5.23. Procedure E: N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)
ethyl)-N-propyl-5,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazol-
6-amine (10a)
Diamine 9a (65 mg, 0.149 mmol) and 98% HCOOH (22 lL,
5.18. N6-(2-(4-Phenylpiperazin-1-yl)ethyl)-N6-propyl-5,6,7,8-
tetrahydronaphthalene-2,3,6-triamine (9b)
0.357 mmol) were heated under N2 at 140 °C for 5 h. After cooling
to room temperature, 5 mL of saturated NaHCO3 were added and
extracted with EtOAc (3 ꢁ 10 mL). The combined organic layers
were dried (Na2SO4), concentrated in vacuo and purified by column
chromatography (Hex/EtOAc/MeOH/Et3N 40:52:4:4) to yield 10a
(45 mg, 67%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3)
d ppm 0.92 (t, J = 7.2 Hz, 3H), 1.53–1.62 (m, 2H), 1.66–1.76 (m, 1H),
2.09–2.12 (m, 1H), 2.63–2.69 (m, 4H), 2.6 (br s, 4H), 2.85–3.17 (m,
11H), 3.84 (s, 3H), 6.84–6.86 (m, 1H), 6.88–6.92 (m, 2H), 6.97–7.02
(m, 1H), 7.34 (s, 2H), 7.99 (s, 2H). MS (ESI): 448.50 (C27H38N5O,
[M+H]+). The free base was converted into HCl salt, mp: 90–
93 °C. Anal. [C27H37N5Oꢃ4HCl ꢃ1.5H2Oꢃ0.4CH3CH2OH] C, H, N.
This compound was prepared from compound 8b (0.9 g,
1.99 mmol) following procedure D to give compound 9b (0.73 g,
84%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm
0.92 (t, J = 7.2 Hz, 3H), 1.46–1.56 (m, 2H), 1.57–1.65 (m, 1H),
1.99–2.01 (m, 1H), 2.52–2.56 (m, 2H), 2.59–2.77 (m, 8H), 2.91–
2.99 (m, 1H), 3.21–3.24 (m, 4H), 3.32 (br s, 1H), 6.43 (s, 1H), 6.44
(s, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.94–6.96 (m, 2H), 7.26–7.30 (m,
2H).
5.19. N7-[2-(4-Phenylpiperazin-1-yl)-ethyl]-N7-propyl-5,6,7,8-
tetrahydro-naphthalene-1,2,7-triamine (9c)
5.24. 6-((2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)
(propyl)amino)-5,6,7,8-tetrahydro-1H-naphtho-[2,3-
d]imidazole-2(3H)-thione (10b)
This compound was prepared from compound 8c (0.9 g,
1.99 mmol) following procedure D to give compound 9c (0.73 g,
84%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm
0.90 (t, J = 7.2 Hz, 3H), 1.47–1.59 (m, 2H), 1.65–1.68 (m, 1H), 1.99
(br s, 1H), 2.52–2.59 (m, 5H), 2.66 (br s, 4H), 2.71–2.80 (m, 5H),
3.20–3.22 (m, 4H), 3.65–3.68 (m, 1H), 6.47–6.49 (m, 1H), 6.56–
6.60 (m, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.2–6.94 (m, 2H), 7.25–7.29
(m, 2H).
A mixture of diamine 9a (100 mg, 0.228 mmol), CS2 (51 mg,
0.663 mmol), KOH (32 mg, 0.570 mmol), H2O (0.1 mL) and EtOH
(2 mL) was refluxed for 3 h. The reaction mixture was evaporated
to dryness and purified by column chromatography (Hex/EtOAc/
MeOH/Et3N 40:52:4:4) offered 10b (92 mg, 84%) as a brown vis-
cous liquid. 1H NMR (400 MHz, DMSO) d ppm 0.86 (t, J = 7.2 Hz,
3H), 1.37–1.46 (m, 2H), 1.54–1.58 (m, 1H), 1.91–1.97 (m, 1H),
2.41–2.64 (m, 10H), 2.74–2.93 (m, 9H), 3.76 (s, 3H), 6.82–6.85
(m, 6H), 12.30 (s, 2H). MS (ESI): 480.50 (C27H38N5OS, [M+H]+).
