1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol- 2-one: A selective high-affinity antagonist for the human dopamine D4 receptor with excellent selectivity over ion channels

Article abstract of DOI:10.1021/jm991029k

After the requirement of pseudocycle formation in the ureas 3 and 7 for hD₄ binding and selectivity was confirmed, structural hybridization with the known hD₄ ligand 2 led to the design and identification of the lead 4-(2- oxo-1,3-dihydroimidazol-2-yl)piperidine 8. Optimization studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD₄ over all other receptors while retaining the good pharmacokinetic properties of the lead. After initial preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective 'four-step/one-pot' procedure was developed which proved to be applicable to rapid investigation of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to the 3-, 4-, or 5-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve selectivity for hD₄ over hD₂ and hD₃. Greater selectivity (> 1000-fold) was ultimately achieved by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31, and 32 all possess the required selectivity for hD₄ over the other dopamine subtypes, but only 32 has > 1000-fold selectivity over all the key counterscreens we tested against. Compound 32 is an antagonist at hD₄ and has a good pharmacokinetic profile in the rat, with excellent estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool to investigate the role of the D₄ receptor.

Full text of DOI:10.1021/jm991029k

2706
J . Med. Chem. 1999, 42, 2706-2715
1-(3-Cya n oben zylp ip er id in -4-yl)-5-m eth yl-4-p h en yl-1,3-d ih yd r oim id a zol-2-on e: A
Selective High -Affin ity An ta gon ist for th e Hu m a n Dop a m in e D4 Recep tor w ith
Excellen t Selectivity over Ion Ch a n n els
Robert W. Carling,* Kevin W. Moore, Christopher R. Moyes, Elizabeth A. J ones, Katrine Bonner,
Frances Emms, Rosemary Marwood, Shil Patel, Smita Patel, Alan E. Fletcher, Margaret Beer, Bindi Sohal,
Andrew Pike, and Paul D. Leeson
Departments of Medicinal Chemistry, Biochemistry, and Pharmacology, Merck Sharp and Dohme Research Laboratories,
Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received March 4, 1999
After the requirement of pseudocycle formation in the ureas 3 and 7 for hD4 binding and
selectivity was confirmed, structural hybridization with the known hD4 ligand 2 led to the
design and identification of the lead 4-(2-oxo-1,3-dihydroimidazol-2-yl)piperidine 8. Optimization
studies were carried out on 8 with the aim of achieving 1000-fold selectivity for hD4 over all
other receptors while retaining the good pharmacokinetic properties of the lead. After initial
preparation of 8 as a minor component in a low-yielding reaction, a novel and regioselective
“four-step/one-pot” procedure was developed which proved to be applicable to rapid investigation
of the SAR of the 1,3-dihydroimidazol-2-one ring. Various changes to substituents attached to
the 3-, 4-, or 5-position of the 1,3-dihydroimidazol-2-one core of 8 did not significantly improve
selectivity for hD4 over hD2 and hD3. Greater selectivity (>1000-fold) was ultimately achieved
by meta substitution of the benzyl group of 8 with various substituents. Compounds 28, 31,
and 32 all possess the required selectivity for hD4 over the other dopamine subtypes, but only
32 has >1000-fold selectivity over all the key counterscreens we tested against. Compound 32
is an antagonist at hD4 and has a good pharmacokinetic profile in the rat, with excellent
estimated in vivo receptor occupancy, thus making it a potentially useful pharmacological tool
to investigate the role of the D4 receptor.
Ta ble 1. Reference Compounds
In tr od u ction
For the debilitating mental illness schizophrenia, it
is widely accepted that brain dopamine receptors are
the primary targets for medical treatment.1 There are
five cloned subtypes of the human dopamine receptor
which have been divided into two pharmacological
classes: D1-like (D1 and D5)2,3 and D2-like (D2, D3, and
D4).4-6 Classical neuroleptic drugs such as haloperidol
are believed to work through nonselective antagonism
of D2-like dopamine receptors;7 however, severe move-
ment disorders8 are also manifested (probably due to
blockade of D2 receptors in the striatum) along with
hyperprolactinemia.9 Since the revelation6 that the
atypical neuroleptic clozapine (1; Table 1), which treats
a
Affinities at cloned human dopamine receptors stably ex-
both the positive and negative symptoms of schizophre-
nia without producing extrapyramidal side effects, has
higher affinity for the human dopamine D4 receptor
than the D2 receptor, there has been a huge surge of
interest in the D4 area as a possible new approach
toward the treatment of schizophrenia.10-30
Further evidence of the possible importance of D4
receptors in schizophrenia has been provided by Mat-
sumoto et al.31 who claimed that human D4 receptors
were localized in areas of the brain that are associated
with antipsychotic activity. In addition, several inde-
pendent groups have claimed that D4 receptor density
is elevated in postmortem schizophrenic brain;32-34
however, this finding has been disputed.35,36 Although
a significant amount of evidence has been accumulated
to support the D4/antipsychotic hypothesis, recently hD4
antagonists have been demonstrated to be ineffective
pressed in cell lines.
in clinical trials of schizophrenia, and thus the hD4
receptor is probably not the prime target through which
clozapine exerts its atypical antipsychotic activity.37
We have previously reported the discovery of the
isoxazolopiperidine10,11 2 (Table 1) as a highly selective
D4 antagonist, but more recently we have also dis-
closed13 that 2 possesses significant activity at voltage-
sensitive sodium and calcium ion channels. These
findings were a potential bar to the use of this compound
in the clinic as an investigational tool since such
activities may be indicative of adverse cardiovascular
effects. In this manuscript we describe the discovery of
a novel series of 4-(2-oxo-1,3-dihydroimidazol-2-yl)-
piperidines, discovered by hybridizing the structures of
the ureas 3 and 7 with the known hD4 antagonist 2, as
10.1021/jm991029k CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/29/1999

1-(Cyanobenzylpiperidinyl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
J ournal of Medicinal Chemistry, 1999, Vol. 42, No.
14 2707
Ta ble 2. 4-Ureido-N-benzylpiperidines
a
b
Proton magnetic resonance chemical shift in DMSO-d6. Affinities at cloned human dopamine receptors stably expressed in cell
lines. c Inhibition of specific binding of [3H]batrachotoxin to rat cortex at 10 µM concentration of test compound. Inhibition of specific
d
binding of [3H]diltiazem to rabbit skeletal muscle at 10 µM concentration of test compound or Ki (µM). e n.d., not determined.
selective human D4 antagonists with generally reduced
ion channel activities.
Resu lts a n d Discu ssion
Biology. Compounds were tested for their ability to
F igu r e 1. 2-Dimensional representation of pseudocyclic con-
displace [3H]spiperone from human cloned receptors, D4
formation of compound 3.
and D3 stably expressed in HEK-393 cells,38 and D2 in
CHO cells.39 The binding data for all compounds are the
geometric mean of at least three independent determi-
nations, and the errors of the mean are within 2-fold of
the mean (see Experimental Section for more details).
Counterscreen activities at voltage-dependent ion chan-
nels (calcium, sodium, and potassium), which may be
indicative of adverse cardiovascular effects in vivo,40-42
are also the geometric means of at least two indepen-
dent determinations, and the relevant radioligand bind-
ing assays are described in detail in the Experimental
Section.
Sch em e 1a
Syn t h esis a n d SAR of N-Ben zyl-4-p ip er id in yl-
u r ea s. Compound 3 (Table 2), prepared by the method
of Ward,43 was identified from in-house screening as a
moderately active and selective hD4 ligand with rela-
tively low activity at sodium ion channels.40 The chemi-
cal shift of the NH proton HA in compound 3 was further
downfield (δ ) 8.7, DMSO-d6) than would normally be
anticipated for such a proton unless intramolecular
hydrogen bonding was invoked to form a six-membered
pseudocycle44 (Figure 1). To evaluate this hypothesis
and elucidate structure-activity relationships within
the series, compounds 4,45 5, 6, and 7 were synthesized
and evaluated.
a
Reagents: (i) PhCH2NCO, CH2Cl2; (ii) (COCl)2, toluene, THF,
0 °C, Et3N; (iii) 2-aminopyridine, 0 °C; (iv) 1-aminoisoquinoline, 0
°C.
presence of triethylamine) followed by reaction with the
appropriate amino heterocycle. In the case of the ben-
zylurea 5, where the possibility of intramolecular hy-
drogen bonding to form a pseudocycle did not exist (δHA
) 5.8, DMSO-d6), the compound was inactive in the
binding assay (Table 2). The phenylurea 4 was also
significantly lower in affinity than 3, and so the pyridy-
lurea 6 was made. Despite the fact that compound 6
apparently existed in a pseudocyclic conformation in
solution (Figure 2; δHA ) 8.2, DMSO-d6), it had only
weak activity at the hD4 receptor presumably due to the
absence of an appropriately positioned phenyl ring.
Thus, the isoquinolylurea 7 was made (Figure 3), and
The benzylurea 5 was prepared by reaction of com-
mercially available 33 with benzyl isocyanate (Scheme
1). The pyridyl- and isoquinolylureas 6 and 7 were
synthesized by in situ formation of a piperidinyl isocy-
anate (derived from 33 by reaction with phosgene in the

2708 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Carling et al.
lar activity at hD4 receptors and 2 orders of magnitude
selectivity over hD2 and hD3 receptors (Table 3). Al-
though the dopamine subtype selectivity of 8 is inferior
to that of 2, the 5-methyl-4-phenyl-1,3-dihydroimidazol-
2-one has a significantly superior ion channel counter-
screen profile having lower than 10 µM binding affinity
in the calcium40 and sodium41 binding assays and only
2.3 µM activity at potassium channels.42 Furthermore,
8 has good pharmacokinetic properties in the rat (>50%
oral bioavailability after a 20 mg/kg dose reaching a
peak plasma concentration > 1100 ng/mL, half-life 1 h),
and the overall profile of this prototypical molecule
made optimization studies in this series compelling.
