Design, Synthesis, and Evaluation of Metabolism-Based Analogues of Haloperidol Incapable of Forming MPP+-like Species

Article abstract of DOI:10.1021/jm0301033

The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K_i(D2) = 33, K_i(D3) = 200, K_i(D4) = 11 nM; K_i(D2)/K_i(D4) = 3] and 9 [K_i(D2) = 44, K_i(D3) = 170, K_i(D4) = 24 nM; K_i(D2)/K_i(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.

Full text of DOI:10.1021/jm0301033

J . Med. Chem. 2004, 47, 497-508
497
Articles
Design , Syn th esis, a n d Eva lu a tion of Meta bolism -Ba sed An a logu es of
Ha lop er id ol In ca p a ble of F or m in g MP P +-lik e Sp ecies
M. Lyles-Eggleston,† R. Altundas,† J . Xia,† D. M. N. Sikazwe,† P. Fan,† Q. Yang,† S. Li,† W. Zhang,† X. Zhu,†
A. W. Schmidt,‡ M. Vanase-Frawley,‡ A. Shrihkande,‡ A. Villalobos,‡ R. F. Borne,§ and S. Y. Ablordeppey*,†
Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy & Pharmaceutical Sciences,
Tallahassee, Florida 32307, Department of Medicinal Chemistry, Laboratory of Applied Drug Design and Discovery,
University of Mississippi, University, Mississippi 38677, and Pfizer Global Research and Development, Eastern Point Road,
Groton, Connecticut 06340
Received March 5, 2003
The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated
to involve several mechanisms. More recently, it has been speculated that the metabolic
transformation to MPP+-like species may contribute to the Parkinsonism-like side effects.
Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy
dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking
the structural features necessary to form neurotoxic quaternary species but retaining their
dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine
analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify
analogues with DA binding profiles similar to that of clozapine at the dopamine receptor
subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of
clozapine was mimicked by 7 [Ki(D2) ) 33, Ki(D3) ) 200, Ki(D4) ) 11 nM; Ki(D2)/Ki(D4) ) 3]
and 9 [Ki(D2) ) 44, Ki(D3) ) 170, Ki(D4) ) 24 nM; Ki(D2)/Ki(D4) ) 2]. A preliminary in-vivo
testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This
profile suggests that there is a need for further evaluation of these two synthetic agents and
their enantiomers for efficacy and lack of catalepsy in animal models.
Haloperidol is a widely used antipsychotic1 whose
therapeutic properties have historically been associated
with its D2 antagonist activity,2 based on the so-called
dopamine hypothesis.3 Unfortunately, haloperidol also
possesses undesirable short- and long-term extrapyra-
midal side effects. Although the short-term side effects
are troublesome, it is the long-term, debilitating, Par-
kinsonism-like side effects, including tardive dyskinesia,
that have hampered its widespread use.4 Consequently,
haloperidol and other typical antipsychotics are being
replaced by atypical antipsychotics possessing minimal
extrapyramidal side effects.
dol. Hence, we have hypothesized that agents possessing
binding profiles similar to haloperidol but lacking the
structural features required to form quaternary pyri-
dinium metabolites can be designed as potential anti-
psychotic agents.
In a recent publication,10 we have shown that no
significant difference exists between haloperidol and its
tropane analogue 1 [Ki(D2) ) 0.31 nM, Ki(D4) ) 12 nM]
Previous studies in several laboratories including
ours5-7 have revealed that haloperidol is converted to
a quaternary pyridinium metabolite (BCPP+ or HPP+)
that, based on its similarity to MPP+, may possess a
potential to cause irreversible, Parkinsonism-like side
effects (Chart 1).
Subsequent investigations have confirmed the pres-
ence of BCPP+ in the brain of postmortem patients
treated with haloperidol8 as well as its neurotoxic
behavior.9 These results suggest that BCPP+ might
contribute to some of the long-term toxicity of haloperi-
in producing acute catalepsy in rats. Since compound 1
could not form BCPP+-like species, we concluded that
BCPP+ may not be responsible for catalepsy during the
acute phase of haloperidol use. Therefore, the potent D2
binding of haloperidol may be responsible for acute
catalepsy and possibly the acute phase of the extrapyr-
amidal side effects associated with haloperidol use in
humans. This observation is consistent with our hy-
pothesis and the occupancy theory of Crocker et al.,11
which indicates that induction of catalepsy is associated
with high D2 occupancy.
* Corresponding author. Tel and Fax: (850) 599-3834. E-mail:
seth.ablordeppey@famu.edu.
† Florida A&M University.
‡ Pfizer Global Research and Development.
§ University of Mississippi.
10.1021/jm0301033 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003

498 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Lyles-Eggleston et al.
Ch a r t 1
Ch a r t 2. Analogues of Haloperidol That Meet the Two
Drug-Design Criteria for Synthesis
However, metabolism of haloperidol to BCPP+ may
contribute to some of the long-term, irreversible, Par-
kinsonim-like side effects including tardive dyskinesia.
On the basis of this hypothesis, we propose the synthesis
of new analogues of haloperidol to meet the following
criteria: (a) Analogues should have structural features
that prevent them from biotransformation to BCPP+-
like species. (b) Analogues should fit at least the
distance requirements of the Humber pharmacophore
model for D2 binding (Figure 1). It is important to note
that the model was not constructed to discriminate
among the DA subtypes. 12 (c) Analogues should have a
clozapine-like D2/D4 affinity ratio i.e., [Ki(D2)/Ki(D4)]
> 113 and a lower affinity for the D2 receptor subtype,
30 < D2 < 150 (Range of clozapine binding in the
literature).
Although there are several hypotheses in the litera-
ture describing the mechanism by which clozapine
produces its superior therapeutic effects in schizo-
phrenic patients,14 we were drawn to the D2/D4 binding
constant ratio, because there are no effective antipsy-
chotic agents that lack D2 affinity and the most selective
D4 ligand was ineffective in clinical trials.14 Thus, the
proposed compounds were also designed to answer
specific structure-activity relationship (SAR) questions
in a search for a clozapine-like binding profile i.e.,
Ki(D2)/Ki(D4) > 1. The target compounds proposed are
presented in Chart 2.
prevents metabolism to quaternary pyridinium spe-
cies.15 Compound 4, would be expected, if dehydration
were to occur, to form an exocyclic double bond in
conjugation with the aromatic ring. The resulting olefin
would not be expected to undergo further oxidation.
Compound 5 takes advantage of a quaternary carbon
at the 4-position of the piperidine ring to not only
prevent dehydration of the primary alcohol but also
aromatization of the piperidine ring, since a double bond
cannot be formed at the quaternary carbon. Compound
6 is a ring-opened analogue of 3 and was designed to
test the hypothesis that an intact piperidine ring may
not be essential for binding to the dopamine receptor
subtypes. Compound 7, a pyrrolidine analogue of halo-
peridol,16 was designed on the basis that a five-
membered pyrrolidine ring cannot form a quaternary
The first target compound (2), is the most obvious
design target, since the first step in the metabolic
transformation of haloperidol to BCPP+ is dehydration.6
Thus, compound 2 should help in shedding light on the
role played by this hydroxy group on the binding
selectivity at the other dopamine receptor subtypes.
Compound 3 is the 4-benzyl analogue of haloperidol and
is based on the suggestion that a benzyl substituent
species, even if it undergoes dehydration and a P450
-
type oxidation similar to haloperidol. However, mea-
surement of the pharmacophoric distances in 7 (Table
2) indicates that distance c is shorter than the range
proposed in the Humber pharmacophore. Compound 8
is the pyrrolidine analogue of 2. To extend distance c
in 7 and bring it in line with the Humber proposal, we
also designed and synthesized compounds 9 and 10.
Compound 9 cannot undergo aromatization to a qua-
ternary species and satisfies all the D2-like pharma-
cophore distance requirements including distance c )
4.45 Å (cf. distance c ) 3.5-5.7 Å for the Humber
model).14 Compound 10 (distance c ) 5.67 Å) was
similarly designed. Replacement of the piperidine ring
in haloperidol with the azepine ring, as in 11, should
produce an analogue incapable of forming the pyri-
dinium-type structure yet meet distance requirements
of the Humber model (Table 2).