The free base was converted into HCl salt, mp: 162–166 °C. Anal.
[C27H37N5OSꢃ3HClꢃ0.7H2Oꢃ0.3CH3CH2OH] C, H, N.
5.20. N2-[2-(4-Phenylpiperazin-1-yl)-ethyl]-N2-propyl-1,2,3,4-
tetrahydronaphthalene-2,7-diamine (( )-9d)
This compound was prepared from compound ( )-8d (7.2 g,
17.04 mmol) following procedure D to give compound ( )-9d
(6.27 g, 97%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3)
d ppm 0.90 (t, J = 7.2 Hz, 3H), 1.46–1.54 (m, 2H), 1.55–1.64 (m, 1H),
1.99 (br s, 1H), 2.50–2.59 (m, 4H), 2.64–2.67 (m, 4H), 2.70–2.81 (m,
4H), 3.19–3.22 (m, 4H), 3.51–3.60 (m, 3H), 6.44–6.57 (m, 2H),
6.83–6.98 (m, 4H), 7.21–7.28 (m, 2H).
5.25. 6-((2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)
(propyl)amino)-5,6,7,8-tetrahydro-1H-naphtho-[2,3-d]
imidazol-2(3H)-one (10c)
Diamine 9a (160 mg, 0.366 mmol) was added to 1,10-carbonyl-
diimidazole (118 mg, 1.574 mmol) in AcCN (5 mL), the mixture
was stirred at room temperature for 2 h and then refluxed over-
night. The solvent was removed and the residue was purified by
column chromatography (Hex/EtOAc/MeOH/Et3N 40:52:4:4) of-
fered 10c (140 mg, 83%) as a brown viscous liquid. 1H NMR
(400 MHz, DMSO) d ppm 0.89 (t, J = 7.2 Hz, 3H), 1.43–1.51 (m,
2H), 1.52–1.61 (m, 1H), 1.97–1.99 (m, 1H), 2.48–2.66 (m, 4H),
5.21. (R)-N2-(2-(4-Phenylpiperazin-1-yl)ethyl)-N2-propyl-
1,2,3,4-tetrahydronaphthalene-2,7-diamine ((+)-9d)
This compound was prepared from compound (+)-8d (0.55 g,
1.26 mmol) following procedure D to give compound (+)-9d
(0.32 g, 65%) as a brown viscous liquid. ½a D25
ꢂ
= +38.4 (c 0.5, MeOH).

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B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
2.69–2.76 (m, 10H), 2.89–3.12 (m, 5H), 3.83 (s, 3H), 6.69–6.71 (m,
2H), 6.84–6.89 (m, 1H), 6.91–6.94 (m, 2H), 6.95–7.01 (m, 1H), 7.34
(s, 2H), 7.68 (s, 2H), 9.20 (s, 1H), 9.27 (s, 1H). MS (ESI): 464.50
(C27H38N5O2, [M+H]+). The free base was converted into HCl salt,
mp: 112–116 °C. Anal. [C27H37N5O2ꢃ3HClꢃ1.4H2Oꢃ0.3CH3CH2OH]
C, H, N.
5.30. 2,2,2-Trifluoro-1-(7-((2-(4-phenylpiperazin-1-yl)
ethyl)(propyl)amino)-5,6,7,8-tetrahydro-1H-benzo[f]indol-1-yl)
ethanone (12)
A cooled mixture of trifluoroacetic anhydride in trifluoroacetic
acid (1:1) was added to compound 11 (0.135 g, 0.27 mmol) at
0 °C. After stirring for 30 min, the cold mixture was diluted with
trifluoroacetic acid (3 mL) and heated at reflux for 2.5 days. After
removal of the solvent under reduced pressure, the residue was ta-
ken into CH2Cl2 (15 mL) and washed with saturated NaHCO3, dried
(Na2SO4) and the solvent evaporated to get crude 12 which was
purified by column chromatography (CH2Cl2/MeOH 5:0.25) to af-
ford pure 12 (50 mg, 37%) as a brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 1.04 (t, J = 6.4 Hz, 3H), 1.90 (m, 3H),
2.44 (m, 1H), 3.03–3.26 (m, 6H), 3.43–3.48 (m, 8H), 3.80 (m, 5H),
6.67–6.70 (m, 1H), 6.95–6.96 (d, J = 7.2 Hz, 2H), 7.02 (t, J = 7.2 Hz,
1H), 7.29–7.33 (m, 3H), 7.43 (br s, 1H), 8.21–8.22 (br s, 1H).