F igu r e 2. 2-Dimensional representation of pseudocyclic con-
formation of compound 6.
F igu r e 3. 2-Dimensional representation of pseudocyclic con-
formation of compound 7.
The synthetic route to 8 was improved by the devel-
opment of a regioselective “four-step/one-pot” procedure
(Scheme 4). Reaction of 4-amino-1-benzylpiperidine (33)
with 2-bromopropiophenone49 at room temperature for
24 h generated the unstable amino ketone 35 in solu-
tion, and this was treated in situ with benzoyl isocyan-
ate to produce the crude tertiary urea intermediate 36.
The solvent was removed by rotary evaporation to leave
a residue (36) which was dissolved in methanol and
treated with sodium methoxide to effect cyclization (37)
and deprotection (38). Finally, addition of trifluoroacetic
acid to the reaction mixture brought about dehydration
to produce the required product 8 in high overall yield
(76%). The improved route was amenable to introducing
diversity to the 3- (R2), 4- (Ar), and 5- (R1) positions of
the 1,3-dihydroimidazol-2-one nucleus (Scheme 5) by
simple variation of the bromo ketones (step i) and
isocyanates (step ii). The N-phenethyl analogue 25 was
prepared in an identical way to 8 but starting with
4-amino-1-phenethylpiperidine (39) which was prepared
by the lengthy route outlined in Scheme 6.
Sch em e 2
Sch em e 3a
A more efficient approach toward exploration of
substituents attached to the basic nitrogen of the
piperidine was developed as outlined in Scheme 7. The
N-benzyl group of 8 was efficiently removed to form 40
in 68% yield, by use of a two-step process involving
reaction with 2-chloroethyl chloroformate followed by
treatment with methanol under reflux. Liberation of the
hydrochloride salt 40 to give the free base 41 was
achieved by treatment with sodium hydroxide solution
and extraction into CH2Cl2. The secondary amine 41
proved to be a valuable intermediate for optimization
of the 1-piperidinyl position, with substituents being
easily introduced by reaction with an appropriate alkyl
bromide in dimethylformamide in the presence of Hunigs
base to give, for example, the m-cyanobenzyl derivative
32 in 60% yield. Reductive alkylations could also be
carried out efficiently on 41 to give, for example, the
N-methyl analogue 23 by reaction with formaldehyde
in the presence of sodium cyanoborohydride.
a
Reagents: (i) PhCOCH(OH)CH3, TFA, toluene, reflux.
the high affinity and selectivity of this compound
indicated that the purported requirements for selective
binding to the hD4 receptor of both a pseudocycle (δ )
10.2, DMSO-d6) and an optimally positioned phenyl ring
were confirmed. By analogy with 3, compound 7 was
also relatively inactive at sodium and calcium ion
channels, but it was only poorly bioavailable in the rat
and was therefore not considered a useful pharmaco-
logical tool.
Design a n d Syn th esis of 4-(2-Oxo-1,3-d ih yd r oim -
id a zolyl)p ip er id in es. Hybridization of the pseudocy-
clic conformation of the lead urea 3 with the known
isoxazole 210,11 led to the design of the 1,3-dihydroimi-
dazol-2-one 8 (Scheme 2). The target molecule 8 was
initially synthesized in low yield by condensation of the
primary urea 3446 with 2-hydroxypropiophenone47 un-
der acidic conditions in refluxing toluene (Scheme 3).48
Also produced in the same reaction was the 4-methyl-
5-phenyl-1,3-dihydroimidazol-2-one regioisomer 9 as the
more abundant product. Evaluation of 8 in the D2-like
dopamine binding assays showed that the designed
target has a very good in vitro profile with subnanomo-
Optim iza tion of 4-(2-Oxo-1,3-dih ydr oim id a zolyl)-
p ip er id in es. The aim of the optimization study de-
scribed in this section was to retain subnanomolar hD4
affinity and increase selectivity to greater than 1000-
fold over all other receptors (including hD2 and hD3)
while retaining the good pharmacokinetic properties of
8. Removal of the methyl group from the 5-position of
the 1,3-dihydroimidazol-2-one nucleus of 8 to give 10
results in 30-fold loss of hD4 binding affinity and
significantly reduces subtype selectivity (Table 4). Re-
introduction of an ethyl group to the 5-position (11)

1-(Cyanobenzylpiperidinyl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
J ournal of Medicinal Chemistry, 1999, Vol. 42, No.
14 2709
Ta ble 3. Comparison of Lead Imidazolone 8 with the Lead Isoxazole 2
a
b
Affinities at cloned human dopamine receptors stably expressed in cell lines. Inhibition of specific binding of [3H]diltiazem to rabbit
skeletal muscle at 10 µM concentration of test compound or Ki (µM). c Inhibition of specific binding of [3H]batrachotoxin to rat cortex at
10 µM concentration of test compound or Ki (µM). n.d., not determined.
d
Sch em e 4a
Sch em e 6a
a
Reagents: (i) Boc2O, CH2Cl2; (ii) H2, 10% Pd-C, MeOH; (iii)
Ph(CH2)2Br, DMF, Hunig’s base; (iv) HCl, MeOH.
Sch em e 7a
a
Reagents: (i) PhCOCH(CH3)Br, Et3N, CH2Cl2, 24 h; (ii)
PhCONCO, 1 h; (iii) evaporation; (iv) MeOH, NaOMe; (v) TFA.
Sch em e 5a
a
Reagents: (i) CH3CH(Cl)OCOCl, CH2Cl2; (ii) MeOH, reflux;
(iii) NaOH, H2O, extraction into CH2Cl2; (iv) RBr, DMF, Hunig’s
base; (v) CH2O, NaCNBH3, MeOH, AcOH.
analogue 12 also has improved affinity over 10 at hD4
receptors, and this must also be due to a conformational
effect on the 4-phenyl ring because the 3,5-dimethyl
derivative 13 does not show a further improvement in
binding affinity. The modest increase of hD2 affinity
seen with the 3-substituted derivatives 12-14 suggests
that there is a beneficial direct hydrophobic effect
adjacent to the 3-position of the 1,3-dihydroimidazol-2-
one ring for binding to the hD2 receptor. In conclusion,
none of the substituent changes to the 1,3-dihydroimi-
a
Reagents: (i) ArCOCH(R1)Br, Et3N, CH2Cl2, 24 h; (ii) R2NCO*,
1 h; (iii) evaporation; (iv) MeOH, NaOMe; (v) TFA. *When R2
PhCO, then the final product has R2 ) H (compounds 8, 10, 11,
and 15-22).
)
restores but does not increase affinity at hD4. This result
suggests that the improved activity of compound 8 over
10 is due to a conformational effect of the 5-methyl
substituent on the 4-phenyl ring and not because of a
direct hydrophobic effect. The 3-methyl-5-desmethyl

2710 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Ta ble 4. Substitution on the Imidazolone Heterocyclic Core
Carling et al.
Ta ble 5. Aromatic Substitution/Replacement on the
Imidazolone Heterocyclic Core
a
Affinities at cloned human dopamine receptors stably ex-
pressed in cell lines.
a
Affinities at cloned human dopamine receptors stably ex-
dazol-2-one nucleus of the lead compound 8 (Table 4)
improved affinity or selectivity for the hD4 subtype.
Substitution and replacement of the phenyl group
attached to the 4-position of the 1,3-dihydroimidazol-
2-one of 8 was investigated next (Table 5). Introduction
of chlorine to the para position of the phenyl ring to give
15 results in retention of hD4 affinity and marginally
improved selectivity over hD2. m-Chloro substitution
(16) produces an order of magnitude reduction in hD4
affinity, while introduction of an o-chlorine atom (17)
has little effect on affinity at any of the human dopam-
ine subtypes. Incorporation of alternative substituents
to the para position was investigated (18-20), but no
improvement in either affinity or selectivity resulted.
Replacement of the 4-phenyl group of 8 with 2-thienyl
(21) compromised selectivity, and substitution with
2-pyridyl (22) reduced hD4 affinity. In summary, none
of the changes to the phenyl group attached to the
4-position of the 1,3-dihydroimidazol-2-one nucleus of
the lead compound 8 (described in Table 5) were
beneficial.
pressed in cell lines.
higher affinity for sodium (Ki ) 1 µM) and potassium
(Ki ) 0.7 µM) ion channels. Substitution of the benzyl
aromatic ring with chlorine at the para position (29) had
little effect on dopamine affinity at all three subtypes,
but both o-chloro (27) and m-chloro (28) substitution
resulted in significantly lower hD2 and hD3 activity,
while binding to hD4 was largely retained. Compound
28 is noteworthy since it meets the target of subnano-
molar affinity at hD4 receptors and >1000-fold selectiv-
ity over other hD2-like receptors. Secondary screening
studies on 28 revealed that the compound has a clean
ion channel profile (Ki’s >10 µM versus calcium, sodium,
and potassium channels) and good pharmacokinetics in
the rat (oral bioavailability ) 70%, half-life ∼1 h).
Further profiling of 28 for activity at other receptors
showed no effect on 5HT2 receptors, but the compound
had significant 5HT1A binding affinity (IC50 ) 70 nM)
and so was not considered further as a potential clinical
tool.