Ch em istr y
Compound 2 was obtained by reduction of the com-
mercially available 12 to form 13, which was then
F igu r e 1. A proposed D2-like pharmacophore model by
Humber et al.14

Analogues of Haloperidol
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 499
Ta ble 1. Binding Affinity Constants of Synthetic Compounds to Dopamine Receptors
binding data, pKi ( SEM, nM (nc)
Ki(D2)/KI(D4)
compda
D2
D3
D4
ratio
haloperidol (1)
9.05 ( 0.30 (3)
7.81 ( 0.14 (3)
8.10
8.34 ( 0.27 (3)
7.34 ( 0.05 (4)
8.05
7.98 ( 0.28 (3)
7.59 ( 0.05 (3)
7.23
6.91 ( 0.05 (3)
7.11 ( 0.02 (3)
6.72 (2)
0.1
0.6
0.1
0.2
0.2
0.1
3.0
1.1
1.8
0.1
0.1
2
3b
4
5
6
7
8
9
10
11
7.62 ( 0.08 (4)
7.81 ( 0.07 (3)
7.58 ( 0.09 (3)
7.48 ( 0.18 (3)
7.81 ( 0.11 (4)
7.36 ( 0.13 (3)
7.64 ( 0.21 (3)
8.96 ( 0.16 (3)
<6.0
7.11 ( 0.08 (4)
6.96 ( 0.12 (3)
6.79 ( 0.04 (3)
6.70 ( 0.14 (3)
8.00 ( 0.16 (4)
6.78 ( 0.04 (3)
7.49 ( 0.09 (3)
8.07 ( 0.05 (4)
<6.0
7.98 ( 0.07 (3)
7.82 ( 0.22 (3)
7.62 ( 0.08 (3)
6.71 ( 0.18 (3)
8.09 ( 0.02 (3)
<6.0
BCPP+
clozapine
6.87 ( 0.10 (3)
6.62 (0.05 (10)
7.27 ( 0.06 (36)
2.4
a
b
All chiral compounds were synthesized and tested as racemic mixtures. Single determinations. c n ) number of determinations.
of Bercz17 was employed to obtain the starting material
21 for the synthesis of 5. Hydrolysis of 21 to form acid
22 followed by esterification and reduction of the ester
yielded intermediate 23. Debenzylation of 23 and sub-
sequent alkylation produced compound 5 in moderate
yields (Scheme 4). The synthesis of 6 utilized 25 as
starting material as depicted in Scheme 5. The acid was
converted to the amide and subsequently reduced with
LiAlH4 to the corresponding amino alcohol, 27. The
alcohol was protected with triisopropyl silyl chloride; the
amino function was then alkylated in the usual way
before deprotection by TBAF to 6. The synthesis of
compound 7 followed the method we previously re-
ported.16 Compound 8 requires two key intermediates
(33 and 36). Intermediate 33 was obtained by converting
4-chlorobenzyl cyanide to the diol and mesylating the
resulting diol to the desired intermediate, 33. The other
intermediate 36 was obtained by substituting the
chloride 34 with an azide to form 35 and then reducing
35 to the primary amine 36, as shown in Scheme 6. The
pyrrolidine ring was constructed by the double alkyla-
tion of the primary amine 36 with intermediate 33 to
form the protected target compound. Deprotection of the
keto group under acidic condition then yielded the
desired compound 8. The key intermediate in synthesiz-
ing compound 9, alcohol 44, was obtained by ring
contraction of the piperidine ring starting with 12, as
shown in Scheme 7. Compound 12 was carbamylated
to 37 and converted to epoxide 38, and the ring was
contracted to aldehyde 39 by BF3‚Et2O. The aldehyde
was reduced to alcohol 40 and deprotected with etha-
nolic KOH, and the resulting amine 41 was alkylated
in the usual manner. Aldehyde 39 in Scheme 7 also
served as the starting material for the synthesis of
Ta ble 2. Measurement of the Humber Pharmacophore Model
Distances for OH-a for Synthesized Pyrrolidine and
Homopiperidine Analogues of Haloperidol
distance a
distance b
distance c
lowest
compda
(4.9-6.9 Å) (4.9-6.0 Å) (3.5-5.7 Å) energyb
haloperidol
7
9
10
11
6.62
6.63
6.75
6.70
6.63
5.76
5.11
4.66
4.47
6.19
3.40
3.00
4.45
5.67
3.69
5.57
11.15
13.46
14.88
16.83
a
The hydroxyl group was placed in the axial position in the
b
starting geometry. Energy measured in kcal/mol.
Sch em e 1a
a
Reagents: (i) 10% Pd/C, H2, MeOH; (ii) R-Cl, K2CO3, KI,
DME.
alkylated with 14 (Scheme 1). The key intermediate for
the synthesis of 3 was constructed by reacting a freshly
generated 4-chlorobenzylmagnesium chloride with a
carbamyl-protected ketone, 15. The resulting alcohol
was decarbamylated in an ethanolic KOH and subse-
quently alkylated in the usual manner (Scheme 2). To
obtain compound 4, pyridine 18 was first reduced to the
racemic alcohol 19 using NaBH4 and further reduced
by hydrogenation to 20. Intermediate 20 was alkylated
in the usual manner to obtain 4 (Scheme 3). The method
Sch em e 2a
a
Reagents: (i) ArCH2MgBr/Et2O. (ii) 20% KOH, EtOH; (iii) R-Cl, K2CO3, KI, DME.
Sch em e 3a
a
Reagents: (i) NaBH4, EtOH; (ii) PtO2, H2; (iii) R-Cl, KHCO3, toluene.

500 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Lyles-Eggleston et al.
Sch em e 4a
a
Reagents: (i) dilute H2SO4, (ii) (a) H2SO4/MeOH, (b) LiBHEt3; (iii) CH3CHClOCOCl, MeOH/reflux; (iv) R-Cl, K2CO3, KI, DME.
Sch em e 5a
a
Reagents: (i) ClCO2Et, NEt3, (ii) LiAlH4/THF; (iii) (iPr)3SiCl3, NEt3, DMAP; (iv) R-Cl, K2CO3, KI, DME; (v) TBAF.
Sch em e 6a
a
Reagents: (i) glyoxylic acid, K2CO3/MeOH; (ii) H2SO4/EtOH; (iii) H2, 10% Pd/C; (iv) LiAlH4; (v) NEt3, DMAP, MsCl; (vi) KI, NaN3;
(vii) PPh3/Et2O; (viii) intermediate 33; (ix) 2 N HCl, reflux.
Sch em e 7a
a
Reagents: (i) ClCO2Et, K2CO3, (ii) mCPBA, (iii) BF3OEt3/Et2O; (iv) NaBH4/EtOH; (v) KOH/EtOH, N2H4; (vi) R-Cl, K2CO3, KI, DME.
Sch em e 8a
a
Reagents: (i) NaHMDS/Ph3P+CH2OCH3; (ii) 4 N HCl; (iii) NaBH4/EtOH; (iv) KOH/EtOH; (v) R-Cl, K2CO3, KI, DME.
compound 10. It was converted to the corresponding
enol ether, which under acidic condition was trans-
formed to a new aldehyde (43) with one more carbon
inserted as shown in Scheme 8. Aldehyde 43 was
similarly reduced to the alcohol, its amino function
deprotected and alkylated as before to obtain compound
10. Finally, as depicted in Scheme 9, ketone 46 was
obtained using the method of Riley et al.18 Compound
44 was ring-expanded and then subjected to Grignard
reaction to form intermediate 47. The carbamate-
protected alcohol 47 was deprotected to 48 in the usual
way and then alkylated as indicated previously (Scheme
9). All chiral compounds were obtained as racemates
and tested as such.

Analogues of Haloperidol
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 501
Sch em e 9a
a
Reagents: (i) N3CH2CO2Et, BF3OEt2; (ii) 4 N KOH/EtOH; (iii) nBuLi, 4-chlorophenyl bromide; (iv) 50% KOH/EtOH, N2H4; (v) R-Cl,
K2CO3, KI, DME.
F igu r e 2. Percent inhibition of apomorphine-induced climbing by compound 7, clozapine, and haloperidol. Data represents mean
values ((SEM) for n ) 10 mice.
Discu ssion
hydroxy group is not essential for binding affinity but
does enhance affinity for the D2-like receptors. In
addition, the decrease in binding affinity in the absence
of the hydroxy group is not uniform at the dopamine
receptor subtypes, providing the first clue that varying
structural features at the DA receptor subtypes can
achieve receptor selectivity.
Among the binding profiles proposed to have efficacy
against positive schizophrenia and a low propensity to
induce movement disorders is the clozapine-like binding
profile Ki(D2)/Ki(D4) > 1.13 Thus, although they were
designed to obviate metabolic transformation to MPP+-
like species, the proposed compounds were also designed
to answer specific SAR questions in a search for cloza-
pine-like binding profile. Comparing the binding affinity
of haloperidol with that of compound 2 reveals that
deoxygenation of haloperidol substantially decreases
binding at the D2 (18-fold) and D3 receptor (9-fold)
subtypes. At the D4 subtype, however, the decrease is
less than 3-fold. This observation suggests that the
According to the Humber pharmacophore (Figure 1),
extending distance b of haloperidol to form 3, transpos-
ing the alcoholic function to the benzylic position as in
4, or introducing a quaternary carbon at position 4 as
in 5 are changes within the Humber specified distances,
yet the binding affinities of 3-5 are lower and lack the
clozapine-like binding profile. The binding affinity of the

502 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Lyles-Eggleston et al.
