Synthesis of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole analogues and their binding affinities for dopamine D2 and D3 receptors

Article abstract of DOI:10.1016/S0968-0896(01)00175-4

A series of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole derivatives was prepared and their affinity for dopamine D₂ and D₃ receptors was measured using in vitro binding assays. Several oxadiazole analogues were also prepared and tested for their affinity for dopamine D₂ and D₃ receptors. The results of receptor binding studies indicated that the incorporation of an imidazole moiety between the phenyl ring and the basic nitrogen did not significantly increase the selectivity for dopamine D₃ receptors, whereas the incorporation of an oxadiazole at the same region resulted in a total loss of affinity for both dopamine receptor subtype binding sites. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-4-(6,7-dimethoxy-1,2,3, 4-tetrahydroisoquinolinomethyl)imidazole (5i), which has a D₃ receptor affinity of 21 nM and a 7-fold selectivity for D₃ versus D₂ receptors. The binding affinity for σ₁ and σ₂ receptors was also measured, and the results showed that several analogues were selective σ₁ receptor ligands.

Full text of DOI:10.1016/S0968-0896(01)00175-4

Bioorganic & MedicinalChemistry 9 (2001) 3113–3122
Synthesis of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole
Analogues and their Binding Affinities for Dopamine D2
and D3 Receptors
Yunsheng Huang,a Robert R. Luedtke,b Rebekah A. Freeman,b
Li Wua and Robert H. Macha,c,*
aDepartment of Radiology-PET Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
bDepartment of Pharmacology, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
cDepartment of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Received 30 July 2000; accepted 7 May 2001
Abstract—A series of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imidazole derivatives was prepared and their affinity for dopamine
D2 and D3 receptors was measured using in vitro binding assays. Several oxadiazole analogues were also prepared and tested for
their affinity for dopamine D2 and D3 receptors. The results of receptor binding studies indicated that the incorporation of an
imidazole moiety between the phenyl ring and the basic nitrogen did not significantly increase the selectivity for dopamine D3
receptors, whereas the incorporation of an oxadiazole at the same region resulted in a total loss of affinity for both dopamine
receptor subtype binding sites. The most selective compound in this series is 2-(5-bromo-2,3-dimethoxyphenyl)-4-(6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinomethyl)imidazole (5i), which has a D3 receptor affinity of 21 nM and a 7-fold selectivity for D3 versus
D2 receptors. The binding affinity for s1 and s2 receptors was also measured, and the results showed that several analogues were
selective s1 receptor ligands. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
situ hybridization studies of dopamine receptor mRNAs
in the brain have revealed a distinct difference between
D2 and D3 receptor expression. D2 receptor mRNA has
been localized mainly in the striatum, the olfactory
tubercle, and the nucleus accumbens,1,6 whereas the D3
receptor mRNA has been found specifically in limbic
regions.6
Molecular biology studies have classified dopamine
receptors into two major groups, D1-like (D1, D5) and
D2-like (D2, D3, and D4), based on amino acid homol-
ogy and G-protein coupled second messenger
pathways.1ꢀ3 The genomic structures of D2, D3 and D4
receptors contain 6, 5, and 3 introns, respectively,
whereas the D1 and D5 receptor genes contain no
introns within their coding region.2,4 Amino acid
sequence analysis revealed that the dopamine receptors
have seven transmembrane spanning regions, which is
characteristic of other members of the G-protein cou-
pled receptor superfamily.5 The D1 and D5 receptors
share an 80% amino acid sequence identity in their
transmembrane domains. The D2 and D3 receptors
share a 75% amino acid sequence identity in their
transmembrane domains, and the D2 and D4 receptors
share a 53% identity in their transmembrane regions. In
The antipsychotic effects of neuroleptics are thought to
be due to their action on the dopaminergic receptors in
the mesolimbic system, whereas the extrapyramidal side
effects are thought to result from the blockade of D2
receptors in the striatum.2,7 The localization of D3
receptors in the limbic regions of brain suggests that this
receptor may be a target for the development of anti-
psychotics with reduced risk of causing extrapyramidal
side effects.8 This hypothesis is supported by the obser-
vation that most conventionalneuroelptics dispaly a
higher affinity for D2 versus D3 receptors and have a
9
tendency to produce extrapyramidalsymptoms.
In
contrast, atypicalantipsychotics have a high affinity for
both D2 and D3 receptors.10ꢀ12 More recent studies
have also indicated that D3 receptor stimulation may
*Corresponding author at Dept of Radiology. Fax: +1-336-716-2029;
e-mail: rmach@wfubmc.edu
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00175-4

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Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
mediate the reinforcing effects of cocaine. Therefore, D3
receptor antagonists are potentially useful for the treat-
ment of cocaine abuse.13ꢀ16
with thionylcholride to form the corresponding 2-
phenyl-4-(chloromethyl)imidazole that was subse-
quently alkylated with an appropriate secondary amine
to give the final products. Alternatively, 2-phenyl-4-
(hydroxymethyl)imidazole 3a or 3b was treated with
PCC in dichloromethane to afford the corresponding
aldehyde intermediate which then underwent reductive
alkylation with an appropriate primary amine using
sodium cyanoborohydride in methanol.
Recently, we reported a number of benzamide analo-
gues that bind with high affinity at both dopamine D2
and D3 receptors.17ꢀ19 The common structuralfeature
of those compounds included a substituted benzamide
moiety and an N-benzylgroup. Repalcement of the N-
benzylgroup with different N-alkyl groups resulted in
compounds with a higher affinity for D2 versus D3
receptors.17 However, an increase in steric bulkiness of
the N-benzylregion enhanced the affinity and seel ctivity
of structurally-related analogues for D3 receptors.20
The 3-(2,3-dimethoxyphenyl)-5-aminoalkyl-1,2,4-oxa-
diazole analogues were synthesized according to proce-
dures outlined in Scheme 3.24,25 The 2,3-
dimethoxybenzonitrile was treated with hydroxylamine
to give the 2,3-dimethoxybenzamide oxime, 6, which
was then condensed with an appropriate methylcar-
boxylate to afford compounds 7a–d.
The goalof the present study was to determine the effect
of modification of the amide region of the benzamide
analogues on binding to D2 and D3 receptors. A series
of 2-phenyl-4-(aminomethyl)imidazoles was found to
bind to dopamine D2 receptors with a wide range of
affinity (0.7–3750 nM), but their binding affinity for D3
receptors was not reported.21 As part of our research
effort to identify compounds with high affinity and
selectivity for dopamine D3 receptors, we investigated a
series of 2-(2,3-dimethoxyphenyl)-4-(aminomethyl)imi-
dazoles and related oxadiazole analogues for their
binding affinity for D2 and D3 receptors. In addition,
since many dopamine antagonists bind to sigma recep-
tors, the binding affinity of the synthesized compounds
for s1 and s2 receptors was also measured. The results
of our study revealed that replacement of the benzamide
moiety with an imidazole ring leads to compounds that
are moderately selective for either D2 or D3 receptors,
with the selectivity being primarily dependent upon the
structure of the tertiary amino moiety.