As the final part of the optimization strategy, changes
to the substituent attached to the basic nitrogen atom
of 8 were explored (Table 6). It is essential to have a
hydrophobic group attached to the 1-position of the
piperidine ring since the 1-methyl derivative 23 is
inactive while the cyclohexylmethyl analogue 24 retains
low-nanomolar affinity. Homologation of the benzyl
group to phenethyl (25) results in retention of activity
at hD4 and improved selectivity over both hD2 and hD3;
however, further homologation to the phenylpropyl
analogue 26 is detrimental to hD4 affinity. Because of
the improved dopamine selectivity profile of 25, the
compound was tested in the ion channel screens de-
scribed previously, and although 25 has only weak
affinity for the calcium ion channel, the compound has
On the basis of the improved dopamine binding profile
of 28, meta substitution of the benzyl ring was explored
further. The methyl compound 30 retained high affinity
at hD4 receptors, but selectivity over hD2 receptors was
only marginally better than that of the lead compound
8. The 3-methoxy derivative 31 had the required affinity
and selectivity for hD4 over other dopamine receptors
and calcium and sodium ion channels (Ki’s >10 µM), but
it was compromised by having significant potassium
channel (Ki ) 0.9 µM) and 5HT1A (IC50 ) 70 nM)
activity. Compound 31 also has relatively poor phar-
macokinetics in the rat (oral bioavailability ) 16%, half-
life ) 0.8 h) and so was considered unsuitable for clinical
evaluation. The m-cyano analogue 32 is the optimal

1-(Cyanobenzylpiperidinyl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
J ournal of Medicinal Chemistry, 1999, Vol. 42, No.
14 2711
Ta ble 6. Substitution on the Basic Nitrogen
for hD4 receptors with some selectivity (>10-fold) over
hD2 receptors. The compound was hypothesized to be
active through adopting a pseudocyclic conformation
brought about by intramolecular hydrogen bonding (δHA
) 8.7 in DMSO-d6), and this was proven to be the case
with the design and evaluation of the isoquinolylurea
analogue 7 (5.5 nM, δHA ) 10.2, DMSO-d6). Although
high in affinity at hD4 receptors with approximately 50-
fold selectivity over hD2 receptors and 1000-fold selec-
tivity over voltage-sensitive calcium and sodium ion
channels, 7 has a poor pharmacokinetic profile. This
issue was addressed by hybridizing the structure of 3
with the known, highly bioavailable hD4 antagonist 5-(4-
chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-
yl)isoxazole (2) to design 1-(1-benzylpiperidin-4-yl)-5-
methyl-4-phenyl-1,3-dihydroimidazol-2-one(8).Compound
8 and analogues with variations at the 3-, 4-, and
5-positions of the 1,3-dihydroimidazol-2-one ring were
efficiently constructed through a novel regioselective
“four-step/one-pot” procedure. Changes to the group
attached to the basic nitrogen of the piperidine ring of
8 were optimally carried out by alkylation of the
advanced intermediate 5-methyl-4-phenyl-1(1H)-piperi-
din-4-yl-1,3-dihydroimidazol-2-one (41). No significant
improvements to hD4 affinity and/or selectivity were
obtained by modification/substitution of the 1,3-dihy-
droimidazol-2-one nucleus or by substitution/replace-
ment of the 4-phenyl group attached to the 1,3-
dihydroimidazol-2-one core. Greater success was obtained
with exploration of aromatic substitution on the benzyl
group attached to the basic piperidine nitrogen with
meta substitution in particular giving rise to several
subnanomolar affinity hD4 ligands with increased se-
lectivity over other hD2-like receptors. The optimal
derivative identified from the studies described in this
manuscript is the m-cyano analogue 32 since it has
subnanomolar affinity for hD4 (0.96 nM) and greater
than 1000-fold selectivity over other dopamine D2-like
receptors as well as voltage-sensitive ion channels and
G-protein-linked receptors. Compound 32 is an antago-
nist of hD4 receptors and has a good pharmacokinetic
profile in the rat (69% oral bioavailability, half-life 1.1
h, brain/plasma ratio ) 0.33) and excellent receptor
occupancy in the rat (estimated ED50 ) 1.6 µg/kg po),
thus making it a potentially useful pharmacological and
clinical tool to investigate the role of the D4 receptor in
vivo.
a
Affinities at cloned human dopamine receptors stably ex-
pressed in cell lines. b Inhibition of specific binding of [3H]diltiazem
to rabbit skeletal muscle at 10 µM concentration of test compound
or Ki (µM). c n.d., not determined.
derivative identified from the studies described in this
manuscript since it has subnanomolar affinity at hD4
receptors and greater than 1000-fold selectivity over
other dopamine receptors and all other previously
mentioned counterscreens (calcium channel, Ki > 10 µM;
sodium channel, Ki > 10 µM; potassium channel, (IKR)
EC25 > 10 µM; 5HT1A, IC50 ) 0.97 µM; 5HT2, IC50 > 10
µM). Compound 32 has a good pharmacokinetic profile
in the rat (69% oral bioavailability after a 3 mg/kg dose
reaching a peak plasma concentration of 815 ng/mL,
half-life 1.1 h, brain/plasma ratio ) 0.33) and has
excellent receptor occupancy in the rat (estimated ED50
) 1.6 µg/kg po) as estimated by an in vivo σ receptor
(IC50 ) 5.9 µM vs [3H]SKF10047 (σ radioligand)) binding
assay.50 Furthermore 32 has been proven to be an
antagonist at the D4 receptor since it blocks the dopam-
ine (1 µM)-mediated inhibition of forskolin (10 µM)-
induced elevation of cAMP levels.38 All of the above
attributes potentially make 1-(3-cyanobenzylpiperidin-
4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one (32)
an attractive tool to study the relevance of selectively
antagonizing hD4 receptors in vivo (p.o).
Exp er im en ta l Section
Bioch em ica l Meth od s. 1. [3H]Sp ip er on e Bin d in g Stu d -
ies.38,39 Clonal cell lines expressing the human dopamine D2,
D3, and D4 receptor subtypes were harvested in PBS (phosphate-
buffered saline) and then lysed in 10 mM Tris-HCl (pH 7.4)
buffer containing 5 mM MgSO4. Membranes were centrifuged
at 50000g for 15 min at 4 °C and the resulting pellets
resuspended in assay buffer (50 mM Tris-HCl (pH 7.4)
containing 5 mM EDTA, 1.5 mM CaCl2, 5 mM MgCl2, 5 mM
KCl, 120 mM NaCl, and 0.1% ascorbic acid) at 20 mg of wet
weight/mL (human D4 HEK cells, 10 mg of wet weight/mL
human D2 CHO cells and D3 HEK cells). Incubations were
carried out for 120 min at ambient temperature (22 °C) in the
presence of 0.2 nM [3H]spiperone for displacement studies and
were initiated by the addition of 20-100 mg of protein in a
final assay volume of 0.5 mL. The incubation was terminated
by rapid filtration over GF/B filters presoaked in 0.3% PEI
(poly(ethylenimine)) and washed with ice-cold 50 mM Tris-
Con clu sion s
1-Benzyl-4-[(phenylcarbonylamino)carbonylamino]-
piperidine (3), identified from screening of the Merck
sample collection, exhibited moderate affinity (34 nM)

2712 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Carling et al.
HCl, pH 7.4. Specific binding was determined by 10 µM
apomorphine and radioactivity determined by counting in a
LKB beta counter. Binding parameters were determined by
nonlinear least-squares regression analysis, from which the
inhibition constant Ki could be calculated for each test
compound.
1-Be n zyl-4-[((1-isoq u in olyl)a m in oca r b on yl)a m in o]-
p ip er id in e (7). This compound was prepared in the same way
as described for compound 6 except using 1-aminoisoquinoline
instead of 2-aminopyridine: mp 190-191 °C; 1H NMR (DMSO)
δ 1.55 (2 H, m), 1.91 (2 H, m), 2.20 (2 H, m), 2.69 (2 H, m),
3.49 (2 H, s), 3.74 (1 H, m), 7.25 (1 H, m) 7.30-7.39 (5 H, m),
7.60 (1 H, t, J ) 7.3 Hz), 7.76 (1 H, t, J ) 7.3 Hz), 7.88 (1 H,
d, J ) 7.8 Hz), 8.05 (1 H, d, J ) 5.8 Hz), 8.62 (1 H, d, J ) 7.8
Hz), 9.56 (1 H, s), 10.19 (1 H, d, J ) 7.4 Hz); MS (CI) m/e 361
[MH]+. Anal. (C22H24N4O) C, H, N.
2. Ion Ch a n n el Activities.40-42 Activity at the voltage-
sensitive calcium channel (diltiazem allosteric site) was evalu-
ated by displacement of [3H]diltiazem (60-87 Ci mmol-1; NEN)
binding to rabbit sketetal muscle.40 Binding to the voltage-
sensitive sodium channel was evaluated by displacement of
[3H]batrachotoxin (30-60 Ci mmol-1; NEN) binding to rat
cerebral cortex.41 Binding to the voltage sensitive potassium
channels (particularly IKR channels) was estimated by mea-
surement of the prolongation of effective refractory (ERP) in
ferret papilliary muscle.42
1-(1-Ben zylp ip er id in -4-yl)-5-m eth yl-4-p h en yl-1,3-d ih y-
d r oim id a zol-2-on e (8) a n d 1-(1-Ben zylp ip er id in -4-yl)-4-
m eth yl-5-p h en yl-1,3-d ih yd r oim id a zol-2-on e (9). 1-Benzyl-
4-[(phenylcarbonylamino)carbonylamino]piperidine (3; 15 g,
0.0445 mol) was dissolved in 50% aqueous methanol (400 mL)
with NaOH (30 g) and stirred at room temperature for 48 h.