F igu r e 3. Plots of mean catalepsy scores at various times for haloperidol, compound 7, and clozapine. Data represents mean
values ((SEM) for n ) 5 rats.
ring-opened analogue of compound 3, i.e., 6 suggests
that the piperidine ring in 4 is not essential for binding
at the D2-like receptor subtypes. Ring contraction to
pyrrolidine analogue 7 results in a decrease in D2 and
D3 binding affinity but essentially no change in D4
binding affinity. Indeed, 7 shows the best selectivity
[Ki(D2)/Ki(D4) ) 3.0] for the D4 subtype among all the
compounds synthesized. Comparing its binding profile
with that of clozapine [Ki(D2)/Ki(D4) ) 2.4] shows the
D2/D4 binding ratio to be similar. In addition, 7 binds
with a lower affinity at the D2 receptor subtype as does
clozapine, raising the possibility that it may serve as
an atypical antipsychotic.12
The deoxygenated analogue of 7, i.e., compound 8,
binds with higher affinity at both D2 and D3 subtypes
but has a 3-fold decrease in binding affinity at the D4
subtype, suggesting that the hydroxy group enhances
affinity for the D4 receptor subtype in a manner similar
to that found in the six-membered ring analogues. This
pattern of binding at the dopamine receptor subtypes
also shows that the five-membered ring analogues can
serve as leads in obtaining selective ligands at the DA
subtypes. Extending distance c in 7 by inserting one
methylene group leads to 9, with a similar binding
affinity ratio [Ki(D2)/Ki(D4) ) 1.8] as clozapine. Inser-
tion of an additional methylene group to form 10 shows
that further increase in distance c produces a decrease
in binding affinity, especially at the D4 subtype. In
addition, the binding affinity ratio [Ki(D2)/Ki(D4) ) 0.1]
deviates substantially from the clozapine-like ratio, thus
suggesting that further extensions would be unproduc-
tive. Ring expansion from six (piperidine) to seven
(homopiperidine), to give compound 11 mimics halo-
peridol binding at the three DA receptor subtypes.
Indeed, the binding profile of 11 and that of haloperidol
is identical within experimental error. Therefore, we are
inclined to suggest that a homopiperidine ring may
serve as a bioisostere of a piperidine ring at the D2-
like receptor subtypes. Finally, we resynthesized7 BCPP+
and investigated its binding affinity at the DA receptor
subtypes. The results clearly show that BCPP+ does not
bind to the D2-like receptors and is therefore unlikely
to produce any of its effects through binding at the D2,
D3, or D4 receptor subtypes. Overall, although all target
compounds satisfy criterion 1 and partially criteria 2
and 3, only compounds 7-9 produce the all-important
binding affinity ratio [Ki(D2)/Ki(D4) > 1].
An in vivo evaluation was conducted on 7 because of
the favorable clozapine-like Ki(D2)/Ki(D4) binding pro-
file. This brief evaluation involves inhibition of apomor-
phine-induced climbing test in male Swiss mice and
catalepsy induction in male Sprague-Dawley rats in a
“bar test”.20 Haloperidol and clozapine served as controls
in the respective assays. The results are shown in

Analogues of Haloperidol
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 503
J ) 12 Hz, 2H), 7.15 (d, J ) 9 Hz, 2H), 7.23 (d, J ) 9 Hz, 2H).
A mixture of 13 (140 mg, 0.60 mmol), K2CO3 (0.33 g, 2.4 mmol),
and KI (15 mg) was stirred in DME (4 mL), and 14 (3.9 ml,
2.4 mmol) was added in a dropwise manner. The reaction
mixture was stirred under N2 at 100 °C overnight and the
crude product was extracted with EtOAc (3 × 100 mL). The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was chro-
matographed on silica gel with gradient elution (0-10%
MeOH/CH2Cl2), to give 160 mg (67% yield) of an oil. The oil
was converted to the HCl salt and recrystallized from MeOH/
Et2O to give a solid. Mp: 208.5-209.5 °C. 1H NMR (300 MHz,
DMSO-d6): δ 2.04 (m, 6H), 2.84 (tt, J ) 4.1, J ) 12.3 Hz, 1H),
3.06 (m, 4H), 3.22 (t, J ) 6.1 Hz, 2H), 3.57 (d, J ) 12.3 Hz,
2H), 7.26 (d, J ) 8.9 Hz, 2H), 7.38 (d, J ) 3.2 Hz, 2H), 7.41 (d,
J ) 3.2 Hz, 2H), 8.07 (dd, J ) 2.1, 8.9 Hz, 2H), 10.6 (s, br,
1H). Anal. (C21H24Cl2FNO): C, H, N.
Figures 2 and 3. Overall, the behavioral profile of 7
mimics the profile of clozapine, while there is a statisti-
cally significant difference between 7 and haloperidol
in both tests. The fact that 7 mimics clozapine’s Ki(D2)/
Ki(D4) ratio and does not produce catalepsy in the bar
test but blocks apomorphine-induced climbing in a
manner similar to clozapine has encouraged us to
vigorously pursue more detailed in vivo studies on 7,
its enantiomeric pair, as well as compound 9 and its
enantiomers. These experiments are currently ongoing.
Con clu sion
In this paper, we have designed and synthesized
haloperidol analogues incapable of undergoing metabo-
lism to pyridinium-type metabolites but possess binding
affinity at DA receptor subtypes. Since the pyridinium-
type metabolites have the potential to contribute to
some long-term side effects through the destruction of
dopaminergic neurons in the nigrostriatum, these com-
pounds have potential advantage over haloperidol. The
fact that compounds 7 and 9 possess D2/D4 binding
affinity ratios similar to that of the atypical antipsy-
chotic clozapine is interesting and necessitates further
evaluation of these compounds in animal models. The
hypothesis that Ki(D2)/Ki(D4) > 1 leads to agents with
efficacy against positive schizophrenia and a low pro-
pensity to induce movement disorders can be validated
using compounds 7 and 9 when their enantiomers are
separated. It is necessary to isolate the enantiomers of
these compounds so as to evaluate the effect of stereo-
chemistry on the binding affinity of the 5- and 7-mem-
bered ring analogues in this paper. After expanded
binding profiles of 7, 9, and 11 are obtained and
enantiomers are separated, we also plan to evaluate
their capacity to reverse apormorphine-induced stereo-
typy and their ability to induce catalepsy in animal
models. These experiments are expected to shed more
light on the D2/D4 binding hypothesis.
4-[4-(4-Ch lor ob en zyl)-4-h yd r oxyp ip er id in -1-yl]-1-(4-
flu or op h en yl)bu ta n -1-on e (3). Into a three-necked flask
equipped with a mechanical stirrer, a nitrogen inlet, an
addition funnel, and a reflux condenser with a drying tube
was added magnesium turnings (3.1 g, 0.129 g-atom), and dry
ether (200 mL). A solution of 4-chlorobenzyl chloride (23.0 g,
120 mmol.) in anhydrous Et2O (100 mL) was added portionwise
and the resulting mixture was refluxed for 2 h to produce
4-chlorobenzylmagnesium chloride. A solution of 4-oxopiperi-
dine-1-carboxylic acid ethyl ester (13.3 g, 0.085 mol.) in dry
THF (100 mL) was rapidly added to the Grignard reagent
produced and the resulting mixture refluxed for 24 h. The
mixture was cooled and 30% NH4Cl solution was added until
all solids dissolved. The aqueous phase was separated and
extracted with ether (3 × 100 mL). The combined organic
phase was shaken with cold 1 N HCl (100 mL) quickly and
then with brine (50 mL) and dried over anhydrous Na2SO4.
The solvent was removed to afford a yellowish brown oil (13.7
g, 60.1%). The oil was further purified by column chromatog-
raphy on silica gel (70-230 mesh) to afford a colorless product.
A mixture of the product (2.5 g, 16 mmol) in absolute EtOH
(70 mL) and 20% aqueous KOH (21 mL) was refluxed under
nitrogen for 12 h. The solution was cooled, solvent was
removed in vacuo, and water (100 mL) was added. The
resulting mixture was extracted with chloroform (3 × 100 mL)
and the combined chloroform extract was washed with water
(50 mL) and dried over anhydrous MgSO4. The solvent was
removed in vacuo to afford the deprotected amino alcohol 17
(1.55 g, 84.6%). 1H NMR (300 MHz, DMSO-d6): δ 1.49 (d, J )
13.5 Hz, 2H), 1.65 (dt, J ) 13.8 Hz, J ) 4.7 Hz, 2H), 2.69 (s,
2H), 2.98 (m, 4H), 4.83 (s, -OH), 7.23 (part of AA′BB′ system,
2H), 7.33 (part of AA′BB′ system, 2H), 7.84 (br, -NH). A
mixture of 17 (1.5 g, 7.6 mmol), 14 (6.0 g, 30 mmol) in DME
(35 mL), K2CO3 (3 g), and KI (100 mg) in DME (40 mL) was
refluxed for 7 h and monitored by TLC for the formation of
product. The mixture was cooled to room temperature, diluted
with H2O (100 mL), and extracted with Et2O (3 × 100 mL).