Receptor binding
The in vitro receptor binding results are shown in Table
1. Compound 5a was reported previously to have a Ki
value of 5.1 nM for dopamine D2 receptors (cloned
from African Green Monkey) but binding data for
dopamine D3 receptors was not reported.21 Therefore,
compound 5a was included for comparison in the cur-
rent study. The binding affinity of compound 5a was
9.2 nM for D2 receptors (Sf9 cells) and 10.1 nM for D3
receptors. Compound 5b, which contains a bromo sub-
stitution on the phenylaromatic ring and a diethyal-
mino moiety, displayed a 10-fold decrease in affinity for
both D2 and D3 receptors in comparison with the bind-
ing data of compound 5a. These results are consistent
with the presence of a conserved secondary aromatic
binding region in both the D2 and D3 dopamine recep-
tor binding sites. While this secondary aromatic binding
site is not important for conferring D2 versus D3 selec-
tivity, it does play a role in determining binding affinity.
Results
Chemistry
Compound 5c contains a N-(1-benzyl)piperidin-4-yl
moiety and thus has two basic nitrogen atoms (not
including the basic N within the imidazole ring). The
binding affinity of 5c for both D2 and D3 receptors was
significantly decreased compared to 5a and 5b. When
substituted at the 50-position on the 2-phenylaromatic
ring with a bromo substituent, the subsequent com-
pound, 5d, had a 6-fold increase in affinity for D2
receptors and a 15-fold increase in affinity for D3
receptors. Compounds 5e and 5f both contain an N-(9-
benzyl)-9-azabicyclo[3.3.1]nonan-3-yl moiety, and thus
also have two basic nitrogen atoms (not including the
basic N within the imidazole ring). Both compounds
showed a significantly lower affinity for D2 and D3
The synthesis of 5-bromo-2,3-dimethoxybenzonitrile
was accomplished via the treatment of N-tert-butyl-5-
bromo-2,3-dimethoxybenzamide with the phosphorus
oxychloride.22 The N-tert-butyl-5-bromo-2,3-dimethoxy-
benzamide was obtained from 2,3-dihydroxybenzoic
acid in 5 steps as shown in Scheme 1. The synthesis of
aminomethylimidazoles is outlined in Scheme 2. The
benzamidine 2a or 2b was prepared according to the
methods described by Boere et al.23 The corresponding
benzamidine was then condensed with dihydroxy-
acetone dimer to give 3a or 3b.21 The 2-phenyl-4-
(hydroxymethyl)imidazole 3a or 3b was then treated
Scheme 1. Reagents: (a) Br2, acetic acid, rt; (b) Me2SO4, acetone, Á; (c) NaOH, MeOH, Á; (d) SOCl2, benzene, Á; (e) t-BuNH2, CH2Cl2, rt; (f)
POCl3, benzene, Á.

Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
3115
Scheme 2. Reagents: (a) BuLi, ether, 0 ꢁC; (b) 1,3-dihydroxyacetone dimer, NH4Cl, NH4OH, 80 ꢁC; (c) SoCl2, benzene, Á; (d) NHR1R2, rt; (e)
PCC,CH2Cl2; (f) NH2R, MeOH, NaBH3CN.
receptors when compared to compound 5a. A bromo
substitution at the 50-position of the 2-phenylaromatic
moiety to afford compound 5f resulted in a 3-fold
increase in affinity for D2 receptors and a 9-fold increase
in affinity for D3 receptors when compared to the bind-
ing data of 5e. The increase in affinity and selectivity for
D2 and D3 receptors by a bromo-substitution at the 50-
position of the 2-phenylmoiety was further demon-
strated by the binding data of compounds 5g and 5h,
both of which contain a 1,2,3,4-tetrahydroisoquinolino
moiety. Compound 5h had a 4-fold higher affinity for
D2 receptors and a 28-fold higher affinity for D3 recep-
tors than compound 5g. As a result, compound 5h is 3-
fold selective for D3 receptors (23.8 nM) versus D2
receptors (78.2 nM), whereas compound 5g was a 2-fold
selective for D2 receptors (315.5 nM) versus D3 recep-
tors (664 nM). When substituted with a 6,7-dimethoxy
Scheme 3. Reagents: (a) NH2OH HCl, K2CO3, ethanol, Á; (b)
RCOOMe, molecular sieve, Á.

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Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
Table 1. Binding affinities for dopamine D2/D3 and sigma s1/s2 receptors
Ki (nM)a
b
c
d
e
Compd
D2
D3
s1
s2
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
9.2ꢂ2.1
97.0ꢂ8.4
1767ꢂ568
283.5ꢂ132
799ꢂ353
243.1ꢂ88
315.5ꢂ140
78.2ꢂ29
10.1ꢂ1.5
90.8ꢂ31.9
1707ꢂ562
113.7ꢂ53.7
1310ꢂ917
145.9ꢂ41.5
664ꢂ148
23.8ꢂ11
16.7ꢂ0.7
>1000
>1000
>1000
33.6ꢂ0.4
84.7ꢂ0.5
586.2ꢂ35.6
>1000
>1000
>1000
140.0ꢂ14.6
>1000
>1000
>1000
>1000
>1000
>1000
>1000
143.0ꢂ48.7
21.2ꢂ4.7
>1000
>1000
>1000
>1000
5k
5l
5m
5n
5o
5p
7a
7b
781.0ꢂ72.5
11.9ꢂ7.4
15.7ꢂ10.8
13.8ꢂ3.2
40.9ꢂ10.8
75.9ꢂ21.7
>1000
>1000
>1000
>1000
10.8ꢂ7.6
40.5ꢂ23.6
36.6ꢂ15.9
57.5ꢂ19.4
146.2ꢂ52.7
>1000
542.1ꢂ19.1
412.0ꢂ37.3
112.9 ꢂ7.0
>1000
>1000
>1000
>1000
236.3ꢂ4.6
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
7c
7d
IABN
MABN
>10000
>10000
277.6ꢂ6.4
6.6ꢂ0.2
>1000
280.3ꢂ0.7
250.9ꢂ6.8
419.3ꢂ31.5
>1000
594.9ꢂ61.0
0.05ꢂ0.006j
0.2ꢂ0.05
1472ꢂ762
0.04ꢂ0.004f
0.4ꢂ0.2
>1000
aMeanꢂSEM, Ki values were determined by at least three experiments.
bKi values for D2 receptors were measured on rat D2(long) expressed in Sf9 cells using [125I]IABN as the radioligand.
cKi values for D3 receptors were measured on rat D3 expressed in Sf9 cells using [125I]IABN as the radioligand.
dKi values for s1 receptors were measured on quinea pig brain membranes using [3H](ꢂ)-pentazocine as the radioligand.
eKi values for s2 receptors were measured on rat liver membranes using [3H]-DTG as the radioligand in the presence of (ꢂ)-pentazocine.
fKd values from Scatchard studies.
moiety at the 1,2,3,4-tetrahydroisoquinolino aromatic
ring of compound 5h, the resulting compound, 5i, had a
2-fold decrease in affinity for D2 receptors and no
change in affinity for D3 receptors. As a result, com-
pound 5i was 7-fold more selective for D3 receptors
(21.2 nM) than for D2 receptors (143.3 nM).
a low affinity for sigma receptors. Surprisingly, the
oxadiazole analogues 7a–7d had no measurable affinity
for dopamine D2 and D3 receptors.