The solvents were removed in vacuo, and the residue obtained
was suspended in water and heated at reflux for 1 h. After
allowing to cool, the required product 34 was collected by
filtration and washed with Et2O (10.4 g, 99%): mp 148 °C; 1H
NMR (DMSO) δ 1.30 (2 H, m), 1.71 (2 H, m), 1.99 (2 H, m),
2.68 (2 H, m), 3.32 (1 H, m), 3.42 (2 H, s), 5.32 (2 H, br s), 5.86
(1 H, d, J ) 7.8 Hz), 7.21-7.34 (5 H, m); MS (CI) m/e 234
[MH]+.
General directions have appeared previously.11
1-Ben zyl-4-[(p h en ylca r b on yla m in o)ca r b on yla m in o]-
p ip er id in e (3). To an ice-bath-cooled solution of benzoyl
isocyanate (7.7 mL, 0.053 mol) in CH2Cl2 (400 mL) was added
4-amino-1-benzylpiperidine (33; 10.72 mL, 0.053 mol), drop-
wise. When the addition was complete the solution was allowed
to stir at room temperature for 1 h; then the solvent was
removed by rotary evaporation. The residue was triturated
with Et2O and collected by filtration to give 3 as a white
solid: 15.4 g (87%); mp 179-180 °C; 1H NMR (DMSO) δ 1.51
(2 H, m), 1.86 (2 H, m), 2.14 (2 H, m), 2.69 (2 H, m), 3.47 (2 H,
s), 3.65 (1 H, m), 7.24-7.33 (5H, m), 7.50 (2 H, t, J ) 7.9 Hz),
7.61 (1 H, t, J ) 7.9 Hz), 7.96 (2 H, d, J ) 7.9 Hz), 8.69 (1 H,
d, J ) 7.8 Hz), 10.67 (1 H, br s); MS (CI) m/e 338 [MH]+. Anal.
(C20H23N3O2) C, H, N.
Compounds 4 and 5 were made in the same way as
described for the synthesis of 3 using the appropriate isocy-
anate.
1-Be n zyl-4-[(p h e n yla m in oc a r b on yl)a m in o]p ip e r i-
d in e (4): free base; mp 170 °C (methanol-ethyl acetate); 1H
NMR (DMSO) δ 1.36 (2 H, m), 1.80 (2 H, m), 2.07 (2 H, m),
2.69 (2 H, m), 3.45 (2 H, s), 3.47 (1 H, m), 6.10 (1 H, d, J ) 7.6
Hz), 6.85 (1 H, t, J ) 7.4 Hz), 7.17-7.45 (9 H, m), 8.30 (1 H,
s); MS (CI) m/e 310 [MH]+. Anal. (C19H23N3O‚0.1H2O) C, H,
N.
Meth od A (Sch em e 3). 4-[(Aminocarbonyl)amino]-1-ben-
zyl-piperidine46 (34; 1.86 g, 0.008 mol) and 2-hydroxypro-
piophenone (1.2 g, 0.008 mol) were suspended in toluene (15
mL) with TFA (3 mL) and heated under reflux, using a Dean-
Stark trap, for 2 h. The solvents were removed under vacuum,
and the residue was partitioned between CH2Cl2 (2 × 40 mL)
and 1 N sodium hydroxide solution (1 × 30 mL). The combined
organic layers were washed with brine (1 × 30 mL), dried
(MgSO4), filtered, and concentrated under vacuum. The resi-
due was purified by flash silica gel chromatography using
0-5% methanol in CH2Cl2 as eluent to give 8 as the less polar
isomer and 9 as the more polar isomer. Compound 8 was
recrystallized from ethyl acetate to give the required compound
as a white solid (0.045 g, 2%): mp 230 °C dec; 1H NMR (DMSO)
δ 1.60 (2 H, m), 2.02 (2 H, m), 2.20 (3 H, s), 2.43 (2 H, m), 2.89
(2 H, m), 3.49 (2 H, s), 3.75 (1 H, m), 7.21-7.40 (10 H, m),
10.25 (1 H, br s); the regiochemistry of this compound was
assigned by observation of an NOE between the methyl
protons at δ 2.20 and the piperidine methine proton at δ 3.75;
MS (CI) m/e 348 [MH]+. Anal. (C22H25N3O‚0.1H2O) C, H, N.
1-B e n zy l-4-[(b e n zy la m in o c a r b o n y l)a m in o ]p ip e r i-
d in e (5): free base; mp 124-125 °C (methanol-ethyl acetate);
1H NMR (DMSO) δ 1.33 (2 H, m), 1.73 (2 H, m), 2.02 (2 H, m),
2.68 (2 H, m), 3.39 (1 H, m), 3.41 (2 H, s), 4.18 (2 H, J ) 5.9
Hz), 5.86 (1 H, d, J ) 7.8 Hz), 6.19 (1 H, t, J ) 5.9 Hz), 7.21-
7.33 (10 H, m); MS (CI) m/e 324 [MH]+. Anal. (C20H25N3O) C,
H, N.
The more polar compound was recrystallized from methanol-
ethyl acetate to give 9 as a white solid (0.24 g, 9%): mp 249
°C; 1H NMR (DMSO) δ 1.49 (2 H, m), 1.74 (2 H, m), 1.89 (3 H,
s), 2.45 (2 H, m), 2.79 (2 H, m), 3.49 (1 H, m), 3.38 (2 H, s),
7.20-7.47 (10 H, m), 10.05 (1 H, br s); MS (CI) m/e 348 [MH]+.
Anal. (C22H25N3O) C, H, N.
1-Be n zyl-4-[((2-p yr id yl)a m in oca r b on yl)a m in o]p ip -
er id in e (6). To an ice-bath-cooled solution of 4-amino-1-
benzylpiperidine (33; 1.07 mL, 0.0052 mol) in THF (40 mL)
was added phosgene (12.9 mL of a CH2Cl2 1.93 M solution in
toluene, 0.021 mol), in one portion. After 5 min triethylamine
(6.9 mL, 0.042 mol) was added in one portion, and the reaction
mixture was stirred at 0 °C for 15 min. The suspension was
filtered, and the filtrate was concentrated by use of rotary
evaporation. The residue was redissolved in THF (40 mL) and
cooled again to ice-bath temperature, 2-aminopyridine (0.75
g, 0.0083 mol) was added, and the reaction mixture was
allowed to slowly warm to room temperature and left to stir
for 18 h. The solvent was removed in vacuo, and the residue
was partitioned between CH2Cl2 (200 mL) and 1 N sodium
hydroxide solution (2 × 60 mL) and then water (2 × 60 mL).
The organic layer was dried (MgSO4), filtered, and concen-
trated under vacuum to leave a residue which was purified
by silica gel chromatography using 0.5% ammonia solution/
3% methanol/96.5% CH2Cl2 to give a product which was
recrystallized from methanol-ethyl acetate to give 6 as a white
1-(1-Ben zylp ip er id in -4-yl)-5-m eth yl-4-p h en yl-1,3-d ih y-
d r oim id a zol-2-on e (8). Meth od B (Sch em e 4). To a solution
of 4-amino-1-benzylpiperidine (33; 35 g, 0.17 mol) in CH2Cl2
(500 mL) were added 2-bromopropiophenone (44 g, 0.2 mol)
and Et3N (60 mL, 0.43 mol), and the reaction mixture was
stirred for 14 h. Benzoyl isocyanate (25.3 g, 0.17 mol) was
added, and the solution was stirred for a further 1 h. Methanol
(200 mL) was added, and the solvents were removed in vacuo.
The residue was redissolved in methanol (500 mL), and sodium
methoxide (27 g, 0.5 mol) was added. After stirring for 1 h,
trifluoroacetic acid (200 mL) was added, and after a further
0.5 h, the reaction mixture was concentrated under vacuum.
The residue was partitioned between CH2Cl2 (1 L) and
saturated potassium carbonate solution (800 mL), then dried
(MgSO4), filtered, and concentrated in vacuo. On reducing the
volume to approximately 200 mL, 8 (37 g) crystallized out and
was collected by filtration. A further amount was isolated using
silica gel chromatography using 0-5% methanol/CH2Cl2 as
eluent, and the combined solids were recrystallized from
methanol-ethyl acetate to give 8 (45 g, 76%) which was
identical with the product obtained using method A.
1
solid: 0.13 g (8%); mp 178-179 °C; H NMR (DMSO) δ 1.43
(2 H, m), 1.83 (2 H, m), 2.13 (2 H, m), 2.50 (2 H, m), 3.47 (2 H,
s), 3.58 (1 H, m), 6.90 (1 H, m) 7.23-7.35 (6 H, m), 7.65 (1 H,
dt, J ) 7.9 and 2.0 Hz), 8.15 (1 H, dd, J ) 5.2 and 2.0 Hz),
8.22 (1 H, d, J ) 7.6 Hz), 9.09 (1 H, s); MS (CI) m/e 311 [MH]+.
Anal. (C18H22N4O) C, H, N.
Compounds 10-12 were all prepared by the procedure
described for the formation of compound 8 described above

1-(Cyanobenzylpiperidinyl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
J ournal of Medicinal Chemistry, 1999, Vol. 42, No.
14 2713
(method B), using the appropriate 2-bromo ketone instead of
2-bromopropiophenone.