After drying over anhydrous Na2SO4, solvent was removed and
the resulting oil was chromatographed over silica gel to afford
a yellowish oil which solidified on standing. Crystallization
from MeOH/Et2O afforded 3 as white crystals (2.7 g, 83%). Mp:
Exp er im en ta l Section
Ch em istr y. Column chromatography was performed with
silica gel (200-425 mesh) as the stationary phase. Precoated
silica gel plates (Analtech F254, 0.25 mm; Merck) were used
for TLC analysis. Melting points were determined in open
capillaries on Gallenkamp electrothermal apparatus. 1H NMR
spectra were recorded either on a Varian EM-300 MHz or on
a Bruker AM 270 MHz instrument, with DMSO-d6 or CDCl3
as the solvent; all values are expressed in δ values (parts per
million). The following abbreviations are used: s ) singlet,
d ) doublet, t) triplet, p ) pentet, dd ) doublet doublet, m )
multiplet, and br ) broad. Compounds were named using
Autonom in Chem Draw version 7.0.1. Elemental analyses
(C, H, N) were performed by Atlantic Microlab, Inc.; the
analytical results were within (0.4% of the theoretical values
for the formula given.
1
79-80 °C. H NMR (300 MHz, CDCl3): δ 2.20 (m, 6H), 2.79
(m, 6H), 3.56 (m, 3H), 4.48 (d, J ) 3.2 Hz, 1H), 7.06 (m, 2H),
7.25 (m, 4H), 7.91 (m, 2H), 11.29 (br, 1H). Anal. (C22H25
-
ClFNO2‚0.4H2O): C, H, N.
4-[4-(4-Ch lor oph en yl)piper idin -1-yl]-1-(4-flu or oph en yl)-
bu ta n -1-on e (2). Compound 12 (1.30 g, 5.7 mmol) was
dissolved in MeOH (110 mL) and the solution was hydroge-
nated (Parr) over 10% Pd/C (310 mg) at 68 psi for 4 h. The
catalyst was removed by filtration (Celite) and the solvent was
removed under reduced pressure. The residue was basified
using saturated NaHCO3 (pH 12) and extracted with EtOAc
(3 × 100 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo to give a dark yellow oily residue. The residue was
converted to the hydrochloride salt 13 (1.3 g, 96.2%). 1H NMR
(300 MHz, CDCl3): δ 1.60 (m, 2H,), 1.77 (d, J ) 3.0 Hz, 2H),
2.32 (brs, 1H), 2.56 (m, 1H), 2.72 (t, J ) 15 Hz, 2H), 3.20 (d,
(4-Ch lor op h en yl)p yr id in -4-ylm eth a n ol (19). A mixture
of NaBH4 (2.4 g, 62 mmol) and 18 (10 g, 46 mmol) in absolute
EtOH (200 mL) at room temperature was stirred for 1.5 h and
then refluxed for 30 min. To the mixture was added H2O (20
mL), 10% HCl (75 mL) on ice, and 20% NaOH (40 mL) to form
a precipitate. The precipitate was recrystallized from 80%
1
MeOH-H2O to give 8.1 g (80%) of product 19. H NMR (300
MHz, CDCl3): δ 2.18 (s, 1H), 3.56 (br, -OH), 7.34 (m, 6H),
8.46 (m, 2H)
(4-Ch lor op h en yl)p ip er id in -4-ylm eth a n ol (20). A mix-
ture of 19 (0.76 g, 3.5 mmol) and PtO2 (76 mg) in EtOH (3.5
mL), H2O (2.7 mL), and concentrated HCl (0.54 mL) was

504 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Lyles-Eggleston et al.
hydrogenated at 3 atm for 30 min. The catalyst was filtered
and the filtrate was concentrated to form a solid. A 20% NaOH
(1 mL) was added to the solution in hot water to precipitate
the product. The white precipitate was recrystallized with 50%
aqueous MeOH to yield 0.59 g (76%) of 20. 1H NMR (300 MHz,
DMSO-d6): δ 1.11 (m, 3H), 1.46 (m, 1H), 1.65 (m, 1H), 2.07 (s,
1H), 2.29 (m, 2H), 2.85 (m, 2H), 4.24 (d, J ) 7 Hz, 1H), 7.27
(m, 2H), 7.35 (m, 2H).
organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuo. The filtrate was chromatographed on silica
gel eluting with a 0-15% MeOH/CH2Cl2 gradient that afforded
compound 26 as a white solid (5.48 g, 81%) yield. Recrystal-
lization from EtOAc-hexane provided an analytical sample.
Mp 123-124 °C. 1H NMR (300 MHz, CDCl3): δ 2.59 (t, J )
5.4 Hz, 2H), 2.79 (s, 3H), 3.31 (t, J ) 5.4 Hz, 2H), 5.81 (m,
1H), 7.41 (d, J ) 8.1 Hz, 2H), 7.90 (d, J ) 8.1 Hz, 2H).
N -Me t h yl-N -4-(4′-c h lo r op h e n yl)-4-h yd r ox y b u t y la -
m in e (27). Amide 26 (4.2 g, 19.8 mmol) was dissolved in THF
(150 mL) then added dropwise to a cooled (0 °C) solution of 2
M LAH in THF (119 mL, 118.8 mmol) and warmed to room
temperature under N2 atmosphere. The reaction mixture was
stirred for 20 h at room temperature, poured onto ice, and
basified with 1 M NaOH. The mixture was extracted with
EtOAc (3 × 100 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo, and the
residue was chromatographed on silica gel eluting with a 20-
50% MeOH/CH2Cl2 (0-15% NH4OH) gradient that afforded
1.89 g (48% yield) of intermediate 27 as a yellowish oil. 1H
NMR (300 MHz, CDCl3): δ 1.16 (m, 2H), 1.31 (m, 2H), 1.97
(s, 3H), 2.19 (m, 2H), 4.18 (dd, J ) 4.7, 7.3 Hz, 1H), 6.94
(m, 4H).
4-{4-[(4-Ch lor op h en yl)h yd r oxym eth yl]p ip er id in -1-yl}-
1-(4-flu or op h en yl)bu ta n -1-on e HCl (4). A mixture of 20
(0.68 g, 3.0 mmol), 14 (0.78 g, 3.9 mmol), KHCO3 (1.2 g), KI
(60 mg), and toluene (30 mL) was allowed to reflux for 48 h.
The mixture was filtered to remove any undissolved materials
and washed with EtOAc, and solvent was removed under
reduced pressure. The residue was chromatographed over
silica gel using EtOAc-MeOH gradient elution to obtain 4 (0.7
1
g, 60%), which was then converted to the HCl salt. H NMR
(300 MHz, CDCl3): δ 1.22 (m, 3H), 1.84 (m, 6H), 2.32 (t, J )
7.3 Hz, 2H), 2.84 (m, 2H), 2.91 (t, J ) 7.3 Hz, 3H), 4.32 (d,
J ) 7.3 Hz, 1H), 7.17 (m, 6H), 7.96 (m, 2H). Anal. (C22H26Cl2-
FNO2): C, H, N.
4-(4′-Ch lor oph en yl)-4-car boxy-1-ph en ylpiper idin e (22).
A mixture of H2O (1 mL) and sulfuric acid (2 mL) was added
to compound 2117 (2 g), and the resulting mixture was refluxed
overnight. Solvent was removed under vacuum to produce a
residue, the residue was dissolved in MeOH (20 mL), and
concentrated sulfuric acid (3 mL) was added. The resulting
mixture was stirred under reflux overnight, cooled to room
temperature, neutralized with Na2CO3, and extracted with
EtOAc (3 × 30 mL). The pooled organic solution was washed
with saturated Na2CO3 and brine, dried over sodium Na2SO4,
and concentrated in vacuo. The residue was chromatographed
N-Meth yl-N-4-(4′-ch lor op h en yl)-4-tr iisop r op ylsilyloxy-
bu tyla m in e (28). A mixture of alcohol 27 (2.2 g, 10.41 mmol),
DMAP (0.12 g, 1 mmol), and NEt3 (1.9 mL, 13.5 mmol) was
stirred in CH2Cl2 (70 mL) at room temperature. TIPSCl (2.9
mL, 13.5 mmol) was added to the resulting solution and stirred
20 h under N2 atmosphere. The reaction mixture was quenched
with water and the crude product extracted with EtOAc (3 ×
100 mL). The combined organic layers were dried over Na2-
SO4, filtered, and concentrated in vacuo. The filtrate was
chromatographed on silica gel eluting with a 10-50% MeOH-
CH2Cl2 (5-15% NH4OH) gradient to give 2.8 g of compound
1
over silica gel with hexane/EtOAc (2/1) to give 22 (1.04 g). H
NMR (300 MHz, CDCl3): δ 7.23 (m, 9H), 3.65 (m 3H), 3.45 (s,
2H), 2.78 (d, 2H), 2.50 (d, 2H), 2.15 (t, 2H), 1.92 (t, 2H).