5.26. N-(2-(4-Phenylpiperazin-1-yl)ethyl)-N-propyl-5,6,7,8-
tetrahydro-1H-naphtho[2,3-d]imidazol-6-amine (10d)
This compound was prepared from compound 9b (0.13 mg,
0.33 mmol) following procedure
E to give compound 10d
(110 mg, 81%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3)
d ppm 0.92 (t, J = 7.2 Hz, 3H), 1.58–1.62 (m, 2H), 1.63–1.80 (m, 1H),
2.27 (br s, 1H), 2.66–2.69 (m, 7H), 2.85–3.13 (m, 8H), 3.18–3.20 (m,
4H), 6.83–6.92 (m, 3H), 7.23–7.27 (m, 4H), 7.35 (s, 2H), 7.97 (s, 1H).
The free base was converted into oxalate salt, mp: 101–103 °C.
Anal. [C26H35N5ꢃ3(COOH)2ꢃH2O] C, H, N.
5.31. N-(2-(4-Phenylpiperazin-1-yl)ethyl)-N-propyl-5,6,7,8-
tetrahydro-1H-benzo[f]indol-7-amine (13)
5.27. N6-(2-(4-Phenylpiperazin-1-yl)ethyl)-N6-propyl-5,6,7,8-
tetrahydro-1H-naphtho[2,3-d]imidazole-2,6-diamine (10e)
A solution of compound 12 (25 mg, 0.05 mmol) in dry MeOH
(5 mL) was heated at reflux for 24 h. Solvent was evaporated in va-
cuo and the residue was purified by column chromatography
(CH2Cl2/MeOH 9:1) to yield pure compound 13 (10 mg, 50%) as a
light brown viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.98
(t, J = 7.2 Hz, 3H), 1.90 (m, 3H), 2.37 (m, 1H), 2.71–2.73 (m, 4H),
2.83–3.36 (m, 14H), 3.78 (br s, 1H), 6.43 (br s, 1H), 6.85–6.91 (m,
3H), 7.15–7.19 (m, 2H), 7.24–7.27 (m, 2H), 7.34 (s, 1H). MS (ESI):
417.1 (C27H37N4, [M+H]+). The free base was converted into HCl
salt, mp: 158–160 °C.
CNBr (68 mg, 0.638 mmol) was added to a solution of 9b
(260 mg, 0.638 mmol) in H2O/EtOH (30 mL, 2:1). The mixture
was stirred overnight and neutralized by ammonia. After extrac-
tion by CH2Cl2 (3 ꢁ 30 mL), the organic layer was evaporated and
the residue was purified by column chromatography (Hex/EtOAc/
MeOH/Et3N 40:52:4:4) offered 10e (130 mg, 47%) as a brown
viscous liquid. 1H NMR (400 MHz, CDCl3)
d ppm 0.91 (t,
J = 7.2 Hz, 3H), 1.54–1.60 (m, 2H), 1.60–1.69 (m, 1H), 1.96 (br
s, 1H), 2.60–2.74 (m, 7H), 3.16–3.29 (m, 8H), 3.36–3.38 (m,
2H), 3.66–3.70 (m, 2H), 5.58 (br s, 2H), 5.80 (br s, 2H), 6.86–
6.94 (m, 3H), 7.24–7.28 (m, 2H). The free base was converted
Anal. [C27H36N4ꢃ3HClꢃ0.6H2Oꢃ0.1C2H5OC2H5)] C, H, N.
