1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction

Article abstract of DOI:10.1021/jm060279f

A new series of dopamine D₄ receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D₄ receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D₄ agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D₄ receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2- ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D ₄ agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D₄ receptor agonists.

Full text of DOI:10.1021/jm060279f

J. Med. Chem. 2006, 49, 5093-5109
5093
1-Aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one Oximes as Potent Dopamine D4 Receptor
Agonists for the Treatment of Erectile Dysfunction
Teodozyj Kolasa,* Mark A. Matulenko, Ahmed A. Hakeem, Meena V. Patel, Kathleen Mortell, Pramila Bhatia, Rodger Henry,
Masaki Nakane, Gin C. Hsieh, Marc A. Terranova, Marie E. Uchic, Loan N. Miller, Renje Chang, Diana L. Donnelly-Roberts,
Marian T. Namovic, Peter R. Hollingsworth, Brenda Martino, Odile El Kouhen, Kennan C. Marsh, Jill M. Wetter,
Robert B. Moreland, Jorge D. Brioni, and Andrew O. Stewart
Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101
ReceiVed March 13, 2006
A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was
designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the
amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy.
Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the
superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group
and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by
(E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-
chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favor-
able pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a
in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results
suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing
leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor
agonists.
Introduction
Selective D4 agonists may also have a therapeutic indication
in ADHD (attention deficit with hyperactivity disorder), memory
consolidation, or novelty seeking.18-21 Therefore, our quest for
a new structurally diverse class of selective D4 agonists has
continued. Most research in the D4 area has focused on discovery
of selective D4 antagonists,18 because of the antipsychotic
activity of clozapine (a preferential D4 antagonist). Only a few
selective D4 agonists 1-7 have been described in the literature
(Chart 1). Compounds 2 and 3 were the first reported selective
D4 agonists.22-24 Recently, four other compounds 4-7 were
described as selective dopamine D4 receptor agonists.25-28 The
agonists 5 and 6 were less efficacious (36% and 31%,
respectively) in functional assays than the recently described
agonist 4 (% E ) 83). The fourth one, 7, was a potent D4 agonist
(EC50 ) 50 nM) and showed high efficacy (83% vs 100%
efficacy of quinpirole).28
Erectile dysfunction (ED) is defined as the inability of the
male to achieve and maintain a penile erection sufficient for
adequate sexual intercourse. ED affects 20 to 30 million men
in the United States and over 150 million men worldwide.1
Pharmacological treatment of ED has been revolutionized since
the introduction of sildenafil, an orally active PDE5 inhibitor.2
Two other phosphodiesterase (PDE5) inhibitors, tadalafil3 and
vardenafil,4 have been approved recently for the treatment of
ED. These drugs can improve erections in >60% of men.
However, there are populations of patients who have low
incidence of erections or have contraindications to the use of
PDE5 inhibitors.5
Penile erection is regulated by peripheral factors and by the
central nervous system. The physiology of penile erection was
extensively reviewed.6-9 Sildenafil and two other PDE5 inhibi-
tors are representatives of the peripherally acting drugs. Dopam-
ine is one of the major modulatory neurotransmitters in the
central nervous system (CNS) responsible for the control of
sexual function.6,10 Two families of dopamine receptors have
been identified.11,12 The D1-like family consists of D1 and D5
receptors, is Gs-coupled, and activates adenylate cyclase. The
D2-like family consists of D2, D3, and D4 receptors, is Gi-
coupled, and inhibits adenylate cyclase. Apomorphine is a
nonselective dopamine D2-like receptor agonist and exhibits
efficacy in patients suffering ED.13
Our strategy to design the next generation of selective D4
agonists was to start from the known D4 agonist and make such
structural modifications that the D4 agonist efficacy would be
preserved in the emerging new class of compounds.
We selected 2 (EC50 ) 8.3 nM, % E ) 60), a selective D4
agonist (>100-fold selectivity over D1, >300-fold over D3, and
>400-fold over D2 receptor, 20-fold selectivity over R1- and
R2-adrenoceptors, 45-fold selectivity over 5HT1A, and 460-fold
selectivity over 5HT2A)
23 as our starting point. Modification of
We have reported that the dopamine D4 receptor subtype
activity is responsible for the erectogenic property of apomor-
phine and that the D2 receptor subtype activity is responsible
for the side effects of apomorphine, like nausea and emesis.14,15
The culmination of our efforts was discovery of 1, a selective
D4 agonist that facilitates penile erection in rats.16,17
the link between aryl and piperazine rings led to the oxime series
(Chart 2), showing good agonist activity at D4 receptors. First,
to improve the stability of 2 and its analogues (as aminals, they
have a limited stability in acidic conditions22), we replaced the
amide group with a methylene-keto group to get ketone.
However, because of carbonyl group metabolic liability,29,30 we
transformed the keto group into an oxime to obtain a novel class
of potent and efficacious dopamine D4 agonists.
* Corresponding author: tel 847-938-7907; fax 847-935-5466; e-mail
teodozyj.kolasa@abbott.com.
10.1021/jm060279f CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/27/2006

5094 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Kolasa et al.
Chart 1. Dopamine D4 Receptor Agonists Reported in Literature
Chart 2. Amide to Oxime Replacement Approach to Obtain
Scheme 2a
Novel D4 Agonists
Chemistry
Mannich reaction31,32 of alkyl aryl ketones 9a-w with
1-arylpiperazines (13a,b, 15a) and paraformaldehyde in the
presence of acid gave piperazinylpropanone derivatives (“ke-
tones”). The partially purified “ketones” were condensed with
hydroxylamine or O-alkylhydroxylamine in pyridine to provide
oximes (17-30, 38-40, 73, 75) or O-alkyloximes (31-37, 41-
71, 74, 76, 85a), respectively. In the case of commercially
available â-chloropropiophenones, the piperazinylpropanone
analogues were prepared by direct condensation of â-chloro-
propiophenones (10a-c, 11, 12) with 1-arylpiperazines (13c-
l, 14, 15b) in N,N-dimethylformamide (DMF) in the presence
of inorganic base or by refluxing of â-chloropropiophenone in
toluene with 2 equiv of 1-arylpiperazine.33 (Scheme 1) Some
O-alkyloximes 32-37 were also prepared by alkylation of an
oxime with an appropriate alkyl halide in the presence of
potassium t-butoxide.34
a Reagents and conditions: (a) K2CO3, DMF, RT; (b) MeONH2‚HCl,
pyridine.
idine with 2-methylpiperazine at 120 °C for 18 h. The oximes
with 4- (70, 71) and 3-piperidine (72a) cores were prepared as
described for piperazine-based analogues. The appropriate 4-
(15a,b) or 3-arylpiperidines 16 were prepared as described in
the literature.18,35-37 These were transformed into oxime deriva-
tives by using procedures applied for the preparation of
arylpiperazine analogues as depicted in Schemes 1 and 2.
R-Hydroxyketones were prepared from the crude 1-aryl-3-
(4-arylpiperazin-1-yl)propan-1-ones by treatment with iodoben-
zene diacetate in basic methanol as reported in the literature.38
Reaction with hydroxylamine or O-alkylhydroxylamine gave
the desired R-hydroxyoximes 79a,b or O-alkyloximes (77a,b,
84ab) (Scheme 3).
The oximes with one (73, 74) or three (75, 76) methylene
links were prepared by condensation of R-haloacetophenone 11
or γ-chlorobutyrophenone 12 with piperazine derivatives, fol-
lowed by reaction with O-methylhydroxylamine as described
for two-methylene link analogues. All of the arylpiperazines
were commercially available except for 3-methyl-1-pyridin-2-
ylpiperazine, which was synthesized by reaction of 2-bromopyr-
The R-methoxy analogues (78a,b, 80a,b) were isolated as
side products of the hydroxylation reaction. Both R-hydroxy
and R-methoxy derivatives reported in this paper were tested
as racemates.
Scheme 1a
a Reagents and conditions: (a) N-arylpiperazine, (CH2O)n, i-PrOH, concentrated HCl, reflux; (b) n ) 0, 1, 2, K2CO3, DMF, RT; (c) n ) 1.2 equiv of
N-arylpiperazine, toluene, reflux; (d) HONH2‚HCl, pyridine; (e) RONH2‚HCl, pyridine; (f) t-BuOK, t-butanol, R-X, reflux.

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5095
Scheme 3a
a Reagents and conditions: (a) (CH2O)n, i-PrOH, concentrated HCl, reflux; (b) (1) PhI(OAc)2, KOH, MeOH, RT, (2) 5% H2SO4, CHCl3, RT; (c) H2NOH‚HCl,
pyridine; (d) H2NOMe‚HCl, pyridine.
Scheme 4a
a Reagents and conditions: (a) (CH2O)n, i-PrOH, concentrated HCl, reflux; (b) MeONH2‚HCl, pyridine, RT.
R-Methyl analogue 81ab was prepared by condensing 4-chlo-
rophenyl ethyl ketone 9x with 4-(2-pyridyl)piperazine 13a
by the described Mannich procedure. Mannich reaction of
3,4′-dichloropropiophenone 10c followed by reaction with
O-methylhydroxylamine provided 82a and 83a (Scheme 4).
D2 binding affinity was determined by use of the D2-like agonist
radioligand [125I]-PIPAT on human D2L expressed in HEK-293
cells.
In earlier publications,17,41 it was demonstrated that the
presence of a 2-pyridine moiety in the 4-position of piperazine
(aryl2 group) provided D4 agonists with good potency and
efficacy. And indeed, a modification of 2 by replacement of
2-cyanophenyl group with 2-pyridyl group provided a compound
8 with better efficacy (71% vs 60% for 2) and almost the same
potency (EC50 ) 12.9 nM vs 8.3 nM for 2) (Chart 3).
Replacement of the amide moiety of 8 with the methyl-
eneoxime group (Chart 2) provided 22a, the prototype 1-aryl-
3-(4-pyridinepiperazin-1-yl)propanone oxime. This compound
was a potent D4 agonist (EC50 ) 2.3 nM vs 8.3 nM for 2 vs
12.9 nM for 8) with efficacy (74%) comparable to 8 (71%) and
2 (60%). The compound’s structure was confirmed by X-ray
crystallography to be the E-isomer (Chart 4).
Results and Discussion
All of the synthesized compounds were first tested for their
functional activity at D4 receptor in a calcium flux assay
(FLIPR), by use of recombinant human D4.4 receptor coex-
pressed with chimeric GRqo5 proteins in HEK-293 cells as
described in the literature.39 The results represent compound
agonist efficacy and compound potency and are shown in the
tables. The agonist efficacy is presented as the maximal efficacy
of agonist in comparison to 10 µM dopamine (100%). Com-
pound potency is expressed as an EC50 value, a concentration
giving half the maximal receptor stimulation. The compounds
were also tested for D2 agonist activity in a similar FLIPR assay
but by use of recombinant human D2L coexpressed with chimeric
GRqo5 proteins in HEK-293 cells.39 D4 ligand binding affinity
was determined by radioligand competition against [3H]-A-
369508,40 with membranes from the engineered HEK-293 cells.
The encouraging results prompted us to further explore the
structure-activity relationships (SAR) describing D4 agonism
in this series. SAR of phenyl substitution (aryl1 group) (Table
1) revealed that both E- and Z-isomers of oximes with
unsubstituted or monosubstituted phenyl with electron-donating