1
28. H NMR (270 MHz, CDCl3): δ 0.96 (m, 21H), 1.37 (p, J )
6.83 Hz, 2H), 1.71 (p, J ) 6.35 Hz, 2H), 2.35 (s, 3H). 2.49 (t,
J ) 8.1 Hz, 2H), 4.76 (t, J ) 8.1 Hz, 1H), 7.24 (m, 4H).
4-(4′-Ch lor op h en yl)-4-m eth ylen eh yd r oxy-1-[4-(4-flu o-
r op h en yl)-4-oxobu tyl]p ip er id in e Hyd r ogen Oxa la te (5).
To a solution of 22 (0.22 g, 0.67 mmol) in THF (4 mL) was
added Superhydride (1.5 mL) and the resulting mixture was
stirred at room temperature for 1 h. The reaction was
quenched with saturated Na2CO3 and extracted with EtOAc
(3 × 100 mL). The combined extracts were washed with brine,
dried over Na2SO4, and concentrated in vacuo to give a crude
product 23. To a solution of the above crude product 23 (202
mg, 0.64 mmol) in CH2Cl2 (5 mL) was added 2-chloroethyl
chloroformate (0.14 mL), and the resulting mixture was stirred
at 60 °C for 2 h. The solvent was removed and MeOH (4 mL)
was added. After the mixture was refluxed for 3 h, it was cooled
to room temperature, solvent was removed, and the residue
was converted to the HCl salt 24. A mixture of 24 (0.34 g, 1.3
mmol), K2CO3 (0.6 g), KI (0.1 g), and 14 (0.51 g, 2.5 mmol) in
DME (10 mL) was stirred at 90 °C overnight and then cooled
to room temperature. EtOAc (30 mL) was added, and the
mixture was washed with brine, dried over Na2SO4, concen-
trated in vacuo, and chromatographed over silica gel to give
the desired crude product (0.14 g, 23%), which was subse-
quently converted to the oxalate salt 5. The resulting colorless,
soft solid could not crystallize and was thus submitted for
N-[4-(4-F lu or op h en yl)-4-oxobu tyl]-N-4-(4′-ch lor op h en -
yl)-4-tr iisop r op ylsilyloxybu tyla m in e (29). A mixture of 28
(2.80 g, 7.57 mmol), 4-chloro-4-flourobutyrophenone (3.72 mL,
22.7 mmol), K2CO3 (3.08 g), and KI (0.22 g) in DME (60 mL)
was refluxed 24 h. The reaction mixture was quenched with
water and the product extracted EtOAc (3 × 100 mL. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. Purification on silica gel and gradient
elution with 0-15% MeOH-EtOAc afforded of 29 (2.09 g, 51%)
1
as a light yellow residue. H NMR (270 MHz CDCl3): δ 0.98
(m, 21H), 1.33 (p, J ) 7.33 Hz, 2H), 1.84 (p, J ) 7.33 Hz, 4H),
2.13 (s, 3H), 2.26 (t, J ) 7.32 Hz, 2H), 2.34 (t, J ) 7.32 Hz,
2H), 2.91 (t, J ) 7.33 Hz, 2H), 4.75 (t, J ) 5.86 Hz, 1H), 7.09
(dd, J ) 8.30, 8.79 Hz, 2H), 7.22 (m, 4H), 7.94 (dd, J ) 5.37,
8.54 Hz, 2H).
N-[4-(4-F lu or op h en yl)-4-oxobu tyl]-N-4-(4′-ch lor op h en -
yl)-4-h yd r oxybu tyla m in e (6). A mixture of 29 (2.0 g, 3.74
mmol) and TBAF (5.2 µL, 5.23 mmol) was stirred in THF (12
mL) under N2 at room temperature for 24 h. The reaction
mixture was poured into H2O (50 mL) and then extracted with
EtOAc (3 × 100 mL). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. Purification on silica
gel eluting with 0-15% MeOH/CH2Cl2 gradient afforded the
target compound as a yellowish oil that was converted into
the HCl salt 6 (1.2 g, 84%). Recrystallization from MeOH/Et2O
provided an analytical sample. Mp: 109-112 °C. 1H NMR (270
MHz, DMSO-d6): δ 1.65 (m, 4H), 1.99 (t, J ) 7.33, 2H), 2.71
(s, 3H), 3.03 (m, 4H), 3.18 (t, J ) 6.84 Hz, 2H), 4.57(s, 1H),
7.35 (m, 6H), 8.05 (dd, J ) 8.79, 5.86, 2H). Anal. (C21H26Cl2-
FNO2‚0.2H2O): C, H. N.
2-(4-Ch lor op h en yl)bu ten -2-d ioic 1,4-Dieth yla te (32). A
mixture of 30 (10 g, 66 mmol), glyoxylic acid monohydrate (12.1
g, 13.2 mmol), and K2CO3 (35.9 g, 26 mol) and MeOH (100
mL) was refluxed for 24 h to give a thick suspension, which
was filtered, stirred with CHCl3 (50 mL) overnight, and filtered
again. The white crude solid (31) was used without purifica-
tion. A mixture of 31, concentrated H2SO4 (20 mL), and EtOH
1
analysis and testing as such. H NMR (300 MHz, CDCl3): δ
8.01 (dd, J ) 5.4, 3.4 Hz, 2H), 7.32 (m, 4H) 7.13 (t, J ) 8.8 Hz,
2H), 3.56 (s, 2H), 2.96 (t, J ) 6.8 Hz, 2H), 2.64 (m, 2H), 2.36
(t, J ) 6.8 Hz, 2H), 2.50 (m, 3H), 1.90 (m, 3H), 1.70 (m, 2H).
Anal. (C24H27ClFNO6): C, H, N.
N-Met h yl-3-(4-ch lor ob en zoyl)p r op ion ic Am id e (26).
Compound 25 (6.4 g, 30 mmol) was stirred in CH2Cl2 (80 mL)
at room temperature until all the solid had dissolved. The
resulting solution was cooled to 0 °C (ice-NaCl bath), Et3N (4.4
mL, 31.5 mmol) and ethyl chloroformate (3.00 mL, 31.5 mmol)
in 20 mL of CH2Cl2 were added, and the mixture was stirred
for 40 min. Keeping the temperature at 0 °C with an ice bath,
CH3NH2 (15.8 mL, 31.5 mmol) (2 M solution in THF) was
added portionwise. The reaction mixture was stirred at that
temperature for 2 h, quenched with water, and the crude
product was extracted with EtOAc (3 × 100 mL). The combined

Analogues of Haloperidol
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 505
(80 mL) was refluxed for 6 h. After removing solvent in vacuo,
saturated aqueous NaHCO3 (150 mL) was added, the mixture
was extracted with CHCl3 (3 × 200 mL), and the organic phase
was dried over Na2SO4. The solvent was removed to give 32
(13.5 g, 72%) as an oil. H NMR (300 MHz, CDCl3): δ 1.28 (t,
J ) 7.1 Hz, 3H), 1.34 (t, J ) 7.1 Hz, 3H), 4.21 (q, 7.1 Hz, 2H),
4.39 (q, J ) 7.1 Hz, 2H), 6.24 (s, 1H), 7.37 (m, 4H).
(1 g, 2.5 mmol) in acetone (5 mL) and 2 N HCl (50 mL) was
refluxed overnight. The reaction mixture was neutralized by
adding 2 M NaOH and then extracted with CH2Cl2 (3 × 50
mL). The organic phase was dried over MgSO4 and removed
under reduced pressure. The crude product was purified by
column chromatography on silica gel with 8:2 EtOAc:MeOH
to yield 8 as an oil (0.77 g, 86%). The free base 8 was converted
1
1
to the oxalate salt. Mp: 143.0-143.8 °C. H NMR (300 MHz,
2-(4-Ch lor op h en yl)bu ta n e-1,4-d im esyla te (33). A solu-
tion of 32 (13.5 g, 47.8 mmol) in EtOH (50 mL) was stirred
with 10% Pd/C (1 g) at room temperature for 2.5 days. After
removing catalyst and solvent, 2-(4-chlorophenyl)succinic acid
diethyl ester (11.6 g, 85%) was obtained as an oil. 1H NMR
(300 MHz, CDCl3): δ 1.19 (m, 6H), 2.63 (dd, J ) 16.8, 5.3 Hz,
1H), 3.16 (dd, J ) 16.8, 10.1 Hz, 1H), 4.10 (m, 5H), 7.27 (m,
4H). A mixture of LiAlH4 (7.73, 0.203 mmol) and the diethyl
ester (11.6 g, 40.8 mmol) was stirred in THF (150 mL) and
refluxed overnight. The reaction was quenched by dropwise
addition of H2O (20 mL) in an ice bath. The mixture was
extracted with CH2Cl2 (2 × 200 mL) and washed with
saturated aqueous NaCl (75 mL). The organic phase was dried
over Na2SO4 and removed in vacuo to give the alcohol (6.9 g,
85.77%) as an oil. The crude oil was used without further
purification. To a solution of the alcohol (6.87 g, 34.96 mmol),
Et3N (10.59 g, 115.36 mmol), and DMAP (1.28 g, 10.5 mmol)
was added methane sulfonyl chloride (12.88 mL, 13.21 g,
115.37 mmol) at room temperature. Stirring was continued
at room temperature overnight. Reaction was diluted with
CH2Cl2 (100 mL) and washed with aqueous NH4Cl solution.