(DMSO) δ 1.91 (2 H, m), 2.18 (3 H, s), 2.75 (2 H, m), 3.12 (2 H,
m), 3.47 (2 H, m), 4.07 (1 H, m), 4.33 (2 H, s), 7.23 (2 H, m),
7.38 (2 H, m), 7.50 (5 H, m), 10.41 (1 H, br s); MS m/z (CI) 366
(M+ + H). Anal. (C22H24 FN3O) C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-4-p h en yl-1,3-d ih yd r oim id a -
1
zol-2-on e (10): mp 306-308 °C; H NMR (DMSO) δ 1.65 (4
H, m), 2.03 (2 H, m), 2.88 (2 H, m), 3.48 (2 H, s), 3.82 (1 H, m),
6.73 (1 H, s), 6.94-7.62 (10 H, m), 10.21 (1 H, s); MS (CI) m/e
334 [MH]+. Anal. (C21H23N3O) C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-5-et h yl-4-p h en yl-1,3-d ih y-
d r oim id a zol-2-on e (11): mp 235 °C; 1H NMR (DMSO) δ 1.42
(3 H, t, J ) 7.3 Hz), 1.56 (2 H, m), 2.03 (2 H, m), 2.53 (4 H, m),
2.88 (2 H, m), 3.49 (2 H, s), 3.55 (1 H, m), 7.21-7.40 (10 H,
m), 10.25 (1 H, s); MS (CI) m/e 362 [MH]+. Anal. (C23H27N3O)
C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-3-m eth yl-4-p h en yl-1,3-d ih y-
d r oim id a zol-2-on e h yd r och lor id e (12): Purified as a hy-
drochloride salt; mp 227 °C dec; 1H NMR (DMSO) δ 2.00 (2 H,
m), 2.29 (2 H, m), 3.15 (2 H, m), 3.33 (3 H, s), 3.38 (2 H, m),
4.20 (1 H, m), 4.30 (2 H, s), 6.61 (1 H, s), 7.35-7.70 (10 H, m),
10.96 (1 H, br s); MS (CI) m/e 348 [MH]+. Anal. (C22H25N3O‚
HCl‚0.4H2O) C, H, N.
Compounds 13 and 14 were both prepared by the procedure
described for the formation of compound 8 described above
(method B), using the appropriate isocyanate instead of
benzoyl isocyanate.
1-(1-Ben zylp ip er id in -4-yl)-4-(4-m eth yl-p h en yl)-5-m eth -
yl-1,3-d ih yd r oim id a zol-2-on e (20): mp 255 °C; 1H NMR
(DMSO) δ 1.59 (2 H, m), 2.01 (2 H, m), 2.17 (3 H, s), 2.29 (3 H,
s), 2.42 (2 H, m), 2.89 (2 H, m), 3.48 (2 H, s), 3.74 (1 H, m),
7.17-7.27 (5 H, m), 7.30-7.36 (4 H, m), 10.19 (1 H, br s); MS
m/z (CI) 362 (M+ + H). Anal. (C23H27 N3O) C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-5-m eth yl-4-th iop h en e-2-yl-
1,3-dih ydr oim idazol-2-on e (21): mp 225 °C; 1H NMR (DMSO)
δ 1.59 (2 H, m), 2.01 (2 H, m), 2.24 (3 H, s), 2.41 (2 H, m), 2.89
(2 H, m), 3.49 (2 H, s), 3.73 (1 H, m), 7.05 (1 H, t, J ) 4 Hz),
7.12 (1 H, d, J ) 4) 7.26 (1 H, m), 7.33 (4 H, m), 7.42 (1 H, d,
J ) 5 Hz), 10.41 (1 H, br s); MS m/z (CI) 354 (M+ + H). Anal.
(C20H23N3OS) C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-5-m eth yl-4-p yr id in -2-yl-1,3-
1
d ih yd r oim id a zol-2-on e (22): mp 194 °C; H NMR (DMSO)
δ 1.60 (2 H, m), 1.99 (2 H, m), 2.45 (2 H, m), 2.53 (3 H, s), 2.89
(2 H, m), 3.49 (2 H, s), 3.77 (1 H, m), 7.12 (1 H, m), 7.26 (1 H,
m) 7.32 (4 H, m), 7.42 (1 H, d, J ) 11 Hz), 7.75 (1 H, m, J )
11 and 3 Hz), 8.49 (1 H, m), 10.46 (1 H, br s); MS m/z (CI) 349
(M+ + H). Anal. (C21H24N4O‚0.3H2O) C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-3,5-d im et h yl-4-p h en yl-1,3-
d ih yd r oim id a zol-2-on e h yd r och lor id e (13): purified as a
hydrochloride salt; mp 295 °C dec; 1H NMR (DMSO) δ 1.62 (2
H, m), 2.04 (2 H, m), 2.06 (3 H, s), 2.40 (2 H, m), 2.90 (2 H, m),
3.33 (3 H, s), 3.49 (2 H, s), 3.79 (1 H, m), 7.24-7.49 (10 H, m),
10.96 (1 H, br s); MS (CI) m/e 362 [MH]+. Anal. (C23H27N3O‚
HCl) C, H, N.
1-(1-Meth ylp ip er id in -4-yl)-5-m eth yl-4-p yr id in -2-yl-1,3-
d ih yd r oim id a zol-2-on e (23). To a solution of 41 (0.5 g,
0.0019 mol) in methanol (75 mL) under nitrogen was added
sodium cyanoborohydride (0.153 g, 1.25 mol equiv) followed
by acetic acid (0.29 mL). The reaction mixture was cooled in
an ice bath, and formaldehyde (0.192 g, 1.25 mol equiv) was
added in methanol (2 mL). After 30 min the reaction mixture
was allowed to warm to room temperature and stirred for 14
h. The reaction mixture was basified with saturated potassium
carbonate solution (20 mL), and the methanol was removed
on the rotary evaporator. The aqueous residue was extracted
into ethyl acetate (3 × 50 mL), dried (MgSO4), filtered, and
evaporated under vacuum to leave a solid which was purified
by chromatography on silica gel using 2-10% methanol in CH2-
Cl2 as eluent. Recrystallization from ethyl acetate/hexane gave
pure product: mp 251-253 °C; 1H NMR (DMSO) δ 1.58 (2 H,
d, J ) 11 Hz), 1.94 (2 H, m), 2.18 (3 H, s), 2.20 (3 H, s), 2.41
(2 H, m), 2.84 (2 H, d J ) 11 Hz), 3.73 (1 H, m), 7.21 (1 H, m),
7.33-7.40 (4 H, m), 10.25 (1 H, s); MS (CI) m/e 272 [MH]+.
Anal. (C16H21N3O) C, H, N.
1-(1-Ben zylp ip er id in -4-yl)-3,4-d ip h en yl-5-m et h yl-1,3-
d ih yd r oim id a zol-2-on e h yd r och lor id e(14): purified as a
hydrochloride salt; mp 253 °C dec; 1H NMR (DMSO) δ 1.98 (2
H, m), 2.18 (3 H, s), 2.79 (2 H, m), 3.12 (2 H, m), 3.44 (2 H, m),
4.23 (1 H, m), 4.30 (2 H, s), 7.03-7.05 (4 H, m), 7.18-7.30 (6
H, m), 7.47 (3 H, m), 7.60 (2 H, m), 10.63 (1 H, br s); MS (CI)
m/e 424 [MH]+. Anal. (C28H29N3O‚HCl‚H2O) C, H, N.
1-(1-Ben zylpiper idin -4-yl)-5-m eth yl-4-(4-ch lor oph en yl)-
1,3-d ih yd r oim id a zol-2-on e (15): This compound was pre-
pared and isolated as the less polar regioisomer using the
procedure described above for the formation of 8 (method A)
using 4′-chloro-2-hydroxypropiophenone instead of 2-hydrox-
1
ypropiophenone: mp 240 °C dec H NMR (DMSO) δ 1.60 (2
H, m), 2.02 (2 H, m), 2.19 (3 H, s), 2.42 (2 H, m), 2.89 (2 H, m),
3.49 (2 H, s), 3.75 (1 H, m), 7.25-7.44 (9 H, m), 10.31 (1 H, br
s); MS (CI) m/e 384 & 382 [MH]+. Anal. (C22H24ClN3O) C, H,
N.
Compounds 16-22 were all prepared by the procedure
described for the formation of compound 8 described above
(method B), using the appropriate 2-bromo ketone instead of
2-bromopropiophenone.
5-Met h yl-1-(1-p h en et h ylp ip er id in -4-yl)-4-p h en yl-1,3-
d ih yd r oim id a zol-2-on e (25). To a solution of 1-benzyl-4-
aminopiperidine (33; 40 g, 0.21 mol) in CH2Cl2 (500 mL) was
added di-tert-butyl dicarbonate (50.4 g, 0.23 mol), and the
reaction mixture was stirred under nitrogen for 18 h at room
temperature. The solvent was removed by rotary evaporation,
and the residue was triturated with Et2O and then collected
by filtration to give 1-benzyl-4-(tert-butyloxycarbonylamino)-
piperidine as a white solid (60.29 g, 99%): mp 135-138 °C;
1H NMR (CDCl3) δ 1.44 (9 H, m), 1.53 (2 H, m), 1.92 (2 H, s),
2.12 (2 H, m), 2.83 (2 H, m), 3.51 (2 H, s), 4.42 (1 H, s), 7.22-
7.32 (5 H, m).
1-(1-Ben zylp ip er id in -4-yl)-4-(3-ch lor op h en yl)-5-m eth -
yl-1,3-d ih yd r oim id a zol-2-on e (16): mp 248 °C; 1H NMR
(DMSO) δ 1.60 (2 H, m), 2.02 (2 H, m), 2.21 (3 H, s), 2.44 (2 H,
m), 2.89 (2 H, m), 3.49 (2 H, s), 3.76 (1 H, m), 7.24-7.42 (9 H,
m), 10.34 (1 H, br s); MS m/z (CI) 382 (M+ + H). Anal. (C22H34
ClN3O) C, H, N.
-
To a suspension of 1-benzyl-4-(tert-butyloxycarbonylamino)-
piperidine (60.29 g, 0.20 mol) in methanol (700 mL) was added
(under nitrogen) 10% palladium on carbon catalyst (3.0 g), and
the mixture was shaken under 50 psi of hydrogen for 18 h.
