Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor

Article abstract of DOI:10.1016/j.bmc.2009.04.031

Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [³H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (K_i) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (-)-10e (K_i; D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (K_i; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (-)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPγS binding study, one of the lead molecules, (-)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.

Full text of DOI:10.1016/j.bmc.2009.04.031

Bioorganic & Medicinal Chemistry 17 (2009) 3923–3933
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Investigation of various N-heterocyclic substituted piperazine versions of
5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naph-
thalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor
Dennis A. Brown a, Manoj Mishra a, Suhong Zhang a, Swati Biswas a, Ingrid Parrington b,
Tamara Antonio b, Maarten E. A. Reith b, Aloke K. Dutta a,
*
a Wayne State University, Department of Pharmaceutical Sciences, Applebaum College of Pharmacy and Health Sciences, Rm# 3128, Detroit, MI 48202, United States
b New York University, Department of Psychiatry, 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:
Received 8 December 2008
Revised 3 April 2009
Accepted 9 April 2009
Available online 19 April 2009
Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-
aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Com-
pounds were subjected to [3H]spiperone binding assays, carried out with HEK-293 cells expressing either
D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (Ki) at these receptors. Results
indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings.
The results also show that in order to maintain high affinity and selectivity for the D3 receptor the het-
erocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds
included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enan-
tiomers of the most potent racemic compound 10e exhibited differential activity with (ꢀ)-10e (Ki;
D2 = 47.5 nM, D3 = 0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enan-
tiomer (+)-10e (Ki; D2 = 113 nM, D3 = 3.73 nM). Additionally, compound (ꢀ)-10e was more potent and
selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric deriv-
atives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for
Keywords:
Dopamine
Dopamine receptor
Parkinson’s disease
D2 and D3 receptors. In the functional GTP
potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.
Ó 2009 Elsevier Ltd. All rights reserved.
cS binding study, one of the lead molecules, (ꢀ)-15, exhibited
1. Introduction
The D2 and D3 receptor subtypes posses 50% overall structural
homology, and 75–80% in the agonist binding sites.9,10
The dopamine (DA) receptor system has been aggressively tar-
geted in pharmacotherapeutic treatments of numerous disorders,
including drugs of abuse, schizophrenia, and Parkinson’s disease
(PD).1,2 DA receptors, belonging to the class of G-protein coupled
receptors, are found throughout the CNS and periphery. So far five
subtypes of DA receptors have been identified.3 The various recep-
tor subtypes can be classified as being either D1-like or D2-like.
These classifications are based on receptor pharmacology and
function.4–7 The D1-like receptors, which include the D1 and D5
subtypes, activate adenylate cyclase activity upon receptor activa-
tion. The D2-like receptors, which include the D2, D3, and D4 sub-
types, inhibit adenylate cyclase activity. Interestingly, the D3
receptor was found to have a distribution in the brain that is differ-
ent than that of the D2 receptor.8 The highest levels of DA D3
receptor expression were found to be in the limbic region of the
brain, which has been implicated in various psychiatric disorders.
DA receptor agonists have been used more extensively in the
treatment of Parkinson’s disease (PD) than any other type of phar-
macotherapy.11,12 PD is a progressive, neurodegenerative disorder
that is characterized by the disintegration of the nigrostriatal dopa-
minergic pathway.13 Recent estimates place the rate of Americans
over the age of 65 affected with PD to be around 1%. The initial goal
of DA agonist therapy was to overcome the numerous drawbacks
to levodopa therapy, including the development of debilitating
dyskinesias, and the inherent toxicity of levodopa to dopaminergic
neurons.14 Dopaminergic agonists are known to posses inherent
antioxidant properties. In this regard, dopamine D3 receptor has
been implicated in neuroprotective therapy for PD.15 It has also
been demonstrated from primate and rodent experiments that
exposure to levodopa leads to over expression of D3 receptor in
the basal ganglia and the resultant levodopa induced dyskinesia
can be reduced substantially with the treatment of D3 preferring
agonists.16,17 Consequently, high affinity agonists for D3 receptor
with high selectivity will be able to delineate more effectively
the functional properties of the D3 receptor and its importance
in various neuro-disorders.
* Corresponding author. Tel.: +1 313 577 1064; fax: +1 313 577 2033.
E-mail address: adutta@wayne.edu (A.K. Dutta).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.04.031

3924
D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
An intensive effort has been directed toward development of
selective agonists and partial agonists. Our SAR studies so far have
demonstrated that the hybrid analogues retain agonist property in
spite of addition of piperazine fragment and most of these mole-
cules exhibit significant selectivity for the D3 receptor. Two of
our lead molecules, D-237 and D-264, shown in Figure 1 exhibited
high affinity and selectivity for D3 receptor in vitro binding assay
and in vivo functional assays. They were also quite potent in an
in vivo PD animal model, indicating their site-specific agonist
activity in the CNS.28,29 In our further quest to understand the role
of piperazine ring and the effect of different N-substitutions in the
piperazine ring, the current compounds were designed. In these
compounds, different N-aromatic heterocyclic substitutions, spe-
cifically various indole substitutions, have been incorporated.
One of our long-term objectives in this project is to develop a reli-
able pharmacophore model for these hybrid compounds with
which we would be able to rationalize the observed DA D2/D3
binding affinities and selectivities of our compounds.
selective ligands for D3 receptor. A large number of compounds
with various selectivities for the D3 receptor have been devel-
oped.18,19 The overall sequence identity between D2 and D3 recep-
tors is very high. Moreover, when the trans membrane domains,
which are the most relevant sites of ligands interaction within
the receptor, are considered then the sequence identity becomes
close to greater than 80%.10 Furthermore, both receptors share
nearly identical active binding sites for agonist interaction which
makes the job of developing selective agonists for D3 receptor even
more challenging.20–22 Some of the well known D3 selective ago-
nists include ropinirole and pramipexole, and these agonists were
shown to exhibit a 4–10-fold higher affinity for the D3 than D2
receptor.23 On the other hand, numerous ligands as antagonists
have been developed so far with a number of lead compounds
showing high selectivity for the D3 receptor. The majority of these
compounds contain a piperazine ring connected to a suitable benz-
amide-type moiety via variable linker size.18,19,24 The template, I,
for these compounds is shown in Figure 1. Numerous different aro-
matic moieties have been introduced as R substituents in the benz-
amide moiety with some of the substituents produced high
selectivity for the D3 receptor. On the other hand only a handful
number of N-phenyl substituents as R0 substituents on the pipera-
zine moiety have been investigated. Some of the lead molecules
derived from this template is listed in Figure 1.18 It is important
to mention here the difficulties in comparing binding data across
laboratories as the conditions of binding assays vary significantly.
We have previously reported a hybrid structure approach as
part of our ongoing effort to design and develop selective agonists
for the DA D3 receptor.25–27 Our hybrid approach combines agonist
aminotetralin or bioisosteric equivalent fragments with arylpiper-
azine fragments via a linker to yield compounds that are DA D3
2. Chemistry
Scheme 1 outlines the syntheses of 9a, 9b and enantiomerically
pure form of 9b, ((+)-9b and (ꢀ)-9b). The starting materials for
these compounds were appropriately substituted 5- and 7-meth-
oxy-2-tetralones 1a–b. These were condensed with propyl amine
under reductive amination conditions to give secondary amines
2a–b, which were then reacted with chloroacetyl chloride to give
a-chloro amides 3a–b. Enantiomeric synthesis of compound 9b
was performed by converting the racemic amine 2b to its diaste-
reomeric salt by using optically active synthetic resolving agent.
The synthesis of this resolving agent (4-(2-chlorophenyl)-5,5-di-
methyl-2-hydroxy 1,3,2-dioxaphosphorinane-2-oxide), commonly
known as chlocyphos, and its resolution to derive two enantiomers
O
N
H2N
HO
(R)-7-OH-DPAT
S
N
N
NH
Pramipexole
N
O
SO2Me
N
SB-414796
R' =
OCH3
R =
BP 897,
OCH3
O
Cl
R'
O
N
N
R' =
R' =
R' =
II =
R =
R =
R
N
H
Cl
Cl
I
S
III =
Cl
Cl
H
N
IV = R =
OH
Cl
N
S
H2N
N
N
N
N
N
N
D-264
(-)-D-237
N
N
N
HO
(+)-D-315
Figure 1. Molecular structure of dopamine D3 selective agonist and antagonist molecules.