5096 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Chart 3. 2-Cyanophenyl to 2-Pyridyl Replacement
Kolasa et al.
Table 2. SAR of O-Alkyl Group of O-Substituted Oximes
human D4 FLIPR
compd
isomer
R
EC50,a nM
% Eb
17a
17b
31a
31b
32a
32b
33a
34a
35a
36a
37a
E
Z
E
Z
E
Z
E
E
E
E
E
H
H
Me
Me
Et
Et
n-Pr
Bu
i-Pr
allyl
CH2CN
4.4 ( 0.2
21.7 ( 1.8
32 ( 1
24.1 ( 0.3
28.5 ( 0.5
45 ( 15
320 ( 99
382 ( 16
164 ( 34
350 ( 100
33 ( 4
70
74
87
85
85
73
64
76
83
69
75
Chart 4. X-ray Crystal Structure of 22a
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%).
of the reaction, only limited examples were characterized. The
EC50 of Z-isomers 17b and 19b were 5 times less potent than
their E-counterparts 17a and 19a, respectively. The EC50 value
of the Z-analogue 18b was equipotent to that of the E-isomer
18a.
The efficacies of E- and Z-isomers of unsubstituted or
monosubstituted phenyl with electron-donating groups showed
comparable values with the exception of 23a, having an electron-
withdrawing cyano group in meta position (48% efficacy).
Another exception was the p-chloro analogue 25a, which had
exhibited reduced potency, also displayed only 46% efficacy.
Table 1. Oxime-Phenyl Ring Substitution SAR
The efficacies as well as potencies of disubstituted phenyl
analogues were substantially affected by the bulkiness of the
second substituent (29a vs 30a vs 22a or 27a vs 22a), whereas
analogues with two fluorines exhibited potencies and efficacies
comparable to monofluoro-substituted analogues (26a vs 20a
and 28a vs 24a). In general, the lack of E/Z selectivity in
efficacy was observed for unsubstituted or monosubstituted
Aryl1 congeners as well as for disubstituted aryl1 analogues.
Consequently, 22a emerged as the most potent compound (EC50
) 2.3 nM) within the oxime analogues, whereas 19a emerged
as the most efficacious analogue (% E ) 82). O-Alkylated
oxime analogues were also examined. First, we evaluated an
effect of alkyl chain elongation in O-alkyl analogues on D4
receptor efficacy and potency. (Table 2).
human D4 FLIPR
compd isomer
aryl1
EC50,a nM
% Eb
17a
17b
18a
18b
19a
19b
20a
21a
22a
23a
24a
25a
26a
26b
27a
28a
29a
30a
E
Z
E
Z
E
Z
E
E
E
E
E
E
E
Z
E
E
E
E
phenyl
phenyl
4.4 ( 0.2
21.7 ( 1.8
24 ( 1
70
74
74
64
82
72
72
73
74
48
74
46
74
70
55
78
4
2-chlorophenyl
2-chlorophenyl
2-methylphenyl
2-methylphenyl
3-fluorophenyl
3-chlorophenyl
3-methylphenyl
3-cyanophenyl
4-fluorophenyl
4-chlorophenyl
3,5-difluorophenyl
3,5-difluorophenyl
3,5-dimethylphenyl
2,4-difluorophenyl
25 ( 1
4.2 ( 0.2
20.3 ( 0.4
17.1 ( 0.7
11.9 ( 0.7
2.3 ( 0.7
13.1 ( 0.2
31 ( 10
475 ( 110
19.4 ( 0.3
17.5 ( 0.4
45.8 ( 0.7
8.9 ( 0.7
As shown in Table 2, O-methyl, both E- and Z-isomers 31a
and 31b, and O-ethyl E-isomer 32a gave agonists with the
highest potency and efficacy. Increasing the size of alkyl group
resulted in a drop of potency, except for cyanomethyl analogue
37a, and in a drop of efficacy except for 35a. The better potency
of 35a than its isomer 33a indicates that an O-alkyl group with
a two-carbon chain is preferred and that elongation of chain to
three-carbon or more leads to a decrease in potency and efficacy
(see also 34a, 36a). Subsequently, only oximes or their
O-methyl- or O-ethyl derivatives were used in the further SAR
studies.
2-benzyloxy-5-methylphenyl >10 000
2-hydroxy-5-methylphenyl 19.2 ( 0.3
73
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%).
Since our SAR studies of oximes started with the 2-pyridyl
derivative 22a, we decided to reexamine the aryl and heteroaryl
substituents in the 4-position of piperazine (aryl2 group). As
evident in Table 3, replacement of the 2-pyridine ring in 17a
with 3-substituted pyridine (38a and 38b) or other heterocycles
(39a, 39b or 40a) resulted in a 4-12-fold drop in potency
groups showed good potencies (EC50 ranging between 2.3 nM
for 22a and 31 nM for 24a). The exception was 25a, where
p-chloro substitution substantially decreased the potency (EC50
) 475 nM) of the agonist. Since Z-isomers were minor products

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5097
Table 3. SAR of 4-Piperazine Substitution (Aryl2 Group)
ortho substituent (41a vs 43a vs 46a vs 47a), with an
o-isopropoxy group affecting not only potency but also efficacy
(see 47a,b). The only exception was o-cyano substitution, which
gave a compound 42a with potency and efficacy similar to 32a.
The increasing size of ortho substituent probably forces a
pyridine ring into a less favorable axial orientation (as described
for pyrimidine analogue 39a), resulting in lower potency and
efficacy. The meta-substituted analogue 44a had low efficacy
(% E ) 30) and a very low potency (EC50 ) 2.7 µmol), whereas
para-substituted analogue 45a was inactive. Substitution of
pyridine in 32a in 3-position with a cyano group led to 48a,
showing lower efficacy (% E ) 64) and 5-fold drop in potency,
whereas the 3-methyl group substitution in 49a provided an
analogue with even lower potency and efficacy than 3-cyano
substitution. Replacing of 2-pyridine in 32a with 2-pyrimidine
(50a) resulted in almost complete loss of agonist activity (% E
) 26).
The possible pyrimidine-oxime interactions in pyrimidine-
based oxime should increase with oxime substitution, and indeed
50a, the O-ethyl analogue of 39a, showed a 15-fold drop in
potency (IC50 ) 601 nM vs 39 nM for 39a) and a 2-fold drop
in efficacy (26% vs 49% for 39a). The 2-thiazole-pyridine
replacement in 32a afforded a compound 51a with lower
efficacy (72% vs 86% for 32a) and almost 3 times lower potency
than 32a, indicating that the thiazole ring has a different
orientation than pyrimidine or that the smaller ring, like thiazole,
is tolerated even in the pseudoaxial orientation.
human D4 FLIPR
compd isomer
R
aryl2
2-pyridine
3-cyano-2-pyridine
3-cyano-2-pyridine
2-pyrimidine
2-pyrimidine
2-thiazole
2-pyridine
phenyl
2-cyanophenyl
2-methoxyphenyl
3-methoxyphenyl
4-methoxyphenyl
2-ethoxyphenyl
EC50,a nM
% Eb
17a
38a
38b
39a
39b
40a
32a
41a
42a
43a
44a
45a
46a
47ac
47bc
48a
49a
50a
51a
E
E
Z
E
Z
E
E
E
E
E
E
E
E
E
Z
E
E
E
E
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
4.4 ( 0.2
18 ( 1
20 ( 1
39.2 ( 10.4
69 ( 22
70
64
49
49
52
44
86
80
82
76
30
5
84
46
59
64
49
26
72
49.5 ( 14.6
28.5 ( 0.5
109 ( 38
48.7 ( 16.9
338 ( 82
2680 ( 1230
>10 000
347 ( 66
594 ( 46
601 ( 60
139 ( 38
253 ( 91
615 ( 189
81.8 ( 0.6
Me 2-isopropoxyphenyl
Me 2-isopropoxyphenyl
Et
Et
Et
Et
3-cyano-2-pyridine
3-methyl-2-pyridine
2-pyrimidine
2-thiazole
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%). c 4-Fluorophenyl group instead of phenyl group.
Chart 5. X-ray Crystal Structure of 39a
In general, only the 2-cyanophenyl group provided analogue
42a with potency and efficacy values similar to the pyridine
analogue 32a. In conclusion, the highest efficacy and the best
potency for oximes as well as for O-alkyloximes were found
for analogues 17a and 32a having unsubstituted pyridine as the
aryl2 moiety.
On the basis of the above results, analogues with unsubstituted
pyridine as aryl2 were selected for further SAR studies. We
demonstrated in Table 1 the effect of aryl1 group substitution
for oximes, and now the effect of phenyl ring (aryl1) substitution
for O-methyl-substituted oximes was reexamined.
As shown in Table 4, in the case of O-methyloximes (both
E- and Z-isomers), aryl1 unsubstituted and monosubstituted
phenyl analogues showed very good agonist potency (EC50
ranging between 13 and 89 nM), except for 55b and 60a, which
had EC50 > 100 nM. We could not identify a specific aryl1
substitution pattern controlling potency of E- and Z-isomers
within O-methyl analogues. Only for 3-substituted phenyl with
electron-donating groups were E-isomers (see 54a, 55a, and 56a)
more potent than their Z-counterparts (54b, 55b, and 56b). The
efficacy in general was very high, and agonists 56a, 58a, and
59a showed almost full efficacy. All E isomers of O-methy-
loximes were only slightly more efficacious than analogous
Z-isomers except for 54b (aryl1 ) 3-fluorophenyl) and 57b (aryl1
) 3-cyanophenyl) agonists. The potency but not the efficacy
of disubstituted phenyl analogues was affected more signifi-
cantly, except for E- and Z-3,5-difluoro analogues 61a,b. Most
disubstituted Z-isomers showed higher potency than the analo-
gous E-isomers (with the exception of 61b and 63b), even if
the efficacy of Z-isomers was on average 10% lower than that
of E-isomers. Replacement of phenyl group with 3-pyridine
provided a compound 68ab with activity as good as phenyl
analogues, indicating that heterocycles could be also tolerated
as aryl1 group. The compound was tested as an E/Z mixture
since the attempts to separate of isomers were unsuccessful.
accompanied by a significant reduction of efficacy. The pyri-
midine analogue 39a showed almost a 10-fold drop in potency
and 30% drop in efficacy when compared to its pyridine
analogue 17a.
The X-ray-crystallography of selected pyridine-based oximes
22a, 25a, and 75a and pyrimidine-based oxime 39a revealed
that the pyridine ring is positioned in pseudoequatorial orienta-
tion (see X-ray structure of 22a in Chart 4), whereas the
pyrimidine ring is in pseudoaxial orientation (see X-ray structure
of 39a in Chart 5). The pseudoaxial orientation could increase
steric and electronic interactions between the pyrimidine in
4-position and propanone oxime group in 1-position of pipera-
zine, which could negatively affect the potency and efficacy of
pyrimidine analogue. As we noticed before, both E- and
Z-isomers showed comparable potency and efficacy within
oxime analogues. In the case of O-alkyl-substituted analogues,
replacing the 2-pyridyl group in 32a with a phenyl moiety lead
to a compound 41a with good efficacy (% E ) 80), but >3
times weaker potency (EC50 ) 109 nM).
Similar to the aryl2 SAR we have seen in other D4 series,41,42
the unsubstituted phenyl analogue (41a) and ortho-substituted
phenyl compounds (42a, 43a, 46a) retained good efficacy.
However, their potencies decreased with increasing size of the
We showed earlier that 25a, an oxime with aryl1 p-chloro
substituent, showed a dramatic loss of potency (EC50 ) 475