Discussion
Replacement of the 1,2,3,4-tetrahydroisoquinolino moi-
ety of 5h with an indolino moiety to afford compound 5j
resulted in a total loss of binding affinity for both D2
and D3 receptors. Similar results were observed for
compound 5k, which had a 1,2,3,4-tetrahydroquinolino
moiety. The low binding affinity of compounds 5j and
5k for D2 and D3 receptors is likely due to the weaker
basic properties of the anilino nitrogen of the indoline
or 1,2,3,4-tetrahydroquinoline.
In a previous study, we reported a series of benzamide
analogues possessing a high affinity and marginal selec-
tivity for dopamine D3 versus D2 receptors.19 Molecular
modeling studies revealed differences in the stereoelec-
tronic properties of the benzamide-binding region of the
D2 and D3 receptors. These subtle differences in the
electrostatic properties of this class of compounds sug-
gests that replacement of the amide group with a het-
erocyclic ring with similar steric properties may result in
a shift in affinity of these compounds for D2 and D3
receptors. The goalof the current study was to deter-
mine if substituting an imidazole ring for the amide
moiety results in D3-selective compounds. A previous
study demonstrated that imidazole derivatives structu-
rally-similar to the analogues reported here bind with
moderate affinity to dopamine D2 receptors, but the
affinity of these compounds for D3 receptors was not
determined.21 The results of the current study revealed
that it is possible to prepare compounds having a mod-
erate affinity and modest selectivity for D3 versus D2
receptors. The affinity and selectivity of this class of
compounds for both D2 and D3 receptors was largely
dependent on substitution pattern in the 2-phenylgroup
and the nature of the amine moiety. The most interest-
ing compound resulting from this study was 5i, which
Compounds with the piperidino substitution (5l, 5m,
and 5n) showed high affinity (10–40 nM) for both D2
and D3 receptors. Compound 5l, which has a (4-
phenyl)-piperidino moiety, displayed similar dopamine
D2/D3 receptor binding affinities to those of compound
5a. Extension of the distance between the primary aro-
matic ring (the 2-phenylimidazole) and the secondary
aromatic ring resulted in a greater reduction in the
binding affinity for D3 versus D2 receptors (5m versus
5l). Compound 5n, which has the (4-hydroxy-4-para-
chlorophenyl)piperidino moiety present in haloperidol,
maintained affinity for D2 receptors, but had a reduced
affinity for D2 receptors relative to 5l. The results of the
sigma binding assays revealed that, with the exception
of 5a, 5c, and 7d, all compounds shown in Table 1 have

Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
3117
had a D3 affinity of ꢃ20 nM and a 7-fold selectivity for
affinity (17–85 nM) for s1 receptors. The bromo sub-
stitution at the 50-position of the phenylaromatic ring
decreased the binding affinity of these analogues for
both s1 and s2 receptors (5a versus 5b, 5c versus 5d,
and 5e versus 5f). The high affinity of 7d for s1 receptors
and low affinity for s2, D2, and D3 receptors suggests
that this compound may be a usefulelad compound for
the development of a s1-selective ligand.
D3 versus D2 receptors.
Previous studies have proposed that the dopamine D2-
like receptors have three aromatic binding pockets,
termed AR1, AR2, and AR3, as well as a site that
recognizes a basic nitrogen atom.28 The benzamide aro-
matic rings of compounds such as sulpiride and clebo-
pride are thought to bind to the AR1 aromatic binding
pocket (primary aromatic binding site), while the
benzylic aromatic groups of MABN, IABN, and related
analogues (e.g., clebopride) bind to either the AR2 or
the AR3 region (Fig. 1).17 In this study, two com-
pounds, 5o and 5p, were made to test the AR1 binding
preference of dopamine D2/D3 receptors for the benza-
mide aromatic ring and the (2-phenyl)imidazole aro-
matic moiety. Compound 5o showed 50- to 100-fold
higher affinity for both D2 and D3 receptors than did
the corresponding compound 5e, and compound 5p
showed significantly higher affinity for D2 receptors
than did the corresponding compound 5f. Therefore,
the results suggest that the benzamide aromatic rings of
compounds 5o and 5p bind to the AR1 region, while the
(2-phenyl)imidazole aromatic moiety bind to either the
AR2 or AR3 region. The lower preference of the AR1
region of the D2/D3 receptors for the (2-phenyl)imida-
zole aromatic moiety may also account for the
decreased affinity of the imidazole analogues (5e, 5f) for
D2/D3 receptors when compared to the corresponding
benzamide analogues (5o, 5p, MABN, IABN). It is of
interest to note that compounds 5h and 5i, which have
the secondary phenylring constrained in a 1,2,3,4-tet-
rahydro-isoquinoline ring system, have a higher affinity
for D3 versus D2 receptors, whereas 5m and 5n have a
higher affinity for D2 versus D3 receptors. Molecular
modeling studies are currently being conducted as a
means of determining if 5h and 5i interact with different
aromatic binding pockets than 5m and 5n.
In conclusion, a number of imidazole and 1,2,4-oxadia-
zole analogues were prepared and their affinities for
dopamine D2 and D3 receptors and sigma receptors
were measured using in vitro binding assays. The imi-
dazole analogues had a lower affinity for D2 and D3
receptors than the benzamide analogues IABN and
MABN. However, imidazole analogues 5h and 5i pos-
sessed a modest affinity and selectivity for D3 versus D2
receptors, whereas 5m and 5n had a modest affinity and
selectivity for D2 versus D3 receptors. These data
demonstrate the importance of the amine moiety in
binding to D2 and D3 receptors. The 1,2,4-oxadiazole
analogues were devoid of significant binding affinity for
both D2 and D3 receptors, which is likely attributed to
the inability of the 1,2,4-oxadiazole analogues to form
an intra-molecular hydrogen bound. The in vitro bind-
ing data of the imidazole analogues was consistent with
our previous studies with the benzamides17ꢀ19 that: (a)
bromo substitution of the 4-position aromatic ring
binding in the AR1 site increases affinity for both D2
and D3 receptors, (b) a basic nitrogen atom linked at an
appropriate position to the primary phenylaromatic
moiety is required for optimalbinding to D /D3 recep-
2
tors, and (c) a secondary aromatic moiety is beneficial
for obtaining high affinity dopamine D2/D3 receptor
binding. The in vitro binding data for compounds 5a,
5h, 5i, 5m, and 5n suggest that it is possible to replace
the benzamide moiety with a p-deficient heterocyclic
ring and maintain a high affinity for D2 and D3 recep-
tors. The observation that 5h and 5i have a 3- to 7-fold
higher affinity for D3 versus D2 receptors suggest that
this approach may lead to D3-selective ligands.