D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
R1
3925
R1
R1
a
O
d
Cl
R2
R2
R2
O
N
N
H
2a, R1 = H, R2 = OMe
2b, R1 = OMe, R2 = H
(+)-2b, R1 = OMe, R2 = H
(-)-2b, R1 = OMe, R2 = H
3a, R1 = H, R2 = OMe
3b, R1 = OMe, R2 = H
(+)-3b, R1 = OMe, R2 = H
(-)-3b, R1 = OMe, R2 = H
R1
1a R1 = H, R2 = OMe
1b R1 = OMe, R2 = H
b, c
Boc
O
N
N
e
f
HN
NH
3a, 3b,
Boc
N
HN
+
R2
N
(+)-3b, (-)-3b
4
5
6a R1 = H, R2 = OMe
6b R1 = OMe, R2 = H
(+)-6b, R1 = OMe, R2 = H
(-)-6b, R1 = OMe, R2 = H
R1
R1
g
h
NH
O
NH
N
N
R2
N
R2
N
8a R1 = H, R2 = OMe
8b R1 = OMe, R2 = H
(+)-8b, R1 = OMe, R2 = H
(-)-8b, R1 = OMe, R2 = H
7a R1 = H, R2 = OMe
7b R1 = OMe, R2 = H
i
(+)-7b, R1 = OMe, R2 = H
(-)-7b, R1 = OMe, R2 = H
9a R1 = H, R2 = OH
9b R1 = OH, R2 = H
(+)-9b, R1 = OMe, R2 = H
(-)-9b, R1 = OMe, R2 = H
Scheme 1. Reagents and conditions: (a) n-propyl amine, NaCNBH3, AcOH, (CH2Cl2)2; (b) (+)- or (ꢀ)-chlocyphos, ethanol, recrystallized from isopropanol; (c) 20% NaOH, rt,
2 h; (d) propionyl chloride, Et3N, CH2Cl2; (e) (Boc)2O, CH2Cl2; (f) K2CO3, CH3CN, reflux; (g) CF3COOH, CH2Cl2; (h) LiAlH4, THF, reflux; (i) BBr3, ꢀ78 °C, CH2Cl2.
was carried out by following a literature procedure and our earlier
publication.28,30 Thus, compound 2b was resolved into the enantio-
meric pure compound (+)-2b and (ꢀ)-2b using (+)- or (ꢀ)-chlocy-
phos by following the procedure reported by us earlier. N-
Alkylation of amines with mono Boc-protected piperazine31 gave
amides 6a–b, (+)-6b and (ꢀ)-6b which were then reduced using
lithium aluminum hydride. Demethylation in the presence of bor-
on tribromide afforded phenol intermediates 9a–b, (+)-9b, (ꢀ)-9b.
Scheme 2 describes the syntheses of indoles 10a–j as well as
enantiomeric pure (+)-10e and (ꢀ)-10e. Secondary amines 9a–b,
(+)-9b and (ꢀ)-9b were condensed with either aldehydes under
reductive amination conditions or carboxylic acids under amide
coupling reactions to yield the final compounds 10a–j, (+)-10e
and (ꢀ)-10e.
21. Amide reduction with borane and demethylation using HBr
completed the synthesis of 22.
3. Results and discussion
In our current report we have designed a series of N-piperazine
substituted novel hybrid derivatives. The majority of compounds
designed represent various substituted indole derivatives with
additional compounds falling in the category of bioisosteric ana-
logues of indole.
Table 1 summarizes the binding data for the indole analogs that
were synthesized. Compound 10e, which is a 5-hydroxy amino-
tetralin compound with a 2-substituted indole amide, proved to
be twice as potent in binding at D2 receptors and almost seven
times more potent at D3 receptors (Ki D2 = 51.2 nM,
D3 = 0.550 nM) than its corresponding 7-OH counterpart 10c (Ki
D2 = 116 nM, D3 = 3.72 nM). The observed differences in D2 bind-
ing affinities between 10c and 10e correlate well with parent hy-
brid compounds D-315 and D-237 (see Table 1). However, the
differences in D3 binding between 10c and 10e are more signifi-
cant than between D-315 and D-237. Thus, the selectivity of 10e
for D3 receptor is much higher than 10c (D2/D3; 93 vs 31 for
10e and 10c, respectively). On the other hand, the 5-hydroxy de-
rived 3-substituted indole-acyl derivative 10f showed less affinity
for D3 receptors compared to its 2-substituted indole 10e counter-
part (Ki; 58.9 and 3.62 nM for D2 and D3 receptors, respectively for
The synthesis of optically active indole (ꢀ)-15 began with com-
pound 5 and is shown in Scheme 3. N-Alkylation with bromoetha-
nol followed by Swern oxidation gave aldehyde 12. Condensation
of 12 with optically active secondary amine 1328 afforded 14.
Deprotection followed by amide coupling with indole-5-carboxylic
acid gave (ꢀ)-15.
Scheme 4 outlines the synthesis of indole 22. 5-Bromoindole
was protected using triisopropylsilyl chloride in the presence of
NaH to provide 17. Coupling of this compound with 5 using
PdCl2[P(o-tol)3]2 and sodium t-butoxide in xylenes gave intermedi-
ate 18 in good yield. Next, cleavage of both amine protecting
groups followed by condensation with
a-chloro amide 3a gave

3926
D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
O
R
10a
10c
R =
R =
10b
10d
a or b, RCHO
or RCOOH
R =
R =
N
9a
N
H
N
H
N
HO
N
O
N
H
N
H
O
O
OH
10e R =
(+)-10e
(-)-10e
R
N
10f
R =
N
b, RCOOH
H
9b, (+)-9b,
N
H
N
(-)-9b
N
O
O
N
R =
R =
10g
10i
R =
R =
10h
10j
N
O
H
O
O
S
N
Scheme 2. Reagents: (a) NaCNBH3, AcOH, ClCH2CH2Cl; (b) EDCI, HOBT, Et3N, CH2Cl2.
OMe
a
b
HN
N Boc
N
N Boc
N
N Boc
c
HO
OHC
NH
5
11
12
13
OMe
OH
O
Boc
N
d, e
N
NH
N
N
N
N
H
N
14
15
HOOC
Scheme 3. Reagents and conditions: (a) 2-bromoethanol, K2CO3, CH3CN; (b) Swern oxidation; (c) Na(OAc)3BH, acetic acid, dichloroethane; (d) aq HBr (48%), reflux, 3 h; (e)
EDCI, HOBt, Et3N.
Boc
Br
Br
N
a
c
b
N
N
N
TIPS
H
16
17
N
TIPS
18
Boc
NH
HN
N
N
N
d
e
O
N
N
N
N
O
N
H
19
H
20
21
NH
f
N
N
HO
N
22
Scheme 4. Reagents and conditions: (a) triisopropylsilyl chloride, NaH, THF; (b) 5, PdCl2[P(o-tol)3]2, NaOtBu, xylenes, reflux, overnight; (c) 1 M Bu4NF, THF, rt, 4 h; (d) TFA,
CH2Cl2; (e) 3a, K2CO3, CH3CN, reflux; (f) (i) BH3, THF; (ii) HBr, reflux.
10f). The other 5-substituted indole amide derivative 10a derived
from the 7-hydroxy series, exhibited higher affinity than its 10c
counterpart in the same series (see Table 1). Compounds 15 and
10a exhibited comparable affinity for the D3 receptor (Ki; 2.27 vs
1.67 nM, respectively) (Table 1).
Next a series of bioisosteric analogues of 5-hydroxy indole
derivative was designed and synthesized. The benzo[b]thiophene
derivative 10i showed high affinity for D2 and D3 receptors
(Ki = 76.9 and 1.69 nM for D2 and D3 receptors, respectively). On
the other hand, the benzofuran derivative 10h was two- to three-
fold less potent in binding compared to 10i (Ki = 132 and 5.23 nM
for D2 and D3 receptors). The quinoline derivative 10j exhibited
similar binding potency as 10h and was the least potent at D2
receptors in this bioisosteric series, with a Ki value of 158 nM.
Interestingly, the indazole derivative 10g exhibited the highest
affinity for D2 in this current series of molecules and was also

D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
3927
Table 1
view, it seems that the role of the indole N-atom is less critical
here, especially in 10e. Our data also show that the nature of the
indole group substitution coupled with the position of the hydro-
xyl group substitution in the aromatic ring play important roles
in determining the D2/D3 binding affinities of hybrid aminotetralin
arylpiperazine molecules as well as their selectivity.
Affinity for cloned D2L and D3 receptors expressed in HEK cells measured by inhibition
of [3H]spiperone binding
Compound
Ki (nM), D2L [3H]spiperone Ki (nM), D3 [3H]spiperone D2L/D3
( )-7-OH-DPAT
311 47
6.19 1.4
1.36 (4) 0.28
0.825 0.136
0.92 0.23
50.2
43
31.5
(ꢀ)-5-OH-DPAT 58.8 (5) 11.0
D-237a
26.0 7.5
264 40
40.6 3.6
116 12
As mentioned above, compound 10e is the most potent and
selective molecule in binding to D3 receptors in the current series
of molecules. Synthesis of enantiomers of 10e was carried out fol-
lowed by characterization of their binding to D2/D3 receptors. As
expected, (ꢀ)-10e exhibited higher affinity and selectivity for D2/
D3 receptors than its corresponding enantiomeric counterpart
(+)-10e (Ki; 47.5 nM and 0.57 nM vs 113 nM and 3.73 nM for D2
and D3 receptors, respectively). In this regard, (ꢀ)-10e exhibited
higher affinity and selectivity for the D3 receptor compared to
either ( )-7-OH-DPAT or (ꢀ)-5-OH-DPAT (Ki; 0.57 nM vs 6.19 and
1.36 nM; D2/D3: 83 vs 50 and 43). Compound (ꢀ)-15 (Ki; 157 nM
and 2.27 nM for D2 and D3, respectively) was selectively synthe-
sized as our current results and previous results consistently dem-
onstrated that in the 5-hydroxy series of hybrid compound, it is the
(ꢀ)-isomeric version which exhibits the highest affinity for the D3
receptor compared to the (+)-version.28 Another interesting aspect
of the results from current SAR studies concerns the role of piper-
azine N-atoms in interacting with D2/D3 receptors. The piperazine
N-atom connected to the aromatic moiety in compound D-264 and
D-237 is expected to be less basic compared to the other pipera-
zine N-atom. In the current indole amides and other heterocyclic
amide derivatives this N-atom is expected to be even lesser basic
in nature. However, this loss of basicity has not impacted their
affinity for D2/D3 receptors, possibly indicating very little or no
involvement of this N-atom in H-bonding and ionic interaction
with the target receptors.