5098 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Table 4. Phenyl Ring Substitution in O-Methyloximes
Kolasa et al.
Table 5. SAR of the Central Ring
human D4 FLIPR
compd isomer
R
R1
aryl2
2-pyridine
2-pyridine
2-pyridine
2-pyridine
2-pyridine
2-pyridine
X
EC50,a nM
% Eb
human D4 FLIPR
59a
59b
69a
69b
70a
70b
71a
71b
72a
E
Z
E
Z
E
Z
E
Z
E
H
H
Me H
Me H
H
H
H
H
H
H
H
N
N
N
N
37.6 ( 0.5 87
56.6 ( 16.3 68
333 ( 39
99 ( 14
195 ( 100 54
compd
isomer
aryl1
EC50,a nM
% Eb
31a
31b
52a
52b
53a
53b
54a
54b
55a
55b
56a
56b
57a
57b
58a
58b
59a
59b
60a
60b
61a
61b
62a
62b
63a
63b
64a
64b
65a
65b
66a
66b
67a
67b
68abc
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E/Z
phenyl
phenyl
2-chlorophenyl
2-chlorophenyl
2-methylphenyl
2-methylphenyl
3-fluorophenyl
3-fluorophenyl
3-chlorophenyl
3-chlorophenyl
3-methylphenyl
3-methylphenyl
3-cyanophenyl
3-cyanophenyl
4-fluorophenyl
4-fluorophenyl
4-chlorophenyl
32 ( 1
89
85
79
73
80
72
76
79
80
69
84
75
63
70
87
79
87
68
72
64
92
86
71
83
78
65
85
71
79
63
89
79
82
71
82
60
45
24.1 ( 0.3
42.3 ( 0.6
57.2 ( 10.7
74 ( 13
H
H
H
H
CH
CH >10 000
10
77
2-pyridine N-oxide CH
2-pyridine N-oxide CH
84 ( 24
46.4 ( 0.9 65
40.1 ( 0.8
44.6 ( 0.2
60.2 ( 10.3
88.9 ( 13.2
113 ( 18
27.6 ( 0.5
61 ( 1
63.7 ( 0.9
27.5 ( 0.5
48.8 ( 0.3
13.6 ( 0.2
37.6 ( 0.5
56.6 ( 16.3
183 ( 44
82 ( 12
37.2 ( 0.8
46.7 ( 0.4
175 ( 66
74.7 ( 17.4
249 ( 55
296 ( 35
148 ( 21
95 ( 17
2-pyridine H
CH2
606 ( 71 48
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%).
Table 6. Effect of Length of the Linker
4-chlorophenyl
4-bromophenyl
4-bromophenyl
human D4 FLIPR
3,5-difluorophenyl
3,5-difluorophenyl
3,5-dimethylphenyl
3,5-dimethylphenyl
2,4-dichlorophenyl
2,4-dichlorophenyl
3-chloro-4-fluorophenyl
3-chloro-4-fluorophenyl
3,4-dichlorophenyl
3,4-dichlorophenyl
4-chloro-3-methylphenyl
4-chloro-3-methylphenyl
3,4-dimethylphenyl
3,4-dimethylphenyl
3-pyridyl
compd
isomer
R
n
EC50,a nM
% Eb
73a
73b
74a
74b
24a
58a
58b
75a
75b
76a
76b
E
Z
E
Z
E
E
Z
E
Z
E
Z
H
H
0
0
0
0
1
1
1
2
2
2
2
>10000
32
49
26
74
74
87
79
62
65
60
59
26 ( 1
4290 ( 1160
43.8 ( 0.7
31 ( 1
Me
Me
H
Me
Me
H
H
Me
Me
48.8 ( 0.3
13.6 ( 0.2
9.5 ( 2.5
59.3 ( 1.6
41.7 ( 0.9
33.5 ( 1.2
542 ( 37
341 ( 49
135 ( 11
98 ( 26
108 ( 26
91 ( 10
33.3 ( 0.7
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%).
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%). c 5:2 Mixture of E:Z isomers.
The drop in potency and efficacy of 70a, a 4-piperidine
analogue of 59a, could be attributed to the axial orientation of
the polar pyridinyl group in the 4-position of the piperidine ring.
For the polar 4-substituents of piperidine, the axial orientation
is favored.45 On the other hand, the oxidation of pyridine to its
N-oxide would force the larger pyridine N-oxide back into an
equatorial position. This should result in pyridine N-oxide-
piperidine conformation similar to pyridine-piperazine ana-
logues. And indeed, as we expected, the D4 potency and efficacy
were restored. Both E-isomer 71a and Z-isomer 71b showed
activity comparable with the activity of piperazine-based oximes.
Since the oxime series originated from the amide to meth-
yleneoxime replacement (Chart 2), our SAR was focused on a
two-methylene linker between the oxime group and a piperazine
ring. In the final step of our SAR study, we evaluated the effect
of the linker length and substitution. Comparison of the length
of linker (Table 6) clearly confirmed that E-oximes, both free
and O-methyl-substituted, with two-methylene linkers offered
the highest efficacy when compared to one-or three-methylene
linker analogues (24a and 58a vs 73b, 74b vs 75a, 76a).
The one-methylene linker E-oxime 73a (same orientation of
O-methyl group as in Z-oximes with two- or three-methylene
linkers) showed very low efficacy and EC50 >10 µM, whereas
the Z-isomer of three-methylene linker oxime 75b was also a
nM) and efficacy (% E ) 46) compared to the o- and m-chloro
analogues (see Table 1). Alkylation of the oxime with a methyl
group restored the potency (EC50 ) 38 nM) and efficacy (% E
) 87) of 59a (see Table 4). This unexpected result could imply
that the more rigid structure of 25a, if we assume an internal
hydrogen bond of oxime with the nitrogen of piperazine, is
forcing a chlorine atom in less favorable orientation. O-
methylation of oxime 25a would eliminate this intramolecular
hydrogen bond and lead to a more favorable orientation of
chlorine in the binding pocket.43,44
The nature of the central ring was also important for activity.
As shown in Table 5, replacement of piperazine ring with
2-methylpiperazine (69a,b), 4-piperidine (70a,b), or 3-piperidine
(72a) resulted in profound loss of potency and efficacy. The
potency and efficacy of E-isomer 70a, a 4-piperidine analogue
of 59a, dropped very significantly and its Z-isomer 70b became
completely inactive. The replacement of piperazine ring with
3-piperidine ring gave even more dramatic results than with
the 4-piperidine replacement. A 3-(2-pyridyl)piperidine ana-
logue, E-isomer 72a (a 1,3 regioisomer of 70a), showed more
than 3-fold loss of potency (EC50 ) 606 nM for 72a vs 195
nM for 70a) even though their efficacies remained almost the
same.

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5099
Table 8. Binding Data for Selected Compounds
Table 7. Evaluation of Linker Substitution
compd
D
4.4, Ki,a nM
D2L, Ki,b nM
D2/D4
17a
31a
32a
37a
51a
53a
54a
54b
55a
56a
56b
57b
58a
58b
59a
61a
61b
64a
65a
66b
67a
68ab
69a
70a
70b
74b
77a
77b
81ab
82a
25.4 ( 2
22.8 ( 6.7
38 ( 9
257 ( 16
172 ( 76
128 ( 55
140 ( 27
257 ( 4
10.3
7.5
3.3
1.6
1.5
10
88 ( 16
168 ( 18
11.4 ( 1.8
13.9 ( 1.4
6.4 ( 0.2
13.5 ( 3.1
8 ( 1.6
32.1 ( 8.0
20.1 ( 1.1
14.2 ( 2.8
53.3 ( 5.8
38.2 ( 8.8
110 ( 33
6.3 ( 1
71.2 ( 11.9
6.4 ( 1.7
11.6 ( 3.7
27.5 ( 3.7
130 ( 7
67.1 ( 8.8
134 ( 17
90 ( 8.8
112 ( 9
101 ( 5
7.5
18
46.6 ( 4.5
98.7 ( 7.4
68.4 ( 4.9
68.0 ( 5.3
125 ( 20.6
168 ( 40
221 ( 17.3
63.8 ( 26.2
132 ( 8
human D4 FLIPR
7.3
8.5
2.1
3.6
3.8
4.2
1.7
1.2
36
compd
aryl1
R1
R2
EC50,a nM
% Eb
77a
77b
78a
78b
79a
79b
80a
80b
4-chlorophenyl OH
4-chlorophenyl OH
4-chlorophenyl OMe
4-chlorophenyl OMe
3-methylphenyl OH
3-methylphenyl OH
3-methylphenyl OMe
3-methylphenyl OMe
Me
46 ( 1
89
94
79
83
66
81
53
69
62
93
60
80
40
Me 22.6 ( 0.3
Me
Me
H
H
H
H
Me
Me
195 ( 1
285 ( 1
44.8 ( 0.5
4.9 ( 2.3
5370 ( 1200
34.5 ( 0.6
459 ( 26
206 ( 41
225 ( 34
171 ( 29.3
64.5 ( 11.6
60.9 ( 2.1
137 ( 20.3
1820 ( 320
76.5 ( 7.9
25.3 ( 1.8
19.4 ( 1.4
2530 ( 170
995 ( 170
368 ( 55
146 ( 21
164 ( 18
2.4
11
5
81abc 4-chlorophenyl Me
82a
83a
4-chlorophenyl CH2NHOCH3
4.9
14.8
1.1
0.2
0.2
1.2
8.8
2.5
0.4
1.4
4-chlorophenyl CH2OCH(CH3)2 Me 3210 ( 120
84abd 3-pyridyl
OH
Me
Et
123
4760 ( 370
85a
a Mean values for agonists (SEM, n g 3). b Efficacy relative to 10 µM
dopamine (100%). c 3:1 mixture of E:Z isomers. d 2:1 mixture of Z:E
isomers.
2050 ( 40
113 ( 11
150 ( 14
346 ( 13
120 ( 11
good D4 agonist. On the other hand, the Z-one-methylene linker
analogue 73b showed potency comparable to its E-two-
methylene linker (24a) and three-methylene linker (75a) coun-
terparts, although the efficacy was significantly lower. The E-O-
methyl analogue 74a had low potency (EC50 ) 4.29 µM) and
efficacy of 26% in comparison to the same stereo-related
Z-isomers of two- and three-methylene linker analogues, 58b
and 76b, respectively. The Z-isomer 74b showed potency and
efficacy almost as good as two-methylene linker compound
58a). The three-methylene linker O-methylated analogues had
almost the same potency and efficacy regardless of Z or E
stereochemistry, and in addition 76b showed D2 agonist activity
in FLIPR (EC50 ) 366 nM and % E ) 65). In conclusion, the
two-methylene linker was confirmed to be the most optimal
linker for further evaluation.
a Mean values for binding affinity with D4-selective agonist radioligand
[3H]-A-36950840 (SEM, n g 4). b Mean values for binding affinity with
D2-like agonist radioligand [125I]-PIPAT (SEM, n g 4).
Compounds were tested for D2 functional agonist activity to
determine functional D2/D4 subtype selectivity, since the D2
agonist activity was associated with the emetic effects of
apomorphine.14,15 Coexpression of D2L receptor with chimeric
GRqo5 in HEK-293 cells allowed determination of functional
selectivity against D2L receptor and in identifying both agonists
and antagonists.39 None of the tested compounds showed D2
agonist (EC50 >10 µM) or antagonist (IC50 >10 µM) activities
in this assay.
Since tested compounds showed no functional D2 agonist
activity and no functional D2 antagonist activity, the selected
compounds were also further evaluated in D4 and D2 binding
assays to further define D2/D4 selectivity. D2-like agonist
radioligand [125I]-PIPAT was utilized to determine binding
affinity for selected oxime-based agonists at human D2L receptor.
The results are shown in Table 8. The fact that compounds have
affinity for D2L receptor but showed no efficacy is not new.
Kenakin and Onaran46 already discussed this lack of correlation
between affinity and efficacy.
As seen in Table 9, only a few analogues, 17a, 53a, 54b,
61b, and 68ab, showed good D2/D4 selectivity based on binding
affinities. In general, the series showed modest binding selectiv-
ity over D2 receptor. Compounds with the 4-piperidine core
(70a,b) were less selective on the basis of the D2 binding assay.
A number of compounds with good D4 activity in FLIPR
were selected for in vivo testing in a rat penile erection model.
In this model,47 rats (n ) 8-30) are observed over a 60 min
period with and without the drug, and the number of incidence
of erections is reported. The results are reported in Table 9.
The compounds 59a and 64a showed the most robust activity
in rat penile erection model. The compounds were as effective
as the most efficacious dose of apomorphine (0.1 µmol/kg), and
59a was 3 times more potent than apomorphine in this model.
Evaluation of substitution of the two-methylene linker was
the final step of optimization (see Table 7). The substitution of
R-carbon of the linker of Z-oxime (equivalent to the E-isomer
with unsubstituted linker) with a hydrogen donor, like hydroxy
or amino groups, preserved or even slightly improved the
efficacy of compounds (for example, 77b and 82a vs 59a or
79b vs 22a). Protection of hydroxy group and eliminating the
possible internal hydrogen bonding resulted in lower potency
as well as efficacy (for example, 78a vs 77a and 78b vs 77b,
or 80a vs 79a and 80b vs 79b). The other non-hydrogen donor
substituents also caused a loss of both potency and efficacy
(81ab, 83a vs 59a), confirming that hydrogen donors in
R-position might stabilize the more active oxime conformation
by internal hydrogen bonding. The R-hydroxy analogue of aryl1
3-pyridine 84ab, however, showed almost 4-fold loss of potency
comparing to the deshydroxy analogue 68ab, even if the efficacy
was preserved. Connecting the R-substituent to the phenyl ring
to form 3,4-dihydro-2H-naphthalen-1-one analogue 85a led to
dramatic loss of potency and efficacy (EC50 ) 4760 nM and %
E ) 40). More SAR studies in substitution of both R- and
â-carbons of the linker, as well as separation of chiral isomers,
are necessary to fully evaluate the effect of linker substitution
on the selectivity and activity of oxime-based D4 agonists.