Several 1,2,4-oxadiazole analogues (7a–d) were also
prepared and their affinity for D2 and D3 receptors
measured. The binding results showed that these com-
pounds had very low affinity for both D2 or D3 recep-
tors. The low binding affinity of the oxadiazole
analogues for dopamine D2/D3 receptors is likely due to
the inability to form an intra-molecular hydrogen
bound between the ortho methoxy oxygen and a proton
donor. Both the NH proton of the amine in benzamides
and the 1-NH proton of the imidazole in (2-phenyl)imi-
dazole analogues can be the proton donor capable of
forming an intra-molecular hydrogen bond with the
ortho methoxy oxygen atom on the phenylring in
physiological conditions.19 The formation of an intra-
molecular hydrogen bound forces a coplanar con-
formation of both the (a) amide and the phenylring in
benzamides and (b) the imidazole ring and the 2-phenyl
aromatic ring of the (2-phenyl)imidazole analogues.
Thus, the 1,2,4-oxadiazole analogues would likely adapt
a non-coplanar conformation between the imidazole
moiety and the phenylring in binding conditions.
Results from the sigma receptor binding studies indi-
cated that compounds 5a and 5d have a relatively high
Fig 1. Structures of MABN, IABN, and Clebopride.

3118
Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
Experimental
amine (5 mL) dropwise. After stirring overnight at room
temperature, the mixture was condensed in vacuo. The
residue was dissolved in dichloromethane (100 mL),
washed with 0.5 N NaOH, water, and dried over Na2SO4.
The solvent was removed to afford N-tert-butyl-2,3-
dimethoxy-5-bromobenzamide (22.60g, 100%). 1H NMR
(CDCl3) d 7.78–7.79 (d, J=2.4 Hz, 1H), 7.10–7.11 (d,
J=2.5 Hz, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 1.45 (s, 9H).
Chemistry
Melting points were measured on a Fisher–Johns melt-
ing point apparatus and are uncorrected. Elemental
analyses were performed at Atlantic Microlab, Inc.,
Norcross, GA, USA. Where molecular formulae were
indicated, analyses were found to be within 0.4% of the
theoretical values, unless otherwise noted. 1H NMR
spectra were recorded at 300 MHz on
a
Bruker
To a solution of N-tert-butyl-2,3-dimethoxy-5-bromo-
benzamide (22.6 g, 0.07 mol) in benzene (100 mL) was
added phosphorus oxychloride (109.5 g, 0.7 mol) por-
tion-wise. The mixture was refluxed for 10 h, then the
solvent was removed in vacuo. The residue was dis-
solved in CH2Cl2 (200 mL) and washed with water and
dried over Na2SO4. The solvent was removed and the
residue was recrystallized from ethyl acetate/pentane to
give 2,3-dimethoxy-5-bromobenzonitrile (15.3 g, 88%),
mp 82–83 ꢁC. 1H NMR (CDCl3) d 7.25–7.26 (d,
J=3 Hz, 1H), 7.19–7.20 (d, J=3 Hz, 1H), 4.01 (s, 3H),
3.89 (s, 3H); analysis (C9H8NO2Br) C, H, N.
ADVANCE300 spectrometer. All 1H NMR spectra were
obtained in either CDCl3 or DMSO-d6 and results are
recorded as parts per million (ppm) downfield to tetra-
methylsilane (TMS). The following abbreviations are used
for multiplicity of NMR signals: s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet, dd=double doub-
let, dt=double triplet, dq=double quartet, br=broad.
Mass spectrometry studies (high resolution FAB) were
conducted by the Washington University Resource for
Biomedicaland Bio-organic Mass Spectrometry, St.
Louis, MO, USA. All starting materials and solvents
were purchased from Aldrich, Fisher, or Lancaster, and
were used without further purification.
Preparation of 2-(2,3-dimethoxyphenyl)-4-(hydroxyme-
thyl)imidazole (3a). A 2.5 M solution of butyllithium in
anhydrous ether (50 mL, 0.125 mol) was added dropwise
Preparation of 2,3-dimethoxy-5-bromobenzonitrile (1).
To a solution of 2,3-dihydroxybenzoic acid (25.0 g,
0.16mol) in acetic acid (200 mL) was added bromine
(25.9g, 0.16 mol) dropwise. The mixture was stirred at
room temperature overnight. The solvent was removed in
vacuo to give a solid which was recrystallized from ethyl
acetate/hexane to give 2,3-dihydroxy-5-bromobenzoic acid
(33.2g, 88%). Mp 203–204ꢁC; anal. (C7H5O4Br) C, H.
to
a
solution of 1,1,1,3,3,3-hexamethyldisilazane
(19.37 g, 0.12 mol) in dry ether (200 mL) at 0 ꢁC, and the
solution was stirred at 0 ꢁC for 30 min. 2,3-Dimethoxy-
benzonitrile (8.15 g, 0.05 mol) was then added and the
reaction mixture was stirred at room temperature for
4 h. The mixture was poured into ice-cold 2 N HCl
(200 mL) and extracted with ether twice. The aqueous
phase was adjusted to pH>10 with 6 N NaOH and
extracted with CH2Cl2 (3ꢄ50 mL) and dried over
Na2SO4. The solvent was removed and the residue was
recrystallized from ethyl acetate/ethanol to give 2,3-
A
mixture of 2,3-dihydroxy-5-bromobenzoic acid
(25.0 g, 0.11 mol), dimethyl sulfate (48.71 g, 0.38 mol),
potassium carbonate (53.4 g, 0.38 mol) in acetone
(200 mL) was refluxed overnight. The solid was filtered
and the solution was condensed to give a liquid which
was than dissolved in methanol (200 mL) and added
with NaOH (40%, 12 mL), and refluxed for 2 h. The
solvent was removed and the residue was dissolved in
water (200 mL) and extracted with ethylacetate
(2ꢄ60 mL), the aqueous phase was adjusted to pHꢅ2
and extracted with ethylacetate (3 ꢄ60 mL) and dried
over Na2SO4. The solvent was removed and the residue
was recrystallized from ethyl acetate/hexane to give 2,3-
dimethoxy-5-bromobenzoic acid (24.2 g, 86%), mp 199–
200 ꢁC. 1H NMR (CDCl3) d 7.84–7.85 (d, J=3 Hz, 1H),
7.25–7.26 (d, J=3 Hz, 1H), 4.07 (s, 3H), 3.93 (s, 3H);
analysis (C9H9O4Br) C, H.
dimethoxybenzamidine (5.6 g, 62%), mp 83–85 ꢁC. H
1
NMR (CDCl3) d 7.15–7.18 (dd, J=1.8, 8 Hz, 1H), 7.07–
7.13 (t, J=4 Hz, 1H), 6.96–6.99 (dd, J=1.5, 8 Hz, 1H),
5.01 (br s, 3H), 3.89 (s, 3H), 3.87 (s, 3H).