D-264b
253
D-315
1.77 0.42
3.72 1.12
4.82 1.10
3.87 0.65
1.67 0.26
2.00 0.48
2.27 0.52
22.9
31.2
20.7
37.2
39.5
15.0
69.2
93.1
83
10c (D-282)
10d (D-283)
10b (D-284)
10a (D-285)
22 (D-286)
(ꢀ)-15 (D-313)
10e (D-328)
100
144
65.9
1
5
9
30.0 4.9
157 35
51.2 7.0
0.550 (4) 0.084
0.570 0.094
3.73 (4) 0.56
3.62 (5) 0.79
2.83 (5) 0.59
5.23 (5) 1.13
1.69 (4) 0.41
5.18 (5) 0.75
(ꢀ)-10e (D-366) 47.5 (5) 6.2
(+)-10e (D-365)
10f (D-329)
10g (D-334)
10h (D-333)
10i (D-332)
10j (D-331)
113 (6) 21
58.9 7.9
28.0 2.4
30.2
16.3
9.89
132
76.9 9.2
158 22
8
25.2
45.5
30.5
Results are means SEM for three to six experiments each performed in triplicate.
a
See Ref. 28.
See Ref. 29.
b
among the D3 compounds with highest binding potency in this
bioisosteric series of compounds (Ki = 28 and 2.83 nM for D2 and
D3, respectively).
5-Substituted indole derivative 10b, with a methylene unit be-
tween the heterocycle and the piperazine fragment, showed affin-
ity for both D2 and D3 that was half as compared to its amide
counterpart 10a (Ki; 144 and 3.87 nM for D2 and D3 receptors,
respectively for 10b). However, such a change in binding affinity
was not observed between the 2-substituted similar indole com-
pounds 10c and 10d. The reason for this is not fully understood.
Compound 22, in which the piperazine moiety is directly attached
to the 5-position of indole, demonstrated high affinity for both D2
and D3 (Ki D2 = 30 nM, D3 = 2 nM).
The above data demonstrates that the position of attachment to
the indole moiety influences the binding affinity profiles for both
D2 and D3 receptors. For example, changing the point of indole
attachment from the 2 position (10e) to the 3 position (10f) results
in a very minor shift in Ki values for D2 receptor (51.2 nM for 10e
vs 58.9 nM for 10f). However, the 2-substituted indole amide 10e
was sevenfold more potent than 10f for binding interaction with
D3 receptors (Ki; 0.55 vs 3.62 nM). It will be interesting to investi-
gate in the future whether such changes in affinities can be ac-
counted for by alteration of any electronic properties in the two
substituted indoles or other factors. From a structural point of
Next we evaluated one of the optically active lead compounds
(ꢀ)-15 and the reference (ꢀ)-5-OH-DPAT in the GTP
cS functionalas-
say for D2 and D3 receptors. The assay was carried out with cloned
humanD2andD3receptorsexpressedinCHO-andAtT-cells, respec-
tively. The half maximalstimulation (EC50) exhibited by (ꢀ)-15 at D2
receptors was in the nanomolar range and at D3 receptors subn-
anomolar (EC50; 10.4 and 0.14 nM for D2 and D3 receptor, respec-
tively) whereas the compound maximally stimulated the GTPcS
signal comparable to the full agonist dopamine itself, indicating full
agonist activity at both D2 and D3 receptor. The functional data
shows that (ꢀ)-15 has a preferential intrinsic stimulatory effect at
D3 receptors compared to D2 receptors (D2/D3 (EC50) = 74, Table 2).
4. Conclusion
In this report, we have demonstrated that N-substitution on the
piperazine ring can accommodate various substituted indole rings.
Table 2
Stimulation of [35S]GTP
c
S binding to the cloned hD2 receptor expressed in CHO cells and cloned hD3 receptor expressed in AtT-20 cells
CHO-D2
%Emax
Compound
AtT-D3
EC50 (nM)
35S]GTP
EC50 (nM)
35S]GTP
cS
%Emax
D2/D3
24.5
[
c
S
[
Dopamine
209 (4) 29
100
8.53 0.62
100
(definition)
(definition)
102 19
78.5 9.5
92.2 5.8
91.2 1.0
D-264b
19.9 0.9
119
6
0.085 0.016
0.121 0.002
0.14 0.03
248
(ꢀ)-D-237a
2.22 0.27
10.4 (4) 1.6
41.2 6.0
63.4 3.5
77.8 0.9
80.0 4.4
18.3
74.3
33.5
(ꢀ)-15 (D-313)
(ꢀ)-5-OH-DPAT
1.23 0.53
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 M (D3) of the full agonist DA (%Emax). Results are means SEM for 3–4 experiments each performed in triplicate.
l
a
See Ref. 28.
See Ref. 29.
b

3928
D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
Our results have also shown that in order to maintain high affinity
and selectivity for the D3 receptor, the heterocyclic ring does not
need to be connected directly to the piperazine ring as the majority
of compounds included here are linked either via an amide or a
methylene linker. Thus, compound (ꢀ)-10e with an amide linker
connected to the 2-position of the indole ring was among the com-
pounds with high affinity and selectivity at the D3 receptor. More-
over, compound (ꢀ)-10e was more potent and selective for the D3
receptor compared to either 7-OH-DPAT or 5-OH-DPAT. As found
from our previous studies on hybrid compounds, compounds
belonging to 5-hydroxy series in general produced higher potency
than those in the 7-hydroxy series. Among the bioisosteric deriva-
tives, the indazole derivative 10g and benzo[b]thiazole 10i exhib-
ited the highest affinity for D2 and D3 receptors. In the
102 mmol), propyl amine (5.5 ml, 68 mmol), and NaCNBH3 (5.3 g,
85 mmol) to give 4.63 g of 2b (62%, free base). 1H NMR (free base)
(400 MHz, CDCl3) 0.92–0.964 (t, 3H, J = 7.6 Hz), 1.39 (br s, 1H),
1.49–1.61 (m, 3H), 2.05–2.10 (m, 1H), 2.53–2.62 (m, 2H), 2.66–
2.70 (t, 3H, J = 7.6 Hz), 2.87–2.94 (m, 2H), 2.98–3.03 (m, 1H), 3.81
(s, 3H), 6.65–6.67 (d, 1H, J = 8 Hz), 6.96–6.71 (d, 1H, J = 8 Hz),
7.07–7.11 (t, 1H, J = 7.2 Hz).
Compound 2b was resolved into its enantiomerically pure
form (+)-2b and (ꢀ)-2b following the procedure reported by us
earlier.
5.3. Procedure B: 2-Chloro-N-(7-methoxy-1,2,3,4-tetrahydro-
naphthalen-2-yl)-N-propyl-acetamide (3a)
functional GTP
c
S studies, compound (ꢀ)-10e exhibited good selec-
Compound 2a (HCl salt, 5.0 g, 19.5 mmol) and Et3N (5.5 ml,
39.1 mmol) was stirred at 0 °C in CH2Cl2 (65 ml) for 15 min. Chlo-
roacetyl chloride (1.9 ml, 23.5 mmol) was added dropwise and the
resulting solution was stirred at room temperature for 20 min, at
which time the reaction mixture was poured into a 1 M solution
of NaOH (50 ml) and the product was extracted with dichloro-
methane, dried (Na2SO4), filtered, and concentrated. The crude
material was purified by column chromatography (Hex/EtOAc,
3:1) to give 5.5 g (95%) of 3a. 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).
tivity at the D3 receptor, conforming to its binding data. Our cur-
rent ongoing SAR studies will shed more light in regards to the
interaction of hybrid molecules which will be used to develop a
pharmacophore model for these compounds.
5. Experimental
Analytical silica gel-coated TLC plates (Silica Gel 60 F254) were
purchased from EM Science and were visualized with UV light or
by treatment with either phosphomolybdic acid (PMA) or ninhy-
drin. Flash chromatography was carried out on Baker Silica Gel
40 mM. 1H NMR spectra were routinely obtained on GE-300 MHz
and Varian 400 MHz FT NMR. The NMR solvent used was either
CDCl3 or CD3OD as indicated. TMS was used as an internal stan-
dard. Elemental analyses were performed by Atlantic Microlab,
Inc. and were within 0.4% of the theoretical value. Optical rota-
tions were recorded on a Perkin Elmer 241 polarimeter. [3H]spipe-
rone (15.0 Ci/mmol) and [35S]GTPS (1250 Ci/mmol) were from
Perkin Elmer (Boston, MA). 7-OHDPAT and (+)-butaclamol were
from Sigma–Aldrich (St. Louis, MO).