5100 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Kolasa et al.
Table 9. In Vivo Proerectile Activity of Selected Oximesa
of oxime series. The representative compound 59a did not elicit
emesis in ferrets at any tested dose (0.03-3 µmol/kg after
subcutaneous administration), confirming the lack of agonist
activity at D2 receptors.
dose giving
max. efficacy,
µmol/kg
max. incidence of
erections in rat, %
compd
apomorphine
2
17a
31a
32a
58a
59a
61a
64a
0.1
0.3
0.3
0.1
0.3
0.3
0.03
0.1
1.0
0.3
0.1
0.3
85
79
60
77
55
50
85
68
85
76
68
77
Conclusion
In conclusion, we demonstrated a successful introduction of
a methyleneoxime functionality that led to a novel class of
dopamine D4 receptor agonists. These compounds showed very
good agonist potencies and high efficacies at D4 receptor.
Among all of the 4-arylpiperazines tested, the highest potency
and efficacy was observed for 4-pyridin-2-yl-piperazine ana-
logues. The 1,4-disubstituted piperazine analogues and two-
methylene linker between oxime and piperazine provided the
most potent and efficacious agonists. Selected compounds
showed good pharmacokinetics and good in vivo activity in the
rat penile erection model. Consequently, 59a and oxime series
represent an exciting lead for developing the next generation
of dopamine D4 receptor agonists, potentially useful in treatment
of erectile dysfunction and other CNS indications.
65a
67a
74b
a The compounds were administered subcutaneously.
Table 10. Pharmacokinetic Profiles of 59a, 64a, and 17a
rat
dog
F, % Vâ, L/kg T1/2,
compd dose,a 1 mg/kg Vâ, L/kg T1/2,
h
h
F, %
59a
59a
64a
64a
17a
17a
sc
po
sc
po
sc
po
4.3
8.2
1.0
1.9
2.3
ntb
UC
0.8
UC
94.8
16.3
nt
18.6
68.1
0.0
4.8
3.8
1.8
6.2
6.1
UC
39.8
42.9
0.0
Experimental Section
Chemistry General. Melting points were taken on a Thomas-
Hoover melting apparatus and are uncorrected. H NMR spectra
1
were recorded on a Nicolet QE-300 (300 MHz) instrument with
Me4Si (TMS) as the internal standard; chemical shifts are expressed
in parts per million (ppm) relative to TMS in δ units. Mass spectra
were obtained with a Hewlett-Packard HP5985 or Finnigan
SSQ7000 spectrometer by use of different techniques such as
desorption chemical ionization (DCI), electrospray ionization (ESI),
or atmospheric pressure chemical ionization (APCI) as specified
for individual compounds. X-ray crystallography was taken on a
PS4 Siemens apparatus with CCD detector. Microanalyses were
performed by the Robertson Microlit Laboratories, Inc., Madison,
NJ. Unless otherwise specified, all solvents and reagents were
obtained from commercial suppliers and used without further
purification.
a Compound was administered subcutaneously (sc) or orally (po). b Not
tested.
Clozapine [3 µmol/kg, administered intraperitoneally (ip)] and
haloperidol (1 µmol/kg, ip) blocked the erectogenic effect of
59a but domperidone (10 µmol/kg, ip) did not. These data
indicate that the effect is mediated via central dopaminergic
mechanism, since the peripheral dopamine antagonist domp-
eridone did not block the proerectile effect of 59a.
The most potent compounds in vivo were further evaluated
in rat and dog to determine pharmacokinetic profiles (Table 10).
Compounds 59a and 64a were found to be orally bioavailable
in rat and dog after 1 mg/kg dose. Compound 59a showed F )
16.3% and T1/2 > 2 h in rat and F ) 39.8% and T1/2 > 6 h in
dog, whereas 64a showed F ) 18.6% in rat and F ) 42.9%
with T1/2 in dog the same as for 59a. Both O-alkyloximes were
characterized by high volumes of distribution values: Vâ ) 4.3
and 8.2 L/kg for 59a and 64a, respectively in rat and Vâ ) 4.8
L/kg for 59a and 3.8 L/kg for 64a, respectively, in dog. For
comparison, the Vâ value of oxime 17a was only 1.0 L/kg in
rat and 1.8 L/kg in dog. The higher volumes of distribution of
59a and 64a than 17a are reflected in the longer elimination
half-lives of O-methyloximes. In conclusion of pharmacokinetic
studies, O-alkyloximes showed good oral bioavailability (∼40%)
and good half-life (T1/2 > 6 h) in dog.
Compound 59a, a representative of the oxime series, was
evaluated for cardiovascular and CNS effects. Compound 59a
was administered in anesthetized rats and achieved over 750
times the estimated efficacious plasma concentration (1.6 ng/
mL in rat PE model) without any sustained dose-related effects
on mean arterial pressure, heart rate, or hindquarters vascular
resistance. Compound 59a showed 14.7% prolongation of canine
cardiac Purkinje fiber repolarization at 100 times the efficacious
plasma level.
N-Arylpiperazines were commercially available except for
3-methyl-1-(pyridin-2-yl)piperazine, the synthesis of which will be
described.
General Procedure for Preparation of 1-Aryl-3-(4-arylpiper-
azin-1-yl)propan-1-one Oximes or O-Alkyloximes: Method A.
1-Aryl-3-(4-arylpiperazin-1-yl)-1-ethanone analogues were prepared
as described in the literature.31 To a mixture of N-arylpiperazine
(7 mmol), 1-arylethanone (10 mmol), and paraformaldehyde (10
mmol) in 2-propanol (20 mL) was added slowly concentrated HCl
(23 mmol) through the top of the condenser, and the resulting
reaction mixture was refluxed for 12-24 h. The reaction was cooled
and concentrated under reduced pressure, and the residue was
treated carefully with saturated solution of NaHCO3. It was then
extracted with ethyl acetate, washed with brine, dried with
anhydrous MgSO4, and concentrated under reduced pressure. The
oily residue was passed through a short pad of silica gel, with ethyl
acetate as eluent to afford a roughly purified ketone, which was
used directly to the next step.
Crude 1-aryl-3-(4-arylpiperazin-1-yl)propan-1-one (∼1 mmol)
was dissolved in pyridine (10 mL) and treated with hydroxylamine
hydrochloride (2 mmol) or O-alkylhydroxylamine hydrochloride
for 12 h at ambient temperature. The reaction mixture was
concentrated under reduced pressure, and the residue was treated
with saturated solution of NaHCO3 and extracted with ethyl acetate.
The acetate layer was washed with brine, dried with anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography with ethyl acetate as eluent
for free oximes and methylene chloride/acetone 4:1 in the case of
O-alkyloximes to provide the desired compounds.
No CNS side effects were observed in mouse Irvin test up to
10 µmol/kg (>2000 times the efficacious dose). Low hypoac-
tivity, piloerection, ptosis, and hypothermia were observed at
10 µmol/kg.
Since D2 agonism was associated with the emetic activity of
apomorphine, ferrets were used to evaluate the emetic potential
General Procedure for Preparation of 1-Aryl-3-(4-arylpiper-
azin-1-yl)propan-1-one O-Alkyloximes: Method B. Crude 1-Aryl-

