Synthesis and evaluation of 3-aryl piperidine analogs as potent and efficacious dopamine D4 receptor agonists

Article abstract of DOI:10.1016/j.bmc.2005.04.060

A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D₄ agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.

Full text of DOI:10.1016/j.bmc.2005.04.060

Bioorganic & Medicinal Chemistry 13 (2005) 4667–4678
Synthesis and evaluation of 3-aryl piperidine analogs as potent
and efficacious dopamine D4 receptor agonists
Xueqing Wang,* Pramila A. Bhatia, Jerome F. Daanen, Steve P. Latsaw,
Jeffrey Rohde, Teodozyi Kolasa, Ahmed A. Hakeem, Mark A. Matulenko,
Masaki Nakane, Marie E. Uchic, Loan N. Miller, Renjie Chang, Robert B. Moreland,
Jorge D. Brioni and Andrew O. Stewart
Neuroscience Research, Global Pharmaceutical Research and Development, AP9A/L16, Abbott Laboratories,
100 Abbott Park Road, Abbott Park, IL 60064, USA
Received 14 March 2005; accepted 22 April 2005
Available online 17 May 2005
Abstract—A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were pre-
pared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure–activity relationship (SAR)
studies that led to the identification of these compounds are discussed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
fied and they can be categorized as being D1- and D2-
like.1 The D1-like family consists of subtypes D1 and
D5 receptors,2,3 while D2-like includes D2, D3, and D4
subtypes.4–6 The fact that clozapine (1, Chart 1), a pref-
erential D4 antagonist, behaves as an atypical antipsy-
The dopamine receptor (DA) belongs to a family of G-
protein-coupled receptors (GPCRs) with seven trans-
membrane domains. Several subtypes have been identi-
OH
N
OH
O
HN
HO
N
N
N
N
H
NH
N
Cl
N
H
Clozapine (1)
Apomophine (2)
3-PPP (3)
PNU 95666E (4)
D2 agonist
OH
F
O
N
N
N
N
Cl
NH
N
N
O
F
B-region
A-region
ABT-724 (5)
A-220528 (6)
Haloperidol (7)
Chart 1. Structures of D4 ligands.
Keywords: Dopamine D4 receptor; Agonist potency; Agonist efficacy; 3-Aryl piperidines.
*
Corresponding author. Tel.: +1 847 936 0362; fax: +1 847 937 9195; e-mail: xueqing.wang@abbott.com
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.04.060

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X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
chotic that lacks the extrapyramidal side effects nor-
mally seen with D2 antagonists led to the belief that
selective D4 antagonists can be used for the treatment
of schizophrenia.6–8 Many highly selective D4 antago-
nists were identified, however, none has shown efficacy
in clinical trials.9–11 It has been reported; that some of
these D4 selective antagonists are in fact D4 partial ago-
nists, which may help explain their lack of efficacy.12
n
Ar
9a
9b
9c
9d
9e
9f
1
2
2
2
2
1
2-thiazolyl
2-pyridyl
HN
a
N
O
Ar
3-pyridyl
(6-methyl)-2-pyridy
2-thienyl
n
n
8a n = 1
9a-f
2-thienyl
8b n = 2
O
N
N
b
Boc
HN
N
Dopamine agonists such as apomophine (2) and (ꢀ)-3-
(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 3)
have been associated with the induction of erectile effects
in animals and in humans.13–16 Apomophine is a nonse-
lective dopaminergic agonist used clinically for the treat-
ment of male erectile dysfunction (MED) but it has been
reported to have emetic side effects.17,18 It has been re-
ported recently that the proerectile action of apomor-
phine in rats is not mimicked by a D2-selective
agonist, PNU 95666E (4), but associated with activation
of D4 receptors.19 Furthermore, studies indicated that
PNU 95666E induces emesis,20 suggesting that D2 recep-
tor activation may be responsible for the emetic effect of
apomophine. With the discovery of ABT-724 (5), it has
been shown that selective D4 agonist can be used as a
potential treatment for MED and is devoid of emetic
side effects.20–22
9h
OH
9g
8b
c
HN
HN
9i
Boc
OH
O
N
N
d
8c
9j
Scheme 1. Reagents and conditions: (a) (i) Boc2O, H2, Pd/C, MeOH,
(ii) PhNTf2, LiHMDS, ꢀ78 ꢁC, THF, (iii) Ar–ZnBr, Pd(Ph3)4, THF,
60 ꢁC, (iv) H2, Pd/C, MeOH, (v) TFA, CH2Cl2; (b) (i) m-CPBA,
CH2Cl2, (ii) HCl, ꢀ78 ꢁC, EtOAc; (c) (i) PhMgBr, THF, (ii) H2,
Pd(OH)2/C, MeOH; (d) (i) 2-bromopyridine, Pd2dba3, BINAP, NaH,
toluene, 75 ꢁC, (ii) TFA.
As part of our ongoing dopamine D4 program with the
goal of identifying D4 agonists for the treatment of D4-
related CNS disorders, a high throughput screen of our
internal compound library was conducted. It is noted
that the interaction of an agonist ligand with a receptor
has two very important but independently measured fea-
tures: (1) %E, the agonist efficacy, also called the intrin-
sic activity is related to a full agonist (in our study
10 lM dopamine), and (2) EC50, the agonist potency,
the concentration at which a compound gives half its
maximal D4 specific efficacy.23,24 Aryl piperidine analog
6 was identified as a D4 agonist (EC50 = 51 nM,
%E = 91), and it has a structure similar to that of halo-
peridol (7), a nonselective D4 antagonist. In this report,
we present some of the structure–activity relationship
(SAR) studies on 6 and our effort to identify novel
and potent efficacious D4 agonists.
aldehyde 12 followed by hydrazine deprotection and
alkylation of 9 with 2-bromoethyl alcohol, respectively.
Compounds 16 and 18 were completed by palladium-
catalyzed arylations. Analogs with structures 10t and
10u were obtained by reductive amination of 9 with
chloroacetaldehyde to produce the b-chloroethyl analog
followed by alkylation with either 2-hydroxybenzthiaz-
ole or 1-methyl-2-benzimidazolinone.
2.2. Biology
Dopamine D4 ligands were evaluated functionally
as agonist or antagonist using a calcium flux assay and
recombinant human D4.4 receptor coexpressed with
Gaqo5 in HEK-293 cells as described.25 Dopamine D4
ligand binding affinity was determined by radioligand
competition against 2-[4-(4-[3H]-2-cyanophenyl)piperaz-
inyl]-N-(2,4,6-[3H]3-3-methylphenyl)acetamide,26 using
membranes from the human dopamine D4.4 cells as
described for the calcium flux assay. Dopamine D2
ligand binding affinity was determined by radio-
ligand competition against [125I]-PIPAT.25
2. Results
2.1. Chemistry
Aryl-substituted piperidines or pyrrolidine 9a–f were
prepared21 as shown in Scheme 1 starting from 8a or
8b. Pyridine N-oxide 9h was prepared by oxidation of
9g followed by deprotection. The haloperidol-like piper-
idine 9i was synthesized by a Grignard reaction followed
by debenzylation. Palladium-catalyzed O-arylation of 1-
Boc-3-hydroxy piperidine with 2-bromopyridine fol-
lowed by acid deprotection afforded analog 9j.
3. Results and discussions
Both enantiomers of 6 were evaluated for their agonist
activity and displayed similar potency and efficacy
(EC50 = 66 nM, %E = 85 for (+)-6 vs EC50 = 90 nM,
%E = 88 for (ꢀ)-6). Based on this lack of stereospecific-
ity, we evaluated subsequent analogs in this series as the
racemates. To help facilitate the SAR studies, the struc-
ture of 6 was arbitrarily divided into two parts, region A
and region B (Chart 1). Region A represents the 3-aryl
piperidine rigid structure, in which the protonated basic
amine presumably interacts with the conserved ASP115
Compounds 10a–q were obtained by alkylation of 9
shown in Scheme 2, which can be used to prepare either
the oxime 10s or tertiary alcohol 10r. Intermediates 15
and 17 were prepared by reductive amination of 9 with

X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
4669
Scheme 2. Reagents and conditions: (a) R1CH2X, K2CO3, NaI, DMF, 70 ꢁC; (b) CH3ONH2ÆHCl, pyridine; (c) MeMgBr, THF; (d) (i) 12, HOAc,
Na(OAc)3BH, CH2Cl2, (ii) NH2NH2ÆH2O, MeOH, 70 ꢁC; (e) 13, Pd2(dba)3, BINAP, t-BuONa, THF, reflux; (f) BrCH2CH2OH, Na2CO3, DME,
reflux; (g) (i) chloroacetaldehyde, HOAc, Na(OAc)3BH, CH2Cl2, (ii) 14, KOH, acetone, reflux.
(3.32) in transmembrane–spanning domain 3 (TM3).27
In analogy to arylpiperazine,23 region A represents the
key feature of the ligand pharmacophore. Region B re-
quires another p-system connected to the basic nitrogen
by a linker (Chart 1), which according to CoMFA stud-
ies,28 is another prerequisite for D4 receptor binding.
Table 1 shows mainly changes made to region A. The
phenyl group on the piperidine ring can be replaced with
a variety of heterocycles. Replacement by 2-pyridyl or 3-
pyridyl resulted in loss of agonist potency by almost one
order of magnitude (10d and 10e) while maintaining
good efficacy. The 2-thiazole (10j) and 2-thiophene
(10i) replacements maintained agonist potency and effi-
cacy with 10j being more active. Pyridine N-oxide 10g
Table 1. In vitro activity in FLIPR assays at human D4.4 receptor
R1
R2
EC50
%Eb
a
Compound
n1
n2
x
6
2
2
2
2
2
2
2
2
2
2
2
2
1
1
3
2
2
2
2
2
2
2
2
2
2
1
2
2
CH2
CH2
CH2
S
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
Phenyl
Phenyl
51 5.3
49 5.3
91
87
38
47
78
69
27
14
43
88
94
80
3
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
Phenyl
Phenyl
4043 590
3608 1740
366 136
477 74.5
134 10.4
>10,000
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
2-Pyridyl
3-Pyridyl
Piperidin-2-yloxy
(1-Oxy)-pyridine-2-yl
(6-Methyl)-2-pyridyl
2-Thienyl
527 89
45 6.3
2-Thiazolyl
2-Thiazolyl
Phenyl
34 13.5
1561 842
>10,000
2-Thienyl
584 256
36
a Mean values for agonists (EC50 in nM) calculated from at least three determinations SEM in FLIPR assay using HEK-293 cells co-transfected
with human D4.4 receptor and Gaqo5
b Efficacy relative to 10 lM dopamine (100%).
.