5.4. 2-Chloro-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-
yl)-N-propyl-acetamide (3b)
This compound was prepared from 2b (4.63 g, 21.1 mmol), tri-
ethyl amine (5.1 ml, 42.2 mmol), and chloroacetyl chloride
(1.80 ml, 25.4 mmol) by following Procedure B to give 3b (5.8 g,
93%). 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), 6.61–6.68 (m, 2H), 6.96–7.04
(m, 1H).
5.1. Procedure A: (7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-
yl)-propyl-amine (2a)
5.5. (+)-2-Chloro-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-
2-yl)-N-propyl-acetamide ((+)-3b)
7-Methoxy-2-tetralone (6.21 g, 35.2 mmol) and acetic acid
(5.3 ml, 105.6 mmol) were dissolved in dichloroethane (100 ml)
and cooled to 0 °C. Propyl amine (5.7 ml, 70.4 mmol) was added
and the mixture was stirred under a N2 atmosphere for 30 min.
NaCNBH3 (5.5 g, 80.8 mmol) in anhydrous MeOH (15 ml) was then
added to the mixture and allowed to stir overnight at ambient tem-
perature. The volatiles were then evaporated and the mixture was
partitioned between ethyl acetate and 1 M NaOH. The organic layer
was separated, dried (Na2SO2), filtered, and concentrated. The
crude residue was then taken up in EtOAc, at which time ethereal
HCl was added, and the material evaporated to dryness. The crude
salt was dissolved in a minimum volume of MeOH, and precipi-
tated by the gradual addition of diethyl ether. The salt was col-
lected via filtration and dried to yield 5.09 g (64%, free base) and
used in the subsequent transformations. 1H NMR (free base)
(400 MHz, CDCl3) 0.91–0.95 (t, 3H, J = 7.6 Hz), 1.38 (br s, 1H),
1.48–1.60 (m, 3H), 2.04–2.09 (m, 1H), 2.54–2.62 (m, 2H), 2.67–
2.71 (t, 3H, J = 7.6 Hz), 2.88–2.92 (m, 2H), 2.97–3.04 (m, 1H), 3.81
(s, 3H), 6.60–6.61 (dd, 1H, J = 1.6 Hz), 6.65–6.78 (m, 1H), 6.95–
6.98 (d, 1H, J = 8.8 Hz).
This compound was prepared from (+)-2b (3.09 g, 14.07 mmol),
triethyl amine (3.4 ml, 28.1 mmol), and chloroacetyl chloride
(1.20 ml, 16.93 mmol) by following Procedure B to give (+)-3b
(3.95 g, 95%). 1H NMR (400 MHz, CDCl3) 0.90–0.97 (m, 3H), 1.65–
1.72 (m, 2H), 3.18–3.27 (m, 2H), 4.00 (s, 3H), 6.607–6.68 (m, 2H),
6.97–7.03 (m, 1H).
5.6. (ꢀ)-2-Chloro-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-
2-yl)-N-propyl-acetamide ((ꢀ)-3b)
This compound was prepared from (ꢀ)-2b (1.98 g, 9.02 mmol),
triethylamine (2.2 ml, 18 mmol), and chloroacetyl chloride
(0.77 ml, 10.85 mmol) by following Procedure B to give (ꢀ)-3b
(2.50 g, 96%). 1H NMR (400 MHz, CDCl3) 0.87–0.95 (m, 3H), 1.63–
1.78 (m, 2H), 3.1–3.30 (m, 2H), 3.89 (s, 3H), 6.61–6.68 (m, 2H),
6.97–7.02 (m, 1H).
5.7. Procedure C: 4-{[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-
2-yl)-propyl-carbamoyl]-methyl}-piperazine-1-carboxylic acid
tert-butyl ester (6a)
5.2. (5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-
amine (2b)
Compound 3a (4.22 g, 14.3 mmol), 5 (4.35 g, 17.2 mmol), K2CO3
(3.94 g, 28.5 mmol) were refluxed in CH3CN (100 ml) for 1 h. The
solution was cooled, filtered, and concentrated. The crude material
was then partitioned between EtOAc and H2O, and the organic layer
This compound was prepared following Procedure A from 5-
methoxy 2-tetralone (6.0 g, 34.0 mmol), acetic acid (5.1 ml,

D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
3929
was separated, dried (Na2SO4), and concentrated. The crude mixture
was purified by column chromatography (EtOAc) to give 5.1 g (71%)
of 6a. 1H NMR (400 MHz, CDCl3) 0.86–0.90 (t, 3H, J = 8 Hz), 1.45 (s,
9H), 1.59–1.82 (m, 2H), 1.87–1.94 (m, 1H), 1.95–1.97 (m, 3H),
2.420 (br s, 2H), 2.50–2.63 (m, 2H), 2.76–2.82 (m, 1H), 2.96–3.20
(m, 3H), 3.88–3.47 (m, 4H), 3.81 (s, 3H), 6.60–6.61 (dd, 1H,
J = 1.6 Hz), 6.65–6.78 (m, 1H), 6.95–6.98 (d, 1H, J = 8.8 Hz).
3H), 1.84–1.97 (m, 3H), 2.55 (m, 1H), 2.80–2.87 (m, 5H),
2.97–3.34 (m, 9H), 3.82 (s, 3H), 6.64–6.71 (m, 2H), 7.06–7.15
(m, 1H).
5.13. (+)-N-(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2-
piperazin-1-yl-N-propyl-acetamide ((+)-7b)
This compound was prepared from (+)-6b (1.65 g, 3.70 mmol),
and TFA (10 ml) by following the Procedure D to give (+)-7b
(1.22 g, 94%). 1H NMR (400 MHz, CDCl3) 0.92–0.97 (t, 3H,
J = 7.6 Hz), 1.62–1.64 (m, 3H), 1.84–1.98 (m, 3H), 2.52–2.55 (m,
1H), 2.80–2.89 (m, 5H), 2.97–3.35 (m, 9H), 3.82 (s, 3H), 6.64–6.70
(m, 2H), 7.06–7.14 (m, 1H).
5.8. 4-{[(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-
carbamoyl]-methyl}-piperazine-1-carboxylic acid tert-butyl
ester (6b)
This compound was prepared from 3b (5.8 g, 19.6 mmol), 5
(5.9 g, 23.6 mmol), and K2CO3 (5.4 g, 41.2 mmol) according to Pro-
cedure C for to give 6b (6.6 g, 74%). 1H NMR (400 MHz, CDCl3)
0.87–0.91 (t, 3H, J = 8 Hz), 1.44 (s, 9H), 1.58–1.81 (m, 2H), 1.88–
1.95 (m, 1H), 1.96–1.98 (m, 3H), 2.40 (br s, 2H), 2.51–2.63 (m,
2H), 2.78–2.83 (m, 1H), 2.95–3.29 (m, 3H), 3.88–3.47 (m, 4H),
3.81 (s, 3H), 6.63–6.70 (m, 2H), 7.10–7.14 (t, 1H, J = 7.2 Hz).
5.14. (ꢀ)-N-(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2-
piperazin-1-yl-N-propyl-acetamide ((ꢀ)-7b)
This compound was prepared from (ꢀ)-6b (1.38 g, 3.08 mmol),
and TFA (10 ml) by following the Procedure D to give (ꢀ)-7b
(1.02 g, 94%). 1H NMR (400 MHz, CDCl3) 0.91–0.97 (t, 3H,
J = 7.6 Hz), 1.62–1.65 (m, 3H), 1.84–1.95 (m, 3H), 2.56 (m, 1H),
2.80–2.88 (m, 5H), 2.97–3.35 (m, 9H), 3.80 (s, 3H), 6.64–6.70 (m,
2H), 7.06–7.16 (m, 1H).
5.9. (+)-4-{[(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-carbamoyl]-methyl}-piperazine-1-carboxylic acid tert-
butyl ester ((+)-6b)
This compound was prepared from (+)-3b (5.22 g, 17.64 mmol), 5
(5.31 g, 21.24 mmol), and K2CO3 (4.86 g, 37.08 mmol) according to
the Procedure C for to give (+)-6b (5.52 g, 69%). 1H NMR (400 MHz,
CDCl3) 0.87–0.91 (t, 3H, J = 8 Hz), 1.45 (s, 9H), 1.60–1.81 (m, 2H),
1.88–1.94 (m, 1H), 1.96–2.00 (m, 3H), 2.40 (br s, 2H), 2.51–2.65
(m, 2H), 2.78–2.82 (m, 1H), 2.99–3.28 (m, 3H), 3.39–3.47 (m, 4H),
3.81 (s, 3H), 6.63–6.70 (m, 2H), 7.10–7.13 (t, 1H, J = 7.2 Hz).