The solution was filtered and the solvent was removed by
rotary evaporation to give 4-(tert-butyloxycarbonylamino)-
1-(1-Ben zylp ip er id in -4-yl)-4-(2-ch lor op h en yl)-5-m eth -
yl-1,3-d ih yd r oim id a zol-2-on e (17): mp 218 °C; 1H NMR
(DMSO) δ 1.61 (2 H, m), 1.95 (3 H, s), 2.01 (2 H, m), 2.40 (2 H,
m), 2.90 (2 H, m), 3.49 (2 H, s), 3.74 (1 H, m), 7.26 (1 H, m),
7.31-7.33 (4 H, m), 7.35-7.38 (3 H, m), 7.51 (1 H, m), 10.08
(1 H, br s); MS m/z (CI) 382 (M++ H). Anal. (C22H34ClN3O‚
0.2H2O) C, H, N.
1
piperidine as a white solid (40 g, 97%): mp 153-155 °C; H
NMR (CDCl3) δ 1.43 (9 H, s), 1.97(4 H, s), 2.65 (2 H, m), 3.60
(2 H, m), 4.47 (1 H, s).
1-(1-Ben zylpiper idin -4-yl)-4-(4-m eth oxyph en yl)-5-m eth -
yl-1,3-d ih yd r oim id a zol-2-on e (18): mp 242 °C; 1H NMR
(DMSO) δ 1.59 (2 H, m), 2.01 (2 H, m), 2.15 (3 H, s), 2.42 (2 H,
m), 2.89 (2 H, m), 3.23 (1 H, m), 3.49 (2 H, s), 3.76 (3 H, s),
6.95 (2 H, d, J ) 8.8 Hz), 7.26 (2 H, d, J ) 8.8 Hz), 7.33 (5 H,
m), 10.16 (1 H, br s); MS m/z (CI) 378 (M+ + H). Anal.
(C23H27N3O2) C, H, N.
To a suspension of 4-(tert-butyloxycarbonylamino)piperidine
(3.5 g, 0.0175 mol) in dimethylformamide (10 mL) were added
ethyldiisopropylamine (6.1 mL, 0.035 mol) and 2-bromoethyl-
benzene (2.64 mL, 0.0193 mol), and the solution was stirred
at room temperature for 42 h under nitrogen. The reaction
mixture was poured into water (500 mL) and extracted with
CH2Cl2 (3 × 250 mL). The combined organic layers were
washed with brine (1 × 30 mL), then dried (MgSO4), filtered,
and concentrated under vacuum. The residue was triturated
1-(1-Ben zylp ip er id in -4-yl)-4-(4-flu or op h en yl)-5-m eth -
yl-1,3-d ih yd r oim id a zol-2-on e (19): mp 235 °C; 1H NMR

2714 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Carling et al.
with Et2O/hexane (1:1) and collected by filtration to give a
white solid, which was dissolved in a saturated solution of
hydrogen chloride in methanol (100 mL) and stirred at room
temperature for 18 h. The solvent was removed by rotary
evaporation; then the residue was triturated with Et2O and
collected by filtration to give 39 as a white solid (1.55 g, 39%):
mp 200-201 °C; 1H NMR δ 1.89 (2 H, m), 2.80 (2 H, m), 3.04
(2 H, m), 3.30 (2 H, m), 3.64 (1 H, m), 3.72 (2 H, s), 3.86 (2 H,
s), 7.26-7.44 (5 H, m).
5-Methyl-1-(1-phenethyl-piperidin-4-yl)-4-phenyl-1,3-dihy-
droimidazol-2-one (25) was prepared using the procedure
described for the formation of compound 8 (method B) using
39 (and an extra molar equivalent of triethylamine) instead
of 4-amino-1-benzylpiperidine: mp 232-236 °C; 1H NMR
(DMSO) δ 1.60 (2 H, m), 2.04 (2 H, m), 2.21 (3 H, s), 2.40 (4 H,
m), 2.74 (2 H, m), 3.05 (2 H, m), 3.75 (1 H, m), 7.16-7.40 (10
H, m), 10.23 (1 H, br s); MS (CI) m/e 362 [MH]+. Anal.
(C23H27N3O) C, H, N.
1-(3-Cya n ob en zylp ip er id in -4-yl)-5-m et h yl-4-p h en yl-
1,3-dih ydr oim idazol-2-on e (32). Compound 8 (40 g, 0.115mol)
was dissolved in CH2Cl2 (600 mL) at 0 °C, and 1-chloroethyl
chloroformate (18.66 mL, 1.5 mol equiv) was added dropwise
over 15 min. The reaction mixture was allowed to warm to
room temperature and stirred for 14 h. The solvents were
removed under vacuum, and the residue was redissolved in
methanol (500 mL) and heated under reflux for 2 h. After
cooling, the solid produced was collected by filtration and
recrystallized from methanol to give a hydrochloride salt (40)
as a white solid (23.14 g, 68%): 1H NMR (DMSO) δ 1.83 (2 H,
m), 2.22 (3 H, s), 2.66 (2 H, m), 3.00 (2 H, m), 3.34 (2 H, m),
4.10 (1 H, m), 7.22-7.44 (5 H, m), 8.66 (1 H, br s), 9.31 (1 H,
br s), 10.36 (1 H, s); MS (CI) m/e 258 [MH]+.
Compound 40 (23.1 g) was added to aqueous sodium
hydroxide (800 mL of 1 M solution), the aqueous solution was
extracted with CH2Cl2 (4 × 200 mL), and the combined organic
layers were washed with brine (1 × 200 mL), dried (MgSO4),
filtered, and concentrated under vacuum to yield a free base
41 (16 g, 80%, mp 235-238 °C) which was used directly in
the formation of compounds 24 and 26-32.
(1 H, m), 7.20-7.54 (9 H, m), 10.27 (1 H, s); MS (CI) m/e 382
[MH]+. Anal. (C23H24N3OCl‚0.2H2O) C, H, N.
1-(3-Ch lor ob en zylp ip er id in -4-yl)-5-m et h yl-4-p h en yl-
1
1,3-d ih yd r oim id a zol-2-on e (28): mp 248-249 °C; H NMR
(DMSO) δ 1.61 (2 H, d, J ) 11 Hz), 2.04 (2 H, m), 2.19 (3 H,
s), 2.44 (2 H, m), 2.88 (2 H, d, J ) 11 Hz), 3.51 (2 H, s), 3.74
(1 H, m), 7.23-7.40 (9 H, m), 10.26 (1 H, s); MS (CI) m/e 382
[MH]+. Anal. (C23H24N3OCl‚0.1H2O) C, H, N.
1-(4-Ch lor ob en zylp ip er id in -4-yl)-5-m et h yl-4-p h en yl-
1,3-d ih yd r oim id a zol-2-on e (29): mp 266 °C; 1H NMR
(DMSO) δ 1.59 (2 H, d, J ) 11 Hz), 2.03 (2 H, m), 2.19 (3 H,
s), 2.45 (2 H, m), 2.87 (2 H, d, J ) 11 Hz), 3.48 (2 H, s), 3.75
(1 H, m), 7.21-7.40 (9 H, m), 10.26 (1 H, s); MS (CI) m/e 382
[MH]+. Anal. (C23H24N3OCl) C, H, N.
1-(3-Met h ylb en zylp ip er id in -4-yl)-5-m et h yl-4-p h en yl-
1,3-d ih yd r oim id a zol-2-on e (30): mp 234-236 °C; 1H NMR
(DMSO) δ 1.60 (2 H, d, J ) 11 Hz), 2.00 (2 H, m), 2.19 (3 H,
s), 2.31 (3 H, s), 2.43 (2 H, m), 2.89 (2 H, d, J ) 11 Hz), 3.44
(2 H, s), 3.74 (1 H, m), 7.05-7.40 (9 H, m), 10.26 (1 H, s); MS
(CI) m/e 362 [MH]+. Anal. (C23H27N3O) C, H, N.
1-(3-Meth oxyben zylp ip er id in -4-yl)-5-m eth yl-4-p h en yl-
1
1,3-d ih yd r oim id a zol-2-on e (31): mp 227-228 °C; H NMR
(DMSO) δ 1.6 (2 H, d, J ) 10 Hz), 2.01 (2 H, m), 2.19 (3 H, s),
2.4 (2 H, m), 2.9 (2 H, d, J ) 11 Hz), 3.46 (2 H, s), 3.75 (4 H,
m), 6.8-6.9 (3 H, m), 7.21-7.4 (6 H, m), 10.26 (1 H, s); MS
(CI) m/e 378 [MH]+. Anal. (C23H27N3O2 ) C, H, N.
Refer en ces
(1) Seeman, P.; Van Tol, H. M. M. Dopamine receptor pharmacology.
Trends Pharmacol. Sci. 1994, 15, 264-270.
(2) Dearry, J . R.; Gingrich, J . A.; Falardeau, R. T.; Fremeau, R. T.;
Bates, M. D.; Caron, M. Molecular cloning and expression of the
gene for a human D1 dopamine receptor. Nature 1990, 347, 146-
151.
(3) Sunahara, R. K.; Guan, H.-C.; O’Dowd, B. F.; Seeman, P.;
Laurier, L. G.; Ng, G.; George, S. R.; Torchia, J .; Van Tol, H. H.
M.; Niznik, H. B. Cloning of the gene for a human dopamine D5
receptor with higher affinity for dopamine than D1. Nature 1991,
350, 614-619.
(4) Grandy, D. K.; Marchionni, M. A.; Makam, H.; Stofko, R. E.;
Alfano, M.; Frothingham, L.; Fischer, J . G.; Burke-Howie, K.
J .; Bunzow, J . R.; Server, A. C.; Civelli, O. Cloning of the cDNA
and gene for a human dopamine D2 receptor. Proc. Natl. Acad.
Sci. U.S.A. 1989, 86, 9762-9766.