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5101
3-(4-arylpiperazin-1-yl)propan-1-one oxime (1 mmol) was dissolved
in tert-butyl alcohol (15 mL) and treated with powdered potassium
t-butoxide (1 mmol). The mixture was refluxed for ∼30 min until
the solution became clear. It was then cooled to ambient temper-
ature, alkyl halide (1 mmol) was added, and the new mixture was
refluxed for an additional 1 h. The solvent was then removed under
reduced pressure and the residue was purified by column chroma-
tography (silica gel, 4:1 methylene chloride/acetone as eluent) to
provide the desired O-alkyloximes.
General Procedure for Preparation of 1-Aryl-3-(4-arylpiper-
azin-1-yl)propan-1-one Oximes or O-Alkyloximes from 3-Aryl-
1-chloro-3-propanones: Method C. A mixture of 1-aryl-3-chloro-
1-propanones (5 mmol) and N-arylpiperazine (10 mmol) in toluene
(35 mL) was refluxed for 8-16 h. The reaction was cooled to
ambient temperature, and the solid was filtered off and washed with
toluene. The filtrate and washings were combined and concentrated
under reduced pressure. The residue was treated with hydroxylamine
hydrochloride (10 mmol) or O-alkylhydroxylamine hydrochloride
(10 mmol) in pyridine (25 mL) for 12-16 h. The solvent was then
removed under reduced pressure and the residue was purified by
column chromatography.
Method D. N-Arylpiperazine (10 mmol), 1-aryl-3-chloro-1-
propanones (10 mmol), and anhydrous potassium carbonate (10
mmol) were combined in DMF (25 mL), and the resulting mixture
was heated at 40 °C for 14 h. It was then poured into water and
extracted with ethyl acetate. The acetate extract was washed with
water and with brine, dried with anhydrous MgSO4, and concen-
trated under reduced pressure. The residue was treated with
hydroxylamine hydrochloride (10 mmol) or O-alkylhydroxylamine
(10 mmol) as described for method C.
(E)-3-(4-Pyridin-2-ylpiperazin-1-yl)-1-(m-tolyl)propan-1-
one Oxime (22a). Compound was prepared from 1-(m-tolyl)-
ethanone, 1-pyridin-2-ylpiperazine, and hydroxylamine hydrochlo-
ride by ethod A in 64% overall yield: mp 146-147 °C; 1H NMR
(300 MHz, DMSO-d6) δ 2.33 (s, 3H), 2.50 (m, 6H), 2.92 (m, 2H),
3.45 (t, J ) 6 Hz, 4H), 6.62 (dd, J ) 7 and 4.5 Hz, 1H), 6.80 (d,
J ) 9 Hz, 1H), 7.18 (d, J ) 6 Hz, 1H), 7.28 (t, J ) 7 Hz, 1H),
7.48 (m, 3H), 8.10 (dd, J ) 4.5 Hz, 3 Hz, 1H); MS (DCI/NH3) m/z
325 (M + H)+. Anal. Calcd (C19H24N4O‚0.1H2O): C, H, N.
10.65 (s, 1H); MS (ESI+) m/z 345 (M + H)+; MS (ESI--) m/z
343 (M-H)-. Anal. Calcd (C18H21ClN4O): C, H; N calcd 16.25,
found 17.75.
(E)-3-(4-Pyridin-2-ylpiperazin-1-yl)-1-(o-tolyl)propan-1-one
Oxime (19a) and (Z)-3-(4-Pyridin-2-ylpiperazin-1-yl)-1-(o-tolyl)-
propan-1-one Oxime (19b). Compounds were prepared from 1-(o-
tolyl)ethanone, 1-pyridin-2-ylpiperazine, and hydroxylamine hy-
drochloride by method A in 49% and 16% overall yield, respectively.
19a: mp 108-110 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s,
3H), 2.38 (m, 6H), 2.86 (t, J ) 7 Hz, 2H), 3.37 (t, J ) 4 Hz, 4H),
6.62 (dd, J ) 7 and 4 Hz, 1H), 6.77 (d, J ) 7 Hz, 1H), 7.22 (m,
6H), 7.49 (m, 1H), 8.08 (m, 1H), 11.00 (s, 1H); MS (ESI+) m/z
325 (M + H)+; MS (ESI-) m/z 323 (M - H)-. Anal. Calcd
(C19H24N4O): C, H, N. 19b: mp 128-130 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.20 (s, 3H), 2.40 (m, 6H), 2.64 (t, J ) 7 Hz, 2H),
3.40 (t, J ) 4 Hz, 4H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.77 (d, J
) 7 Hz, 1H), 7.10 (m, 1H), 7.20 (m, 3H), 7.50 (m, 1H), 8.08 (m,
1H), 10.48 (s, 1H); MS (ESI+) m/z 325 (M + H)+; MS (ESI-)
m/z 323 (M - H)-. Anal. Calcd (C19H24N4O): C, H, N.
(E)-1-(3-Fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-
1-one Oxime (20a). Compound was prepared from 1-(3-fluorophe-
nyl)ethanone, 1-pyridin-2-ylpiperazine, and hydroxylamine hydro-
1
chloride by method A in overall 45% yield: mp 152-153 °C; H
NMR (300 MHz, DMSO-d6) δ 2.50 (m, 6H), 2.94 (m, 2H), 3.22
(t, J ) 4 Hz, 4H), 6.61 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 7
Hz, 1H), 7.20 (m, 1H), 7.46 (m, 4H), 8.09 (m, 1H), 11.42 (s, 1H);
MS (ESI+) m/z 329 (M + H)+; MS (ESI-) m/z 327 (M - H)-.
Anal. Calcd (C18H21FN4O‚0.25H2O): C, H, N.
(E)-1-(3-Chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one Oxime (21a). Compound was prepared from 1-(3-
chlorophenyl)ethanone, 1-pyridin-2-ylpiperazine, and hydroxy-
lamine hydrochloride by method A in overall 42% yield: mp 139-
140 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.50 (m, 6H), 2.94 (m,
2H), 3.22 (t, J ) 4 Hz, 4H), 6.61 (dd, J ) 7 and 4 Hz, 1H), 6.80
(d, J ) 7 Hz, 1H), 7.43 (m, 2H), 7.50 (m, 1H), 7.60 (m, 1H), 7.67
(m, 1H), 8.10 (m, 1H), 11.44 (s, 1H); MS (ESI+) m/z 345 (M +
H)+; MS (ESI-) m/z 343 (M - H)-. Anal. Calcd (C18H21ClN4O):
C, H, N.
3-[1-Hydroxyimino-3-(4-pyridin-2-ylpiperazin-1-yl)propyl]-
benzonitrile (23a). Compound was prepared from 3-acetylben-
zonitrile, 1-pyrid-2-ylpiperazine, and hydroxylamine hydrochloride
(E)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one
Oxime (17a) and (Z)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one Oxime (17b). Compounds were prepared from
3-chloro-1-phenylpropan-1-one, 1-pyridin-2-ylpiperazine, and hy-
droxylamine hydrochloride by method D in 55% and 10% overall
1
by method A in overall 20% yield: mp 147-149 °C; H NMR
(300 MHz, DMSO-d6) δ 2.48 (m, 6H), 2.96 (t, J ) 7 Hz, 2H),
3.22 (t, J ) 4 Hz, 4H), 6.61 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J
) 7 Hz, 1H), 7.46 (m, 1H), 7.60 (t, J ) 7 Hz, 1H), 7.82 (m, 1H),
8.00 (m, 1H), 8.09 (m, 2H), 11.60 (s, 1H); MS (ESI+) m/z 336 (M
+ H)+; MS (ESI-) m/z 334 (M - H)-. Anal. Calcd (C19H21N5O‚
0.2EtOAc): C, H, N.
1
yield, respectively. E-isomer: mp 169-170 °C; H NMR (300
MHz, DMSO-d6) δ 2.50 (m, 6H), 2.95 (t, J ) 7 Hz, 2H), 3.42 (t,
J ) 4.5 Hz, 4H), 6.61 (dd, J ) 7 and 4 Hz, 1H), 6,80 (d, J ) 9 Hz,
1H), 7.22 (t, J ) 9 Hz, 2H), 7.39 (m, 3H), 7.51 (m, 1H), 7.65 (m,
2H), 8.10 (m, 1H), 11.13 (s, 1H); MS (DCI/NH3) m/z 311 (M +
H)+. Anal. Calcd (C18H22N4O‚0.25H2O): C, H, N. Z-isomer: mp
130-132 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.40 (m, 4H), 2.70
(t, J ) 7 Hz, 2H), 3.35 (m, 2H), 3.42 (m, 4H), 6.61 (dd, J ) 7 and
4 Hz, 1H), 6,79 (d, J ) 9 Hz, 1H), 7.40 (m, 6H), 8.09 (m, 1H),
10.58 (s, 1H); MS (DCI/NH3) m/z 311 (M + H)+.
(E)-1-(4-Fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-
1-one Oxime (24a). Compound was prepared from 3-chloro-1-(4-
fluorophenyl)-1-propanone, 1-pyridin-2-ylpiperazine, and hydrox-
ylamine hydrochloride by method D in overall 57% yield: mp 159-
160 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.50 (m, 6H), 2.93 (m,
2H), 3.43 (t, J ) 4.5 Hz, 4H), 6.61 (dd, J ) 9 and 6 Hz, 1H), 7.80
(d, J ) 9 Hz, 1H), 7.22 (t, J ) 9 Hz, 2H), 7.51 (m, 1H), 7.70 (m,
2H), 8.10 (m, 1H), 11.26 (s, 1H); MS (DCI/NH3) m/z 329 (M +
H)+. Anal. Calcd (C18H21FN4O‚0.5H2O): C, H, N.
(E)-1-(4-Chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one Oxime (25a). Compound was prepared from 3-chloro-
1-(4-chlorophenyl)propan-1-one, 1-pyridin-2-ylpiperazine, and hy-
droxylamine hydrochloride by method C in overall 61% yield: mp
188-190 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.50 (m, 6H), 2.93
(m, 2H), 3.43 (t, J ) 4.5 Hz, 4H), 6.61 (dd, J ) 7 and 4 Hz, 1H),
6.80 (d, J ) 9 Hz, 1H), 7.50 (m, 3H), 7.66 (m, 2H), 8.10 (m, 1H),
11.38 (s, 1H); MS (DCI/NH3) m/z 345 (M + H)+. Anal. Calcd
(C18H21ClN4O): C, H, N.
(E)-1-(2-Chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one Oxime (18a) and (Z)-1-(2-Chlorophenyl)-3-(4-pyridin-
2-ylpiperazin-1-yl)propan-1-one Oxime (18b). Compounds were
prepared from 1-(2-chlorophenyl)ethanone, 1-pyridin-2-ylpipera-
zine, and hydroxylamine hydrochloride by method A in 43% and
1
15% overall yield, respectively. 18a: mp 161-162 °C; H NMR
(300 MHz, DMSO-d6) δ 2.35 (t, J ) 4 Hz, 4H), 2.40 (t, J ) 7 Hz,
2H), 2.93 (t, J ) 7 Hz, 2H), 3.35 (t, J ) 4 Hz, 4H), 6.62 (dd, J )
7 and 4 Hz, 1H), 6.77 (d, J ) 7 Hz, 1H), 7.39 (m, 3H), 7.49 (m,
2H), 8.08 (m, 1H), 11.26 (s, 1H); MS (ESI+) m/z 345 (M + H)+;
MS (ESI-) m/z 343 (M - H)-. Anal. Calcd (C18H21ClN4O‚
(E)-1-(3,5-Difluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one Oxime (26a) and (Z)-1-(3,5-Difluorophenyl)-3-(4-
pyridin-2-ylpiperazin-1-yl)propan-1-one Oxime (26b). Com-
pounds were prepared from 1-(3,5-difluorophenyl)ethanone, 1-pyridin-
2-ylpiperazine, and hydroxylamine hydrochloride by method A in
1
0.15H2O): C, H, N. 18b: mp 155-157 °C; H NMR (300 MHz,
DMSO-d6) δ 2.40 (t, J ) 4 Hz, 6H), 2.64 (t, J ) 7 Hz, 2H), 3.40
(t, J ) 4 Hz, 4H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.77 (d, J ) 7
Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.48 (m, 2H), 8.08 (m, 1H),