5.15. Procedure E: (7-methoxy-1,2,3,4-tetrahydro-naphthalen-
2-yl)-(2-piperazin-1-yl-ethyl)-propyl-amine (8a)
To a suspension of LiAlH4 (1.6 g, 40.5 mmol) in THF (100 ml) in
an ice bath was added 7a (3.8 g, 11.0 mmol) dissolved in a solu-
tion of THF (25 ml). After addition, the mixture was refluxed for
3 h and cooled to 0 °C. 10% NaOH was added dropwise, and the
mixture stirred for 20 min, and filtered. The solution was dried
(Na2SO4), filtered, and concentrated to give 8a (3.21 g, 97%),
which was used without further purification. 1H NMR (400 MHz,
CDCl3) 0.91–0.96 (t, 3H, J = 7.6 Hz), 1.40–1.59 (m, 3H), 1.97–2.22
(m, 1H), 2.41–3.11 (m, 19H), 3.82 (s, 3H), 5.2 (br s, 1H), 6.61–
6.62 (dd, 1H, J = 1.6 Hz), 6.66–6.79 (m, 1H), 6.96–6.99 (d, 1H,
J = 8.8 Hz).
5.10. (ꢀ)-4-{[(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-carbamoyl]-methyl}-piperazine-1-carboxylic acid tert-
butyl ester ((ꢀ)-6b)
This compound was prepared from 3b (2.23 g, 7.54 mmol), 5
(2.26 g, 9.08 mmol), and K2CO3 (2.08 g, 15.85 mmol) according
to the Procedure
C
for to give 6b (2.62 g, 76%). 1H NMR
(400 MHz, CDCl3) 0.87–0.92 (t, 3H, J = 8 Hz), 1.44 (s, 9H), 1.58–
1.82 (m, 2H), 1.88–1.97 (m, 1H), 1.96–2.00 (m, 3H), 2.41 (br s,
2H), 2.51–2.60 (m, 2H), 2.78–2.85 (m, 1H), 2.95–3.31 (m, 3H),
3.88–3.46 (m, 4H), 3.81 (s, 3H), 6.63–6.70 (m, 2H), 7.10–7.13 (t,
1H, J = 7.2 Hz).
5.16. (5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-
piperazin-1-yl-ethyl)-propyl-amine (8b)
This compound was prepared from 7b (4.8 g, 13.8 mmol) and
LiAlH4 (2.0 g, 55.2 mmol) by following Procedure E to give 8b
(4.2 g, 91%). 1H NMR (400 MHz, CDCl3) 0.92–0.96 (t, 3H,
J = 7.6 Hz), 1.41–1.59 (m, 3H), 1.98–2.22 (m, 1H), 2.41–3.1 (m,
19H), 3.81 (s, 3H), 5.2 (br s, 1H), 6.58–6.60 (d, 1H, J = 8 Hz), 6.70–
6.72 (d, 1H, J = 8 Hz), 7.04–7.1 (t, 1H, J = 8 Hz).
5.11. Procedure D: N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-
2-yl)-2-piperazin-1-yl-N-propyl-acetamide (7a)
Compound 6a (5.1 g, 11.5 mmol) was dissolved in 40 ml of
dichloromethane and 40 ml of trifluoroacetic acid was added. The
mixture was stirred for 3 h, at which time the solution was concen-
trated to dryness, dissolved in satd NaHCO3, and extracted with
EtOAc. The organic layer was dried (Na2SO4), filtered, and concen-
trated to yield 3.8 g (96%) of 7a, which was used as is in the next
reaction. 1H NMR (400 MHz, CDCl3) 0.93–0.96 (t, 3H, J = 7.6 Hz),
1.62 (m, 3H), 1.85–1.97 (m, 3H), 2.56 (m, 1H), 2.81–2.88 (m, 5H),
2.98–3.34 (m, 9H), 3.81 (s, 3H), 6.60–6.61 (dd, 1H, J = 1.6 Hz),
6.65–6.78 (m, 1H), 6.95–6.98 (d, 1H, J = 8.8 Hz).
5.17. (+)-5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-
piperazin-1-yl-ethyl)-propyl-amine ((+)-8b)
This compound was prepared from (+)-7b (1.22 g, 3.51 mmol)
and LiAlH4 (0.510 g, 14.05 mmol) by following the Procedure E to
give (+)-8b (1.00 g, 85%). 1H NMR (400 MHz, CDCl3) 0.92–0.97 (t,
3H, J = 7.6 Hz), 1.41–1.60 (m, 3H), 1.98–2.24 (m, 1H), 2.41–3.12
(m, 19H), 3.80 (s, 3H), 5.22 (br s, 1H), 6.58–6.61 (d, 1H, J = 8 Hz),
6.70–6.73 (d, 1H, J = 8 Hz), 7.04–7.11 (t, 1H, J = 8 Hz).
5.18. (ꢀ)-5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-
piperazin-1-yl-ethyl)-propyl-amine ((ꢀ)-8b)
5.12. N-(5-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2-
piperazin-1-yl-N-propyl-acetamide (7b)
This compound was prepared from (ꢀ)-7b (1.02 g, 2.93 mmol)
and LiAlH4 (0.42 g, 11.72 mmol) by following the Procedure E to
give (ꢀ)-8b (0.90 g, 92%). 1H NMR (400 MHz, CDCl3) 0.92–0.98 (t,
This compound was prepared from 6b (6.6 g, 14.8 mmol), and
TFA (40 ml) by following Procedure D to give 7b (4.8 g, 92%). 1H
NMR (400 MHz, CDCl3) 0.92–0.964 (t, 3H, J = 7.6 Hz), 1.63 (m,

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D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
3H, J = 7.6 Hz), 1.41–1.61 (m, 3H), 1.98–2.20 (m, 1H), 2.40–3.20 (m,
19H), 3.83 (s, 3H), 5.19 (br s, 1H), 6.58–6.60 (d, 1H, J = 8 Hz), 6.70–
6.72 (d, 1H, J = 8 Hz), 7.04–7.12 (t, 1H, J = 8 Hz).
CDCl3) d 0.87 (t, 3H, J = 7.2 Hz), 1.40–1.54 (m, 3H), 1.93 (d, 1H,
J = 10.0 Hz), 2.45–2.78 (m, 14H), 2.86–2.91 (m, 1H), 3.70 (m, 4H),
6.45 (d, 1H, J = 2.0 Hz), 6.55–6.58 (m, 2H), 6.87 (d, 1H, J = 8.0 Hz),
7.21–7.24 (m, 2H), 7.33 (d, 1H, J = 8.4 Hz), 7.71 (s, 1H), 8.79 (1H,
bs). The free base of 10a was converted into oxalate salt. Mp
194–199 °C. Anal. [C28H38N4Oꢁ2.0(COOH)2] C, H, N.
5.19. Procedure F: 7-[(2-Piperazin-1-yl-ethyl)-propyl-amino]-
5,6,7,8-tetrahydro-naphthalen-2-ol (9a)
Compound 8a (3.21 g, 9.70 mmol) was dissolved in 120 ml of
CH2Cl2 and cooled to -78 °C. 1 M boron tribromide (30 ml) was
added dropwise and the mixture was allowed to warm to ambi-
ent temperature and was stirred overnight. Satd NaHCO3 was
added and the product extracted with dichloromethane, dried
(Na2SO4), filtered, and concentrated to yield the crude product.
Column chromatography (7:3:1 CH2Cl2/MeOH/Et3N) afforded
2.41 g (84%) of 9a. 1H NMR (400 MHz, CDCl3) 0.98–1.02 (t, 3H,
7.6 Hz), 1.27–1.31 (m, 2H), 1.70–1.82 (m, 3H), 2.25–2.28 (m,
1H), 2.58–2.06 (m, 1H), 2.73–2.78 (m, 4H), 2.97–3.09 (m, 5H),
3.16–3.20 (m, 9H), 6.45 (s, 1H), 6.53–6.55 (d, 1H, J = 9.2 Hz),
6.84–6.85 (d, 1H, J = 8.4 Hz).
5.24. 7-({2-[4-(1H-Indol-5-ylmethyl)-piperazin-1-yl]-ethyl}-
propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ol (10b)
Compound 10b was prepared according to Procedure A using 9a
(65 mg, 0.20 mmol) and indole-5-carboxaldehyde (35 mg,
0.24 mmol) to give 10b (29 mg, 32%) after column chromatogra-
phy. 1H NMR (400 MHz, CDCl3) d 0.84 (t, 3H, J = 7.2 Hz), 1.33–
1.44 (m, 3H), 1.85 (d, 1H, J = 10.0 Hz), 2.41–2.82 (m, 19H), 3.60
(s, 2H), 6.35 (d, 1H, J = 2.0 Hz), 6.49–6.58 (m, 2H), 6.85 (d, 1H,
J = 8.4 Hz), 7.14–7.20 (m, 2H), 7.31 (d, 1H, J = 8.4 Hz), 7.54 (s, 1H),
8.38 (br s, 1H). The free base of 10b was converted into oxalate salt.
Mp 198–203 °C. Anal. [C28H38N4Oꢁ2.5(COOH)2ꢁ3H2O] C, H, N.
5.20. 6-[(2-Piperazin-1-yl-ethyl)-propyl-amino]-5,6,7,8-
tetrahydro-naphthalen-1-ol (9b)
5.25. (4-{2-[(7-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-2-yl)-
methanone (10c)
This compound was prepared from 8b (4.2 g, 12.6 mmol), and
boron tribromide (39 ml) following Procedure F to give 9b (3.1 g,
78%). 1H NMR (400 MHz, CDCl3) 0.99–1.02 (t, 3H, 7.6 Hz), 1.28–
1.30 (m, 2H), 1.71–1.83 (m, 3H), 2.26–2.29 (m, 1H), 2.57–2.06
(m, 1H), 2.72–2.77 (m, 4H), 2.97–3.07 (m, 5H), 3.16–3.21 (m,
9H), 6.58–6.59 (d, 1H, J = 8 Hz), 6.61–6.28 (m, 1H, J = 8 Hz), 6.92–
6.95 (t, 1H, J = Hz).