To a solution of 41 (1.0 g, 3.9 mmol) in anhydrous dimeth-
ylformamide (50 mL) were added bromo-m-tolunitrile (0.84 g,
4.4 mmol) and ethyldiisopropylamine (1.35 mL, 7.8 mmol), and
the reaction mixture was stirred at room temperature for 18
h under nitrogen. This mixture was poured into sodium
hydroxide solution (200 mL, 1 M) and extracted into CH2Cl2
(3 × 100 mL). The combined organic layers were washed with
brine (2 × 100 mL) and dried (MgSO4), and the solvent was
removed by rotary evaporation to yield the crude product
which was recrystallized from ethyl acetate/hexane to yield
32 (0.86 g, 60%): mp 254-256 °C dec; 1H NMR (DMSO) δ 1.61
(2 H, d, J ) 11 Hz), 2.06 (2 H, m), 2.19 (3 H, s), 2.44 (2 H, m),
2.88 (2 H, d, J ) 11 Hz), 3.56 (2 H, s), 3.75 (1 H, m), 7.21-
7.75 (9 H, m), 10.26 (1 H, s); MS (CI) m/e 373 [MH]+. Anal.
(C23H24N4O) C, H, N.
(5) Sokoloff, P.; Giros, B.; Martres, M.-P.; Bouthenet, M.-L.; Schwartz,
J .-C. Molecular cloning and characterization of a novel dopamine
receptor (D3) as a target of neuroleptics. Nature 1990, 347, 146-
151.
(6) Van Tol, H. H. M.; Bunzow, J . R.; Guan, H.-C.; Sunahara, R.
K.; Seeman, P.; Niznik, H. B.; Civelli, O. Cloning of the gene for
a
human dopamine D4 receptor with high affinity for the
antipsychotic clozapine. Nature 1991, 350, 610-614.
(7) Snyder, S. H. Dopamine receptors, neuroleptics and schizophre-
nia. Am. J . Psychiatry 1981, 138, 461-464.
(8) Baldessarini, R. J .; Tarsey, D. Dopamine and the pathophysi-
ology of dyskinesias induced by antipsychotic drugs. Annu. Rev.
Neurosci. 1980, 3, 23.
(9) Ben-J ohnathon, N. Dopamine. A prolactin inhibiting hormone.
Endocr. Rev. 1985, 6, 564.
The following compounds were made in the same way as
described for 32 using the appropriate alkyl halide.
(10) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms, F.;
Marwood, R.; Patel, S.; Patel, S.; Ragan, C. I.; Freedman, S.;
Leeson, P. D. 5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)-
piperidin-4-yl) isoxazole: A potent, selective Antagonist at
Human cloned dopamine D4 receptors. J . Med. Chem. 1996, 39,
1943-1945.
(11) Rowley, M.; Collins, I.; Broughton, H. B.; Davey, W. D.; Baker,
R.; Emms, F.; Marwood, R.; Patel, S.; Patel, S.; Ragan, C. I.;
Freedman, S.; Leeson, P. D. Heterocyclylpiperidines as selective
high-affinity ligands at the Human Dopamine D4 Receptor. J .
Med. Chem. 1996, 39, 2374-2385.
(12) Kulagowski, J . K.; Broughton, H. B.; Curtis, N. R.; Mawer, I.
M.; Ridgill, M. P.; Baker, R.; Emms, F.; Freedman, S.; Marwood,
R.; Patel, S.; Patel, S.; Ragan, C. I.; Leeson, P. D. 3-[[4-(4-
Chlorophenyl) piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine:
An antagonist with high affinity and selectivity for the human
dopamine D4 receptor. J . Med. Chem. 1996, 39, 1941-1942.
(13) Collins, I.; Rowley, M.; Davey, W. B.; Emms, F.; Marwood, R.;
Patel, S.; Patel, S.; Fletcher, A.; Ragan, I. C.; Leeson, P. D.; Scott,
A. L.; Broten, T. 3-(1-Piperazinyl)-4,5-dihydro-1H-benzo[g]inda-
zoles: High affinity ligands for the human dopamine D4 receptor
with improved selectivity over ion channels. Bioorg. Med. Chem.
1998, 6, 743-753.
1-(Cycloh exylm eth ylp ip er id in -4-yl)-5-m eth yl-4-p h en -
yl-1,3-d ih yd r oim id a zol-2-on e (24): mp 255-256 °C; 1H
NMR (DMSO) δ 0.83 (2 H, m), 1.17-1.24 (4 H, m), 1.46 (1 H,
m), 1.58-1.76 (6 H, m), 1.91 (2 H, m), 2.08 (2 H, d, J ) 7.2
Hz), 2.19 (3 H, s), 2.40 (2 H, m), 2.89 (2 H, d, J ) 11 Hz), 3.72
(1 H, m), 7.25 (1 H, m), 7.33-7.40 (4 H, m), 10.25 (1 H, s); MS
(CI) m/e 354 [MH]+. Anal. (C22H31N3O) C, H, N.
1-(P h en ylp r op ylp ip er id in -4-yl)-5-m eth yl-4-p h en yl-1,3-
d ih yd r oim id a zol-2-on e (26): mp 181-182 °C; 1H NMR
(DMSO) δ 1.60 (2 H, d, J ) 11 Hz), 1.74 (2 H, m), 2.04 (2 H,
m), 2.18 (3 H, s), 2.29 (2 H, m), 2.44 (2 H, m), 2.61 (2 H, m),
2.88 (2 H, d, J ) 11 Hz), 3.73 (1 H, m), 7.34-7.58 (10 H, m),
10.26 (1 H, s); MS (CI) m/e 376 [MH]+. Anal. (C24H29N3O) C,
H, N.
1-(2-Ch lor ob en zylp ip er id in -4-yl)-5-m et h yl-4-p h en yl-
1,3-d ih yd r oim id a zol-2-on e (27): mp 236-237 °C; 1H NMR
(DMSO) δ 1.62 (2 H, d, J ) 11 Hz), 2.14 (2 H, m), 2.20 (3 H,
s), 2.45 (2 H, m), 2.93 (2 H, d, J ) 11 Hz), 3.59 (2 H, s), 3.77

1-(Cyanobenzylpiperidinyl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one
J ournal of Medicinal Chemistry, 1999, Vol. 42, No.
14 2715
(14) Boydfield, I.; Brown, T. H.; Coldwell, M. C.; Cooper, D. G.;
Hadley, M. S.; Hagan, J . J .; Healy, M. A.; J ohns, A.; King, R. J .;
Middlemiss, D. N.; Nash, D. J .; Riley, G. J .; Scott, E. E.; Smith,
S. A.; Stemp, G. Design and synthesis of 2-naphthoate esters as
selective dopamine D4 Antagonists. J . Med. Chem. 1996, 39,
1946-1948.
(33) Murray, A. M.; Hyde, T. M.; Knable, M. B.; Herman, M. M.;
Bigelow, L. B.; Carter, J . M.; Weinberger, D. R.; Kleinman, J .
E. Distribution of putative D4 dopamine receptors in postmortem
striatum from patients with schizophrenia. J . Neurosci. 1995,
15, 2186-2191.
(34) (a) Sumiyoshi, T.; Stockmeier, C. A.; Overholser, J . C.; Thomp-
son, P. A.; Meltzer, H. Y. Dopamine D4 receptors and effects of
guanine nucleotides on [3H]raclopride binding in postmortem
caudate nucleus of subjects with schizophrenia or major depres-
sion. Brain Res. 1995, 681, 109-116. (b) Stefanis, N. C.;
Bresnick, J . N.; Kerwin, R. W.; Schofield, W. N.; McAlister, G.
Elevation of D4 dopamine receptor mRNA in postmortem
schizophrenic brain. Mol. Brain Res. 1998, 53, 112-119.
(35) Reynolds, G. P.; Mason, S. L. Are striatal dopamine D4 receptors
increased in schizophrenia? J . Neurochem. 1994, 63, 1576-1577.
(36) Mulcrone, J .; Kerwin, R. W. No difference in the expression of
the D4 gene in post-mortem frontal cortex from control and
schizophrenics. Neurosci. Lett. 1996, 219, 163-166.
(37) Kramer, M.; Lasr, B.; Zimbroff, D.; Hafez, D.; Alpert, M.; Allan,
E.; Rotrosen, J .; McEvoy, J .; Kane, J .; Kronig, M.; Merideth, C.;
Silva, J . A.; Ereshefsky, L.; Marder, S.; Wirshimg, W.; Conley,
R.; Getson, A.; Chavez-Eng, C.; Cheng, H.; Reines, S. The effects
of a selective D4 receptor antagonist (L-745,870) in acutely
psychotic schizophrenic patients. Arch. Gen. Psychiatry 1997,
54, 567-572.
(15) Boydfield, I.; Coldwell, M. C.; Hadley, M.; Healy, M. A.; J ohns,
A.; Nash, D. J .; Riley, G. J .; Scott, E. E.; Smith, S. A.; Stemp,
G.; Wilson, K. N-(Substituted-phenyl) piperazines: Antagonists
with high binding and functional selectivity for dopamine D4
receptors. Bioorg. Med. Chem. Lett. 1996, 6, 1227-1232.
(16) TenBrink, R. E.; Bergh, C. L.; Duncan, J . N.; Harris, D. W.; Huff,
R. M.; Lahti, R. A.; Lawson, C. F.; Lutzke, B. S.; Martin, I. J .;
Rees, S. A.; Schlacter, S. K.; Sih, J . C.; Smith, M. W. (S)-[2-
(Isochromanyl)ethylpiperazinyl]benzenesulfonamide, a selective
dopamine D4 antagonist. J . Med. Chem. 1996, 39, 2435-2437.