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X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
lost agonist potency completely. Substitutions on the
pyridine ring also diminished both potency and efficacy
(10h). Overall, thiazole (10j) is the best R2 group. The
linker length between region A and region B was sur-
veyed. Changing from three to two carbons (6 vs 10a)
did not result in significant loss of either the potency
or efficacy. A significant drop in potency, however,
was observed when the linker was shortened from two
carbon atoms to one (10j and 10k). A piperidine ring ap-
pears to be crucial for agonist activity based on the lack
of potency and efficacy found with pyrrolidine analogs,
regardless if R2 was phenyl or thienyl (10l and 10m).
Other types of modifications to the 3-aryl piperidine
ring, such as substituting one of the ring methylene
groups with sulfur (10c), adding a hydroxyl at the 3-po-
sition (10b), or inserting an oxygen between the aryl and
piperidine ring (10f), all led to significant loss of agonist
potency or efficacy or both.
Having identified thiazole-substituted piperidine as the
optimum region A group, various region B groups were
studied (Table 2). Tertiary alcohol 10r and oxime 10s
both had lower potency and efficacy than 10j. Sulfone
10o, compared to ketone 10n, lost almost all agonist po-
tency and efficacy.
Bicyclic groups in region B were also investigated. Benz-
imidazole analogs 10p and 10q both displayed reduced
agonist potency and efficacy. Compounds that have
benzoxazole or benzimidazole as region B with an addi-
tional heteroatom linker were all potent, efficacious ago-
nists (16a–b, 18a–b), while benzothiazole analog (18c)
was slightly less potent and efficacious. The nitrogen
connected to the ring could be replaced by oxygen with-
out losing agonist activity (18a vs 16a, 18b vs 16b).
When the thiazole ring in region A was switched back
to phenyl ring, analogous compounds were less active
Table 2. In vitro activity in FLIPR assays at human D4.4 receptor
R1
Ar
EC50
%Eb
a
Compound
O
10j
2-Thiazolyl
34 13.5
94
F
F
HO
10r
10s
2-Thiazolyl
2-Thiazolyl
289 42
240 13
84
77
O
N
F
O
10n
10o
2-Thiazolyl
2-Thiazolyl
16 2.0
95
32
O2
S
5290 1660
N
10p
10q
2-Thiazolyl
2-Thiazolyl
454 71
148 20
70
66
N
H
H
N
N
N
N
O
O
O
N
10t
2-Thiazolyl
435 51
40
S
10u
16a
2-Thiazolyl
2-Thiazolyl
978 90
15 1.7
55
86
N
H
O
N
N

X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
4671
Table 2 (continued)
R1
Ar
EC50
%Eb
a
Compound
H
N
N
O
16b
18a
18b
2-Thiazolyl
12 2.6
24 6.5
28 4.2
78
90
86
N
O
2-Thiazolyl
2-Thiazolyl
N
N
S
O
O
N
N
N
18c
16c
2-Thiazolyl
Phenyl
50 8.3
82 20
80
78
H
N
O
H
N
N
16d
16e
18d
Phenyl
167 15
58 8.0
86 16
63
81
70
N
H
N
N
2-Thiazolyl
N
N
O
2-Thiazolyl
N
a Mean values for agonists (EC50 in nM) calculated from at least three determinations SEM in FLIPR assay using HEK-293 cells co-transfected
with human D4.4 receptor and Gaqo5
.
b Efficacy relative to 10 lM dopamine (100%).
(16c vs 16a, 16d vs 16b), confirming the superiority of
having thiazole in region A. Interestingly, similar ana-
logs with heteroatom-linked benzoazoles as region B
and 4-piperazine as region A were reported to be potent
D4 antagonists.29 Expansion of the 6,5-fused rings to
6,6-fused ring (16e, 18d) also afforded potent, efficacious
agonists.
which is believed to cause emesis. D2 antagonist studies
also indicated that they have only weak interaction with
the D2 receptor (IC50 > 2 lM, data not shown).
4. Conclusions
We have demonstrated 3-aryl piperidine analogs as a
series of novel D4 agonists. Thiazole was identified to
be the optimum group in region A. When combined
with a benzoazole ring in region B with a heteroatom
linker, potent D4 agonists were obtained and were repre-
sented by 16a, 18a, and 18b, which exhibited double di-
git nanomolar potency and full agonism. The spatial
orientation between A and B regions is key to providing
agonist potency and efficacy. These full agonists can be
used as valuable tools to study D4 agonism related thera-
peutic indications.
The close structure similarities of region B between ana-
logs 10u and 18c and 10t and 18b are noted, yet they ex-
hibit dramatically different biochemical profiles. The
weaker efficacy, however, could be explained by the pro-
posal that the intrinsic activity (efficacy to activate the
receptor) is determined by the interaction of the region
B heterocycle unit with the aromatic cluster in TM6 that
is in proximity to the conserved serine residue in
TM5.28,30 Consistent with the report, compounds with
identical region A but slightly different region B can ex-
hibit very different agonist activity profiles. The weaker
EC50 of 10u and 10t may reflect weaker affinity for the
receptor due to the spatial misorientation of region A
and region B, which may also be related to the attenu-
ated interaction with TM6 microdomain that constitutes
the agonist efficacy (intrinsic activity).30
5. Experimental
5.1. Chemistry
Melting points were recorded on a Uni-melt apparatus
(Arthur H. Thomas Company, Philadelphia, PA) and
are uncorrected. Low-resolution mass spectra were ob-
tained with a Finnigan SSQ7000 single quad mass spec-
trometer. Elemental analyses were performed by
Robertson Microlit Laboratories, Inc., Madison, NJ.
Some of the compounds from this series were also evalu-
ated for their D4 binding affinity using radioligand com-
petition study against D4 agonist.26 As shown in Table
3, all the compounds have high affinity for the D4 recep-
tor. None of these compounds showed any D2 agonism,