Compound 10c was prepared following Procedure G using 9a
(100 mg, 0.32 mmol) and indole-2-carboxylic acid (61 mg,
0.38 mmol) to give 10c (125 mg, 86%) after column chromatogra-
phy. 1H NMR (400 MHz, CDCl3) d 0.88 (t, 3H, J = 7.2 Hz,), 1.42–
1.64 (m, 3H), 1.94 (br s, 1H), 2.51–2.75 (m, 14H), 2.88–2.96 (m,
1H), 3.95 (br s, 4H), 6.53 (br s, 1H), 6.59–6.61 (m, 1H), 6.75 (s,
1H), 6.90 (d, 1H, J = 12.0 Hz), 7.11–7.18 (m, 1H), 7.22–7.26 (m,
1H), 7.40 (d, 1H, J = 8.4 Hz), 7.62 (d, 1H, J = 8.0 Hz), 9.72 (s, 1H).
The free base of 10c was converted into HCl salt. Mp 203–205 °C.
Anal. [C28H36N4O2ꢁ2HClꢁ1.2H2O] C, H, N.
5.21. (+)-6-[(2-Piperazin-1-yl-ethyl)-propyl-amino]-5,6,7,8-
tetrahydro-naphthalen-1-ol ((+)-9b)
This compound was prepared from (+)-8b (1.00 g, 3.00 mmol),
and boron tribromide (10 ml) by following the Procedure F to give
(+)-9b (0.78 g, 82%). 1H NMR (400 MHz, CDCl3) 0.99–1.02 (t, 3H,
7.6 Hz), 1.28–1.32 (m, 2H), 1.73–1.83 (m, 3H), 2.24–2.29 (m, 1H),
2.57–2.07 (m, 1H), 2.73–2.77 (m, 4H), 2.97–3.06 (m, 5H), 3.16–
3.20 (m, 9H), 6.58–6.60 (d, 1H, J = 8 Hz), 6.59–6.28 (m, 1H,
J = 8 Hz), 6.92–6.97 (t, 1H, J = Hz).
5.26. 7-({2-[4-(1H-Indol-2-ylmethyl)-piperazin-1-yl]-ethyl}-
propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ol (10d)
Compound 10d was prepared according to Procedure A using 9a
(100 mg, 0.32 mmol) and 1H-indole-2-carbaldehyde (100 mg,
0.69 mmol) to give 10d (125 mg, 85%) after column chromatogra-
phy. 1H NMR (400 MHz, CDCl3) d 0.86 (t, 3H, J = 7.2 Hz), 1.39–
1.50 (m, 3H), 1.89 (br s, 1H), 2.41–2.73 (m, 18H), 2.82–2.88 (m,
1H), 3.65 (s, 2H), 6.35 (s, 1H), 6.44 (br s, 1H), 6.54–6.57 (m, 1H),
6.87 (d, 1H, J = 8.8 Hz), 7.04–7.08 (m, 1H),7.10–7.16 (m, 1H), 7.30
(d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 8.0 Hz), 8.63 (s, 1H). The free base
of 10d was converted into oxalate salt. Mp 135–137 °C. Anal.
[C28H38N4Oꢁ3.0(COOH)2ꢁ0.3H2O] C, H, N.
5.22. (ꢀ)-6-[(2-Piperazin-1-yl-ethyl)-propyl-amino]-5,6,7,8-
tetrahydro-naphthalen-1-ol ((ꢀ)-9b)
This compound was prepared from (ꢀ)-8b (0.90 g, 2.70 mmol),
and boron tribromide (9 ml) by following the Procedure F to give
(ꢀ)-9b (0.62 g, 73.3%). 1H NMR (400 MHz, CDCl3) 0.99–1.02 (t,
3H, 7.6 Hz), 1.28–1.30 (m, 2H), 1.71–1.82 (m, 3H), 2.24–2.29 (m,
1H), 2.57–2.08 (m, 1H), 2.72–2.77 (m, 4H), 2.97–3.09 (m, 5H),
3.16–3.23 (m, 9H), 6.58–6.59 (d, 1H, J = 8 Hz), 6.61–6.27 (m, 1H,
J = 8 Hz), 6.92–6.96 (t, 1H, J = Hz).
5.27. (4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-2-yl)-
methanone (10e)
5.23. Procedure G: (4-{2-[(7-hydroxy-1,2,3,4-tetrahydro-naph-
thalen-2-yl)-propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-5-
yl)-methanone (10a)
Compound 10e was prepared following Procedure G using 9b
(43 mg, 0.14 mmol) and indole-2-carboxylic acid (30 mg,
0.19 mmol) to give 10e (32 mg, 62%) after column chromatogra-
phy. 1H NMR (400 MHz, CD3OD) d 1.02–1.06 (t, 3H, J = 7.2 Hz),
1.77–1.79 (m, 3H), 2.27 (m, 1H), 2.63–2.66 (br s, 4H), 3.03–3.16
(m, 5H), 3.30–3.41 (m, 3H), 3.89 (br s, 4H), 6.59–6.61 (d, 1H,
J = 7.6 Hz), 6.63–6.65 (d, 1H, J = 8 Hz), 6.84 (s, 1H), 6.94–6.98 (t,
1H, J = 7.2 Hz), 7.04–7.08 (t, 1H, J = 7.2 Hz), 7.19–7.23 (t, 1H,
J = 7.2 Hz), 7.41–7.61 (d, 1H, J = 8 Hz), 7.59–7.61 (d, 1H, J = 8 Hz).
The free base of 10e was then converted into its HCl salt. Mp
166–165 °C. Anal. [C28H36N4O2ꢁ3HCl] C, H, N.
Indole-5-carboxylic acid (30 mg, 0.19 mmol), EDCI (45 mg,
0.24 mmol), HOBT (31 mg, 0.24 mmol), triethylamine (31 mg,
0.32 mmol), and compound 9a (50 mg, 0.16 mmol) were dissolved
in dry CH2Cl2 (10 ml) and stirred at ambient temperature over-
night. The mixture was poured into satd NaHCO3 and extracted
with dichloromethane. The organic extract was dried (Na2SO4), fil-
tered and concentrated to yield the crude product. Column chro-
matography afforded 10a (26 mg, 37%). 1H NMR (400 MHz,

D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
3931
5.28. (+)-(4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-
5.32. Benzofuran-2-yl-(4-{2-[(5-hydroxy-1,2,3,4-tetrahydro-
yl)-propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-2-yl)-
methanone ((+)-10e)
naphthalen-2-yl)-propyl-amino]-ethyl}-piperazin-1-yl)-
methanone (10h)
Compound (+)-10e was prepared following the Procedure G
using (+)-9b (30 mg, 0.094 mmol) and indole-2-carboxylic acid
(23 mg, 0.14 mmol) to give 10e (18.5 mg, 51.4%) after column
Compound 10h was prepared following Procedure G using 9b
(214 mg, 0.674 mmol) and benzofuran-2-carboxylic acid (131 mg,
0.809 mmol) to give 10h (108 mg, 35%) after column chromatogra-
phy. 1H NMR (400 MHz, CD3OD) d 0.94–0.98 (t, 3H, J = 7.2 Hz),
1.60–1.68 (m, 3H), 2.14–2.65 (m, 8H), 2.77–3.03 (m, 8H), 3.87 (br
s, 4H), 6.55–6.60 (m 2H), 6.89–6.93 (t, 1H, J = 7.2 Hz), 7.29–7.33
(t, 1H, J = 6.4 Hz), 7.36 (s, 1H), 7.42–7.45 (t, 1H, J = 7.2 Hz), 7.56–
7.58 (d, 1H, J = 8.8 Hz), 7.70–7.72 (d, 1H, J = 7.2 Hz). The free base
of 10h was converted in to its HCl salt. Mp decomp at 140 °C. Anal.
[C28H35N3Oꢁ2HClꢁ1.5H2O] C, H, N.
chromatography, [a]
D +22 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d 0.88–0.92 (t, 3H, J = 7.6 Hz), 1.48–1.63 (m, 3H), 1.98–2.10 (m, 1H),
2.53–2.99 (m, 15H), 3.96 (br s, 4H), 6.57–6.59 (d, 1H, J = 7.6 Hz),
6.63–6.66 (d, 1H, J = 7.6 Hz), 6.78 (s, 1H), 6.96–7.03 (t, 1H,
J = 7.6 Hz), 7.12–7.16 (t, 1H, J = 7.6 Hz), 7.26–7.30 (m, 1H), 7.41–
7.43 (d, 1H, J = 8.4 Hz), 7.64–7.66 (d, 1H, J = 8.0 Hz). The free base
of (+)-10e was then converted into its HCl salt. Mp 169–170 °C.
Anal. [C28H36N4O2ꢁ2HCl] C, H, N.