(17) Kula, N. S.; Baldessarini, R. J .; Kebabian, J . W.; Bakthavacha-
lam, V.; Xu, L. RBI-257: A highly potent dopamine D4 receptor-
selective ligand. Eur. J . Pharmacol. 1997, 331, 333-336.
(18) Wright, J . L.; Gregory, T. F.; Heffener, T. G.; MacKenzie, R. G.;
Pugsley, T. A.; Vander Meulen, S.; Wise, L. D. Discovery of
selective dopamine D4 receptor antagonists: 1-Aryloxy-3-(4-
aryloxypiperidinyl)-2-propanols. Bioorg. Med. Chem. Lett. 1997,
7, 1337-1380.
(19) Haworth, K. E.; Harrison, T.; Kulagowski, J . J .; Leeson, P. D.;
Owens, A. P.; Ridgill, M. P.; Teall, M. R.; Fielding, M.; Chapman,
K.; Emms, F.; Marwood, R.; Patel, S.; Moss, K. L. 4-Heterocy-
clyltetrahydropyridines as selective ligands for the human
dopamine D4 receptor. Bioorg. Med. Chem. Lett. 1997, 7, 2211-
2216.
(38) McAllister, G.; Knowles, M. R.; Ward-Booth, S. M.; Sinclair, H.
A.; Patel, S.; Marwood, R.; Emms, F.; Patel, S.; Smith, A.;
Seabrook, G. R.; Freedman, S. B. Functional coupling of human
D2, D3, and D4 dopamine receptors in HEK293 cells. J . Recept.
Sig. Trans. Res. 1995, 15, 267-281.
(20) (a) Showell, G. A.; Emms, F.; Marwood, R.; O’Connor, D.; Patel,
S.; Leeson, P. D. Binding of 2,4-disubstituted morpholines at
human D4 dopamine receptors. Bioorg. Med. Chem. 1998, 6,
1-8. (b) Bourrain, S.; Collins, I.; Neduvelil, J . G.; Rowley, M.;
Leeson, P. D.; Patel, S.; Patel, S.; Emms, F.; Marwood, R.;
Chapman, K. L.; Fletcher, A. E.; Showell, G. A. Substituted
pyrazoles as novel selective ligands for the human dopamine D4
receptor. Bioorg. Med. Chem. 1998, 6, 1731-1743.
(21) Unangst, P. C.; Capiris, T.; Connor, D. T.; Heffner, T. G.;
Mackenzie, R. G.; Miller, S. R.; Pugsley, T. A.; Wise, L. D.
Chromeno[3,4-c] pyridin-5-ones: Selective human dopamine D4
receptor antagonists as potential antipsychotic agents. J . Med.
Chem. 1997, 40, 2688-2693.
(39) Freedman, S. B.; Patel, S.; Marwood, R.; Emms, F.; Seabrook,
G. R.; Knowles, M. R.; McAllister, G. Expression and pharma-
cological characterisation of the human D3 dopamine receptor.
J . Pharmacol. Exp. Ther. 1994, 268, 417-426.
(40) Catterall, W. A.; Morrow, C. S.; Daly, J . W.; Brown, G. B. Binding
of batrachotoxinin A 20-R-benzoate to a receptor site associated
with sodium channels in synaptic nerve ending particles. J . Biol.
Chem. 1981, 256, 8922-8927.
(41) Reynolds, I.; Snowman, A. M.; Snyder, S. H. (-)-[3H]Desmethoxy-
verapamil labels multiple calcium channel modulator receptors
in brain and skeletal muscle membranes: Differentiation by
temperature and dihydropyridines. J . Pharmacol. Exp. Ther.
1986, 237, 731-738.
(22) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella,
V. 1-(2-Methoxyphenyl)-4-alkylpiperazines: Effect of the N-4
substituent on the affinity and selectivity for dopamine D4
receptor. Bioorg. Med. Chem. Lett. 1997, 7, 1327-1330.
(23) He, X. S.; Woodruff, K.; Brodbeck, R. A new series of selective
dopamine D4 ligands: 3-([4-Arylpiperazin-1-yl]alkylamino)-2H-
1,4-benzoxazines. Bioorg. Med. Chem. Lett. 1997, 7, 2399-2402.
(24) Thurkauf, A.; Yuan, J .; Chen, X.; He, X. S.; Wasley, W. F.;
Hutchison, A.; Woodruff, K. H.; Meade, R.; Hoffman, D. C.;
Donovan, H.; J ones-Herzog, D. K. 2-Phenyl-4(5) -[[4-9-pyrimi-
din-2-yl) piperazin-1-yl]methyl]imidazole. A highly selective
antagonist at cloned human D4 receptors. J . Med. Chem. 1997,
40, 1-3.
(25) Romero, A. G.; Leiby, J . A.; Darlington, W. H.; Martin, V. A.;
Poel, T. J .; Schlachter, S. Novel D4 receptor antagonists as
potential antipsychotics. Book of Abstracts, 211th ACS National
Meeting, New Orleans, LA, March 24-28, 1996; MEDI-030
Publisher: American Chemical Society, Washington, DC, 1996.
(26) Ohmori, J .; Maeno, K.; Hidaka, K.; Nakato, K.; Matsumoto, M.;
Tada, S.; Hattori, H.; Sakamoto, S.; Tsukamoto, S.; Usuda, S.;
Mase, T.Dopamine D3 and D4 Receptor Antagonists: Synthesis
and Structure-Activity Relationships of (S)-(+)-N-(1-Benzyl-3-
pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl)amino]-2-meth-
oxybenzamide (YM-43611) and Related Compounds. J . Med.
Chem. 1996, 39, 2764-2772.
(42) Baskin, E. P.; Serik, C. M.; Wallace, A. A.; Brookes, L. M.; Selnik,
H. G.; Claremon, D. A.; Lynch, J . J . Effects of new and potent
methanesulfonanilide class III antiarrhythmic agents on myo-
cardial refractoriness and contractility in isolated cardiac muscle.
J . Cardiovasc. Pharmacol. 1991, 18, 406-414.
(43) Ward, T. J . Preparation of piperidine derivatives as pharma-
ceuticals or Intermediates. GB 2034305 800604.
(44) Vidaluc, J . L.; Calmel, F.; Bigg, D.; Carilla, E.; Stenger, A.;
Chopin, P.; Briley, M. Novel [2-(4-piperidinyl)ethyl](thio)ureas:
Synthesis and antiacetylcholinesterase activity. J . Med. Chem.
1994, 37, 689-695.
(45) Wild, H.; Bender, W.; Haebich, D.; Heine, H. G.; Raddatz, S.;
Roeben, W.; Hansen, J .; Paessens, A. Preparation of chromans
as HIV inhibitors. EP 628310 A1.
(46) Schroth, W.; Kluge, H.; Frach, R.; Hodek, W.; Schaedler, H. D.
The dehydration of ureas by two-phase dichlorocarbene reaction,
a synthetic access to substituted cyanamides. J . Prakt. Chem.
1983, 32, 787-802.
(47) Moriarty, R. M.; Berglund, B. A.; Penmasta, R. Direct R-hy-
droxylation of ketones under acidic conditions using [bis-
(trifluoroacetoxy)]iodobenzene. Tetrahedron Lett. 1992, 33, 6065-
6068.
(48) Butler, A. R.; Hussain, I. Mechanistic studies in the chemistry
of urea. Part 8. Reactions of urea, 1-methylurea, and 1,3-
dimethylurea with some acyloins and butane-2,3-dione (diacetyl)
in acid solution. J . Chem. Soc., Perkin Trans. 2 1981, 2, 310-
316.
(49) Bellesia, F.; Ghelfi, F.; Grandi, R.; Pagnoni, U. M. Regioselective
R-bromination of carbonyl compounds with trimethylbromosi-
lane-dimethyl sulfoxide. J . Chem. Res. Synop. 1986, 11, 428-
429.
(50) Patel, S.; Freedman, S.; Chapman, K. L.; Emms, F.; Fletcher,
A. E.; Knowles, M.; Marwood, R.; Mcallister, G.; Myers, J .; Patel,
S.; Curtis, N.; Kulagowski, J . J .; Leeson, P. D.; Ridgill, M.;
Graham, M.; Matheson, S.; Rathbone, D.; Watt, A. P.; Bristow,
L. J .; Rupniak, N. M. J .; Baskin, E.; Lynch, J . J .; Ragan, C. I.
Biological profile of L-745,870, a selective antagonist with high-
affinity for the dopamine D4 receptor. J . Pharmacol. Exp. Ther.
1997, 283, 636-647.
(27) Hadley, M. S. D4 Receptors and their antagonists. Med. Res.
Rev., 1996, 16, 507-526.
(28) Kulagowski, J . J .; Patel, S. Curr. Pharm. Des. 1997, 3, 355-
366.
(29) Liegeois, J . F.; Eyrolles, L.; Bruhwyler, J .; Delarge, J . Dopamine
D4 receptors: A new opportunity for research on schizophrenia.
Curr. Med. Chem. 1998, 5, 77-100.
(30) Arlt, M.; Bottcher, H.; Riethmuller, A.; Schneider, G.; Bartoszyk,
G. D.; Greiner, H.; Seyfried, C. A. SAR of novel biarylmethy-
lamine dopamine D4 receptor ligands. Bioorg. Med. Chem. Lett.
1998, 8, 2033-2038.
(31) Matsumoto, M.; Hidaka, K.; Tada, S.; Tasaki, Y.; Yamaguchi,
T. Full-length cDNA cloning and distribution of human dopam-
ine D4 receptor. Mol. Brain Res. 1995, 29, 157-162.
(32) Seeman, P.; Guan, H.-C.; Van Tol, H. H. M. Dopamine D4
receptors elevated in schizophrenia. Nature 1993, 365, 441-445.
J M991029K