A
mixture of 2,3-dimethoxybenzamidine (2.5 g,
0.014 mol), 1,3-dihydroxyacetone dimer (2.5 g, 0.014 mol),
and NH4Cl(3 g, 0.056 mo)l in NH 4OH (20 mL) was
heated to reflux for 30 min. The mixture was poured
into ice-cold water, extracted with CH2Cl2, and dried
over Na2SO4. The solvent was removed and the product
was recrystallized from ethyl acetate to give 2-(2,3-
dimethoxyphenyl)-4-(hydroxymethyl)imidazole (1.98 g,
61%), mp 154–155 ꢁC. H NMR (CDCl3) d 7.81–7.84
1
(dd, J=1.2, 6.7 Hz, 1H), 7.12–7.17 (dt, J=1, 8 Hz, 1H),
7.06 (s, 1H), 6.89–6.92 (d, J=8 Hz, 1H), 4.72 (s, 2H),
3.91 (s, 6H); analysis (C12H14N2O3) C, H, N.
A
solution of 2,3-dimethoxy-5-bromobenzoic acid
(20.0 g, 0.08 mol) and thionyl chloride (18.2 g, 0.15 mol)
in benzene (200 mL) was stirred at reflux overnight. The
solvent was removed and the residue was recrystallized
from ethylacetate/hexane to give 2,3-dimethoxy-5-bro-
mobenzoylcholride (20.3 g, 95%), mp 65–66 ꢁC. 1H
NMR (CDCl3) d 7.61–7.62 (d, J=3 Hz, 1H), 7.23–7.24
(d, J=3 Hz, 1H), 3.90 (s, 6H).
2-(2,3-Dimethoxy-5-bromophenyl)-4-(hydroxymethyl)imi-
dazole (3b). Compound 3b was obtained by the same
method as described in 3a in 34% yield, mp 162–163 ꢁC.
1H NMR (CDCl3) d 7.99–8.00 (d, J=3 Hz, 1H), 7.07 (s,
1H), 7.00–7.01 (d, J=2.1 Hz, 1H), 4.71 (s, 2H), 3.91 (s,
3H), 3.90 (s, 3H); analysis (C12H13N2O3Br) C, H, N.
To a solution of 2,3-dimethoxy-5-bromobenzoyl chlo-
ride (20.0 g, 0.07 mol) in dry dichloromethane (200 mL)
was added tert-butylamine (7.3 g, 0.1 mol) and triethyl-
Preparation of 2-(2,3-dimethoxyphenyl)imidazole-4-car-
boxaldehyde (4a). To a solution of 2-(2,3-dimethoxy-

Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
3119
phenyl)-4-(hydroxymethyl)imidazole (0.23 g, 1.0 mmol)
in CH2Cl2 (20 mL) was added pyridinium chloro-
chromate (0.54 g, 2.5 mmol). After stirring at room
temperature for 30 min, the solid was filtered off, the
solution was washed with 1 N NaOH, water, and dried
over Na2SO4. The solvent was removed and the product
was purified by silica gel column to give 2-(2,3-dim-
ethoxyphenyl)imidazole-4-carboxaldehyde (0.12 g, 52%),
2-(2,3-Dimethoxy-5-bromophenyl)-4-(1-benzylpiperidin-4
-yl-aminomethyl)-imidazole (5d). Twenty-seven percent
yield from 2-(2,3-dimethoxy-5-bromophenyl)imidazole-
4-carboxaldehyde (4b), mp 159–161 ꢁC. H NMR (free
1
amine in CDCl3) d 7.99 (d, J=3 Hz, 1H), 7.22–7.31 (m,
5H), 7.04 (d, J=3 Hz, 1H), 6.96 (s, 1H), 3.89 (s, 3H),
3.87 (s, 3H), 3.81 (br s, 2H), 3.78 (m, 1H), 3.48 (s, 2H),
2.91–2.95 (d, J=12 Hz, 2H), 1.87–2.00 (m, 4H), 1.67–
1.73 (m, 2H); analysis (C24H29N4O2Brꢆ 2H2O) C, H, N.
mp 129–130 ꢁC. H NMR (CDCl3) d 9.74 (s, 1H), 7.83–
1
7.93 (m, 2H), 7.16–7.22 (t, J=9 Hz, 1H), 7.00–7.03 (d,
J=9 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H); anal.
(C12H12N2O3) C, H, N.
2-(2,3-Dimethoxyphenyl)-4-(9-benzylazabicyclo[3.3.1]no-
nan - 3ꢀ - ylaminomethyl)imidazole (5e). Thirty percent
yield from 2-(2,3-dimethoxyphenyl)imidazole-4-carbox-
2-(2,3-Dimethoxy-5-bromophenyl)imidazole-4-carboxal-
dehyde (4b). Compound 4b was obtained by the same
method as described in 4a in 60% yield, mp 142–143 ꢁC.
1H NMR (CDCl3) d 9.74 (s, 1H), 8.07–8.08 (dd, J=2,
10.6 Hz, 1H), 7.88 (s, 1H), 7.10–7.11 (dd, J=2.3, 8.6 Hz,
1H), 3.99 (s, 3H), 3.92 (s, 3H); anal. (C12H11N2O3Br) C,
H, N.
aldehyde (4a), mp 178–180 ꢁC (HClsatl).
1H NMR
(DMSO-d6) d 7.74–7.78 (dd, J=1.4, 8 Hz, 1H), 7.40–
7.50 (br s, 1H), 7.22–7.32 (m, 5H), 4.18 (s, 2H), 3.90–
4.05 (d, J=12 Hz, 9H), 3.11–3.16 (br s, 2H), 2.30–2.45
(br s, 2H), 1.95–2.10 (m, 4H), 1.45–1.55 (m, 4H); ms
(C27H34N4O2, Mr=446.2682) 447.2765 (m+1). Anal.
(C27H37N4O2Cl) C, H, N.