The organic phase was dried over Na2SO4 and removed in
vacuo. The crude product was purified on column (silica gel)
with EtOAc/hexane to give 33 as a colorless oil (11.2 g, 89.8%).
1H NMR (300 MHz, CDCl3): δ 2.06 (m, 1H), 2.32 (m, 1H), 2.84
(s, 3H), 2.90 (s, 3H), 3.21 (m, 1H), 4.01 (m, 1H), 4.19 (m, 1H),
4.32 (ddd, J ) 18.4, 10.0 & 7.0 Hz, 2H), 7.29 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 30.85, 36.87, 41.26, 67.23, 72.69, 76.58,
127.63, 127.74, 128.81, 138.23.
CDCl3): δ 1.85 (m, 1H), 1.97 (m, 2H), 2.27 (m, 1H), 2.68 (m,
6H), 3.03 (t, J ) 8.3 Hz, 2H), 3.32 (m, 1H), 7.13 (m, 6H), 7.99
(m, 2H). Anal. (C20H21ClFNO‚0.4C2H2O4): C, H, N.
4-(4-Ch lor op h en yl)-1,2,3,6-t et r a h yd r op yr id in e-1-ca r -
boxylic Acid Eth yl Ester (37). A mixture of ClCOOEt (68.1
g, 0.43 mol), 12‚HCl (6.9 g, 30.0 mmol), and K2CO3 (60 g, 0.63
mol) in acetone (150 mL) was refluxed overnight under an
atmosphere of N2. The mixture was filtered to remove solid
materials and the solution was concentrated in vacuo. An
excess amount of ClCOOEt was quenched by the addition of
4% NaOH (100 mL) in methanol. After evaporating off MeOH,
the residue was extracted with ethyl acetate (3 × 100 mL) and
100 mL of saturated NaCl solution. The organic phase was
dried over MgSO4 and concentrated in vacuo. The residue was
purified on column chromatography (silica gel) to yield 37 (6.7
g, 95%). 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J ) 7.0 Hz,
3H), 2.45 (m, 2H), 3.63 (m, 2H), 4.04 (m, 2H), 4.12 (m, 2H),
5.73 (brs, 1H), 7.25 (m, 4H).
6-(4-Ch lor op h en yl)-7-oxa -3-a za bicyclo[4.1.0]h ep ta n e-
3-ca r boxylic Acid Eth yl Ester (38). A mixture of 37 (0.7 g,
2.60 mmol) and 0.59 g of mCPBA in 7.8 mL of CH2Cl2 was
stirred for 16 h. After addition of another 0.59 g of mCPBA,
the mixture was stirred for 2 h before the addition of Na2SO3
(30 mL). The organic phase was exhaustively extracted, dried
over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography over silica gel (1:1 EtOAc:
hexane) to yield 0.58 g (79%) of epoxide 38. 1H NMR (300 MHz,
CDCl3): δ 1.29 (m, 3Η), 3.22 (m, 1H), 3.56 (m, 2H), 4.05 (m,
2H), 4.15 (m, 2H), 4.30 (m, 2H), 7.39 (m, 3H), 7.85 (m, 1H).
3-(4-Ch lor op h en yl)-3-for m ylp yr r olid in e-1-ca r b oxylic
Acid Eth yl Ester (39). A mixture of BF3‚Et2O (7.7 g, 54.5
mmol) and epoxide 38 (0.45 g, 1.6 mmol) in 4 mL of anhydrous
Et2O under an atmosphere of N2 was refluxed for 5 h, 5 N
NaOH (20 mL) was added, and the reaction vessel was allowed
to cool to ice-bath temperature. The mixture was then ex-
tracted with Et2O (3 × 30 mL) and dried over Na2SO4. After
removing solvent in vacuo, crude material was purified on a
column (silica gel, 3:7 EtOAc:hexane) to yield aldehyde 39 (0.4
g, 90%). 1H NMR (300 MHz, CDCl3): δ 1.25 (m, 3 H), 2.14 (m,
1H), 2.76 (m, 1H), 3.54 (m, 2H), 4.12 (m, 2H), 4.35 (t, J ) 10.4
Hz, 1H), 7.10 (m, 2H), 7.33 (m, 2H), 9.93 (s, 1H).
3-(4-Ch lor oph en yl)-3-h ydr oxym eth ylpyr r olidin e-1-car -
boxylic Acid Eth yl Ester (40). A mixture of NaBH4 (0.75 g,
19.9 mmol) and aldehyde 39 (2.8 g, 10 mmol) in EtOH (20 mL)
was stirred for 1.5 h and then refluxed for 30 min. H2O (10
mL) was added to the reaction and solid material was removed.
The filtrate was concentrated in vacuo and extracted with CH2-
Cl2 (3 × 50 mL). The combined organic phase was dried over
Na2SO4 and removed in vacuo. The crude product was sepa-
rated on a column (silica gel, 1:9 MeOH:EtOAc) to yield alcohol
40 (2.6 g, 93%). 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J ) 7.0
Hz, 3H), 2.06 (m, 1H), 2.35 (m, 1H), 3.55 (m, 3H), 3.59 (m,
2H), 3.85 (d, J ) 10.9 Hz, 1H), 4.22 (q, J ) 7.0 Hz, 2H), 7.14
(m, 2H), 7.33 (m, 2H).
2-(3-Azidopr opyl)-2-(4-flu or oph en yl)[1,3]dioxolan e (35).
A mixture of 2-(3-chloropropyl)-2-(4-fluorophenyl)[1,3]dioxolane
(34) (10 g, 40.9 mmol), NaN3 (10.62 g, 16.4 mmol), and KI (3
g) in DMF (80 mL) was heated to 130 °C and stirred overnight.
The reaction mixture was extracted with EtOAc (3 × 200 mL)
and washed with saturated NaCl (150 mL). The organic phase
was dried over Na2SO4 and removed in vacuo to produce a
residue. The crude material was purified on column (silica gel,
1
9:1 hexane:EtOAc) to give 35 as an oil (10 g, 97.4%). H NMR
(300 MHz, CDCl3): δ 1.63 (m, 2H), 1.91 (m, 2H), 3.24 (t, J )
6.9 Hz, 2H), 3.75 (m, 2H), 3.96 (m, 2H), 6.99 (m, 2H), 7.39
(m, 2H).
2-(3-am in opr opyl)-2-(4-flu or oph en yl)[1,3]dioxolan e (36).
To a solution of azide 35 (10 g, 39.8 mmol) in Et2O (100 mL)
was added PPh3 (18.8 g, 71.6 mmol) in a portionwise manner
at 0 °C. After gas evolution, the reaction was stirred at room
temperature for 3 h and subsequently overnight after the
addition of H2O (10 mL). The reaction mixture was extracted
with ether (2 × 200) and washed with saturated aqueous NaCl
(20 mL), and the organic phase was dried over Na2SO4. After
solvent was evaporated under reduced pressure, the crude
product was chromatographed over silica gel with 9:1:1 CH2-
Cl2:MeOH:NH4OH to give 36 (7 g, 78%) as a white solid. Mp:
116-117 °C. 1H NMR (300 MHz, CDCl3): δ 1.44 (m, 2H), 1.87
(m, 2H), 2.63 (t, J ) 7.0 Hz, 2H), 3.72 (m, 2H), 3.96 (m, 2H),
6.98 (m, 2H), 7.39 (m, 2H).
4-[3-(4-Ch lor op h en yl)p yr r olid in -1-yl]-1-(4-flu or op h en -
yl)bu ta n -1-on e (8). A mixture of dimesylate 33 (1 g, 2.8 mmol)
and amine 36 (3 g, 13.2 mmol) was heated at 150 °C for 24 h.
The mixture was extracted with CH2Cl2 (3 × 50 mL) and
aqueous NaCl (50 mL). The organic phase was dried over
NaSO4 and the solvent was removed under reduced pressure.