5.32. Procedure F for the syntheses of compounds 14a–f
into
oxalate
salt,
mp:
105–108 °C.
Anal.
[C28H36N4O2ꢃ3(COOH)2ꢃ3H2O] C, H, N.
4-Substituted benzenesulfonyl chloride/benzoyl chloride/acetyl
chloride (1 equiv) was added to cooled solution (0 °C) of 9d
(1 equiv) in pyridine (5 mL). The mixture was stirred at RT over-
night. The solvent was removed in reduced pressure and the resi-
due was purified by column chromatography (CH2Cl2/MeOH 9:1)
to yield pure 14a–f.
5.28. N-(2-(4-Phenylpiperazin-1-yl)ethyl)-N-propyl-6,7,8,9-
tetrahydro-1H-naphtho[1,2-d]imidazol-8-amine (10f)
This compound was prepared from compound 9c (0.43 mg,
1.05 mmol) following procedure to give compound 10f
E
(300 mg, 68%) as a brown viscous liquid. 1H NMR (400 MHz, CDCl3)
d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.49–1.55 (m, 2H), 1.72–1.77 (m, 1H),
2.10–2.17 (m, 1H), 2.58–2.66 (m, 8H), 2.2.77–2.81 (m, 2H), 2.87–
3.01 (m, 4H), 3.19–3.20 (m, 5H), 6.83–6.87 (m, 2H), 6.84–6.89
(m, 1H), 6.91–6.93 (m, 2H), 7.02–7.04 (m, 1H), 7.24–7.28 (m,
3H), 7.99–8.0 (m, 1H). The free base was converted into oxalate
salt, mp: 98–100 °C. Anal. [C26H35N5ꢃ3(COOH)2ꢃH2O] C, H, N.
5.33. 4-Chloro-N-(7-((2-(4-phenylpiperazin-1-
yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-2-
yl)benzenesulfonamide (14a)
This compound was prepared following procedure F in which
compound ( )-9d (37 mg, 0.09 mmol) and 4-chloro benzenesulfo-
nyl chloride (20 mg, 0.09 mmol) were used to afford compound
14a (42 mg, 80%) as a light brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.96 (t, J = 7.2 Hz, 3H), 1.76 (m, 3H),
2.36 (m, 1H), 2.67–2.99 (13H, m), 3.24 (br s, 4H), 6.87–6.92 (m,
6H), 7.27 (t, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.74 (d,
J = 8.8 Hz, 2H). The free base was converted into HCl salt, mp:
164–166 °C. Anal. [C31H39ClN4O2Sꢃ2HClꢃH2O] C, H, N.
5.29. N7-(2,2-Diethoxyethyl)-N2-(2-(4-phenylpiperazin-1-yl)
ethyl)-N2-propyl-1,2,3,4-tetrahydronaphthalene-2,7-diamine
(11)
A
solution of 9d (0.3 g, 0.764 mmol), Na2CO3 (81 mg,
0.764 mmol), and bromoacetaldehyde diethyl acetal (0.166 g,
0.84 mmol) in EtOH (3 mL), was heated at reflux for 1.5 days. The
solvent was removed in vacuo and the residue was purified by col-
umn chromatography (CH2Cl2/MeOH 5:0.25) to yield pure com-
pound 11 (0.23 g, 60%) as a brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.92 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz,
6H), 1.52–1.64 (m, 3H), 2.03 (m, 1H), 2.58 (m, 5H), 2.65–2.68 (m,
5H), 2.77 (m, 5H), 3.04 (br s, 1H), 3.19–3.22 (m, 6H), 3.53–3.60
(m, 2H), 3.68–3.76 (m, 2H), 4.67 (t, J = 6.8 Hz, 1H), 6.38 (m, 1H),
6.43–6.47 (m, 1H), 6.83–6.94 (m, 4H), 7.25 (d, J = 8.0 Hz, 1H),
7.27 (d, J = 8.0 Hz, 1H).