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X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
Table 3. Binding affinities of selected compounds at human D4.4
receptors
gel, 95:5 hexane/EtOAc) to obtain 5-trifluoro-
methanesulfonyloxy-3,4-dihydro-2H-pyridine-1-carbox-
ylic acid tert-butyl ester as an oil (7.8 g, 24%): 1H NMR
(300 MHz, chloroform-d) d 7.07–7.40 (m, 1H), 3.53 (m,
2H), 2.43 (m, 2H), 1.94 (m, 2H), 1.48 (m, 9H); MS (DCI/
NH3) m/z 349 (M+NH4)+. To the mixture of 2-thiazolyl
zinc bromide (20 mL, 10 mmol, 0.5 M solution) in dry
THF (30 mL) at 0 ꢁC were added the above triflate
(3.3 g, 10 mmol) and Pd(PPh3)4 (10% mol, 1.1 g). The
mixture was heated at 50 ꢁC for 2 h, cooled to rt, brine
was added, and extracted with EtOAc. The organic layer
was dried with MgSO4, concentrated in vacuo, and puri-
fied by flash chromatography (silica gel, 75:25 hexane/
EtOAc) to obtain the 5-thiazol-2-yl-3,4-dihydro-2H-
pyridine-1-carboxylic acid tert-butyl ester as colorless
a
Compound
EC50
%Eb
Binding affinity Kic
hD4
16a
16b
16c
15 1.7
12 2.6
167 15
86
78
63
227 13
12.5 3.7
53 1.6
a Mean values for agonists (EC50 in nM) calculated from at least three
determinations SEM in FLIPR assay using HEK-293 cells co-
transfected with human D4.4 receptor and Gaqo5
.
b Efficacy relative to 10 lM dopamine (100%).
1
c Mean values for binding affinity (Ki in nM) calculated from at least
three determinations SEM versus 2-[4-(4-[3H]-2-cyanophenyl)pip-
erazinyl]-N-(2,4,6-[3H]3-3-methylphenyl)acetamide.
oil (1.4 g, 60%): H NMR (300 MHz, chloroform-d) d
7.70 (d, J = 3 Hz, 1H), 7.21 (d, J = 3 Hz, 1H) 7.05 (m,
1H), 3.59 (m, 2H), 2.44 (m, 2H), 1.95 (m, 2H), 1.48
(m, 9H); MS (DCI/NH3) m/z 265 (M+H)+. The above
tetrahydropyridine was taken up in MeOH (100 mL)
and hydrogenated with 20% Pd/C (0.3 g) at rt for 4 days.
The solution was filtered and concentrated to give 3-
thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester
Proton nuclear magnetic resonance (1H NMR) spectra
were recorded at 300 MHz (Varian Mercury 300),
400 MHz (Varian Unity 400), or 500 MHz (Varian
Unity 500) as indicated. Chemical shifts are reported
in ppm (d) relative to the residual chloroform resonance
(d 7.24), acetone resonance (d 2.05), benzene resonance
(d 7.15), or dimethylsulfoxide resonance (d 2.50) down-
field from tetramethylsilane (d 0.00). Splitting patterns
are designated as singlet (s), doublet (d), triplet (t), quar-
tet (q), multiplet (m). NMR coupling constants (J) in
hertz are indicated parenthetically.
1
as yellow oil (1.42 g, 100 %): H NMR (300 MHz, chlo-
roform-d) d 7.70 (d, J = 3 Hz, 1H), 7.21 (d, J = 3 Hz,
1H), 4.42 (m, 1H), 4.13 (m, 1H), 3.18 (m, 2H), 2.93
(m, 1H), 2.23 (m, 1H), 1.81 (m, 2H), 1.61 (m, 1H),
1.48 (m, 9H); MS (DCI/NH3) m/z 267 (M+H)+. The
above piperidine compound (1.2 g, 4.5 mmol) was
deprotected in 25% TFA/CH2Cl2 (10 mL) for 2 h, con-
centrated in vacuo, neutralized with saturated NaHCO3
and extracted with CH2Cl2to obtain the 3-thiazol-2-yl-
Analytical thin-layer chromatography (TLC) was car-
ried out on E. Merck TLC plates coated with silica gel
60 F254 (0.25 mm layer thickness). TLC visualization
was carried out using a UV lamp and/or charring solu-
tion as indicated. Flash chromatography was performed
as described31 on a Biotage Flash 40 chromatography
system (Charlottesville, VA) using 40 g, 90 g, or 120 g
1
piperidine (9a) as yellow oil (0.53 g, 76%): H NMR
(300 MHz, chloroform-d) d 7.70 (d, J = 3 Hz, 1H),
7.21 (d, J = 3 Hz, 1H), 3.40 (m, 1H), 3.19 (m, 1H),
3.07 (m, 1H), 2.88 (dd, J = 12 Hz, 9 Hz, 1H), 2.71 (m,
1H), 2.22 (m, 1H), 1.77 (m, 2H), 1.62 (m, 1H); MS
(DCI/NH3) m/z 169 (M+H)+.
˚
cartridges at 32–63 lm, 60 A silica gel. Solvent mixtures
used for TLC and flash chromatography are reported in
V:V total.
The following compounds were prepared in a manner
similar to that of compound 9a.
5.1.2. 10,20,30,40,50,60-Hexahydro-[2,30]bipyridinyl (9b).
The compound was prepared in 12% overall yield as yel-
low oil: 1H NMR (300 MHz, MeOD-d4) d 8.84 (d,
J = 5 Hz, 1H), 8.66 (m, 1H), 8.16 (d, J = 8 Hz, 1H),
8.05 (m, 1H), 3.70 (m, 2H), 3.48 (m, 2H), 3.15 (m,
1H), 2.25 (m, 1H), 2.07 (m, 3H); MS (DCI/NH3) m/z
163 (M+H)+.
Preparative HPLC was performed on a Waters Symme-
try C8 column (25 mm · 100 mm, 7 lm particle size)
using a gradient of 10% to 100%:0.1% aqueous TFA
over 8 min (10 min run time) at a flow rate of 40
mL/min.
5.1.1. 3-Thiazol-2-yl-piperidine (9a). A solution of diiso-
propylamine (13.1 mL, 110 mmol) in dry THF (150 mL)
was cooled to ꢀ10 ꢁC. To the solution was added n-
BuLi (2.5 M in hexane, 44 mL, 110 mmol) via syringe.
The mixture was stirred for 30 min, cooled to ꢀ78 ꢁC,
and then to it added a solution of tert-butyl 3-oxo-1-pip-
eridinecarboxylate (16 g, 80 mmol) in THF (50 mL).
The mixture was stirred for 15 min and then was added
a solution of N-phenyl-bis-trifluoromethnaesulfonamide
(35.0 g, 110 mmol) in THF (60 mL). The reaction mix-
ture was stirred for 15 min and allowed to warm to rt,
quenched with saturated NaHCO3 solution (75 mL),
and diluted with Et2O (150 mL). The organic phase
was washed with brine, dried with MgSO4, concd in
vacuo, and purified by flash chromatography (silica
5.1.3. 1,2,3,4,5,6-Hexahydro-[3,30]bipyridinyl (9c). The
compound was prepared in 8% overall yield as yellow
oil and used directly in the next step.
5.1.4. 6-Methyl-10,20,30,40,50,60-Hexahydro-[2,30]bipyridin-
yl (9d). The compound was prepared in 12% overall
yield as yellow oil and used directly in the next step.
5.1.5. 3-Thiophen-2-yl-piperidine (9e). The compound
was prepared in 10% overall yield as HCl salt: white
1
solid; mp 202–204 ꢁC. H NMR (300 MHz, MeOD-d4)
d 7.31 (m, 1H), 6.99 (m, 2H), 3.54 (m, 1H), 3.39

X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
4673
(m, 1H), 3.28 (m, 1H), 3.03 (m, 2H), 2.21 (m, 1H), 2.05
vent was removed to give the product (0.45 g, 52%) as
colorless oil: 1H NMR (300 MHz, chloroform-d) d
7.51 (m, 2H), 7.31 (m, 3H), 3.64 (m, 1H), 3.47 (m,
1H), 3.28 (m, 2H), 2.10 (m, 4H), 2.00 (m, 2H), 1.70
(m, 3H); MS (DCI/NH3) m/z 178.1 (M+H)+.
(m, 1H), 1.86 (m, 2H); MS (DCI/NH3) m/z 168 (M+H)+.
5.1.6. 3-Thiophen-2-yl-pyrrolidine (9f). The compound
was prepared in 15% overall yield as yellow oil: 1H
NMR (300 MHz, chloroform-d) d 7.14 (d, J = 5 Hz,
1.2 Hz, 1H), 6.93 (dd, J = 5 Hz, 4 Hz, 1H), 6.83 (m,
1H), 3.51 (m, 1H), 3.33 (m, 1H), 3.14 (m, 1H), 3.05
(m, 1H), 2.91 (m, 1H), 2.28 (m, 1H), 1.91 (m, 1H); MS
(DCI/NH3) m/z 154 (M+H)+.
5.1.10. 2-(Piperidin-3-yloxy)-pyridine (9j). To a solution
of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl es-
ter (2.02 g, 10 mmol) and 2-bromopyridine (1.66 g,
10.5 mmol) in toluene (10 mL) was added NaH (60%
in mineral oil, 570 mg, 14.2 mmol) portionwise and
heated to 75 ꢁC for 15 min then cooled to rt. To this
were added Pd2(dba)3 (275 mg, 0.3 mmol), racemic BI-
NAP (250 mg, 0.4 mmol) in toluene and the reaction
mixture heated to 75 ꢁC for 2 h. The reaction mixture
was concentrated and purified by flash chromatography
(silica gel, 13:1 hexane/EtOAc) to obtain 3-(pyridin-2-
yloxy)-piperidine-1-carboxylic acid tert-butyl ester as
5.1.7. 30,40,50,60-Tetrahydro-20H-[2,30]bipyridinyl-10-carb-
oxylic acid tert-butyl ester (9g). The title compound was
prepared as an intermediate to 9b in 21% yield as yellow
oil: 1H NMR (300 MHz, chloroform-d) d 8.54 (d,
J = 4 Hz, 1H), 7.61 (m, 1H), 7.14 (m, 2H), 4.15 (m,
2H), 3.01 (m, 1H), 2.83 (m, 2H), 2.04 (m, 1H), 1.78
(m, 2H), 1.61 (m, 1H), 1.45 (m, 9H); MS (DCI/NH3)
m/z 263 (M+H)+.
1
yellow oil (2.52 g, 90%): H NMR (300 MHz, chloro-
form -d) d 8.12 (m, 1H), 7.55 (m, 1H), 6.84 (m, 1H),
6.69 (d, J = 8 Hz, 1H), 5.05 (m, 1H), 3.24–3.73 (m,
4H), 1.85 (m, 3H), 1.54 (m, 1H), 1.37 (s, 9H); MS
(DCI/NH3) m/z 328 (M+H)+. The above compound
(2.1 g, 7.5 mmol) was deprotected in neat TFA (7 mL)
for 2 h, concentrated in vacuo, neutralized with satu-
rated NaHCO3, and extracted with CH2Cl2. The organic
layers were combined, dried, and concentrated. The res-
idue was purified by flash chromatography (silica gel,
10:1 CH2Cl2/MeOH) to obtain 2-(piperidin-3-yloxy)-
pyridine as yellow oil (1.18 g, 87%): 1H NMR
(300 MHz, chloroform-d) d 8.10 (m, 1H), 7.57 (m,
1H), 6.85 (m, 2H), 5.32 (m, 1H), 3.18 (m, 3H), 2.99
(m, 1H), 2.05 (m, 1H), 1.95 (m, 2H), 1.74 (m, 1H); MS
(DCI/NH3) m/z 179 (M+H)+.
5.1.8. 10,20,30,40,50,60-Hexahydro-[2,30]bipyridinyl 1-oxide
(9h). To a solution of 9g (980 mg, 3.7 mmol) in CH2Cl2
(20 mL) at 0 ꢁC was added dropwise a solution of m-
CPBA (1.21 g, 7.0 mmol) in CH2Cl2 (10 mL). The solu-
tion was warmed to room temperature and stirring was
continued for 2 h. The reaction mixture was washed
with saturated NaHCO3 and brine, dried with Na2SO4,
and concentrated. The residue was purified by column
chromatography (silica gel, 30:1 CH2Cl2/MeOH) to pro-
vide 0.90 g (87%) of the desired N-oxide as yellow oil: 1H
NMR (300 MHz, chloroform-d) d 8.29 (d, J = 9 Hz,
1H), 7.24 (d, J = 6 Hz, 1H), 7.16 (m, 2H), 4.19 (m,
1H), 3.97 (m, 1H), 3.65 (m, 1H), 3.02 (m, 2H), 2.18
(m, 1H), 1.67 (m, 3H), 1.47 (m, 9H); MS (APCI) m/z
279 (M+H)+. The above N-oxide (870 mg, 3.2 mmol)
was dissolved in EtOAc and HCl gas was bubbled
through for 15 min. The resulting solution was warmed
to rt and the solvent was removed in vacuo to afford an
5.1.11. 1-(4-Fluoro-phenyl)-3-(3-phenyl-piperidin-1-yl)-propan-
A
mixture of 3-chloro-40-fluoropro-
1-one (10a).
piophenone (63 mg, 0.34 mmol), 3-phenylpiperidine (67
mg, 0.34 mmol), K2CO3 (118 mg, 0.85 mmol), NaI
(51 mg, 0.34 mmol), and DMF (5 mL) was stirred at
70 ꢁC for 2 h. The mixture was diluted with EtOAc
(30 mL), washed with brine. After extractive work-up,
the reaction mixture was purified by flash chromatogra-
phy (silica gel, 4:1 hexane/EtOAc) to obtain the product
as yellow oil: 1H NMR (300 MHz, chloroform-d) d 7.98
(dd, J = 9 Hz, 6 Hz, 1H), 7.25 (m, 5H), 7.12 (t, J = 9 Hz,
1H), 3.17 (t, J = 7 Hz, 2H), 3.02 (m, 2H), 2.84 (m, 3H),
2.08 (m, 2H), 1.93 (m, 1H), 1.75 (m, 2H), 1.47 (m, 1H);
MS (DCI/NH3) m/z 312 (M+H)+.
1
amorphous solid (680 mg, 97%): H NMR (300 MHz,
MeOD-d4) d 7.96 (m, 2H), 7.60 (m, 1H), 7.47 (d,
J = 8 Hz, 1H), 3.98 (m, 1H), 3.71 (m, 1H), 3.49 (m,
1H), 3.11 (m, 2H), 2.16 (m, 2H), 1.99 (m, 2H); MS
(APCI) m/z 179 (M+H)+.
5.1.9. 3-Phenyl-piperidin-3-ol (9i). To a solution of 1-
benzyl-3-piperidone (2.32 g, 12,3 mmol) in anhydrous
THF at 0 ꢁC was added phenylmagnesium bromide
(3 M in Et2O, 5 mL, 15 mmol) dropwise. The reaction
was quenched with H2O after 18 h. Saturated NaHCO3
was added to the reaction mixture and it was extracted
with EtOAc (3 · 50 mL). The organic layers were com-
bined, washed with brine, dried with Na2SO4, concen-
trated in vacuo, and purified by flash chromatography
(silica gel, 4:1 CH2Cl2/EtOAc) to give the product as yel-
low oil (2.3 g, 71%): 1H NMR (300 MHz, chloroform-d)
d 7.49 (m, 2H), 7.32 (m, 6H), 7.23 (m, 2H), 3.58
(d, J = 2.0 Hz, 2H), 2.93 (m, 1H), 2.75 (m, 1H), 2.32
(d, J = 11 Hz, 1H), 2.00 (m, 2H), 1.70 (m, 3H); MS
(DCI/NH3) m/z 268 (M+H)+. To a solution of the above
compound (1.33 g, 5 mmol) in MeOH (10 mL) was
added Pd(OH)2/C (20% wt, 0.27 g). The reaction was
hydrogenated on a Parr shaker under 60 psi of H2 for
17 h. The catalyst was removed by filtration and the sol-
The following compounds were prepared in a manner
similar to that of compound 10a.
5.1.12. 1-(4-Fluoro-phenyl)-3-(3-hydroxy-3-phenyl-piperi-
din-1-yl)-propan-1-one (10b). The compound was pre-
pared in 40% yield, purified by HPLC, and isolated as
1
TFA salt as yellow oil: H NMR (300 MHz, MeOD-
d4) d 8.11 (m, 2H), 7.57 (m, 2H), 7.41 (m, 2H), 7.28
(m, 3H), 3.59 (m, 5H), 3.41 (s, 2H), 3.15 (m, 1H), 2.37
(m, 1H), 2.16 (m, 1H), 1.96 (m, 2H); MS (DCI/NH3)
m/z 328 (M+H)+. Anal. Calcd for C20H22FNO2Æ1.6
TFA: C, 54.66; H, 4.67; N, 2.75; Found: C, 54.94; H,
4.78; N, 2.79.