The crude product was purified on a column (silica gel) with
7:3 EtOAc:MeOH to give the dioxalane-protected ketone an
4-[3-(4-Ch lor op h en yl)-3-h yd r oxym et h ylp yr r olid in -1-
yl]-1-(4-flu or op h en yl)bu ta n -1-on e (9). To a solution of 40
(1.1 g, 3.9 mmol) in EtOH (50 mL) were added 50% NaOH (20
mL) and hydrazine (5 mL). The reaction mixture was refluxed
for 2 days. H2O (100 mL) was added to the resulting mixture
and extracted with CH2Cl2 (3 × 100 mL). The organic phase
was dried over Na2SO4 and solvent was removed in vacuo. The
crude material was purified on column (silica gel, 9:1:1 MeOH:
CH2Cl2:NH4OH) to yield the free amine 41. A mixture of 41
(1 g, 4.73 mmol), 4-chloro-4-flourobutyrophenone (3.8 g, 18.9
mmol), K2CO3 (2.61 g, 18.9 mmol), and KI (0.2 g) in DME (10
mL) was refluxed overnight under an atmosphere of N2. The
1
oil (1 g, 91.7%). H NMR (300 MHz, CDCl3): δ 1.55 (m, 2H),
1.85 (m, 4H), 2.41 (m, 5H), 2.77 (m, 1H), 2.97 (t, J ) 8.3 Hz,
2H), 3.31 (m, 2H), 3.74 (m, 2H), 3.99 (m, 2H), 6.98 (m, 2H),
7.22 (m, 4H), 7.40 (m, 2H). A mixture of the protected ketone

506 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Lyles-Eggleston et al.
excess DME was removed in vacuo and residue was extracted
with CH2Cl2 (3 × 50 mL) and saturated NaCl (50 mL). The
pooled organic phase was dried over MgSO4 and the solvent
was removed under reduced pressure. The crude product was
purified on a column (silica gel) with 8:2 EtOAc:MeOH to yield
etate (3.0 g, 26.3 mmol) in anhydrous Et2O (6 mL) were
simultaneously added over a 20 min period to a solution of 44
(3.0 g, 17.3 mmol) in anhydrous Et2O (20 mL) maintained at
-25 to -30 °C (dry ice-iPrOH bath). After the additions were
completed, the reaction was maintained at -25 to -30 °C for
1 h and then allowed to warm to room temperature. The
solution was washed with 30% K2CO3 (100 mL) and extracted
with EtOAc (3 × 100 mL). The organic phase was separated,
dried on Na2SO4, and concentrated in vacuo to give a crude
orange oil, which was purified on silica gel column eluted with
1
of 9 (1.2 g, 68%) as an oil. H NMR (300 MHz, CDCl3): δ 1.99
(m, 2H), 2.11 (m, 6H), 3.01 (dt, J ) 7.1, 1.3 Hz, 2H), 3.21 (dt,
J ) 8.3, J ) 3.0 Hz, 1H), 3.42 (t, J ) 10.0 Hz, 2H), 3.63 (d,
J ) 10 Hz, 1H), 7.26 (m, 6H), 7.87 (m, 2H). An analytical com-
pound was obtained by converting the oil to the 9‚HCl salt
(68%). Mp: 120-122 °C. Anal. (C21H24Cl2FNO2): C, H, N.
1
30% EtOAc/hexane to give 45 (4.0 g 88.8%). H NMR (Bruker
AM 270 MHz, CDCl3) δ 1.25 (m, 6H), 2.02 (m, 2H), 2.66 (m,
2H), 3.44 (m, 2H), 3.69 (t, J ) 6.8 Hz, 1H), 3.80 (m, 2H), 4.16
(m, 4H).
3-(4-Ch lor op h en yl)-3-(2-oxoet h yl)p yr r olid in e-1-ca r -
boxylic Acid Eth yl Ester (42). A solution of NaHMDS in
THF (1 M, 14.3 mL) was added to a solution of (methoxymeth-
yl)triphenylphosphonium chloride (5.14 g, 15 mmol) in THF
(15 mL) at -78 C. After 1 h, a solution of aldehyde 39 (1.92 g,
6.82 mmol) in THF (10 mL) was added dropwise. The mixture
was stirred at -78 C for 2 h and then quenched with saturated
aqueous NaHCO3 and extracted with CH2Cl2 (3 × 100 mL).
The organic phase was dried over MgSO4 and solvent removed
in vacuo. The crude product was purified on a column (silica
gel, 1:1 EtOAc:hexane) to afford 1.497 g (71%) colorless liquid.
The mixture of (E)/(Z)-enol ether 42 was used without char-
acterization.
4-Oxoa zep a n e-1-ca r boxylic Acid Eth yl Ester (46). To
a solution of intermediate 45 (1.0 g, 3.9 mmol) in EtOH (75
mL) was added 4 M KOH (75 mL) and the mixture was stirred
at room temperature for 24 h. The mixture was extracted with
EtOAc (3 × 75 mL) and the organic phase was separated, dried
(Na2SO4), and concentrated in vacuo to yield a residue. The
residue was chromatographed on silica gel to give a clear oil
1
(606 mg, 84%). H NMR (Varian 300 MHz, CDCl3): δ 1.22 (t,
J ) 7.1 Hz, 3H), 1.77 (m, 2H), 2.62 (m, 4H), 3.61 (m, 4H), 4.10
(q, J ) 7.1 Hz, 2H).
To a solution of 42 (1.5 g, 4.8 mmol) in THF (35 mL) was
added 4 M HCl (22 mL) and the mixture stirred at ambient
temperature overnight. Thereafter, the reaction was quenched
with saturated aqueous NaHCO3 and solvent was removed
under reduced pressure. The crude product was taken up in
aqueous NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 100
mL). The combined organic phase was dried over Na2SO4 and
the solvent was removed under reduced pressure. The crude
product was purified by column chromatography (silica gel
with elution solvent, 1:1 EtOAc:C6H12) to afford a colorless
4-(4-Ch lor op h en yl)-4-h yd r oxya zep a n e-1-ca r b oxylic
Acid Eth yl Ester (47). A solution of 4-chlorophenyl bromide
(310.5 mg, 1.6 mmol) in anhydrous THF (8 mL) was cooled to
-78 °C and a 1.6 M n-Butyllithium (35 mL, 2.2 mmol) in THF
was added with stirring for 2 h. Then a solution of 1-carbeth-
oxyperhydroazepin-4-one (200 mg, 1.08 mmol) in THF (2 mL)
was added at -78 °C. The reaction mixture was allowed to
warm to room temperature and then stirred for an additional
1 h, quenched with saturated NH4Cl (40 mL), and extracted
with CH2Cl2 (3 × 50 mL). The organic solvent was pooled and
evaporated under reduced pressure. The resulting residue was
chromatographed and purified on silica gel column to give
product (186 mg, 64.3%). 1H NMR (Bruker AM270 MHz,
CDCl3): δ 1.24 (m, 3H), 1.84 (m, 6H), 3.28 (m, 2H), 3.68 (m,
2H), 4.13 (q, J ) 6.8 Hz, 2H), 7.32 (m, 4H).
1
liquid, 43 (1.33 g, 93.2%). H NMR (300 MHz, CDCl3): δ 1.25
(t, J ) 7.1 Hz, 3H), 2.24 (m, 1H), 2.74 (m, 3H), 3.47 (br, 2H),
3.70 (t, J ) 10.1 Hz, 2H), 4.13 (q, J ) 7.1 Hz, 2H), 7.18 (m,
2H), 7.30 (m, 2H), 9.47 (t, J ) 2.2 Hz, 1H).
4-[3-(4-Ch lor op h en yl)-3-(2-h yd r oxyeth yl)p yr r olid in -1-
yl]-1-(4-flu or op h en yl)bu ta n -1-on e (10). To a solution of 43
(0.57 g, 1.9 mmol) in EtOH (20 mL) at 0 °C was added NaBH4
(0.15 g, 3.8 mmol). The reaction mixture was stirred for 3 h
and then quenched with H2O. EtOH was removed in vacuo
and organic crude material was extracted with CH2Cl2 (3 ×
50 mL) and washed with brine (50 mL). The pooled organic
phase was dried over Na2SO4 and the solvent removed. The
crude product was purified on a Chromatotron (2 mm, silica
gel) using 9:1 EtOAc:MeOH to afford the protected amino
alcohol (320 mg, 56%) as a colorless liquid. 1H NMR (300 MHz,
CDCl3) δ 1.27 (t, J ) 7.1 Hz, 2H), 2.06 (m, 5H), 3.47 (m, 4H),
3.70 (t, J ) 10.5 Hz, 2H), 4.13 (q, J ) 7.1 Hz, 2H), 7.24 (AA′BB′
system, 4H). A mixture of the carbamate-protected amino
alcohol (0.32 g, 1.1 mmol) in EtOH (30 mL) and 50% aqueous
NaOH (30 mL) was refluxed for 17 h. H2O (100 mL) was added
to the reaction mixture and extracted with (3 × 100 mL) CH2-
Cl2. The organic phase was dried over Na2SO4 and solvent was
removed in vacuo to give a quantitative yield of free amine
which was used without further purification. A mixture of free
amine (0.24 g, 1.1 mmol), 14 (0.42 g, 2.1 mmol), K2CO3 (0.6 g,
4.2 mmol), and KI (100 mg) in DME (10 mL) was refluxed
under N2 overnight. The excess DME was removed in vacuo
and the residue was extracted with CH2Cl2 (3 × 50 mL) in
NaCl (50 mL). The pooled organic phase was dried over MgSO4
and removed under reduced pressure. The crude product was
purified on a Chromatotron (4 mm, silica gel) with 8:2 EtOAc:
MeOH to afford compound 10 (74 mg, 15%). 1H NMR (300
MHz, CDCl3): δ 1.72 (dt, J ) 15.2, J ) 3.4 Hz, 1H), 1.91 (m,
1H), 2.01 (m, 2H), 2.24 (m, 2H), 2.60 (m, 4H), 3.02 (td, J )
7.1, J ) 1.2 Hz, 2H), 3.45 (m, 4H), 3.68 (td, J ) 10.0, J ) 2.9
Hz, 1H), 7.10 (m, 4H), 7.24 (m, 2H), 7.97 (m, 2H). The free
base was converted to the HCl salt. Mp: 142-143 °C. Anal.