5102 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Kolasa et al.
overall 38% and 5% yield, respectively. 26a: mp 150-151 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.50 (m, 6H), 2.95 (t, J ) 7 Hz,
2H), 3.24 (t, J ) 4 Hz, 4H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80
(d, J ) 7 Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.46 (m, 1H), 8.09
(m, 1H), 11.60 (s, 1H); MS (ESI+) m/z 347 (M + H)+; MS (ESI-)
m/z 345 (M - H)-. Anal. Calcd (C18H20F2N4O): C, H, N. 26b:
mp 123-126 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.42 (m, 4H),
2.50 (m, 2H), 2.70 (t, J ) 7 Hz, 2H), 3.42 (t, J ) 4 Hz, 4H), 6.62
(dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 7 Hz, 1H), 7.20 (m, 3H),
7.50 (m, 1H), 8.09 (m, 1H), 10.90 (s, 1H); MS (ESI+) m/z 347 (M
+ H)+; MS (ESI-) m/z 345 (M - H)-.
3H), 6.08 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9
Hz, 1H), 7.45 (m, 3H), 7.60 (m, 1H), 7.70 (m, 2H), 8.16 (m, 1H);
MS (DCI/NH3) m/z 325 (M + H)+. Anal. Calcd (C19H24N4O‚
1
C4H4O4): C, H, N. 31b maleate salt: mp 96-98 °C; H NMR
(300 MHz, DMSO-d6) δ 2.97 (m, 2H), 3.30 (m, 10H), 3.79 (s,
3H), 6.08 (s, 2H), 6.74 (dd, J ) 7 and 4 Hz, 1H), 6.94 (d, J ) 9
Hz, 1H), 7.45 (m, 5H), 7.60 (m, 1H), 8.16 (m, 1H); MS (DCI/
NH3) m/z 325 (M + H)+. Anal. Calcd (C19H24N4O‚C4H4O4‚
0.25H2O): C, H, N.
E-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Ethyloxime (32a) and Z-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-
yl)propan-1-one O-Ethyloxime (32b). Compounds were prepared
from a crude 1-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-
one oxime and iodoethane by method B in 43% and 4% overall
(E)-1-(3,5-Dimethylphenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one Oxime (27a). Compound was prepared from 1-(3,5-
dimethylphenyl)ethanone, 1-pyridin-2-ylpiperazine, and hydroxy-
lamine hydrochloride by method A in overall 67% yield: mp 127-
1
yield, respectively. 32a maleate salt: mp 150-151 °C; H NMR
1
128 °C; H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 6H), 2.50 (m,
(300 MHz, DMSO-d6) δ 1.28 (t, J ) 7 Hz, 3H), 3.25 (m, 12H),
4.21 (t, J ) 7 Hz, 2H), 6.07 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz,
1H), 6.95 (d, J ) 9 Hz, 1H), 7.44 (m, 3H), 7.60 (m, 1H), 7.70 (m,
2H), 8.16 (m, 1H); MS (DCI/NH3) m/z 339 (M + H)+. Anal. Calcd
6H), 2.95 (m, 2H), 3.24 (t, J ) 4 Hz, 4H), 6.62 (dd, J ) 7 and 4
Hz, 1H), 6.80 (d, J ) 7 Hz, 1H), 7.00 (m, 1H), 7.24 (m, 2H), 7.46
(m, 1H), 8.09 (m, 1H), 11.12 (s, 1H); MS (ESI+) m/z 339 (M +
H)+; MS (ESI-) m/z 337 (M - H)-. Anal. Calcd (C20H26N4O):
C, H, N.
1
(C20H26N4O‚C4H4O4): C, H, N. 32b: oil; H NMR (300 MHz,
DMSO-d6) δ 1.13 (t, J ) 7 Hz, 3H), 2.41 (m, 6H), 2.70 (t, J ) 7
Hz, 2H), 3.42 (t, J ) 4.5 Hz, 4H), 3.99 (t, J ) 7 Hz, 2H), 6.61 (dd,
J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9 Hz, 1H), 7.40 (m, 5H), 7.70
(m, 1H), 8.09 (m, 1H); MS (DCI/NH3) m/z 339 (M + H)+.
(E)-1-(2,4-Difluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one Oxime (28a). Compound was prepared from 1-(2,4-
difluorophenyl)ethanone, 1-pyridin-2-ylpiperazine, and hydroxy-
lamine hydrochloride by method A in overall 23% yield: mp 115-
(E)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Propyloxime (33a). Compound was prepared from a crude 1-phen-
yl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one oxime and 1-io-
dopropane by method B in 48% overall yield: maleate salt, mp
153-154 °C; 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J ) 7 Hz,
3H), 1.71 (sextet, J ) 7 Hz, 2H), 3.25 (m, 12H), 4.18 (t, J ) 7 Hz,
2H), 6.07 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9
Hz, 1H), 7.44 (m, 3H), 7.60 (m, 1H), 7.70 (m, 2H), 8.16 (m, 1H);
MS (DCI/NH3) m/z 353 (M + H)+. Anal. Calcd (C21H28N4O‚
C4H4O4): C, H, N.
(E)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Butyloxime (34a). Compound was prepared from a crude 1-phenyl-
3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one oxime and 1-iodob-
utane by method B in 27% overall yield: maleate salt, mp 154-
155 °C; 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J ) 7 Hz, 3H),
1.40 (sextet, J ) 7 Hz, 2H), 1.68 (q, J ) 7 Hz, 2H), 3.25 (m,
12H), 4.18 (t, J ) 7 Hz, 2H), 6.07 (s, 2H), 6.73 (dd, J ) 7 and 4
Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.44 (m, 3H), 7.60 (m, 1H), 7.70
(m, 2H), 8.16 (m, 1H); MS (DCI/NH3) m/z 367 (M + H)+. Anal.
Calcd (C22H30N4O‚C4H4O4‚0.4H2O): C, H, N.
1
117 °C; H NMR (300 MHz, DMSO-d6) δ 2.48 (m, 6H), 2.93 (t,
J ) 7 Hz, 2H), 3.32 (m, 4H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.78
(d, J ) 7 Hz, 1H), 7.10 (m, 1H), 7.27 (m, 1H), 7.50 (m, 2H), 8.07
(m, 1H), 11.40 (s, 1H); MS (ESI+) m/z 347 (M + H)+; MS (ESI-)
m/z 345 (M - H)-.
(E)-1-(2-Benzyloxy-5-methylphenyl)-3-(4-pyridin-2-ylpiper-
azin-1-yl)propan-1-one Oxime (29a) and (Z)-1-(2-Benzyloxy-5-
methylphenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-oneOxime
(29b). Compounds were prepared from 1-(2-benzyloxy-5-meth-
ylphenyl)ethanone, 1-pyridin-2-ylpiperazine, and hydroxylamine
hydrochloride by method A in 61% and 12% overall yield,
respectively. 29a: mp 176-177 °C; 1H NMR (300 MHz, DMSO-
d6) δ 2.22 (s, 3H), 2.28 (t, J ) 4 Hz, 4H), 2.37 (t, J ) 7 Hz, 2H),
2.81 (t, J ) 7 Hz, 2H), 3.35 (t, J ) 4 Hz, 4H), 5.21 (s, 2H), 6.61
(dd, J ) 7 and 4 Hz, 1H), 6.77 (d, J ) 7 Hz, 1H), 7.01 (m, 2H),
7.12 (m, 1H), 7.40 (m, 5H), 7.50 (m, 1H), 8.10 (m, 1H), 10.94 (s,
1H); MS (ESI+) m/z 431 (M + H)+; MS (ESI-) m/z 429 (M -
H)-. Anal. Calcd (C26H30N4O2): C, H, N. 29b: mp 149-152 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.38 (m, 6H), 2.60
(t, J ) 7 Hz, 2H), 3.40 (t, J ) 4 Hz, 4H), 5.05 (s, 2H), 6.61 (dd,
J ) 7 and 4 Hz, 1H), 6.77 (d, J ) 7 Hz, 1H), 6.92 (m, 1H), 7.00
(m, 1H), 7.08 (m, 1H), 7.38 (m, 5H), 7.50 (m, 1H), 8.08 (m, 1H),
10.38 (s, 1H); MS (ESI+) m/z 431 (M + H)+; MS (ESI-) m/z
429 (M - H)-.
(E)-1-(2-Hydroxy-5-methylphenyl)-3-(4-pyridin-2-ylpiperazin-
1-yl)propan-1-one Oxime (30a). (E)-1-(2-Benzyloxy-5-methylphe-
nyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one oxime (86 mg,
0.2 mmol) was treated with 33% HBr/AcOH at room temperature
for 4 h. The mixture was then concentrated under reduced pressure
and the residue was treated with saturated NaHCO3. The product
was extracted with EtOAc and dried over anhydrous MgSO4.
Concentration under reduced pressure and chromatography (EtOAc
as eluent) provided 25 mg (37%) of product: mp 157-158 °C; 1H
NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.55 (m, 6H), 3.00 (t,
J ) 7 Hz, 2H), 3.46 (t, J ) 4 Hz, 4H), 6.62 (dd, J ) 7 and 4 Hz,
1H), 6.77 (d, J ) 7 Hz, 1H), 6.82 (d, J ) 7 Hz, 1H), 7.03 (m, 1H),
7.25 (m, 1H), 7.50 (m, 1H), 8.10 (m, 1H), 11.01 (s, 1H), 11.50 (s,
1H); MS (ESI+) m/z 341 (M + H)+; MS (ESI-) m/z 339 (M -
H)-. Anal. Calcd (C19H24N4O2): C, H, N.
(E)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Isopropyloxime (35a). Compound was prepared from a crude
1-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one oxime and
2-iodopropane by method B in 52% overall yield: maleate salt,
1
mp 156-157 °C; H NMR (300 MHz, DMSO-d6) δ 1.28 (d, J )
7 Hz, 6H), 3.25 (m, 12H), 4.42 (q, J ) 7 Hz, 1H), 6.07 (s, 2H),
6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.44 (m,
3H), 7.60 (m, 1H), 7.70 (m, 2H), 8.16 (m, 1H); MS (DCI/NH3)
m/z 353 (M + H)+. Anal. Calcd (C21H28N4O‚C4H4O4‚0.6H2O): C,
H, N.
(E)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Allyloxime (36a). Compound was prepared from a crude 1-phenyl-
3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one oxime and 3-bro-
mopropene by method B in 51% overall yield: maleate salt, mp
1
136-137 °C; H NMR (300 MHz, DMSO-d6) δ 3.25 (m, 12H),
4.70 (m, 2H), 5.30 (m, 2H), 6.07 (s + m, 3.4H), 6.73 (dd, J ) 7
and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.44 (m, 3H), 7.60 (m,
1H), 7.70 (m, 2H), 8.16 (m, 1H); MS (DCI/NH3) m/z 351 (M +
H)+. Anal. Calcd (C21H26N4O‚1.2C4H4O4): C, H, N.
(E)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Methyloxime (31a) and (Z)-1-Phenyl-3-(4-pyridin-2-ylpiperazin-
1-yl)propan-1-one O-Methyloxime (31b). Compounds were pre-
pared from 3-chloro-1-phenylpropan-1-one, 1-pyridin-2-ylpiperazine,
and O-methylhydroxylamine hydrochloride by method D in 47%
and 19% overall yield, respectively. 31a maleate salt: mp 142-
144 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.20 (m, 12H), 3.98 (s,
[1-Phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)propylideneaminooxy]-
acetonitrile (37a). Compound was prepared from a crude 1-phenyl-
3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one oxime and bromoac-
etonitrile by method B in 36% overall yield: maleate salt, mp 127-
128 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.30 (m, 12H), 5.13 (s,
2H), 6.07 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9
Hz, 1H), 7.50 (m, 3H), 7.60 (m, 1H), 7.73 (m, 2H), 8.16 (m, 1H);