4674
X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
5.1.13. 1-(4-Fluoro-phenyl)-3-(2-phenyl-thiomorpholin-4-
yl)-propan-1-one (10c). The compound was prepared in
5.1.19. 1-(4-Fluoro-phenyl)-3-(3-thiophen-2-yl-piperidin-1-
yl)-propan-1-one (10i). The compound was prepared in
1
70% yield as yellow oil: H NMR (300 MHz, MeOD-
1
47% yield as yellow oil: H NMR (300 MHz, chloro-
d4) d 7.97 (m, 2H), 7.32 (m, 5H), 7.13 (m, 1H), 4.01
(m, 1H), 3.19 (m, 4H), 2.96 (m, 3H), 2.57 (m, 3H); MS
(DCI/NH3) m/z 330 (M+H)+.
form-d) d 8.00 (m, 2H), 7.13 (m, 3H), 6.94 (dd,
J = 4.5 Hz, 3.9 Hz, 1H), 6.83 (d, J = 4.5 Hz, 1H), 3.16
(m, 2H), 3.11 (m, 2H), 2.87 (m, 3H), 2.13 (m, 1H),
2.08 (m, 2H), 1.72 (m, 2H), 1.45 (m, 1H); MS (DCI/
NH3) m/z 318 (M+H)+.
5.1.14. 1-(4-Fluoro-phenyl)-3-(30,40,50,60-tetrahydro-20H-
[2,30]bipyridinyl-10-yl)-propan-1-one (10d). The com-
pound was prepared in 26% yield as yellow oil: 1H
NMR (300 MHz, chloroform-d) d 8.56 (d, J = 6 Hz,
1H), 7.96 (dd, J = 9 Hz, 6 Hz, 2H), 7.63 (td, J = 8 Hz,
3 Hz, 1H), 7.14 (m, 4H), 3.22 (m, 3H), 2.97 (m, 4H),
2.33 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H), 1.81 (m,
2H), 1.63 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+.
Anal. Calcd for C19H21FN2O: C, 73.05; H, 6.78; N,
8.97; Found: C, 73.51; H, 7.03; N, 9.11.
5.1.20. 1-(4-Fluoro-phenyl)-3-(3-thiazol-2-yl-piperidin-1-yl)-
propan-1-one (10j). The compound was prepared in 66%
yield as yellow oil: 1H NMR (300 MHz, chloroform-d) d
7.95 (dd, J = 6 Hz, 3 Hz, 2H), 7.69 (d, J = 3 Hz, 1H),
7.21 (d, J = 3 Hz, 1H), 7.14 (t, J = 9 Hz, 2H), 3.33 (m,
1H), 3.22 (m, 2H), 2.93 (m, 4H), 2.18 (m, 1H), 2.10 (m,
2H), 1.83 (m, 1H), 1.63 (m, 2H); MS (DCI/NH3) m/z
319 (M+H)+. Anal. Calcd for C17H19FN2OS: C, 64.13;
H, 6.01; N, 8.80; Found: C, 64.21; H, 6.32; N, 8.41.
5.1.15. 1-(4-Fluoro-phenyl)-3-(3,4,5,6-tetrahydro-2H-[3,30]-
bipyridinyl-1-yl)-propan-1-one (10e). The compound was
prepared in 5% yield as yellow oil: 1H NMR (300 MHz,
chloroform-d) d 8.26 (m, 1H), 7.91 (m, 2H), 7.56 (m,
2H), 7.43 (m, 2H), 7.08 (m, 1H), 3.96 (m, 1H), 3.11
(m, 2H), 2.85 (m, 3H), 2.59 (m, 1H), 2.23 (m, 2H),
2.06 (m, 1H), 1.83 (m, 1H), 1.65 (m, 1H), 1.52 (m,
1H); MS (DCI/NH3) m/z 313 (M+H)+.
5.1.21. 1-(4-Fluoro-phenyl)-2-(3-thiazol-2-yl-piperidin-1-yl)-
ethanone (10k). The compound was prepared in 4% yield
as yellow oil: 1H NMR (300 MHz, chloroform-d) d 8.06
(dd, J = 9 Hz, 3 Hz, 2H), 7.68 (d, J = 3 Hz, 1H), 7.21 (d,
J = 3 Hz, 1H), 7.14 (t, J = 9 Hz, 2H), 3.85 (d, J = 6 Hz,
2H), 3.43 (m, 1H), 3.31 (m, 1H), 2.96 (m, 1H), 2.58 (t,
J = 9 Hz, 1H), 2.33 (m, 1H), 2.18 (m, 1H), 1.81 (m,
2H), 1.68 (m, 1H); MS (DCI/NH3) m/z 305 (M+H)+.
Anal. Calcd for C16H17FN2OSÆ0.25 H2O: C, 62.14; H,
5.73; N, 9.07; Found: C, 61.90; H, 5.34; N, 9.18.
5.1.16. 1-(4-Fluoro-phenyl)-3-[3-(pyridin-2-yloxy)-piperidin-
1-yl]-propan-1-one (10f). The compound was prepared
1
in 68% yield as yellow oil: H NMR (300 MHz, chloro-
form-d) d 8.12 (dd, J = 5 Hz, 2 Hz, 1H), 7.98 (m, 2H),
7.54 (m, 2H), 7.54 (m, 1H), 7.12 (m, 2H), 6.83 (m,
1H), 6.72 (d, J = 9 Hz, 1H), 5.17 (m, 1H), 3.16 (m,
2H), 2.98 (dd, J = 10 Hz, 3 Hz, 1H), 2.87 (t, J = 7 Hz,
2H), 2.65 (m, 1H), 2.38 (m, 2H), 1.99 (m, 1H), 1.85
(m, 1H), 1.65 (m, 2H); MS (DCI/NH3) m/z 329
(M+H)+. Anal. Calcd for C19H21FN2O2Æ0.1 H2O: C,
69.11; H, 6.47; N, 8.48; Found: C, 68.93; H, 6.46; N,
8.56.
5.1.22. 1-(4-Fluoro-phenyl)-3-(3-phenyl-pyrrolidin-1-yl)-
propan-1-one (10l). The compound was prepared in
1
92% yield as yellow oil: H NMR (300 MHz, chloro-
form-d) d 7.85 (m, 2H), 7.24 (m, 5H), 7.06 (m, 2H),
3.27 (m, 2H), 3.00 (m, 3H), 2.57 (m, 1H), 2.31 (q,
J = 8 Hz, 1H), 2.16 (m, 1H), 1.82 (m, 3H); MS (DCI/
NH3) m/z 298 (M+H)+.
5.1.23. 1-(4-Fluoro-phenyl)-3-(3-thiophen-2-yl-pyrrolidin-1-
yl)-propan-1-one (10m). The compound was prepared in
25% yield, purified by HPLC, and isolated as TFA salt
as yellow oil: 1H NMR (300 MHz, MeOD-d4) d
8.12 (m, 1H), 7.35 (m, 1H), 7.27 (m, 2H), 7.02 (m,
2H), 4.07 (m, 1H), 3.87 (m, 2H), 3.71 (m, 2H), 3.59
(m, 3H), 2.57 (m, 1H), 2.22 (m, 2H); MS (DCI/NH3)
m/z 304 (M+H)+.
5.1.17. 1-(4-Fluoro-phenyl)-3-(1-oxy-30,40,50,60-tetrahydro-
20H-[2,30]bipyridinyl-10-yl)-propan-1-one (10g). The com-
pound was prepared in 37% yield as maleic acid salt as
amorphous solid: 1H NMR (300 MHz, MeOD-d4) d
8.34 (d, J = 5.5 Hz, 1H), 8.03 (m, 2H), 7.53 (m, 2H),
7.40 (m, 1H), 7.22 (m, 2H), 3.79 (m, 1H), 3.28–3.20
(m, 3H), 2.97–2.77 (m, 3H), 2.31–2.13 (m, 2H), 1.99
(m, 1H), 1.85–1.53 (m, 3H); MS (APCI) m/z 329
(M+H)+. Anal. Calcd for C19H21FN2O2Æ1.0 C4H4O4:
C, 62.15; H, 5.67; N, 6.30; Found: C, 62.02; H, 5.27;
N, 6.24.
5.1.24. 1-Phenyl-3-(3-thiazol-2-yl-piperidin-1-yl)-propan-
1-one (10n). The compound was prepared in 51% yield
as yellow oil: 1H NMR (300 MHz, chloroform-d) d
7.96 (m, 2H), 7.67 (d, J = 3 Hz, 1H), 7.58 (m, 1H),
7.45 (m, 2H), 7.18 (d, J = 3 Hz, 1H), 3.21 (m, 3H),
2.91 (m, 3H), 2.36 (m, 1H), 2.21 (m, 2H), 1.81 (m,
1H), 1.63 (m, 3H); MS (DCI/NH3) m/z 301 (M+H)+.
Anal. Calcd for C17H20N2OSÆ0.25 H2O: C, 66.96; H,
6.89; N, 9.20; Found: C, 66.63; H, 6.69; N, 8.94.
5.1.18. 1-(4-Fluoro-phenyl)-3-(6-methyl-30,40,50,60-tetrahy-
dro-20H-[2,30]bipyridinyl-10-yl)-propan-1-one (10h). The
compound was prepared in 3% yield as yellow oil: H
1
NMR (300 MHz, chloroform-d) d 7.99 (m, 2H), 7.45
(t, J = 9 Hz, 1H), 7.14 (t, J = 9 Hz, 2H), 6.96 (d,
J = 9 Hz, 2H), 3.11 (m, 3H), 2.85 (m, 4H), 2.52 (s,
3H), 2.39 (m, 1H), 2.18 (m, 1H), 1.96 (m, 1H), 1.79
(m, 1H), 1.61 (m, 1H), 1.52 (m, 1H); MS (DCI/NH3)
m/z 327 (M+H)+. Anal. Calcd for C20H23FN2O: C,
73.59; H, 7.10; N, 5.82; Found: C, 73.81; H, 7.03; N,
5.97.
5.1.25. 1-(2-Benzenesulfonyl-ethyl)-3-thiazol-2-yl-piper-
idine (10o). The compound was prepared in 49% yield
as yellow oil: 1H NMR (300 MHz, chloroform-d) d
7.93 (m, 2H), 7.65 (m, 2H), 7.56 (m, 2H), 7.20 (d,
J = 3 Hz, 1H), 3.34 (m, 2H), 3.04 (m, 2H), 2.85 (m,
2H), 2.72 (d, J = 10.2 Hz, 1H), 2.24 (t, J = 10.2 Hz,