5.34. N-(7-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-2-yl)-4-
(trifluoromethyl)benzenesulfonamide (14b)
This compound was prepared following procedure F in which
compound ( )-9d (54 mg, 0.14 mmol) and 4-(trifluoromethyl) ben-
zenesulfonyl chloride (34 mg, 0.14 mmol) were used to afford
compound 14b (58 mg, 71%) as a light brown viscous liquid. 1H
NMR (400 MHz, CDCl3) d ppm 0.95 (t, J = 7.2 Hz, 3H), 1.72 (m,
3H), 2.18 (m, 1H), 2.65–2.97 (13H, m), 3.23 (br s, 4H), 6.85–6.92

B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
3173
(m, 6H), 7.27 (t, J = 8.0 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.93 (d,
5.39. (R)-4-Methoxy-N-(7-((2-(4-phenylpiperazin-1-yl)ethyl)
J = 8.0 Hz, 2H). The free base was converted into HCl salt, mp:
172–174 °C. Anal. [C32H39F3N4O2Sꢃ3HCl] C, H, N.
(propyl)amino)-5,6,7,8-tetrahydronaphthalen-2-
yl)benzenesulfonamide ((+)-14f)
5.35. N-(7-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-2-yl)benzamide (14c)
This compound was prepared following procedure F in which
compound (+)-9d (35 mg, 0.09 mmol) and 4-methoxy benzenesul-
fonyl chloride (19 mg, 0.09 mmol) were used to afford compound
This compound was prepared following procedure F in which
compound ( )-9d (34 mg, 0.09 mmol) and benzoyl chloride
(10 lL, 0.09 mmol) were used to afford compound 14c (33 mg,
(+)-14f (35 mg, 70%) as a light brown viscous liquid. ½a D25
ꢂ
=
+106.4 (c 0.5, MeOH). 1H NMR (400 MHz, CDCl3) d ppm 0.91 (t,
J = 7.2 Hz, 3H), 1.52–1.70 (m, 3H), 2.08 (m, 1H), 2.58–2.92 (m,
16H), 3.21 (br s, 4H), 3.81 (s, 3H), 6.80–6.96 (m, 8H), 7.26 (t,
J = 7.6 Hz, 2H), 7.72 (d, J = 6.8 Hz, 2H). 13C NMR (400 MHz, CDCl3)
d ppm 11.98, 21.80, 25.41, 29.16, 29.93, 48.10, 49.14, 53.53,
53.84, 57.77, 58.08, 114.36, 116.31, 119.71, 119.86, 120.07,
121.95, 122.80, 129.37, 129.51, 129.65, 130.33, 131.18, 134.64,
151.33, 163.17. The free base was converted into HCl salt, mp:
232–234 °C. Anal. [C32H42N4O3Sꢃ2HClꢃ2H2O] C, H, N.
78%) as a light brown viscous liquid. 1H NMR (400 MHz, CDCl3) d
ppm 0.96 (t, J = 7.6 Hz, 3H), 1.82–1.84 (m, 3H), 2.36 (m, 1H),
2.73–3.19 (m, 18H), 3.51 (br s, 1H), 6.87–6.91 (m, 3H), 6.97–7.03
(m, 1H), 7.24–7.29 (m, 2H), 7.41–7.58 (m, 5H), 7.97 (d, J = 7.2 Hz,
2H), 8.50 (br s, 1H). The free base was converted into HCl salt,
mp: 162–164 °C. Anal. [C32H40N4Oꢃ3HCl] C, H, N.
5.36. N-(7-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-2-yl)-acetamide (14d)
5.40. Procedure G for the syntheses of 16a, 16b, and 18
This compound was prepared following procedure F in which
compound ( )-9d (50 mg, 0.13 mmol) and acetyl chloride (9 lL,
To cooled solution (0 °C) of 15 or 17 (1 equiv) in DCM (5 mL),
were added Et3N (3 equiv) and 4-Substituted benzenesulfonyl
chloride (1.5 equiv). The mixture was stirred at room temperature
overnight. The reaction mixture was extracted with DCM and H2O.
Solvent was removed in reduced pressure and the residue was
purified by column chromatography (CH2Cl2/MeOH 9:1) to yield
pure products.