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5103
MS (DCI/NH3) m/z 350 (M + H)+. Anal. Calcd (C20H23N5O‚
C4H4O4): C, H, N.
H)+. 43a maleate salt: mp 146-147 °C; 1H NMR (300 MHz, CD3-
OD) δ 1.37 (t, J ) 7 Hz, 3H), 3.29 (m, 6H), 3.86 (s, 3H), 3.49 (m,
6H), 4.30 (q, J ) 7 Hz, 2H), 6.25 (s, 2H), 7.00 (m, 4H), 7.42 (m,
3H), 7.71 (m, 2H). Anal. Calcd (C22H29N3O2‚C4H4O4): C, H, N.
(E)-2-[4-(3-Hydroxyimino-3-phenylpropyl)piperazin-1-yl]ni-
cotinonitrile (38a) and (Z)-2-[4-(3-Hydroxyimino-3-phenylpro-
pyl)piperazin-1-yl]nicotinonitrile (38b). Compounds were pre-
pared from 3-chloro-1-phenylpropan-1-one, 2-piperazin-1-ylnico-
tinonitrile, and hydroxylamine hydrochloride by method D in 66%
and 8% overall yield, respectively. 38a: mp 168-170 °C; 1H NMR
(300 MHz, DMSO-d6) δ 2.50 (m, 2H), 2.57 (t, J ) 4.5 Hz, 4H),
2.94 (m, 2H), 3.58 (t, J ) 4.5 Hz, 4H), 6.91 (dd, J ) 7.5 and 4.8
Hz, 1H), 7.37 (m, 3H), 7.64 (m, 2H), 8.05 (dd, J ) 7.5 and 2.0
Hz, 1H), 8.40 (dd, J ) 4.8 and 2.0 Hz, 1H); MS (DCI/NH3) m/z
336 (M + H)+. Anal. Calcd (C19H21N5O): C, H, N. 38b: mp 169-
3-[4-(3-Methoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-
one O-Ethyloxime (44a). Compound was prepared from 3-chloro-
1-phenylpropan-1-one, 1-(3-methoxyphenyl)piperazine, and O-eth-
ylhydroxylamine hydrochloride by method D in 30% overall
yield: 1H NMR (300 MHz, DMSO-d6) δ 1.33 (t, J ) 7.5 Hz, 3H),
2.53 (m, 6H), 2.92 (m, 2H), 3.10 (m, 4H), 3.65 (s, 3H), 4.24 (q, J
) 7.5 Hz, 2H), 6.41 (m, 3H), 7.10 (t, J ) 7 Hz, 1H), 7.42 (m, 3H),
7.65 (m, 2H); MS (DCI/NH3) m/z 368 (M + H)+. 44a maleate
1
salt: mp 148-149 °C; H NMR (300 MHz, CD3OD) δ 1.37 (t, J
1
171 °C, H NMR (300 MHz, DMSO-d6) δ 2.46 (m, 6H), 2.69 (t,
) 7 Hz, 3H), 3.30 (m, 6H), 3.48 (m, 6H), 3.77 (s, 3H), 4.30 (q, J
) 7 Hz, 2H), 6.25 (s, 2H), 6.58 (m, 3H), 7.20 (t, J ) 7 Hz, 1H),
7.43 (m, 3H), 7.72 (m, 2H). Anal. Calcd (C22H29N3O2‚C4H4O4):
C, H, N.
J ) 7 Hz, 2H), 3.56 (t, J ) 4.5 Hz, 4H), 6.91 (dd, J ) 7.5 and 4.8
Hz, 1H), 7.39 (m, 5H), 8.05 (dd, J ) 7.5 and 2.0 Hz, 1H), 8.39
(dd, J ) 4.8 and 2.0 Hz, 1H); MS (DCI/NH3) m/z 336 (M + H)+.
Anal. Calcd (C19H21N5O‚0.20H2O): C, H, N.
3-[4-(4-Methoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-
one O-Ethyloxime (45a). Compound was prepared from 3-chloro-
1-phenylpropan-1-one, 1-(3-methoxyphenyl)piperazine, and O-eth-
ylhydroxylamine hydrochloride by method D in 25% overall
yield: 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J ) 7.5 Hz, 3H),
2.52 (m, 6H), 3.03 (m, 6H), 3.65 (s, 3H), 4.25 (q, J ) 7.5 Hz, 2H),
6.83 (m, 4H), 7.41 (m, 3H), 7.62 (m, 2H); MS (DCI/NH3) m/z 368
(M + H)+. 45a maleate salt: mp 129-131 °C; 1H NMR (300 MHz,
CD3OD) δ 1.37 (t, J ) 7 Hz, 3H), 3.30 (m, 6H), 3.38 (m, 3H),
3.52 (m, 3H), 3.75 (s, 3H), 4.30 (q, J ) 7 Hz, 2H), 6.25 (s, 2.4H),
6.88 (d, J ) 9 Hz, 2H), 7.00 (d, J ) 9 Hz, 2H), 7.43 (m, 3H), 7.71
(m, 2H). Anal. Calcd (C22H29N3O2‚1.2C4H4O4‚0.3H2O): C, H, N.
3-[4-(2-Ethoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-one
O-Ethyloxime (46a). Compound was prepared from 3-chloro-1-
phenylpropan-1-one, 1-(3-methoxyphenyl)piperazine, and O-eth-
ylhydroxylamine hydrochloride by method D in 23% overall
yield: maleate salt, mp 108-109 °C; 1H NMR (300 MHz, DMSO-
d6) δ 1.30 (t, J ) 7 Hz, 3H), 1.35 (t, J ) 7 Hz, 3H), 3.25 (m,
12H), 4.03 (q, J ) 7 Hz, 2H), 4.23 (q, J ) 7 Hz, 2H), 6.05 (s, 2H),
6.95 (m, 4H), 7.45 (m, 3H), 7.72 (m, 2H); MS (DCI/NH3) m/z 382
(M + H)+. Anal. Calcd (C23H31N3O2‚C4H4O4): C, H, N.
(E)-3-[4-(2-Isopropoxyphenyl)-piperazin-1-yl]-1-phenylpro-
pan-1-one O-Ethyloxime (47a) and (Z)-3-[4-(2-Isopropoxyphen-
yl)piperazin-1-yl]-1-phenylpropan-1-one O-Methyloxime (47b).
2-Isopropoxyaniline (3.5 g, 23 mmol) was added slowly to bis(2-
chloroethyl)amine hydrochloride in n-butanol and then refluxed for
48 h. The reaction mixture was cooled to ambient temperature,
treated with anhydrous Na2CO3 (9 g, 85 mmol), and refluxed for
the next 48 h. The mixture was diluted with dicholoromethane and
treated with a solution of 3 N NaOH. The organic layer was dried
over anhydrous MgSO4 and concentrated under reduced pressure
to give 2.3 g (63%) of crude 1-(2-isopropoxyphenyl)piperazine.
MS (DCI/NH3) m/z 221(M + H)+.
(E)-1-Phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)propan-1-
one Oxime (39a) and (Z)-1-Phenyl-3-(4-pyrimidin-2-ylpiperazin-
1-yl)propan-1-one Oxime (39b). Compounds were prepared from
3-chloro-1-phenylpropan-1-one, 2-piperazin-1-ylpyrimidine, and
hydroxylamine hydrochloride by method D in 44% and 4% overall
1
yield, respectively. 39a: mp 175-177 °C; H NMR (300 MHz,
DMSO-d6) δ 2.50 (m, 6H), 2.95 (m, 2H), 3.70 (t, J ) 4.5 Hz, 4H),
6.61 (t, J ) 4.5 Hz, 1H), 7.39 (m, 3H), 7.64 (m, 2H), 8.33 (d, J )
4.5 Hz, 1H), 11.23 (s, 1H); MS (DCI/NH3) m/z 312 (M + H)+.
Anal. Calcd (C17H21N5O‚0.15H2O): C, H; N calcd 22.30, found
1
21.79. 39b: mp 159-161 °C; H NMR (300 MHz, DMSO-d6) δ
2.40 (m, 6H), 2.69 (t, J ) 7 Hz, 2H), 3.67 (t, J ) 4.5 Hz, 4H),
6.60 (t, J ) 4.5 Hz, 1H), 7.40 (m, 5H), 8.35 (d, J ) 4.5 Hz, 1H),
10.58 (s, 1H); MS (DCI/NH3) m/z 312 (M + H)+.
(E)-1-Phenyl-3-(4-thiazol-2-ylpiperazin-1-yl)propan-1-one
Oxime (40a). Compound was prepared from 3-chloro-1-phenyl-
propan-1-one, 1-thiazol-2-ylpiperazine, and hydroxylamine hydro-
1
chloride by method D in 49% overall yield: mp 153-155 °C; H
NMR (300 MHz, acetone-d6) δ 2.22 (m, 4H), 2.63 (m, 4H), 3.12
(m, 2H), 4.05 (m, 2H), 6.70 (d, J ) 3 Hz, 1H), 7.51 (d, J ) 3 Hz,
1H), 7.35 (m, 3H), 7.70 (m, 2H). MS (DCI/NH3) m/z 317 (M +
H)+. Anal. Calcd (C16H20N4OS): C, H, N.
1-Phenyl-3-(4-phenylpiperazin-1-yl)propan-1-one O-Ethyl-
oxime (41a). Compound was prepared from 3-chloro-1-phenyl-
propan-1-one, 1-phenylpiperazine, and O-ethylhydroxylamine hy-
drochloride by method D in 39% overall yield: 1H NMR (300 MHz,
CDCl3) δ 1.25 (t, J ) 7 Hz, 3H), 2.65 (m, 6H), 3.03 (m, 2H), 3.21
(m, 4H), 4.25 (q, J ) 7 Hz, 2H), 6.85 (m, 1H), 6.95 (d, J ) 7.5
Hz, 2H), 7.30 (m, 2H), 7.44 (m, 3H), 7.65 (m, 2H); MS (DCI/
1
NH3) m/z 338 (M + H)+. 41a maleate salt: mp 151-152 °C; H
NMR (300 MHz, CD3OD) δ 1.37 (t, J ) 7 Hz, 3H), 3.30 (m, 6H),
3.48 (m, 6H), 4.49 (q, J ) 7 Hz, 2H), 6.24 (s, 2H), 6.92 (t, J ) 7
Hz, 1H), 7.01 (d, J ) 7 Hz, 2H), 7.28 (m, 2H), 7.42 (m, 3H), 7.70
(m, 2H). Anal. Calcd (C21H27N3O‚C4H4O4): C, H, N.
The title compounds were prepared from 3-chloro-1-(4-fluo-
rophenyl)propan-1-one, 1-(2-isopropoxyphenyl)piperazine, and O-
methylhydroxylamine hydrochloride by method D in 14% and 5%
overall yield, respectively. 47a maleate salt: mp 141-143 °C; 1H
NMR (300 MHz, DMSO-d6) δ 1.27 (d, J ) 7 Hz, 6H), 3.25 (m,
12H), 3.97 (s, 3H), 4.61 (septet, J ) 7 Hz, 1H), 6.05 (s, 2H), 6.93
(m, 4H), 7.30 (t, J ) 9 Hz, 2H), 7.77 (dd, J ) 9 and 4 Hz, 2H);
MS (DCI/NH3) m/z 400 (M + H)+. Anal. Calcd (C23H30FN3O2‚
2-[4-(Ethoxyimino-3-phenylpropyl)piperazin-1-yl]benzoni-
trile (42a). Compound was prepared from 3-chloro-1-phenylpropan-
1-one, 2-piperazin-1-ylbenzonitrile, and O-ethylhydroxylamine
1
hydrochloride by method D in 37% overall yield. H NMR (300
MHz, CDCl3) δ 1.32 (t, J ) 7 Hz, 3H), 2.75 (m, 6H), 3.04 (br s,
2H), 3.25 (br s, 4H), 4.25 (q, J ) 7 Hz, 2H), 7.01 (m, 2H), 7.35
(m, 4H), 7.45 (m, 1H), 7.55 (dd, J ) 9 Hz, 3 Hz, 1H), 7.70 (m,
2H); MS (DCI/NH3) m/z 363 (M + H)+. 42a maleate salt: mp
1
C4H4O4): C, H, N. 47b maleate salt: mp 103-105 °C; H NMR
1
(300 MHz, CD3OD) δ 1.34 (d, J ) 7 Hz, 6H), 3.30 (m, 9H), 3.48
(m, 3H), 4.03 (s, 3H), 4.63 (septet, J ) 7 Hz, 1H), 6.05 (s, 2H),
6.99 (m, 4H), 7.18 (t, J ) 9 Hz, 2H), 7.77 (dd, J ) 9 and 4 Hz,
2H); MS (DCI/NH3) m/z 400 (M + H)+.
125-126 °C; H NMR (300 MHz, CD3OD) δ 1.37 (t, J ) 7 Hz,
3H), 3.30 (m, 6H), 3.50 (m, 6H), 4.31 (q, J ) 7 Hz, 2H), 6.25 (s,
2H), 7.22 (m, 2H), 7.42 (m, 3H), 7.70 (m, 4H). Anal. Calcd
(C22H26N4O‚C4H4O4): C, H, N.
3-[4-(2-Methoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-
one O-Ethyloxime (43a). Compound was prepared from 3-chloro-
1-phenylpropan-1-one, 1-(2-methoxyphenyl)piperazine, and O-eth-
ylhydroxylamine hydrochloride by method D in 44% overall yield.
1H NMR (300 MHz, CDCl3) δ 1.33 (t, J ) 7.5 Hz, 3H), 2.74 (m,
6H), 3.1 (m, 6H), 3.82 (s, 3H), 4.25 (q, J ) 7.5 Hz, 2H), 6.92 (m,
4H), 7.44 (m, 3H), 7.7 (m, 2H); MS (DCI/NH3) m/z 368 (M +
2-[4-(3-Ethoxyimino-3-phenylpropyl)piperazin-1-yl]nicotino-
nitrile (48a). Compound was prepared from 1-phenyl-3-(4-pyridin-
2-ylpiperazin-1-yl)propan-1-one, 2-piperazin-1-ylnicotinonitrile, and
O-ethylhydroxylamine by method D in 37% overall yield: maleate
salt, mp 120-121 °C; H NMR (300 MHz, DMSO-d6) δ 1.29 (t,
J ) 7 Hz, 3H), 3.25 (m, 12H), 4.21 (q, J ) 7 Hz, 2H), 6.06 (s,
2H), 7.03 (m, 1H), 7.43 (dd, J ) 6 and 3 Hz, 3H), 7.70 (m, 2H),
1