X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
4675
1H), 2.09 (m, 2H), 1.71 (m, 1H), 1.52 (m, 2H); MS (DCI/
5.1.29. 1-(4-Fluoro-phenyl)-3-(3-thiazol-2-yl-piperidin-1-yl)-
propan-1-one O-methyl-oxime (10s). A mixture of 10j
(190 mg, 0.6 mol) and O-methylhydroxylamine hydro-
chloride (50.1 mg, 0.6 mmol) were placed in a round
bottomed flask under a condenser. Pyridine (5 mL)
was added at room temperature from the top of the con-
denser and the resulting mixture was stirred at ambient
temperature for 12 h. The pyridine was concentrated un-
der reduced pressure, saturated NaHCO3 was added and
the mixture was extracted with EtOAc. The extract was
washed with brine, dried with Na2SO4, and concen-
trated under reduced pressure to give yellow oil
NH3) m/z 337 (M+H)+.
5.1.26. 2-[2-(3-Thiazol-2-yl-piperidin-1-yl)-ethyl]-1H-benzo-
imidazole (10p). The compound was prepared in 48%
yield, purified by HPLC, and isolated as TFA salt as
amorphous solid: 1H NMR (300 MHz, MeOD-d4) d
7.76 (m, 2H), 7.66 (d, J = 3 Hz, 1H), 7.56 (d, J = 3 Hz,
1H), 7.54 (m, 2H), 3.87 (m, 1H), 3.75 (m, 6H), 3.58
(m, 2H), 2.28 (m, 1H), 1.99 (m, 3H); MS (DCI/NH3)
m/z 313 (M+H)+. Anal. Calcd for C17H20N4SÆ2.5
TFA: C, 44.22; H, 3.80; N, 9.38; Found: C, 44.52; H,
3.56; N, 9.39.
1
(137 mg, 63%): H NMR (300 MHz, DMSO-d6) d 7.69
(m, 3H), 7.58 (m, 1H), 7.22 (m, 2H), 3.90 (s, 3H), 3.13
(m, 2H), 2.90 (m, 2H), 2.71 (m, 1H), 2.50 (m, 2H),
2.22 (m, 1H), 2.03 (m, 2H), 1.66 (m, 1H), 1.51 (m,
2H); MS (DCI/NH3) m/z 348 (M+H)+.
5.1.27. N-(1-Methyl-1H-benzoimidazol-2-yl)-2-(3-thiazol-
round
2-yl-piperidin-1-yl)-acetamide (10q). To
a
bottomed flask containing THF (300 mL) was added
2-amino-1-methylbenzimidazole (20 g, 136 mmol) and
the mixture was cooled to 0 ꢁC. To the flask were added
TEA (34.42 g, 340 mmol, 2.5 equiv) followed by chloro-
acetychloride (17.27 g, 136 mmol) and the reaction mix-
ture was warmed to room temperature and stirred for
12 h. The reaction mixture was poured into EtOAc
(300 mL) and washed with HCl (1 N), saturated with
NaHCO3, brine, dried over Na2SO4, and concentrated
in vacuo to yield yellow oil: 1H NMR (300 MHz,
MeOD-d4) d 7.25–7.50 (m, 4H), 4.70 (s, 2H), 3.30 (s,
3H); MS (DCI/NH3) m/z 224 (M+H)+. To a round bot-
tomed flask containing dry toluene (20 mL) were added
the above a-chloro acetamide (1.13 g, 6.7 mmol), com-
pound 9a and diisopropylethylamine (1.73 mg, 13.50
mmol, 2.0 equiv) and the reaction mixture was heated
at 80 ꢁC for 24 h. The reaction mixture was washed with
H2O, concentrated in vacuo, and the residue was puri-
fied by flash chromatography (silica gel, 10:1 CH2Cl2/
MeOH) to yield the product (0.52 g, 22% yield): 1H
NMR (300 MHz, MeOD-d4) d 7.67 (d, J = 3.4 Hz,
1H), 7.54 (m, 1H), 7.46 (m, 2H), 7.28 (m, 2H), 3.61 (s,
3H), 3.46 (m, 1H), 3.36 (m, 4H), 3.02 (m, 1H), 2.41
(m, 1H), 2.22 (m, 1H), 1.84 (m, 2H), 1.66 (m, 1H); MS
(DCI/NH3) m/z 356 (M+H)+. Anal. Calcd for
C18H21N5OSÆ0.10 H2O: C, 58.79; H, 5.57; N, 12.10;
Found: C, 58.64; H, 5.51; N, 12.06.
5.1.30. 1-Methyl-3-[2-(3-thiazol-2-yl-piperidin-1-yl)-ethyl]-
1,3-dihydro-benzoimidazol-2-one (10t). To a solution of
9a (113 mg, 0.67 mmol) in CH2Cl2 (10 mL) were added
Na(OAc)3BH (148 mg. 0.67 mmol), HOAc (40 mg,
0.67 mmol) followed by addition of chloroacetaldehyde
(50% aqueous solution, 105 mg, 0.67 mmol). The reac-
tion mixture was stirred for 20 min before quenched
with saturated NaHCO3. The reaction mixture was ex-
tracted with CH2Cl2 (3 · 10 mL). The organic layers
were combined, dried, and concentrated to give a yel-
lowish residue. In a separate vial was charged with 2-
hydroxybenzothiazole (101 mg, 0.67 mmol) with KOH
(38 mg, 0.67 mmol) in acetone/H2O (1:1, 3 mL). To this
suspension was added the above yellowish residue and
the reaction temperature was raised to 80 ꢁC for 1 h.
The product was purified by flash chromatography (sil-
ica gel, 30:1 CH2Cl2/MeOH) to give the desired com-
pound as yellow oil (127 mg, 55%): 1H NMR
(300 MHz, chloroform-d) d 7.66 (d, J = 3 Hz, 1H),
7.52 (dd, J = 7.5 Hz, 1 Hz, 1H), 7.40 (m, 1H), 7.36
(dd, J = 7.5 Hz, 1 Hz, 1H), 7.30 (m, 1H), 7.20 (m, 1H),
4.20 (m, 2H), 3.26 (m, 1H), 2.90 (m, 1H), 2.85 (m,
2H), 2.52 (m, 2H), 2.06 (m, 2H), 1.78 (m, 1H), 1.65
(m, 2H); MS (DCI/NH3) m/z 346 (M+H)+. Anal. Calcd
for C17H19N3OS2Æ0.10 H2O: C, 58.79; H, 5.57; N, 12.10;
Found: C, 58.64; H, 5.51; N, 12.06.
5.1.28. 2-(4-Fluoro-phenyl)-4-(3-thiazol-2-yl-piperidin-1-yl)-
butan-2-ol (10r). To a solution of 10j in dry THF (5 mL)
at 0 ꢁC was added methylmagnesium bromide (3.0 M in
THF, 0.2 mL, 0.6 mmol). The reaction mixture was al-
lowed to warm to rt and stirred under N2 for 16 h before
it was quenched with saturated NH4Cl (10 mL), and ex-
tracted with EtOAc (3 · 30 mL). The organic layers
were combined, washed with brine, dried with MgSO4,
filtered, concentrated, and purified by flash column
chromatography (silica gel, 95:5 CH2Cl2/MeOH) to give
5.1.31. 3-[2-(3-Thiazol-2-yl-piperidin-1-yl)-ethyl]-3H-benzo-
thiazol-2-one (10u). The title compound was prepared
using a similar procedure as outlined for compound
10t substituting 1-methyl-2-benzimidazolinone for 2-
hydroxybenzothiazole in step 2 and purified by HPLC
in 35% yield as TFA salt as yellow oil: 1H
NMR (300 MHz, MeOD-d4) d 7.56 (d, J = 3 Hz, 1H),
7.21 (m, 5H), 4.41 (t, J = 6 Hz, 2H), 4.17 (m, 1H), 3.92
(m, 1H), 3.63 (m, 3H), 3.45 (s, 3H), 3.11 (m, 1H), 2.26
(m, 2H), 1.94 (m, 3H); MS (DCI/NH3) m/z 343
(M+H)+. Anal. Calcd for C18H22N4OSÆ1.60 TFA: C,
48.51; H, 4.53; N, 10.67; Found: C, 48.34; H, 4.43; N,
10.62.
1
the desired alcohol as an oil (0.0580 g, 58%): H NMR
(300 MHz, chloroform-d) d 7.68 (d, J = 3 Hz, 1H),
7.45 (dd, J = 6 Hz, 3 Hz, 2H), 7.21 (d, J = 3 Hz, 1H),
7.04 (t, J = 9 Hz, 2H), 3.43 (m, 1H), 3.22 (m, 3H), 2.93
(m, 1H), 2.18 (m, 2H), 2.08 (m, 2H), 1.83 (m, 2H),
1.58 (m, 2H), 1.51 (s, 3H); MS (DCI/NH3) m/z 335
(M+H)+. Anal. Calcd for C18H23FN2OSÆ0.1 CH2Cl2:
C, 63.39; H, 6.82; N, 8.17; Found: C, 63.50; H, 6.51;
N, 8.09.
5.1.32. (1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetaldehyde
(12). To a solution of 2-phthalimidoacetaldehyde dieth-
ylacetal (4.86 g, 18.5 mmol) in THF (25 mL) was added
HCl (6 N, 90 mL) and stirred at rt overnight. The