5.33. Benzo[b]thiophen-2-yl-(4-{2-[(5-hydroxy-1,2,3,4-tetrahydro-
naphthalen-2-yl)-propyl-amino]-ethyl}-piperazin-1-yl)-metha-
none (10i)
5.29. (ꢀ)-(4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-
yl)-propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-2-yl)-
methanone ((ꢀ)-10e)
Compound 10i was prepared following Procedure G using 9b
(175 mg, 0.551 mmol) and benzo[b]thiophene-2-carboxylic acid
(118 mg, 0.661 mmol) to give 10i (263 mg, 64%) after column chro-
matography. 1H NMR (400 MHz, CD3OD) 0.91–0.97 (t, 3H,
J = 7.2 Hz), 1.53–1.68 (m, 3H), 2.50–2.63 (m, 7H), 2.78–3.02 (m,
7H), 3.77–3.79 (br s, 4H), 6.55–6.59 (t, 2H, J = 8 Hz), 6.89–6.93 (t,
1H, J = 8.4 Hz), 7.40–7.46 (m, 2H), 7.61 (s, 1H), 7.85–7.91 (m, 2H).
The free base of 10i was converted into its HCl salt. Mp 131–
134 °C. Anal. [C28H35N3O2Sꢁ2HClꢁ1.5H2O] C, H, N.
Compound (ꢀ)-10e was prepared following the Procedure G
using (ꢀ)-9b (50 mg, 0.16 mmol) and indole-2-carboxylic acid
(51 mg, 0.31 mmol) to give (ꢀ)-10e (33 mg, 55%) after column
chromatography, [
a
]
D
ꢀ21.6 (c 1, CH2Cl2). 1H NMR (400 MHz,
CDCl3) d 0.885–0.92 (t, 3H, J = 7.2 Hz), 1.51–1.61 (m, 3H), 2.10
(m, 1H), 2.50–2.99 (m, 15H), 3.96 (br s, 4H), 6.58–6.65 (dd, 2H,
J = 18.6, 6.84), 6.78 (s, 1H), 6.96–7.00 (t, 1H, J = 8.0 Hz), 7.12–7.16
(t, 1H, J = 7.2 Hz), 7.26–7.30 (t, 1H, J = 7.6 Hz), 7.41–7.43 (d, 1H,
J = 8.4 Hz), 7.64–7.66 (d, 1H, J = 7.6 Hz). The free base of (ꢀ)-10e
was then converted into its HCl salt. Mp 168–169 °C. Anal.
[C28H36N4O2ꢁ2HCl] C, H, N.
5.34. (4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-amino]-ethyl}-piperazin-1-yl)-quinolin-3-yl-
methanone (10j)
5.30. (4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-3-yl)-
methanone (10f)
Compound 10j was prepared following Procedure G using 9b
(172 mg, 0.542 mmol) and quinoline-3-carboxylic acid (112 mg,
0.650 mmol) to give 10j (256 mg, 85%) after column chromatogra-
phy. 1H NMR (400 MHz, CD3OD) 0.93–0.96 (t, 3H, J = 7.2 Hz), 1.57–
1.59 (m, 3H), 2.18 (m, 2H), 2.55–3.00 (m, 14H), 3.55 (br s, 2H), 3.85
(br s, 2H), 6.53–6.58 (t, 2H, J = 8 Hz), 6.88–6.91 (t, 1H, J = 11.2 Hz),
7.81–7.72 (t, 1H, J = 7.6 Hz), 7.85–7.88 (t, 1H, J = 7.6 Hz), 8.03–8.1
(m, 2H), 8.45 (br s, 1H), 8.89 (br s, 1H). The free base of 10j was
converted into its HCl salt. Mp 142–146 °C. Anal. [C29H36N4O2ꢁ
3HClꢁ2H2O] C, H, N.
Compound 10f was prepared following Procedure G using
9b (50 mg, 0.16 mmol) and indole-3-carboxylic acid (35 mg,
0.21 mmol) to give 10f (38 mg, 53%) after column chromatogra-
phy. 1H NMR (400 MHz, CD3OD) d 1.03–1.07 (t, 3H, J = 7.2 Hz),
1.83–1.96 (m, 3H), 2.32 (s, 1H), 2.53–2.67 (m, 5H), 2.81–2.83
(m, 2H), 3.09–3.18 (m, 4H), 3.41–3.47 (m, 2H), 3.56–3.59
(m, 1H), 3.79 (br s, 4H), 6.61–6.63 (d, 1H, J = 8.4 Hz), 6.64–6.66
(d, 1H, J = 8.4 Hz), 6.96–6.99 (t, 1H, J = 7.2 Hz), 7.13–7.21
(m, 1H), 7.41–7.51 (m, 1H), 7.62–7.64 (m, 1H), 7.71–7.73 (d, 1H,
J = 7.2 Hz), 7.83–7.84 (1H, J = 7.2 Hz). The free base of 10f
was converted into its HCl salt. Mp 147–151 °C. Anal.
[C28H36N4O2ꢁ3HCl] C, H, N.
5.35. 4-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-
butyl ester (11)
To a mixture of compound 5 (3.00 g, 16.11 mmol), potassium
carbonate (2.33 g, 48.32 mmol) in acetonitrile (50 ml) was added
2-bromoethanol (3.00 g, 24.17 mmol) under nitrogen atmosphere.
The mixture was refluxed for 4 h, cooled, filtered, and concen-
trated. The crude mixture was purified by column chromatography
(EtOAc/MeOH, 9:1) to give 11 (2.76 g, 75%). 1H NMR (400 MHz,
5.31. (4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-
propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indazol-3-yl)-
methanone (10g)
CDCl3)
d 1.46 (s, 9H), 2.45 (t, 4H, J = 5.2 Hz), 2.55 (t, 2H,
J = 5.2 Hz), 3.44 (t, 4H, J = 5.2 Hz), 3.62 (t, 2H, J = 5.2 Hz).
Compound 10g was prepared by following Procedure G, using
9b (50 mg, 0.158 mmol) and indazole 3-carboxylic acid (45 mg,
0.277 mmol) to give 10g (34 mg, 47%) after column chromatogra-
phy. 1H NMR (400 MHz, CD3OD) d 1.04–1.07 (t, 3H, J = 6.8 Hz),
1.83–1.93 (m, 3H), 2.31 (m, 1H), 2.62–2.70 (m, 5H), 2.81 (br s,
2H), 3.08–3.47 (m, 8H), 3.89 (br s, 2H), 4.08 (br s, 2H), 6.61–
6.62 (m, 2H), 6.95–6.99 (t, 1H, J = 7.2 Hz), 7.22–7.26 (t, 1H,
J = 8 Hz), 7.41–7.45 (t, 1H, J = 6.4 Hz), 7.57–7.59 (d, 1H,
J = 8.8 Hz), 7.94–7.96 (d, J = 8 Hz). The free base of 10g was con-
verted in to its HCl salt. Mp 167–170 °C. Anal. [C27H35N5O2ꢁ
3HClꢁ2.5H2O] C, H, N
5.36. (S)-tert-Butyl-4-(2-((5-methoxy-1,2,3,4-tetrahydronaphth-
alen-2-yl)(propyl) amino)ethyl)piperazine-1-carboxylate (14)
To a solution of oxalyl chloride (0.76 ml, 8.76 mmol) in CH2Cl2
(20 ml) was added DMSO (1.10 ml, 17.52 mmol) at ꢀ78 °C and
stirred for 5 min. Compound 11 (1.0 g, 4.38 mmol) was added to
the mixture and was kept stirring for 30 min. The reaction temper-
ature was raised to room temperature after addition of triethyl-
amine (3.64 ml, 26.3 mmol). The solution was quenched with

3932
D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
water and extracted with dichloromethane. The organic layer was
dried over sodium sulfate and evaporated to afford crude 12
(0.99 g) in quantitative yield and was used in the next reaction
without any further purification. Compound 12 (0.99 g,
4.34 mmol) was then reacted with 13 (0.87 g, 3.9 mmol) following
7.13 (d, 1H, J = 2.0 Hz), 7.20 (d, 1H, J = 3.2 Hz), 7.40 (d, 1H,
J = 9.2 Hz).
5.40. tert-Butyl 4-(1H-indole-5-yl)-piperazine-1-carboxylate (19)
Procedure A to provide 14 (1.1 g, 67%). ½a D20
ꢂ
ꢀ32.43 (c 1.03, CHCl3).
To a stirring solution of compound 18 (1.10 g, 2.40 mmol) in
THF (20 ml) was added tetrabutylammonium fluoride (1 M in
THF, 15 ml). The reaction mixture was stirred for 3 h to complete
the reaction. The solvent was evaporated in vacuo and triturated
with diethyl ether (100 ml). The ether layer was washed with sat-
urated NaHCO3 (20 ml) and brine (20 ml), dried over MgSO4 and
evaporated in vacuo. The crude product was purified by flash col-
umn chromatography over silica gel using ethyl acetate/hexanes
(30:70) to afford 19 (0.71 g, 95%). 1H NMR (400 MHz, CDCl3) d
1.49 (s, 9H), 3.07 (t, 4H, J = 4.8 Hz), 3.61 (t, 4H, J = 5.2 Hz), 6.46–
6.47 (m, 1H), 6.94–6.97 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz,), 7.16 (m,
2H), 7.30 (d, 1H, J = 8.8 Hz), 8.15 (br s, 1H).