Preparation of 2-(2,3-dimethoxy-5-bromophenyl)-4-
(N,N-diethylaminomethyl)imidazole (5b). A solution of
2-(2,3-dimethoxy-5-bromophenyl)-4-(hydroxymethyl)-
imidazole (0.16 g, 0.5 mmol) thionyl chloride (0.6 g,
5.0 mmol) in CH2Cl2 (20 mL) was heated at reflux for
30 min. The solvent was removed in vacuo to afford a
brown solid that was dissolved in CH2Cl2 (20 mL).
Diethylamine (0.06 g, 0.8 mmol) and triethylamine
(0.5 mL), was added and the mixture was stirred at
room temperature overnight. Solvent was removed in
vacuo and the residue was dissolved in CH2Cl2 (30 mL)
and washed with 0.5 N NaOH, water and dried over
Na2SO4. The solvent was removed and the residue was
purified by silica gel column chromatography and eluted
with CHCl3/ethanol(9:1) to give an oilthat was then
converted into the oxalate salt (0.23 g, 83%), mp 162–
2-(2,3-Dimethoxy-5-bromophenyl)-4-(9-benzylazabicy-
clo[3.3.1]nonan-3ꢀ-ylaminomethyl)imidazole (5f). Forty-
six percent yield from 2-(2,3-dimethoxy-5-bromopheny-
l)imidazole-4-carboxaldehyde (4b), mp 193–195 ꢁC. H
1
NMR (CDCl3) d 7.91–7.92 (d, J=1.9 Hz, 1H), 7.47 (br
s, 1H), 7.22–7.30 (m, 5H), 6.99–7.00 (d, J=1.9 Hz, 1H),
4.15–4.22 (b, 2H), 3.98 (br s, 2H), 3.89 (s, 6H) 3.05–3.15
(br s, 2H), 2.35–2.45 (br s, 2H), 1.90–2.10 (m, 4H), 1.45–
1.60 (m, 4H); ms (C27H33N4O2Br, Mr=524.1787)
525.1879 (m+1).
2-(2,3-Dimethoxyphenyl)-4-(1,2,3,4-tetrahydroisoquino-
lino-aminomethyl)imidazole (5g). Fifty-six percent yield
from 2-(2,3-dimethoxyphenyl)-4-(hydroxymethyl)-imi-
dazole (3a), mp 163–165 ꢁC (HClsat)l.
1H NMR
(CDCl3) d 7.85–7.90 (b, 1H), 7.05–7.20 (m, 5H), 6.95–
7.03 (m, 1H), 6.88–6.91 (d, J=8 Hz, 1H), 3.90 (s, 6H),
3.85 (br s, 2H), 3.78 (s, 2H), 2.81–2.95 (br s, 4H); ms
(C21H23N3O2, Mr=349.1790) 350.1875 (m+1).
164 ꢁC. H NMR (free amine in CDCl3) d 8.00–8.10 (br
1
s, 1H), 6.97–7.10 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.62
(s, 2H), 2.50–2.60 (m, 4H), 1.00–1.08 (t, J=4 Hz, 6H);
anal. (C20H26N3O10Brꢆ 1/2 H2O) C, H, N.
2-(2,3-Dimethoxy-5-bromophenyl)-4-(1,2,3,4-tetrahydro-
Sixty-two
Preparation of 2-(2,3-dimethoxyphenyl)-4-(1-benzylpi-
peridin-4-ylaminomethyl)imidazole (5c). A solution of 2
- (2,3 - dimethoxyphenyl)imidazole - 4 - carboxaldehyde
(0.23 g, 1.0 mmol) and 4-amino-1-benzylpiperidine
(0.19 g, 1.0 mmol) in methanol (20 mL) was stirred at
room temperature for 2 h, then NaBH3CN (0.06 g,
1.0 mmol) was added and the reaction mixture stir-
red at room temperature overnight. The solvent was
removed and the residue was dissolved in CH2Cl2
(30 mL), washed with 0.5 N NaOH, water, and
dried over Na2SO4. The solvent was removed in
vacuo and the residue was purified by silica gel
column chromatography (CHCl3/ethanol=8:2) to give
an oilthat was then converted into the corresponding
hydrochloride salt (0.35 g, 67%), mp 173–176 ꢁC. 1H
NMR (DMSO-d6) d 8.00 (br s, 1H), 7.83–7.85 (m, 1H),
7.71–7.74 (br s, 1H), 7.63 (b, 1H), 7.36–7.43 (m, 5H),
4.58 (s, 2H), 4.27 (s, 2H), 4.05 (s, 3H), 3.93 (s, 3H),
3.70 (m, 1H), 3.45–3.49 (d, J=12 Hz, 2H), 2.50-2.60
(m, 6H); ms (C24H30N4O2, Mr=406.2369) 407.2454
(m+1).
isoquinolino-aminomethyl)imidazole
(5h).
percent yield
2-(2,3-dimethoxy-5-bromophenyl)-4-
(hydroxy-methyl)imidazole (3b), mp 150–152ꢁC. 1H
NMR (CDCl3) d 8.00–8.10 (br s, 1H), 6.95–7.15 (m, 6H),
3.89 (s, 6H), 3.82 (br s, 2H), 3.77 (s, 2H), 2.80–2.94 (br s,
4H); ms (C21H22N3O2Br, Mr=427.0895) 428.0966 (m+1).
2-(2,3-Dimethoxy-5-bromophenyl)-4-(6,7-dimethoxy-
1,2,3,4 - tetrahydro - isoquinolinoaminomethyl)imidazole
(5i). Seventy-five percent yield from 2-(2,3-dimethoxy-
5-bromophenyl)-4-(hydroxymethyl)imidazole (3b), mp
103–105 ꢁC. H NMR (CDCl3) d 8.00–8.08 (dd, J=2,
1
21 Hz, 1H), 7.06–7.09 (dd, J=2, 8 Hz, 1H), 6.97–7.05
(m, 1H), 6.59–6.60 (d, J=3 Hz, 1H), 6.48–6.52 (d,
J=11 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H),
3.83 (s, 3H), 3.82 (s, 2H), 3.81 (s, 2H), 2.76–2.85 (m,
4H); anal. (C23H26N3O4Brꢆ H2O) C, H, N.
2-(2,3-Dimethoxy-5-bromophenyl)-4-(indolinoaminom-
ethyl)imidazole (5j). Eighty-four percent yield from 2-
(2,3-dimethoxy-5-bromophenyl)-4-(hydroxymethyl)imi-

3120
Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
dazole (3b), mp 131–132 ꢁC. H NMR (CDCl3) d 7.95–
8.05 (br s, 1H), 6.95–7.15 (m, 5H), 6.60–6.75 (br s, 2H),
4.35 (s, 2H), 3.90 (s, 6H), 3.43–3.50 (t, J=5 Hz, 2H), 2.93–
3.00 (t, J=5 Hz, 2H); anal. (C20H20N3O2Br) C, H, N.