4676
X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
solution was concentrated and treated with saturated
NaHCO3, and extracted with CH2Cl2 (3 · 50 mL). The
organic layers were combined, washed with brine, dried
with MgSO4, and concentrated to give the desired prod-
uct (2.80 g, 80%): white solid; mp 98–100 ꢁC. H NMR
(300 MHz, chloroform-d) d 9.66 (s, 1H), 7.90 (m, 2H),
7.76 (d, J = 5.4 Hz, 3.0 Hz, 2H), 4.56 (s, 2H); MS
(DCI/NH3) m/z 189 (M+H)+, 207 (M+NH4)+.
(m, 1H), 3.51 (m, 2H), 3.35 (m, 1H), 2.27 (m, 1H),
1.99 (m, 3H); MS (DCI/NH3) m/z 329 (M+H)+. Anal.
Calcd for C17H20N4OSÆ2.0 TFA: C, 45.33; H, 3.98; N,
10.07; Found: C, 45.47; H, 3.88; N, 9.99.
1
The following compounds were prepared in a manner
similar to that of compound 16a.
5.1.36. (1-Methyl-1H-benzoimidazol-2-yl)-[2-(3-thiazol-2-
yl-piperidin-1-yl)-ethyl]-amine (16b). The compound
was prepared and purified by flash chromatography
(silica gel, 10:1 CH2Cl2/MeOH) in 45% yield as yellow
5.1.33. 2-(3-Phenyl-piperidin-1-yl)-ethylamine (15a). To a
solution of 3-phenyl piperidine hydrochloride (358 mg,
1.81 mmol) in CH2Cl2 (10 mL) was added Na(OAc)3BH
(444 mg, 2.0 mmol) followed by portionwise addition of
the compound 12 (378 mg, 2.0 mmol). The reaction
mixture was quenched after 4 h with saturated
NaHCO3, and extracted with CH2Cl2 (3 · 10 mL). The
organic layers were combined, washed with brine, dried
with Na2SO4, and concentrated. The residue was
purified by flash chromatography (silica gel, 30:1
CH2Cl2/MeOH) to give the product as yellow oil
1
oil: H NMR (300 MHz, MeOD-d4) d 7.69 (d, J = 3.4
Hz, 1H), 7.44 (d, J = 3.4 Hz, 1H), 7.26 (m, 1H), 7.13
(m, 1H), 7.01 (m, 2H), 3.62 (t, J = 6.6 Hz, 2H), 3.52 (s,
3H), 3.23 (m, 1H), 2.95 (m, 1H), 2.75 (m, 2H), 2.41
(m, 1H), 2.29 (m, 1H), 2.12 (m, 1H), 1.75 (m, 4H); MS
(DCI/NH3) m/z 342 (M+H)+. Anal. Calcd for
C18H23N5SÆ0.7 H2OÆ0.2 toluene: C, 62.33, H, 7.03; N,
18.80; Found: C, 62.49; H, 6.73; N, 18.44.
1
(380 mg, 63%): H NMR (300 MHz, chloroform-d) d
5.1.37. Benzooxazol-2-yl-[2-(3-phenyl-piperidin-1-yl)-ethyl]-
amine (16c). The compound was prepared and purified
as HCl salt as yellow oil in 30% yield: 1H NMR
(300 MHz, MeOD-d4) d 7.44 (m, 2H), 7.33 (m, 7H),
3.98 (t, J = 6 Hz, 2H), 3.75 (m, 2H), 3.54 (m, 2H), 3.19
(m, 3H), 2.09 (m, 3H), 1.85 (m, 1H); MS (DCI/NH3)
m/z 322 (M+H)+. Anal. Calcd for C20H23N3OÆ2.1
HClÆ0.3 toluene: C, 62.36: H, 6.51; N, 9.87; Found: C,
62.00; H, 6.12; N, 9.56.
7.84 (m, 2H), 7.71 (m, 2H), 7.23 (m, 5H), 3.84 (t, J =
8 Hz, 2H), 3.07 (m, 1H), 3.01 (m, 1H), 2.73 (tt,
J = 12 Hz, 3 Hz, 1H), 2.65 (td, J = 8 Hz, 3 Hz, 2H),
2.07 (t, 10 Hz, 2H), 1.88 (m, 1H), 1.95 (m, 1H), 1.61
(m, 1H), 1.46 (m, 1H); MS (DCI/NH3) m/z 335
(M+H)+. To a solution of the above compound
(372 mg, 1.1 mmol) in MeOH (5 mL) was added hydra-
zine monohydrate (83 mg, 1.67 mmol) and the reaction
mixture was heated at 80 ꢁC for 2 h. A solid came out
upon cooling. Et2O was added to the mixture and the
solid was filtered out. The solid was washed with Et2O
(1 · 10 mL). The filtrate was washed with NaOH solu-
tion (5 mL, 2 N), dried with Na2SO4, concentrated,
5.1.38. (1-Methyl-1H-benzoimidazol-2-yl)-[2-(3-phenyl-piper-
idin-1-yl)-ethyl]-amine (16d). The compound was prepared
in 30% yield, purified by HPLC, and isolated as TFA
salt as yellow oil: 1H NMR (300 MHz, MeOD-d4) d
7.47 (m, 2H), 7.33 (m, 7H), 3.98 (t, J = 6 Hz, 2H), 3.73
(m, 2H), 3.69 (s, 3H), 3.55 (td, J = 6 Hz, 3 Hz, 2H),
3.16 (m, 3H), 2.06 (m, 3H), 1.85 (m, 1H); MS (DCI/
NH3) m/z 335 (M+H)+; Anal. Calcd for C21H26N4Æ2.2
TFA: C, 52.12: H, 4.86; N, 9.57; Found: C, 52.04; H,
4.84; N, 9.50.
1
and used directly in the next step (153 mg, 68%): H
NMR (300 MHz, chloroform-d) d 7.26 (m, 5H), 2.97
(m, 2H), 2.81 (m, 3H), 2.44 (t, J = 6 Hz, 2H), 2.03 (m,
1H), 1.95 (m, 2H), 1.71 (m, 2H), 1.46 (m, 1H); MS
(DCI/NH3) m/z 205 (M+H)+.
5.1.34. 2-(3-Thiazol-2-yl-piperidin-1-yl)-ethylamine (15b).
The title compound was prepared using a procedure
similar to that outlined for compound 15a substituting
compound 9a for 3-phenylpiperidine: 1H NMR
(300 MHz, MeOD-d4) d 7.69 (d, J = 3 Hz, 1H), 7.47
(d, J = 3 Hz, 1H), 3.35 (m, 1H), 3.11 (m, 1H), 2.84 (m,
1H), 2.77 (t, J = 6 Hz, 2H), 2.50 (t, J = 6 Hz, 2H), 2.34
(m, 1H), 2.21 (m, 1H), 2.11 (m, 1H), 1.73 (m, 3H); MS
(DCI/NH3) m/z 212 (M+H)+.
5.1.39. Quinoxalin-2-yl-[2-(3-thiazol-2-yl-piperidin-1-yl)-
ethyl]-amine (16e). The title compound was prepared
using a procedure similar to that outlined for compound
16c substituting 2-chloroquinoxazoline for 2-chloro-
benzoxazole and purified by HPLC as the TFA salt as
1
yellow oil: H NMR (300 MHz, MeOD-d4) d 8.35 (s,
1H), 7.91 (m, 2H), 7.81 (m, 1H), 7.71 (m, 1H), 7.56 (t,
J = 4.1 Hz, 2H), 7.38 (m, 1H), 4.00 (m, 1H), 3.83 (q,
J = 5.9 Hz, 2H), 3.69 (m, 2H), 3.40 (m, 1H), 3.16 (m,
2H), 2.16 (m, 1H), 1.85 (m, 4H); MS (DCI/NH3) m/z
340 (M+H)+. Anal. Calcd for C18H21N5SÆ2.5 TFAÆ0.3
ethanol: C, 44.41; H, 3.99; N, 10.97; Found: C, 44.80;
H, 3.64; N, 10.68.
5.1.35. Benzooxazol-2-yl-[2-(3-thiazol-2-yl-piperidin-1-yl)-
ethyl]-amine (16a). To a solution of the compound 15a
(70 mg, 0.33 mmol) in THF (5 mL) under N2 were
added 2-chlorobenzoxazole (26.5 lL, 0.23 mmol),
Pd2(dba)3 (15.1 mg, 0.017 mmol), racemic BINAP
(32 mg, 0.05 mmol), and sodium tert-butoxide (22 mg,
0.23 mmol). The reaction mixture was heated to 80 ꢁC
for 4 h. The reaction mixture was concentrated and puri-
fied by HPLC to give the desired product as TFA salt in
5.1.40. 2-(3-Thiazol-2-yl-piperidin-1-yl)-ethanol (17). A
mixture of compound 9a (1.80 g, 10.7 mmol), 2-bromo-
ethanol (1.34 g, 10.7 mmol), K2CO3 (4.43 g, 32.1 mmol),
NaI (790 mg, 5.3 mmol) in 1,2-dimethoxyethane
(50 mL) was heated at 80 ꢁC for 3 h before H2O was
added in. The water layer was extracted with EtOAc
(3 · 30 mL). The organic layers were combined, dried
1
43% yield: H NMR (300 MHz, MeOD-d4) d 7.49 (m,
1H), 7.34 (d, J = 6 Hz, 1H), 7.23 (m, 1H), 7.18 (m,
1H), 7.11 (m, 2H), 3.87 (m, 3H), 3.80 (m, 2H), 3.75