0.13 mmol) were used to afford compound 14d (30 mg, 55%) as a
light brown viscous liquid. 1H NMR (400 MHz, CDCl3) d ppm 0.99
(t, J = 7.2 Hz, 3H), 1.86 (m, 3H), 2.18 (s, 3H), 2.34 (m, 1H), 2.77–
3.22 (m, 18H), 3.59 (br s, 1H), 6.87–6.93 (m, 3H), 7.00 (d,
J = 8.4 Hz, 1H), 7.21–7.29 (m, 3H), 7.39 (s, 1H), 7.67 (br s, 1H). MS
(ESI): 435.1 (C27H39N4O, [M+H]+). The free base was converted into
HCl salt, mp: 172–174 °C. Anal. [C27H38N4Oꢃ3HClꢃ0.3C2H5OC2H5] C,
H, N.
5.41. (S)-6-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-1-yl 4-methylbenzenesulfonate
(16a)
5.37. 4-Methyl-N-(7-((2-(4-phenylpiperazin-1-yl)ethyl)
(propyl)amino)-5,6,7,8-tetrahydronaphthalen-2-
yl)benzenesulfonamide (14e)
This compound was prepared following procedure G in which
compound 15 (50 mg, 0.13 mmol), triethyl amine (53 lL,
0.38 mmol), and 4-methyl benzenesulfonyl chloride (36 mg,
This compound was prepared following procedure F in which
compound ( )-9d (50 mg, 0.13 mmol) and 4-methyl benzenesulfo-
nyl chloride (25 mg, 0.13 mmol) were used to afford compound
14e (45 mg, 65%) as a light brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.93 (t, J = 6.4 Hz, 3H), 1.52–1.82 (m,
3H), 2.37 (s, 3H), 2.39 (m, 1H), 2.50–3.18 (m, 16H), 3.22 (br s,
4H), 6.80–6.96 (m, 6H), 7.22 (t, J = 8.0 Hz, 2H), 7.27 (d, J = 8.4 Hz,
2H), 7.66 (d, J = 8.4 Hz, 2H). 13C NMR (400 MHz, CDCl3) d ppm
11.88, 21.80, 25.31, 28.84, 29.94, 47.88, 49.04, 53.44, 53.68,
58.78, 116.38, 119.66, 119.95, 120.20, 121.66, 122.68, 127.50,
129.39, 129.83, 130.27, 134.96, 136.69, 143.74, 151.19. The free
base was converted into HCl salt, mp: 225–227 °C. Anal.
[C32H42N4O2Sꢃ2HClꢃ2H2O] C, H, N.
0.19 mmol) were used to afford compound 16a (52 mg, 74%) as a
light brown viscous liquid. ½a D25
ꢂ
= ꢀ34.4 (c 0.5, MeOH). 1H NMR
(400 MHz, CDCl3) d ppm 0.90 (t, J = 7.2 Hz, 3H), 1.50 (m, 3H), 2.00
(m, 1H), 2.47 (s, 3H), 2.48–3.00 (m, 15H), 3.21 (m, 4H), 6.74 (d,
J = 7.2 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H),
6.98–7.40 (m, 2H), 7.27 (t, J = 7.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H),
7.77 (d, J = 7.6 Hz, 2H). 13C NMR (400 MHz, CDCl3) d ppm 12.07,
21.99, 24.49, 25.15, 32.31, 48.27, 49.25, 53.52, 53.97, 57.20,
58.34, 116.28, 119.47, 119.97, 126.56, 128.42, 128.59, 129.35,
130.05, 130.57, 133.58, 139.33, 145.53, 148.16, 151.47. The free
base was converted into HCl salt, mp: 220–222 °C. Anal.
[C32H41N3O3Sꢃ2HClꢃ2H2O] C, H, N.