Preparation of 2,3-dimethoxybenzamide oxime (6). A
mixture of 2,3-dimethoxybenzonitrile (6.53 g, 0.04 mol),
hydroxylamine hydrochloride (8.34 g, 0.12 mol), potas-
sium carbonate (11.06 g, 0.08 mol) and ethanol (100 mL)
was refluxed for 16 h. The mixture was poured into ice-
cold water and 2 N NaOH was added to adjust the
pHꢇ12. The product was extracted with CH2Cl2,
washed with water and dried over Na2SO4. The solvent
was removed and the residue was recrystallized from
ethylacetate/hexane to give 2,3-dimethoxybenzamide
oxime (5.38 g, 68%), mp 149–151 ꢁC. 1H NMR (CDCl3)
d 7.24–7.27 (dd, J=1.6, 8 Hz, 1H), 7.04–7.10 (t,
J=8 Hz, 1H), 6.95–6.98 (dd, J=1.6, 8 Hz, 1H), 5.50 (br
s, 2H), 3.89 (s, 3H), 3.85 (s, 3H); anal. (C9H12N2O3) C,
H, N.
1
2-(2,3-Dimethoxy-5-bromophenyl)-4-(1,2,3,4-tetrahydro-
quinolinoamino - methyl)imidazole (5k). Ninety-five per-
cent yield from 2-(2,3-dimethoxy-5-bromophenyl)-4-
(hydroxy-methyl)imidazole (3b), mp 120–121 ꢁC. 1H
NMR (CDCl3) d 7.95–8.02 (br s, 1H), 6.93–7.02 (m,
4H), 6.82–6.86 (br s, 1H), 6.65–6.68 (br s, 1H), 4.53 (s,
2H), 3.88–3.90 (d, J=5.5 Hz, 6H), 3.42–3.52 (m, 2H),
2.73–2.83 (m, 2H), 1.95–2.05 (m, 2H); anal.
(C20H22N3O2Br) C, H, N.
2-(2,3-Dimethoxy-5-bromophenyl)-4-(4-phenylpiperidi-
noamino - methyl)imidazole (5l). Eighty percent yield
Preparation of 3-(2,3-dimethoxyphenyl)-5-(1-benzylpyr-
rolidin-2-yl)-1,2,4-oxadiazole (7a). A solution of 2,3-
dimethoxybenzamide oxime (0.4 g, 2.0 mmol) and NaH
(0.05 g, 2.0 mmol) in THF (25 mL) was stirred under
refluxing for 1 h. After cooling, the mixture was added
with N-benzyl-dl-Proline methyl ester (0.44 g, 2.0 mmol)
and 4 A molecular sieves (2.0 g) and continued to stir
under refluxing overnight. The mixture was poured into
ice-cold water and extracted with CH2Cl2, washed with
water and dried over Na2SO4. The solvent was removed
and the residue was purified by silica gel column to
afford an oilwhich was converted into the correspond-
ing oxalic salt and recrystallized from ethyl acetate/ethanol
to give 3-(2,3-dimethoxyphenyl)-5-(1-benzylpyrrolidin-2-
yl)-1,2,4-oxadiazole oxalate (0.45 g, 49%), mp 62–65 ꢁC.
1H NMR (free amine in CDCl3) d 7.52–7.56 (dd, J=1.6,
8 Hz, 1H), 7.20–7.34 (m, 5H), 7.13–7.19 (t, J=8 Hz,
1H), 7.04–7.08 (dd, J=1.6, 8 Hz, 1H), 4.07–4.12 (dd,
J=2.5, 6 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 5H), 3.07–3.14
(m, 1H), 2.51–2.60 (m, 1H), 2.30–2.36 (m, 1H), 2.20–
2.27 (m, 1H), 2.02–2.12 (m, 1H), 1.88–1.94 (m, 1H);
from
2-(2,3-dimethoxy-5-bromophenyl)-4-(hydroxy-
methyl)imidazole (3b), mp 130–131 ꢁC. 1H NMR
(CDCl3) d 7.18–7.34 (m, 6H), 6.96–7.05 (m, 2H), 3.88–
3.92 (d, J=1.3 Hz, 9H), 3.60–3.65 (d, J=8 Hz, 4H),
3.16–3.24 (d, J=8 Hz, 2H), 2.98–3.06 (d, J=8 Hz, 2H);
anal. (C23H26N3O2Br) C, H, N.
2-(2,3-Dimethoxy-5-bromophenyl)-4-(4-benzylpiperidi-
noamino - methyl)imidazole (5m). Seventy percent yield
from
methyl)imidazole (3b), mp 156–158 ꢁC (HClsatl).
2-(2,3-dimethoxy-5-bromophenyl)-4-(hydroxy-
1H
NMR (CDCl3) d 8.22–8.25 (d, J=3 Hz, 1H), 6.97–7.33
(m, 7H), 4.82–4.88 (s, 2H), 4.22 (s, 3H), 3.90 (s, 3H),
3.20–3.45 (m, 4H), 2.56–2.63 (d, J=8 Hz, 2H), 1.70–1.90
ꢆ
(m, 5H); anal. (C24H30N3O2BrCl2 0.25H2O) C, H, N.
2-(2,3-Dimethoxy-5-bromophenyl)-4-(4-hydroxy-4-(4-
chlorophenyl) - piperidinoaminomethyl)imidazole (5n).
Sixty-seven percent yield from 2-(2,3-dimethoxy-5-bro-
mophenyl)-4-(hydroxymethyl)imidazole (3b), mp 90–
92 ꢁC. 1H NMR (CDCl3) d 7.97–8.07 (d, J=21 Hz, 1H),
7.42–7.46 (d, J=8 Hz, 2H), 7.29–7.33 (d, J=8 Hz, 2H),
6.97–7.10 (m, 2H), 3.87–3.94 (d, J=2 Hz, 8H), 3.63–
3.72 (d, J=9 Hz, 2H), 2.52–2.60 (m, 2H), 1.70–1.85 (m,
4H); anal. (C23H25N3O3BrCl) C, H, N.
ꢆ
anal. (C23H25N3O7 H2O) C, H, N.
3-(2,3-Dimethoxyphenyl)-5-(1-benzylpiperidin-2-yl)-1,2,4
-oxadiazole (7b). Fifty-seven percent yield (an oil) from
2,3-dimethoxybenzamide oxime (6). 1H NMR (free
amine in CDCl3) d 7.58–7.62 (dd, J=1.5, 8 Hz, 1H),
7.23–7.35 (m, 5H), 7.15–7.21 (t, J=8 Hz, 1H), 7.05–7.09
(dd, J=1.5, 8 Hz, 1H), 4.05–4.09 (t, J=6 Hz, 1H), 3.96
(s, 3H), 3.93 (s, 3H), 3.50 (d, J=13 Hz, 1H), 3.25 (d,
J=13 Hz, 1H), 2.95–3.02 (m, 1H), 2.32–2.40 (m, 1H),
1.99–2.05 (m, 2H), 1.76–1.84 (m, 1H), 1.62–1.68 (m,
2H), 1.45–1.56 (m, 1H); anal. (C22H25N3O3) C, H, N.