X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
4677
with Na2SO4, concentrated, and purified by flash chro-
matography (silica gel, 20:1:0.1 CH2Cl2/MeOH/
NH4OH) to give the desired product as yellow oil
6. Biological procedures
6.1. D4.4 calcium flux assay (agonist mode)
1
(1.80 g, 79%): H NMR (300 MHz, MeOD-d4) d 7.69
(d, J = 3.4 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 3.70 (t,
J = 6 Hz, 2H), 3.34 (m, 1H), 3.21 (m, 1H), 2.94 (m,
1H), 2.59 (t, J = 6.2 Hz, 2H), 2.33 (d, J = 9 Hz, 1H),
2.16 (m, 2H), 1.79 (m, 2H), 1.63 (m, 1H); MS (DCI/
NH3) m/z 213 (M+H)+.
Human D4.4 was coexpressed with Gaqo5 in HEK-293
cells as described.25 Cells were plated into 96-well,
black-wall/clear-bottom microplates (Biocoat, Becton
Dickinson, Boston, MA) at 20,000 cells per well. After
2 days of culture, the culture medium was removed by
aspiration and replaced by 0.1 mL of DPBS (Dulbeccoꢀs
phosphate buffered saline with D-glucose and sodium
pyruvate) containing 0.04% Pluronic F-127 and 4 lM
Fluo-4, fluorescent calcium indicator dye. After incuba-
tion for 1 h at room temperature, the cells were washed
four times with DPBS in a plate washer (Molecular De-
vices). After the final wash, 150 lL of DPBS was added
to each well. Fluorometric imaging plate reader
(FLIPR384, Molecular Devices) transferred 50 lL from
the compound plate to the cells and made fluorescence
reading for 3 min (every second for the first minute and
every 5 s for the next 2 min). The instrument software
normalizes the fluorescent reading to give equivalent ini-
tial readings at time zero and all the data were normal-
ized with the response of 10 lM dopamine.
5.1.41. 2-[2-(3-Thiazol-2-yl-piperidin-1-yl)-ethoxy]-benzo-
oxazole (18a). The title compound was prepared using a
procedure similar to that outlined for compound 16c
substituting compound 17 for 15a and purified by flash
chromatography (silica gel, 20:1:0.1 CH2Cl2/MeOH/
NH4OH) in 42% yield: light tan solid; mp 112–114 ꢁC.
1H NMR (300 MHz, chloroform-d)
d
7.69 (d,
J = 3.4 Hz, 1H), 7.48 (m, 1H), 7.35 (m, 1H), 7.35 (m,
1H), 7.20 (m, 3H), 4.69 (t, J = 5.6 Hz, 2H), 3.30 (m,
2H), 2.93 (m, 3H), 2.47 (m, 1H), 2.32 (m, 1H), 2.11
(m, 1H), 1.72 (m, 3H); MS (DCI/NH3) m/z 330
(M+H)+. Anal. Calcd for C17H19N3O2S: C, 61.98; H,
5.81; N, 12.76; Found: C, 61.85; H, 5.63; N, 12.46.
The following compounds were prepared in a manner
similar to that of compound 18a.
6.2. Radioligand binding assay
5.1.42. 1-Methyl-2-[2-(3-thiazol-2-yl-piperidin-1-yl)-ethoxy]-
1H-benzoimidazole (18b). The compound was prepared
Binding assays were initiated by addition of 250 lL of
membrane to 200 lL of 2-[4-(4-[3H]-2-cyanophenyl)-
piperazinyl]-N-(2,4,6-[3H]3-3-methylphenyl)acetamide,
88.1 Ci/mmol)26 and were incubated at room tempera-
ture for 1 h. Nonspecific binding was determined in the
presence of 10 lM PD 168077 (RBI-Sigma). The incuba-
tion buffer consisted of 50 mM Tris–HCl, pH 7.4, 5 mM
KCl, 120 mM NaCl, 5 mM MgCl2, and 1 mM EDTA. In
competition binding studies, agonists or antagonists
were prepared with 0.1% ascorbic acid and 0.5% IBMX
(3-isobutyl-1-methylxanthine) in the buffer. The final
concentration for 2-[4-(4-[3H]-2-cyanophenyl)piperazi-
nyl]-N-(2,4,6-[3H]3-3-methylphenyl)acetamide was 2.0 nM.
The reaction was terminated by rapid filtration through
UniFilter-96 GF/B filers, pre-soaked in 0.5% PEI
(poly(ethyleneimine)), using a Filtermate Harvester
(Packard, Meriden, CT). Filters were washed three times
with 1 mL of ice cold 50 mM Tris–HCl, pH 7.4. Radio-
activity was measured by TopCount Microplate Scintil-
lation Counter (Packard, Meriden, CT). Proteins were
determined by BCA Protein Assay Kit (Pierce, Rock-
ford, IL) using BSA as a standard.
1
in 76% yield as yellow oil: H NMR (300 MHz, chloro-
form-d) d 7.69 (d, J = 3.4 Hz, 1H), 7.54 (m, 1H), 7.19 (d,
J = 3.4 Hz, 1H), 7.15 (m, 3H), 4.70 (m, 2H), 3.55 (s, 3H),
3.31 (m, 2H), 2.93 (m, 3H), 2.50 (m, 1H), 2.34 (m, 1H),
2.13 (m, 1H), 1.79 (m, 1H), 1.65 (m, 2H); MS (DCI/
NH3) m/z 343 (M+H)+. Anal. Calcd for C18H22N4OS:
C, 63.12; H, 6.48; N, 16.36; Found: C, 62.61; H, 6.45;
N, 16.01.
5.1.43. 2-[2-(3-Thiazol-2-yl-piperidin-1-yl)-ethoxy]-benzo-
thiazole (18c). The compound was prepared in 42%
yield: 1H NMR (300 MHz, MeOD-d4) d 7.72 (dd,
J = 7.5 Hz, 0.8 Hz, 1H), 7.69 (d, J = 3.4 Hz, 1H), 7.62
(dd, J = 7.5 Hz, 0.8 Hz, 1H), 7.42 (d, J = 3.4 Hz, 1H),
7.37 (td, J = 7.5 Hz, 0.8 Hz, 1H), 7.24 (td, J = 7.5 Hz,
0.8 Hz, 1H), 4.72 (t, J = 5.6 Hz, 2H), 3.35 (m, 1H),
3.23 (m, 1H), 2.93 (m, 3H), 2.46 (m, 1H), 2.35 (m,
1H), 2.11 (m, 1H), 1.80 (m, 1H), 1.65 (m, 2H); MS
(DCI/NH3) m/z 346 (M+H)+. Anal. Calcd for
C17H19N3OS2: C, 59.10; H, 5.54; N, 12.16; Found: C,
59.17; H, 5.37; N, 11.91.
Acknowledgments
5.1.44. 2-[2-(3-Thiazol-2-yl-piperidin-1-yl)-ethoxy]-quinoxa-
line (18d). The compound was prepared in 40% yield,
purified by reverse HPLC, and isolated as TFA salt as
amorphous solid: 1H NMR (300 MHz, MeOD-d4) d
8.59 (b, 1H), 8.03 (dd, J = 8.7 Hz, 1.5 Hz, 1H), 7.86
(m, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.56 (m, 1H),
7.52 (m, 1H), 4.97 (m, 2H), 4.16 (m, 1H), 3.87 (m,
1H), 3.75 (m, 2H), 3.61 (m, 1H), 3.32 (m, 1H), 3.21
(m, 1H), 2.35 (m, 1H), 2.17 (m, 1H), 1.97 (m, 2H); MS
(DCI/NH3) m/z 341 (M+H)+. Anal. Calcd for
C18H20N4OSÆ1.6 TFA: C, 48.70; H, 4.16; N, 10.71;
Found: C, 48.80; H, 4.22; N, 10.84.
The authors would like to thank Mr. Adam Huffman
and Dr. Tom Pagano for their helpful NMR character-
izations and Dr. Steven Hannick and Mr. Bryan Macri
for high pressure hydrogenation.
References and notes
1. Kebabian, J. W.; Calne, D. B. Nature 1979, 277, 93.
2. Dearry, A.; Gingrich, J. A.; Falandeau, P.; Fremear, R.
T., Jr.; Bates, M. D.; Caron, M. G. Nature 1990, 347, 72.