5.42. (S)-6-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-1-yl 4-methoxybenzenesulfonate
(16b)
5.38. 4-Methoxy-N-(7-((2-(4-phenylpiperazin-1-yl)ethyl)
(propyl)amino)-5,6,7,8-tetrahydronaphthalen-2-
yl)benzenesulfonamide (( )-14f)
This compound was prepared following procedure G in which
compound 15 (45 mg, 0.11 mmol), triethyl amine (48 lL,
0.34 mmol), and 4-methoxy benzenesulfonyl chloride (35 mg,
This compound was prepared following procedure F in which
compound ( )-9d (50 mg, 0.13 mmol) and 4-methoxy benzenesul-
fonyl chloride (26 mg, 0.13 mmol) were used to afford compound
( )-14f (45 mg, 63%) as a light brown viscous liquid. 1H NMR
(400 MHz, CDCl3) d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.52–1.70 (m,
3H), 2.08 (m, 1H), 2.58–2.92 (m, 16H), 3.21 (br s, 4H), 3.81 (s,
3H), 6.80–6.96 (m, 8H), 7.26 (t, J = 7.6 Hz, 2H), 7.72 (d, J = 6.8 Hz,
2H). 13C NMR (400 MHz, CDCl3) d ppm 11.98, 21.80, 25.41, 29.16,
29.93, 48.10, 49.14, 53.53, 53.84, 57.77, 58.08, 114.36, 116.31,
119.71, 119.86, 120.07, 121.95, 122.80, 129.37, 129.51, 129.65,
130.33, 131.18, 134.64, 151.33, 163.17. The free base was con-
0.17 mmol) were used to afford compound 16b (47 mg, 73%) as a
light brown viscous liquid. ½a D25
ꢂ
= ꢀ39.2 (c 0.5, MeOH). 1H NMR
(400 MHz, CDCl3) d ppm 0.91 (t, J = 7.2 Hz, 3H), 1.53 (m, 3H),
2.04 (m, 1H), 2.42–3.04 (m, 15H), 3.21 (m, 4H), 3.90 (s, 3H), 6.74
(d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H),
6.96–7.04 (m, 4H), 7.26 (t, J = 7.6 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H).
13C NMR (400 MHz, CDCl3) d ppm 12.02, 21.80, 24.42, 25.05,
32.18, 48.20, 49.22, 53.50, 53.92, 55.99, 57.33, 57.93, 114.60,
116.29, 119.58, 119.99, 126.58, 127.86, 128.36, 129.35, 130.51,
130.82, 139.08, 148.16, 151.43, 164.32. The free base was con-
verted
into
HCl
salt,
mp:
230–232 °C.
Anal.
[C32H42N4O3Sꢃ2HClꢃ2H2O] C, H, N.

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B. Gopishetty et al. / Bioorg. Med. Chem. 21 (2013) 3164–3174
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verted
into
HCl
salt,
mp:
225–227 °C.
Anal.
[C32H41N3O4Sꢃ2HClꢃ2H2O] C, H, N.
5.43. (R)-7-((2-(4-Phenylpiperazin-1-yl)ethyl)(propyl)amino)-
5,6,7,8-tetrahydronaphthalen-2-yl 4-methoxybenzenesulfonate
(18)
This compound was prepared following procedure G in which
compound 17 (35 mg, 0.09 mmol), triethyl amine (37 lL,
0.27 mmol), and 4-methoxy benzenesulfonyl chloride (28 mg,
0.13 mmol) were used to afford compound 18 (37 mg, 74%) as a
light brown viscous liquid. ½a D25
ꢂ
= +26.2 (c 0.5, MeOH). 1H NMR
(400 MHz, CDCl3) d ppm 0.92 (t, J = 7.2 Hz, 3H), 1.50–1.72 (m,
3H), 2.15 (m, 1H), 2.60–2.88 (m, 14H), 3.20 (m, 5H), 3.88 (s, 3H),
6.64 (d, J = 8.0 Hz, 1H), 6.74–7.02 (m, 7H), 7.26 (t, J = 8.0 Hz, 2H),
7.75 (d, J = 8.4 Hz, 2H). 13C NMR (400 MHz, CDCl3) d ppm 11.97,
21.35, 25.43, 29.20, 31.73, 48.06, 49.13, 53.45, 53.82, 55.98,
57.84, 114.55, 116.34, 120.05, 120.12, 123.16, 127.11, 129.37,
129.79, 130.92, 135.17, 147.79, 151.30, 164.28. The free base was
converted
[C32H41N3O4Sꢃ2HClꢃ2H2O] C, H, N.
into
HCl
salt,
mp:
195–197 °C.