(C23 H26Cl2FNO): C, H, N.
4-[4-(4-Ch lor op h en yl)-4-h yd r oxya zep a n -1-yl]-1-(4-flu o-
r op h en yl)bu ta n -1-on e Hyd r ogen Oxa la te (11). A mixture
of compound 47 (232 mg 7.8 mmol), hydrazine (3 mL), EtOH
(5 mL), and 50% KOH (5 mL) was refluxed overnight. The
mixture was allowed to cool to room temperature and extracted
with CH2Cl2 (3 × 50 mL). The combined organic portion was
washed with H2O (50 mL) and dried (MgSO4) and solvent was
evaporated under reduced pressure. The residue was separated
by column chromatography on silica gel and the desired
1
compound 48 was obtained in good yield (130 mg, 73.8%). H
NMR (Bruker AM270 MHz, CDCl3): δ 1.96 (m, 6H), 2.91 (m,
2H), 3.22 (m, 2H), 7.24 (m, 2H), 7.39 (m, 2H). A mixture of
compound 48 (276 mg, 1.2 mmol), 14 (990 mg, 4.9 mmol),
K2CO3 (680 mg, 4.9 mmol), and KI (300 mg) in DME (10 mL)
was refluxed with stirring under an atmosphere of N2 for over
12 h. The solvent was removed under reduced pressure, brine
(50 mL) was added, and the resulting mixture was extracted
with CH2Cl2 (3 × 50 mL). The pooled organic phase was dried
(MgSO4), solvent removed under reduced pressure, and the
residue chromatographed over silica gel. Elution with EtOAc/
MeOH (7:3) yielded the desired product as an oil (300 mg, 63%)
and was converted to the oxalate salt. Mp 172-174 °C). 1H
NMR (Varian 300 MHz, CDCl3) δ 1.91 (m, 8H), 2.50 (m, 1H),
2.57 (t, J ) 7.1 Hz, 2H), 2.66 (m, 1H), 2.89 (m, 2H), 3.00 (t,
J ) 7.1 Hz, 2H), 7.13 (t, J ) 8.4 Hz, 2H), 7.25 (d, J ) 8.7 Hz,
2H), 7.37 (d, J ) 8.7 Hz, 2H), 7.98 (dd, J ) 2.1, 8.4 Hz, 2H).
Anal. (C22H27ClFNO6): C, H, N.
Molecu la r Mod elin g. Measurements of the pharmaco-
phoric distances for haloperidol and synthesized compounds
were conducted using SYBYL 6.8 (Tripos Associates, Inc., St
Louis, MO.). The X-ray crystal structure of haloperidol was
used as the initial structure. The structures of synthetic
compounds were built from SYBYL SKETCH with the chair
conformation for pyrrolidine and an axial hydroxyl group as
starting geometry. This structure was minimized by the Powell
5-Oxoazepan e-1,4-dicar boxylic Acid Dieth yl Ester (45).
Solutions of BF3‚Et2O (3.23 g, 22.8 mmol) and ethyl diazoac-

Analogues of Haloperidol
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 507
method with 0.001 kcal/(mol Å) as the termination method.
The minimized structure was then subjected to a systematic
search for possible allowed conformations. The distance be-
tween the center of ring A and the nitrogen was constrained
by the range allowed within the Humber pharmacophore
model, i.e., 4.9-6.9 Å. The conformation with the lowest energy
from the search results was used for measuring the distances
reported in Table 1. For compounds 9 and 10, an additional
distant constraint was imposed using the b distant range (4.9-
6.0 Å) given in the Humber Model.
was given for every 5 s (2 min maximum) the animal remained
on the bar. Mean scores from five animals per time point were
recorded for catalepsy (Figure 3).
Sta tistica l An a lysis. The Student’s t-test was used to
compare the three compounds used in the animal behavioral
tests. Results were considered significant at p < 0.05.
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institute of General
Medical Studies (NIGMS) for MBRS grant # GM 08111,
RCMI grant number G12 RR 03020 from NCRR, Title
III, and a Pfizer Graduate Research Grant in support
of M. L.-E. We are also grateful to Dr. Tom Gedris of
the Florida State Chemistry department for running the
NMR samples reported here.
Biology. Recep tor Bin d in g Stu d ies. Radioligand binding
studies were performed according to standard receptor binding
procedures.19 Briefly, an appropriate weight of frozen cell paste
expressing human dopamine D2, D3, or D4 receptors was
homogenized using a Brinkman Polytron model PT3000 (set-
ting 15 000 rpm, 15 s) in 50 mM Tris HCl buffer pH 7.4
containing 2 mM MgCl2. The homogenate was centrifuged for
10 min at 40 000g, washed, and recentrifuged. The final pellet
was resuspended in 50 mM Tris HCl buffer pH 7.4 containing
100 mM NaCl and 1 mM MgCl2 for the D2 cell homogenate;
50 mM Tris HCl buffer pH 7.4 containing 120 mM NaCl, 5
mM KCl, 2 mM CaCl2 and 5 mM MgCl2 for the D3 cell
homogenate; and 50 mM Tris HCl buffer pH 7.4 containing
120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM MgCl2 for
the D4 cell homogenate. Incubations were initiated by the
addition of tissue homogenate to wells of 96-well plates
containing [3H]spiperone (0.20 nM, 0.10 nM, for D2 and D4
assays, respectively) or 3H-7OH-DPAT (0.40 nM, for D3
assays) and varying concentrations of test compound, buffer,
or (+)-butaclamol in a final volume of 250 µL. Nonspecific
binding was defined as the radioactivity remaining in the
presence of a saturating concentration of a known inhibitor
(10 µM (+)-butaclamol). After a 15 min incubation at 37 °C
for D2 and D3 receptor assays or a 45 min incubation at 30°C
for D4 receptor assays, assay samples were filtered onto GF/B
filtermats that had been presoaked in 0.5% polyethylenimine,
using a Skatron cell harvester (Molecular Devices) and washed
with ice-cold 50 mM Tris buffer pH 7.4. Radioactivity was
quantified by liquid scintillation counting (Betaplate, Wallac
Instruments). The IC50 value (concentration at which 50%
inhibition of specific binding occurs) was calculated by linear
regression of the concentration-response data. Ki values were
calculated according to the Cheng-Prusoff equation, where
Ki ) IC50/(1 + (L/Kd)), where L is the concentration of the
radioligand used in the experiment and the Kd value is the
dissociation constant for the radioligand (determined previ-
ously by saturation analysis).
Ap om or p h in e-In d u ced Clim bin g Ster eotyp y. A modi-
fied climbing test by Needham et al. was used.20 Swiss male
mice (20-25 g, N ) 125) in groups of five per time point (30
min and 1, 2, 4, and 6 h) were injected ip with 0.1 mL/kg of
vehicle (0.1% lactic acid and 0.9 of saline) or increasing moles/
kilogram equivalent doses of dopamine antagonists haloperi-
dol, compound 7 (i.e., 5.3 × 10-7, 1.9 × 10-6, 3.2 × 10-6, 5.3 ×
10-6), and clozapine (3.1 × 10-5, 9.2 × 10-5, 1.5 × 10-4, 2.4 ×
10-4). Animals were then challenged with 2.8 × 10-6 mol/kg
of the agonist apomorphine placed in cylindrical wire cages
(12 cm in diameter, 14 cm in height) and observed for climbing
behavior at 10 and 20 min postdose. Climbing behavior was
assessed as follows: 4 paws on the cage floor ) 0 score; 2 or 3
paws on the cage ) 1 score; 4 paws on the cage ) 2 scores.
Scores were expressed as mean percent climbing inhibition and
are plotted in Figure 2.
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