4678
X. Wang et al. / Bioorg. Med. Chem. 13 (2005) 4667–4678
3. Sunhara, R. K.; Guan, H.-C.; Oꢀdowd, B. F.; Seeman, P.;
20. Brioni, J. D.; Moreland, R. B.; Cowart, M.; Hsieh, G. C.;
Stewart, A. O.; Hedlund, P.; Donnelly-Roberts, D. L.;
Nakane, M.; Lynch, J. J., III; Kolasa, T.; Ploakowski, J.
S.; Osinski, M. A.; Marsh, K. C.; Andersson, K.-E.;
Sullivan, J. P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
6758.
21. Cowart, M.; Latshaw, S. P.; Bhatia, P.; Daanen, J. F.;
Rohde, J.; Nelson, S. L.; Patel, M.; Kolasa, T.; Nakane,
M.; Uchic, M. E.; Miller, L. N.; Terranova, M. A.;
Hollingsworth, P. R.; Martino, B.; Lynch, J. J.; Sullivan,
J. P.; Hsieh, G. C.; Moreland, R. B.; Moreland, R. B.;
Brioni, J. D.; Stewart, A. O. J. Med. Chem. 2004, 47, 2348.
22. Matulenko, M. A.; Hakeem, A. A.; Kolasa, T.; Nakane,
M.; Terranova, M. A.; Uchic, M. E.; Miller, L. N.; Chang,
R.; Donnelly-Roberts, D.; Namovic, M. T.; Moreland, R.
B.; Brioni, J. D.; Stewart, A. O. Bioorg. Med. Chem. 2004,
12, 3471.
Laurier, L. G.; Ng, G.; George, S. R.; Torchia, J.; Van
Tol, H. H. M.; Niznik, H. B. Nature 1991, 350, 614.
4. Grandy, D. k.; Marchionni, M. A.; Makam, H.; Stofko,
R. E.; Alfano, M.; Frothingham, L.; Fischer, J. B.; Burke-
Howie, K. J.; Bunzow, J. R.; Server, A. C.; Civelli, O.
Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 9762.
5. Sokoloff, P.; Giros, B.; Martres, M.-P.; Bouthenet, M.-L.;
Schwartz, J.-C. Nature 1990, 347, 146.
6. Van Tol, H. H. M.; Bunzow, J. R.; Guan, H.-C.; Sunhara,
R. K.; Seeman, P.; Niznik, H. B.; Civelli, O. Nature 1991,
350, 610.
7. Kulagowski, J. J.; Patel, S. Curr. Pharm. Des. 1997, 3, 355.
8. Hrib, N. J. Drugs Future 2000, 25, 587.
9. Bristow, L. J.; Kramer, M.; Kulagowski, J.; Patel, S.;
Ragan, C.; Seabrook, G. R. Trends Pharmacol. Sci. 1997,
18, 186.
10. Bristow, L. J.; Collinson, N.; Cook, J. P.; Curtis, N.;
Freedman, S. B.; Kulagowski, J. J.; Leeson, P. D.; Patel,
S.; Ragan, C. I.; Ridgill, M.; Saywell, K. L.; Trickleback,
M. D. J. Pharmacol. Exp. Ther. 1997, 283, 1256.
11. Mansbach, R. S.; Brooks, E. W.; Sanner, M. A.; Zorn, S.
H. Psychopharmacology 1998, 135, 194.
12. Gazi, L.; Bobirnac, I.; Danzeisen, M.; Schupbach, E.;
Bruinvels, A. T.; Geisse, S.; Sommer, B.; Hoyer, D.;
Tricklebank, M.; Schoeffter, P. Br. J. Pharmacol. 1998,
124, 889.
13. Andersson, K.-E. Pharmacol. Rev. 2001, 53, 417.
14. Vogel, H. P.; Schiffter, R. Pharmacopsychiatry 1983, 16,
107.
15. Melis, A.; Argiolas, A. Neurosci. Biobehav. Rev. 1995, 19,
19.
23. Stewart, A. O.; Cowart, M.; Moreland, R. B.; Latshaw, S.
P.; Matulenko, M. A.; Bhatia, P. A.; Wang, X.; Daanen, J.
F.; Nelson, S. L.; Terranova, M. A.; Namovic, M. T.;
Donnelly-Roberts, D. L.; Miller, L. N.; Nakane, M.;
Sullivan, J. P.; Brioni, J. D. J. Med. Chem. 2004, 47, 2348.
24. Kenakin, T.; ONaran, O. Trends Pharmacol. Sci. 2002, 23,
275.
25. Moreland, R. B.; Nakane, M.; donnelly-Roberts, D. L.;
Miller, L. N.; Chang, R.; Uchic, M. E.; Terranova, M. A.;
Gubbins, E. J.; Helfrich, R. J.; Voss, M. H.; Namovic, M.
T.; N., M. J.; Brioni, J. D. Biochem. Pharmacol. 2004, 68,
761.
26. Matulenko, M. A.; Surber, B.; Fan, L.; Kolasa, T.;
Nakane, M.; Terranova, M. A.; Uchic, M. E.; Miller, L.
N.; Chang, R.; Donnelly-Roberts, D. L.; Namovic, M. T.;
Moreland, R. B.; Brioni, J. D.; Stewart, A. O. Bioorg.
Med. Chem. Lett. 2004, 14, 5095.
16. Dula, E.; Keating, W.; Siami, P.; Edmonds, A.; OꢀNeil, J.;
Butler, S. Urology 2000, 56, 130–135.
17. Holdsworth, J. D.; Furness, M. B.; Roulston, R. G. Br. J.
Anaesth. 1974, 46, 526.
27. Shi, L.; Javitch, J. A. Annu. Rev. Pharmacol. Toxicol.
2002, 42, 437.
18. Tattersall, F. D.; Rycroft, W.; Hill, R. G.; Hargreaves, R.
J. Neuropharmacology 1994, 33, 259.
28. Lanig, H.; Utz, W.; Gmeiner, P. J. Med. Chem. 2001, 44,
1151.
19. Hsieh, G. C.; Hollingsworth, P. R.; Martino, B.; Chang,
R.; Terranova, M. A.; Oꢀneil, A. B.; Lynch, J. J.;
Moreland, R. B.; Donnelly-Roberts, D.; Kolasa, T.;
Mikusa, J. P.; McVey, J. M.; Marsh, K. C.; Sullivan, J.
P.; Brioni, J. D. J. Pharmacol. Exp. Ther. 2004, 308,
330.
29. He, X.; Neurogen Corporation: U.S. Patent 6284759B1,
2001.
30. Lober, S.; Hubner, H.; Utz, W.; Gmeiner, P. J. Med.
Chem. 2001, 44, 2691.
31. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.