Anal.
5.44. Assessment of affinity for and activation of dopamine D2
and D3 receptors
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Binding potency was monitored by inhibition of [3H]spiroper-
idol (16.2 Ci/mmole, Perkin-Elmer) binding to dopamine rD2 and
rD3 receptors expressed in HEK293 cells, in a buffer containing
0.9% NaCl under conditions corresponding to our ‘high [radioli-
gand] protocol’ as described by us previously.23,37 Observed IC50
values were converted to inhibition constants (Ki) by the Cheng–
Prusoff equation.23 Functional activity of test compounds in acti-
vating dopamine hD2 and hD3 receptors expressed in CHO cells
26. Ghosh, B.; Antonio, T.; Gopishetty, B.; Reith, M.; Dutta, A. Bioorg. Med. Chem.
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S.; Deininger, D. D.; Drumm, J. E.; Gross, C. H.; LeTiran, A.; Liao, Y.; Mani, N.;
Nicolau, D. P.; Perola, E.; Ronkin, S.; Shannon, D.; Swenson, L. L.; Tang, Q.;
Tessier, P. R.; Tian, S. K.; Trudeau, M.; Wang, T.; Wei, Y.; Zhang, H.; Stamos, D. J.
Med. Chem. 2008, 51, 5243.
was measured by stimulation of [35S]GTP
cS (1250 Ci/mmole, Per-
kin–Elmer) binding in comparison to stimulation by the full ago-
nist dopamine as described by us previously.23
Acknowledgments
30. Yang, Y. H.; Cheng, M. S.; Wang, Q. H.; Nie, H.; Liao, N.; Wang, J.; Chen, H. Eur. J.
Med. Chem. 2009, 44, 1808.
31. Pelletier, J. C.; Chengalvala, M.; Cottom, J.; Feingold, I.; Garrick, L.; Green, D.;
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C.; Mehlmann, J.; Rogers, J.; Shanno, L.; Wrobel, J. Bioorg. Med. Chem. 2008, 16,
6617.
32. Wentland, M. P.; Ye, Y.; Cioffi, C. L.; Lou, R.; Zhou, Q.; Xu, G.; Duan, W.;
Dehnhardt, C. M.; Sun, X.; Cohen, D. J.; Bidlack, J. M. J. Med. Chem. 2003, 46, 838.
33. Zheng, X.; Oda, H.; Takamatsu, K.; Sugimoto, Y.; Tai, A.; Akaho, E.; Ali, H. I.;
Oshiki, T.; Kakuta, H.; Sasaki, K. Bioorg. Med. Chem. 2007, 15, 1014.
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V. Eur. J. Med. Chem. 2005, 40, 481.
This work is supported by National Institute of Neurological
Disorders and Stroke/National Institute of Health (NS047198,
A.K.D.). We are grateful to Dr. K. Neve, Oregon Health and Science
University, Portland, USA, for rD2L and D3 expressing HEK cells.
We are also grateful to Dr. J. Shine, Garvan Institute for Medical Re-
search, Sydney, Australia, for hD2L expressing CHO cells.
Supplementary data
35. Stjernlof, P.; Ennis, M. D.; Hansson, L. O.; Hoffman, R. L.; Ghazal, N. B.; Sundell,
S.; Smith, M. W.; Svensson, K.; Carlsson, A.; Wikstrom, H. J. Med. Chem. 1995,
38, 2202.
36. Kortagere, S.; Cheng, S. Y.; Antonio, T.; Zhen, J.; Reith, M. E.; Dutta, A. K.
Biochem. Pharmacol. 2011, 81, 157.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2013.03.059.
37. Zhen, J.; Antonio, T.; Dutta, A. K.; Reith, M. E. J. Neurosci. Methods 2010, 188, 32.
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