2-(2,3-Dimethoxyphenyl)-4-(3ꢀ-(2,3-dimethoxybenza-
mido) - bicyclo[3.3.1]nonan - 9 - azamethyl)imidazole (5o).
Twenty-nine percent yield from 2-(2,3-dimethoxy-
phenyl)-4-(hydroxymet hyl)imidazole (3a), mp 65–66 ꢁC.
1H NMR (CDCl3) d 7.79–7.83 (dd, J=1.5, 8 Hz, 1H),
7.64–7.68 (dd, J=1.6, 8 Hz, 1H), 7.26 (s, 1H), 7.10–7.16
(m, 2H), 7.02–7.06 (dd, J=1.5, 8 Hz, 1H), 6.88–6.92 (dd,
J=1.4, 8 Hz, 1H), 4.90–5.00 (m, 1H), 3.88–3.95 (m,
14H), 2.88–2.95 (br s, 2H), 1.60–2.10 (m, 10H); ms
(C29H36N4O5, Mr=520.2686) 521.2787 (m+1).
3-(2,3-Dimethoxyphenyl)-5-(1-benzylpiperidin-3-yl)-1,2,4
-oxadiazole (7c). Sixty-six percent yield from 2,3-dim-
ethoxybenzamide oxime (6), mp 139–140 ꢁC (oxalate).
1H NMR (free amine in CDCl3) d 7.48–7.51 (dd, J=1.5,
8 Hz, 1H), 7.20–7.32 (m, 5H), 7.13–7.18 (t, J=8 Hz,
1H), 7.03–7.06 (dd, J=1.5, 8 Hz, 1H), 3.92 (s, 3H), 3.91
(s, 3H), 3.58 (s, 2H), 3.24–3.33 (m, 1H), 3.13–3.21 (m,
1H), 2.82–2.62 (m, 1H), 2.38–2.45 (m, 1H), 2.09–2.20 (m,
2H), 1.78–1.86 (m, 2H); anal. (C24H27N3O7) C, H, N.
2-(2,3-Dimethoxy-5-bromophenyl)-4-(3ꢀ-(2,3-dimethoxy-
benzamido) - bicyclo[3.3.1]nonan - 9 - azamethyl)imidazole
(5p). Eighteen percent yield from 2-(2,3-dimethoxy-5-
bromophenyl)-4-(hydroxymethyl)imidazole (3b), mp
83–84 ꢁC. 1H NMR (CDCl3) d 7.95–8.05 (br s, 1H),
7.64–7.67 (d, J=8 Hz, 1H), 7.10–7.20 (m, 1H), 6.95–
7.05 (m, 3H), 4.90–5.00 (m, 1H), 3.85–3.95 (m, 14H),
2.90–3.05 (br s, 2H), 1.60–2.10 (m, 10H); ms
(C29H35N4O5Br, Mr=598.1791) 599.1864 (m+1).
3-(2,3-Dimethoxyphenyl)-5-(1-benzylpiperidin-4-yl)-1,2,4
- oxadiazole (7d). 53% yield from 2,3-dimethoxy-
benzamide oxime (6), mp 69–70 ꢁC, 1H NMR (free

Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
3121
amine in CDCl3) d 7.49–7.53 (dd, J=1.5, 8 Hz, 1H),
7a
7b
7c
7d
Oxalate saltꢆ H2O
C
H
N
C
H
N
C
H
N
C
H
N
58.34 58.01
7.25–7.34 (m, 5H), 7.13–7.18 (t, J=8 Hz, 1H), 7.03–7.07
(dd, J=1.5, 8 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.54 (s,
2H), 2.93–3.06 (m, 3H), 1.96–2.21 (m, 6H); analysis
(C22H25N3O3) C, H, N.
5.75
8.87
5.42
8.44
Free base
Oxalate salt
Free base
69.64 69.79
6.64 6.77
11.07 10.82
61.40 61.36
In vitro binding assays
5.80
8.95
5.83
8.90
In vitro dopamine receptor binding studies were con-
ducted using membranes prepared from Spodoptera
frugiperda (Sf9) cells that express a high density of either
rat D2(long) or rat D3 receptors. The radioligand used
was [125I]IABN and the assay conditions were as pre-
viously described.17 The Ki values were calculated from
the corresponding IC50 values using the method of
Cheng and Prusoff.26
69.64 69.73
6.64 6.58
11.07 10.97
Acknowledgements
In vitro s1 receptor binding affinity was measured in
guinea pig brain membranes (Rockland Biological, Gil-
bertsville, PA, USA) using the s1-selective radioligand,
[3H](+)-pentazocine (DuPont-NEN, Bilerica, MA,
USA) according to the methods as described pre-
viously.27 In vitro s2 receptor binding affinity was mea-
sured in rat liver membranes using [3H]DTG (DuPont-
NEN, Bilerica, MA) as the radioligand in the presence
of (+)-pentazocine (100 nM) as previously described.27
This research was supported by PHS grants DA 09142,
DA 09147 and DA 12647 from the NationalInstitute on
Drug Abuse and by the Scottish Rite Schizophrenia
Research Program.
References and Notes
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Elemental analyses
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Compd Form
Element Calcd Found
5b
5d
5e
5i
HClꢆ 0.5H2O
C
H
N
C
H
N
43.10 43.16
4.88
7.54
4.84
7.19
Free baseꢆ 2H2O
55.28 55.27
5.60 5.81
10.74 10.70
HClC
61.54 61.50
H
N
C
5.87
6.53
55.44 54.51
5.91
6.53
Free baseꢆ H2O
Free base
Free base
H
N
C
H
N
C
5.57
8.30
57.98 58.09
4.87 4.92
10.14 10.07
58.88 58.96
5.58
8.19
5j
5k
H
N
5.18
9.81
5.16
9.72
5lFree base
C
60.53 60.63
5.74
9.21
H
N
C
5.83
9.13
5m
5n
6
HClꢆ 1/4H2O
52.62 52.63
H
N
C
5.61
7.67
54.40 54.29
5.68
7.62
Free base
—
H
N
C
H
N
4.97
8.29
55.09 55.20
6.16 6.17
14.28 14.26
4.98
8.23

3122
Y. Huang et al. / Bioorg. Med. Chem. 9 (2001) 3113–3122
21. Thurkauf, A.; Hutchison, A.; Peterson, J.; Cornfield,
L.; Meade, R.; Huston, K.; Harris, K.; Ross, P. C.; Ger-
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