1H NMR (400 MHz, CDCl3) d 0.88 (t, 3H, J = 7.2 Hz), 1.46–1.61 (m,
12H), 2.04 (br s, 1H), 2.34–2.55 (m, 8H), 2.67–3.01 (m, 7H),
3.41–3.43 (m, 4H), 3.80 (s, 3H), 6.40 (d, 1H, J = 8.0 Hz), 6.70 (d,
1H, J = 7.6 Hz), 7.08 (m, 1H).
5.37. (S)-(4-{2-[(5-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-
yl)-propyl-amino]-ethyl}-piperazin-1-yl)-(1H-indol-5-yl)-
methanone (15)
Compound 14 (1.1 g, 3.9 mmol) was refluxed in 48% HBr (30 ml)
for 2 h, at which time the solution was cooled and concentrated to
dryness. The crude hydrobromic salt was basified by the addition
of satd NaHCO3 and the free base extracted with ethyl acetate.
The organic layer was dried (Na2SO4), filtered, and concentrated
to give the crude phenol, which was used as is in the next reaction.
The synthesis of 15 was completed by reacting this material
290 mg, 0.67 mmol) with indole-5-carboxylic acid (130 mg,
0.81 mmol) following Procedure G to give 230 mg (74%) after col-
5.41. 2-[4-(1H-Indol-5-yl)-piperazin-1-yl]-N-(7-methoxy-
1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (21)
To a stirring solution of compound 19 (800 mg, 2.65 mmol) in
dry CH2Cl2 (20 ml) was added trifluoroacetic acid (20 ml). After
stirring for 2 h at room temperature the solvent was removed in
vacuo and the crude semi solid residue collected was triturated
with ethyl acetate and filtered to get 20 (780 mg, 94%). Com-
pound 20 (780 mg, 3.87 mmol), 3a (1.15 g, 3.87 mmol), K2CO3
(474 mg, 3.44 mmol), and acetonitrile (75 ml) were refluxed for
3 h. The reaction mixture was cooled, filtered, and concentrated.
The crude material was purified by column chromatography
(EtOAc/MeOH, 95:5) to yield 21 (220 mg, 22%). 1H NMR
(400 MHz, CDCl3) d 0.81 (t, 3H, J = 7.2 Hz), 1.38–1.46 (m, 2H),
1.51–1.61 (m, 1H), 1.94 (d, 1H, J = 12.0 Hz), 2.46 (t, 2H,
J = 7.2 Hz), 2.61–2.75 (m, 4H), 2.96–3.08 (m, 5H), 3.40 (s, 2H),
3.56–3.85 (m, 4H), 6.40 (br s, 1H), 6.47 (d, 1H, J = 2.0 Hz), 6.51–
6.54 (dd, 1H, J = 2.4 Hz and 8.0 Hz), 6.82 (d, 1H, J = 8.0 Hz),
6.88–6.90 (dd, 1H, J = 2.0 Hz and 8.8 Hz), 7.09–7.11 (m, 2H),
7.25 (d, 1H, J = 8.8 Hz), 8.12 (br s, 1H).
umn chromatography.
½
a 2D0
ꢂ
ꢀ21.0 (c 1, CHCl3). 1H NMR
(400 MHz, CDCl3) d 0.88 (t, 3H, J = 7.2 Hz), 1.41–1.571 (m, 3H),
2.02 (br s, 1H), 2.48–2.80 (m, 13H), 2.87–2.95 (m, 2H), 3.63 (br s,
4H), 6.54–6.67 (m, 2H), 6.94–6.98 (m, 1H), 7.24–7.26 (m, 2H)
7.36–7.38 (m, 1H), 7.71 (s, 1H), 8.48 (s, 1H). The free base of 15
was converted into its oxalate salt. Mp 94–96 °C. Anal.
[C28H36N4O2?2.5(COOH)2] C, H, N.
5.38. 5-Bromo-1-triisopropylsilyl-1H-indole (17)
5-Bromoindole (1.4 g, 7.14 mmol) was dissolved in dry THF
(50 ml) and cooled to 0 °C, which was followed by the addition
of NaH (0.34 g, 14.28 mmol) portion wise. The reaction mixture
was allowed to stir at room temperature for 1 h. The reaction mix-
ture was again cooled to 0 °C and triisopropylsilyl chloride (1.78 g,
9.28 mmol) was added drop wise. The mixture was allowed to
warm to room temperature and was stirred overnight. The solvent
was evaporated under reduced pressure and triturated with ethyl
acetate (100 ml). The organic layer was washed with brine
(50 ml) and dried over Na2SO4 and evaporated. The compound
was purified by flash column chromatography using pure hexanes
to afford colorless oily product 17 (1.90 g, 76%). 1H NMR (400 MHz,
CDCl3) d 1.13 (d, 18H, J = 8.0 Hz), 1.63–1.71 (m, 3H), 6.56 (d, 1H,
J = 3.2 Hz), 7.20–7.25 (m, 2H), 7.37 (d, 1H, J = 8.8 Hz), 7.74 (d, 1H,
J = 2.0 Hz).
5.42. 7-((2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)(propyl)-
amino)-5,6,7,8-tetrahydro-naphthalen-2-ol (22)
To
a stirring cold solution of compound 21 (220 mg,
0.492 mmol) in dry THF was added BH3ꢁTHF (211 mg, 2.46 mmol)
and the reaction mixture was refluxed overnight. After cooling
the reaction mixture to room temperature, 1 ml of methanol was
added and the solvent was evaporated. The residue was dissolved
in 15 ml of concd HBr and refluxed for 1 h. The solvent was evap-
orated and the crude product was dissolved in dichloromethane
(50 ml). The organic layer was washed with saturated NaHCO3
(30 ml) and dried over Na2SO4. The solvent was evaporated and
the crude product was purified by flash column chromatography
over silica gel using ethyl acetate/MeOH/Et3N (95:5:0.2) to afford
22 (20 mg). 1H NMR (400 MHz, CD3OD) d 0.95 (t, 3H, J = 7.6 Hz),
1.53–1.67 (m, 3H), 2.08 (d, 1H, J = 9.6 Hz), 2.60–2.88 (m, 14H),
3.10–3.13 (m, 5H), 6.35 (d, 1H, J = 2.8 Hz), 6.52–6.55 (m, 2H),
6.87 (d, 1H, J = 8.8 Hz), 6.91–6.94 (dd, 1H, J = 8.8 Hz and 2.4 Hz),
7.16–7.17 (m, 2H), 7.29 (d, 1H, J = 8.8 Hz). Free base converted into
oxalate salt. Mp 179–183 °C.
5.39. 4-(1-Triisopropylsilyl-1H-indole-5-yl)-piperazine-1-
carboxylate (18)
A mixture of compound 17 (1.8 g, 5.10 mmol), 5 (0.86 gm,
4.59 mmol), sodium tert-butoxide (0.638 gm, 6.64 mmol) and
PdCl2[P(o-tol)3]2 (0.20 g, 0.23 mmol, 5% wt) in 100 ml of xylenes
was heated at 110 °C overnight. The reaction mixture was diluted
with diethyl ether/hexanes (50:50) and filtered through a silica
plug and eluted with 10% ethyl acetate in hexanes. All organic
fractions were collected and evaporated in vacuo and the crude
product was purified by flash column chromatography using
diethyl ether/hexanes (20:80) to afford 18 (1.10 g, 52%). 1H
NMR (400 MHz, CDCl3) d 1.13 (d, 18H, J = 6.4 Hz), 1.48 (d, 9H),
1.63–1.70 (m, 3H), 3.08 (t, 4H, J = 4.4 Hz), 3.60 (t, 4H, J = 5.2 Hz),
6.53 (d, 1H, J = 2.4 Hz), 6.86–6.89 (dd, 1H, J = 2.4 Hz, J = 9.2 Hz),
5.43. Biological experiments: potencies at DA D2 and D3
receptors
Compounds were tested for inhibition of radioligand binding
to DA receptors as described in our previous study.29 Briefly,

D. A. Brown et al. / Bioorg. Med. Chem. 17 (2009) 3923–3933
3933
membranes from human embryonic kidney (HEK) 293 cells
Supplementary data
expressing rat D2L and D3 receptors were incubated with each
test compound and [3H]spiperone (0.6 nM, 15 Ci/mmol, Perkin
Elmer) for 1 h at 30 °C in 50 mM Tris–HCl (pH 7.4), 0.9% NaCl,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.04.031.
and 0.025% ascorbic acid. (+)-Butaclamol (2 lM) was used to de-
fine nonspecific binding. Assays were terminated by filtration in
the MACH 3-96 Tomtec harvester (Wallac, Gaithersburg, MD).
IC50 values were estimated by nonlinear regression analysis with
the logistic model in the least squares fitting program ORIGIN,
and converted to inhibition constants (Ki) by the Cheng–Prusoff
equation.32 In this conversion, the Kd values for [3H]spiperone
binding were 0.057 nM for D2 receptors and 0.125 nM for D3
receptors.
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Acknowledgments
This work is supported by National Institute of Neurological
Disorders and Stroke/National Institute of Health (NS047198,
AKD). We are grateful to Dr. K. Neve, Oregon Health and Science
University, Portland, USA, 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.