5104 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Kolasa et al.
8.15 (m, 1H), 8.26 (m, 1H); MS (DCI/NH3) m/z 364 (M + H)+.
Anal. Calcd (C21H25N5O‚C4H4O4): C, H, N.
(C19H23FN4O‚C4H4O4): C, H, N. 54b maleate salt: mp 122-124
°C; 1H NMR (300 MHz, DMSO-d6) δ 3.00 (m, 2H), 3.30 (m, 10H),
3.79 (s, 3H), 6.08 (s, 2.5H), 6.74 (dd, J ) 7 and 4 Hz, 1H), 6,94
(d, J ) 9 Hz, 1H), 7.33 (m, 3H), 7.50 (m, 1H), 7.60 (m, 1H), 8.16
(m, 1H); MS (DCI/NH3) m/z 343 (M + H)+. Anal. Calcd (C19H23-
FN4O‚1.25C4H4O4‚0.4H2O): C, H, N.
3-[4-(3-Methylpyridin-2-yl)piperazin-1-yl]-1-phenylpropanon-
1-one O-Ethyloxime (49a). Compound was prepared from 3-chloro-
1-phenylpropan-1-one, 1-(3-methylpiperidin-2-yl)piperazine, and
O-ethylhydroxylamine hydrochloride by method D in 20% overall
yield: maleate salt, mp 132-134 °C; 1H NMR (300 MHz, DMSO-
d6) δ 1.30 (t, J ) 7 Hz, 3H), 2.25 (s, 3H), 3.25 (m, 12H), 4.23 (q,
J ) 7 Hz, 2H), 6.05 (s, 2H), 7.00 (dd, J ) 9 and 4 Hz, 1H), 7.45
(m, 3H), 7.55 (m, 1H), 7.70 (m, 2H), 8.14 (m, 1H); MS (DCI/
NH3) m/z 353 (M + H)+. Anal. Calcd (C21H28N4O‚C4H4O4): C, H,
N.
(E)-1-(3-Chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one O-Methyloxime (55a) and (Z)-1-(3-Chlorophenyl)-3-
(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime (55b).
Compounds were prepared from 1-(3-chlorophenyl)ethanone, 1-(py-
ridin-2-ylpiperazine, and O-methylhydroxylamine hydrochloride by
method A in 24% and 15% overall yields, respectively. 55a maleate
salt: mp 170-172 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.24 (m,
12H), 3.98 (s, 3H), 6.08 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H),
6.95 (d, J ) 9 Hz, 1H), 7.50 (m, 2H), 7.62 (m, 2H), 7.73 (m, 1H),
8.16 (m, 1H); MS (DCI/NH3) m/z 359 (M + H)+. Anal. Calcd
(C19H23ClN4O‚C4H4O4): C, H, N. 55b maleate salt: mp 145-147
°C; 1H NMR (300 MHz, DMSO-d6) δ 3.30 (m, 12H), 3.79 (s, 3H),
6.08 (s, 2H), 6.74 (dd, J ) 7 and 4 Hz, 1H), 6.94 (d, J ) 9 Hz,
1H), 7.46 (m, 3H), 7.58 (m, 2H), 8.16 (m, 1H); MS (DCI/NH3)
m/z 359 (M + H)+. Anal. Calcd (C19H23ClN4O‚C4H4O4‚0.4H2O):
C, H, N.
1-Phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)propanon-1-one
O-Ethyloxime (50a). Compound was prepared from 3-chloro-1-
phenylpropan-1-one, 2-piperazin-1-ylpyrimidine, and O-ethylhy-
droxylamine hydrochloride by method D in 40% overall yield:
1
maleate salt, mp 147-148 °C; H NMR (300 MHz, DMSO-d6) δ
1.30 (t, J ) 7 Hz, 3H), 2.25 (s, 3H), 3.25 (m, 12H), 4.21 (q, J )
7 Hz, 2H), 6.07 (s, 2H), 6.73 (m, 1H), 7.44 (m, 3H), 7.68 (m, 2H),
8.42 (d, J ) 6 Hz, 2H); MS (DCI/NH3) m/z 340 (M + H)+. Anal.
Calcd (C19H25N5O‚C4H4O4): C, H, N.
1-Phenyl-3-(4-thiazol-2-ylpiperazin-1-yl)propanon-1-one O-
Ethyloxime (51a). Compound was prepared from 3-chloro-1-
phenylpropan-1-one, 1-thiazol-2-ylpiperazine, and O-ethylhydrox-
ylamine hydrochloride by method D in 17% overall yield: maleate
(E)-3-(4-Pyridin-2-ylpiperazin-1-yl)-1-(m-tolyl)propan-1-
one O-Methyloxime (56a) and (Z)-3-(4-Pyridin-2-ylpiperazin-
1-yl)-1-(m-tolyl)propan-1-one O-Methyloxime (56b). Compounds
were prepared from 1-(m-tolyl)ethanone, 1-pyridin-2-ylpiperazine,
and O-methylhydroxylamine hydrochloride by method A in 34%
and 24% overall yields, respectively. 56a maleate salt: mp 124-
1
salt, mp 122-124 °C; H NMR (300 MHz, DMSO-d6) δ 1.28 (t,
J ) 7 Hz, 3H), 3.25 (m, 12H), 4.21 (q, J ) 7 Hz, 2H), 6.07 (s,
2H), 6.95 (m, 1H), 7.22 (d, J ) 3 Hz, 1H), 7.45 (m, 3H), 7.70 (m,
2H); MS (DCI/NH3) m/z 345 (M + H)+. Anal. Calcd (C18H24N4-
OS‚C4H4O4): C, H, N.
1
125 °C; H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.25 (m,
12H), 3.90 (s, 3H), 6.08 (s, 2H), 6.72 (dd, J ) 7 and 4 Hz, 1H),
6.91 (d, J ) 9 Hz, 1H), 7.28 (m, 4H), 7.60 (m, 1H), 8.16 (m, 1H);
MS (DCI/NH3) m/z 339 (M + H)+. Anal. Calcd (C20H26N4O‚
C4H4O4‚0.4H2O): C, H, N. 56b maleate salt: mp 119-121 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 2.87 (m, 2H), 3.30
(m, 12H), 3.74 (s, 3H), 6.08 (s, 2H), 6.74 (dd, J ) 7 and 4 Hz,
1H), 6.94 (d, J ) 9 Hz, 1H), 7.14 (m, 1H), 7.25 (m, 4H), 7.60 (m,
1H), 8.16 (m, 1H); MS (DCI/NH3) m/z 339 (M + H)+. Anal. Calcd
(C20H26N4O‚C4H4O4‚0.5H2O): C, H, N.
(E)-1-(2-Chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one O-Methyloxime (52a) and (Z)-1-(2-Chlorophenyl)-3-
(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime (52b).
Compounds were prepared from 1-(2-chlorophenyl)ethanone, 1(py-
ridin-2-yl)piperazine, and O-methylhydroxylamine hydrochloride
by method A in 29% and 28% overall yields, respectively. 52a
maleate salt: mp 129-130 °C; 1H NMR (300 MHz, DMSO-d6) δ
3.30 (m, 12H), 3.93 (s, 3H), 6.09 (s, 2.8H), 6.72 (m, 1H), 6.90 (d,
J ) 9 Hz, 1H), 7.50 (m, 5H), 8.15 (m, 1H); MS (DCI/NH3) m/z
359 (M + H)+. Anal. Calcd (C19H23ClN4O‚1.4C4H4O4): C, H, N.
52b maleate salt: mp 113-116 °C; 1H NMR (300 MHz, DMSO-
d6) 2.93 (m, 2H), 3.35 (m, 10H), 3.75 (s, 3H), 6.73 (dd, J ) 7 and
4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.32 (m, 1H), 7.42 (m, 2H),
7.60 (m, 2H), 8.16 (m, 1H); MS (DCI/NH3) m/z 359 (M + H)+.
Anal. Calcd (C19H23ClN4O‚1.6C4H4O4): C, H, N.
(E)-4-[1-Methoxyimino-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pyl]benzonitrile (57a) and (Z)-4-[1-Methoxyimino-3-(4-pyridin-
2-ylpiperazin-1-yl)propyl]benzonitrile (57b). Compounds were
prepared from 3-acetylbenzonitrile, 1-pyridin-2-ylpiperazine, and
O-methylhydroxylamine hydrochloride by method A in 25% and
13% overall yields, respectively. 57a maleate salt: mp 161-163
°C; 1H NMR (300 MHz, DMSO-d6) δ 3.20 (m, 12H), 4.00 (s, 3H),
6.08 (s, 2.8H), 6.74 (dd, J ) 7 and 4 Hz, 1H), 6.96 (d, J ) 9 Hz,
1H), 7.64 (m, 2H), 7.93 (m, 1H), 8.03 (m, 1H), 8.10 (m, 1H), 8.16
(m, 1H); MS (DCI/NH3) m/z 350 (M + H)+. Anal. Calcd
(C20H23N5O‚1.4C4H4O4): C, H, N. 57b: mp 105-108 °C; 1H NMR
(300 MHz, DMSO-d6) δ 2.38 (m, 6H), 2.73 (t, J ) 7 Hz, 2H),
3.40 (m, 4H), 3.73 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d,
J ) 9 Hz, 1H), 7.50 (m, 1H), 7.62 (t, J ) 9 Hz, 1H), 7.75 (m, 1H),
7.83 (m, 1H), 7.89 (m, 1H), 8.09 (m, 1H); MS (DCI/NH3) m/z 350
(M + H)+. Anal. Calcd (C20H23N5O): C, H, N.
(E)-3-(4-Pyridin-2-ylpiperazin-1-yl)-1-(o-tolyl)propan-1-one
O-Methyloxime (53a) and (Z)-3-(4-Pyridin-2-ylpiperazin-1-yl)-
1-(o-tolyl)propan-1-one O-Methyloxime (53b). Compounds were
prepared from 1-(o-tolyl)ethanone, 1-pyridin-2-ylpiperazine, and
O-methylhydroxylamine hydrochloride by method A in 38% and
1
12% overall yields, respectively. 53a: oil; H NMR (300 MHz,
DMSO-d6) δ 2.34 (s, 3H), 2.46 (m, 4H), 2.91 (m, 2H), 3.30 (m,
2H), 3.42 (m, 4H), 3.90 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H),
6,80 (d, J ) 9 Hz, 1H), 7.21 (m, 1H), 7.30 (t, J ) 7 Hz, 1H), 7.50
(m, 3H), 8.10 (m, 1H); MS (DCI/NH3) m/z 339 (M + H)+. Anal.
Calcd (C20H26N4O): C, H, N. 53b: oil; 1H NMR (300 MHz,
DMSO-d6) δ 2.31 (s, 3H), 2.40 (m, 6H), 2.68 (t, J ) 7 Hz, 2H),
3.21 (m, 4H), 3.70 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6,80 (d,
J ) 9 Hz, 1H), 7.18 (m, 3H), 7.28 (m, 1H), 7.50 (m, 1H), 8.10 (m,
1H); MS (DCI/NH3) m/z 339 (M + H)+. Anal. Calcd (C20H26-
N4O): C, H, N.
(E)-1-(3-Fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-
1-one O-Methyloxime (54a) and (Z)-1-(3-Fluorophenyl)-3-(4-
pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime (54b).
Compounds were prepared from 1-(3-fluorophenyl)ethanone, 1-(py-
ridin-2-ylpiperazine, and O-methylhydroxylamine hydrochloride by
method A in 35% and 18% overall yields, respectively. 54a maleate
salt: mp 157-159 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.30 (m,
12H), 3.98 (s, 3H), 6.08 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H),
6.95(d, J ) 9 Hz, 1H), 7.30 (m, 1H), 7.52 (m, 3H), 7.60 (m, 1H),
8.16 (m, 1H); MS (DCI/NH3) m/z 343 (M + H)+. Anal. Calcd
(E)-1-(4-Fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-
1-one O-Methyloxime (58a) and (Z)-1-(4-fluorophenyl)-3-(4-
pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime (58b).
Compounds were prepared from 1-(4-fluorophenyl)ethanone, 1-py-
ridin-2-ylpiperazine, and O-methylhydroxylamine hydrochloride by
method A in 31% and 7% overall yields, respectively. 58a maleate
salt: mp 157-159 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.20 (m,
12H), 3.98 (s, 3H), 6.08 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H),
6.95 (d, J ) 9 Hz, 1H), 7.30 (m, 1H), 7.55 (m, 4H), 8.16 (m, 1H);
MS (DCI/NH3) m/z 343 (M + H)+. Anal. Calcd (C19H23FN4O‚
1
C4H4O4): C, H, N. 58b maleate salt: mp 122-124 °C; H NMR
(300 MHz, DMSO-d6) δ 3.30 (m, 12H), 3.80 (s, 3H), 6.08 (s, 2.5H),
6.75 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.34 (m,
3H), 7.50 (m, 1H), 7.61(m, 1H), 8.16 (m, 1H); MS (DCI/NH3) m/z
343 (M + H)+. Anal. Calcd (C19H23FN4O‚C4H4O4): C, H, N.
(E)-1-(4-Chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one O-Methyloxime (59a) and (Z)-1-(4-Chlorophenyl)-3-

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5105
(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime (59b).
Compounds were prepared from 3-chloro-1-(4-chlorophenyl)-
propan-1-one, 1-pyridin-2-ylpiperazine, and O-methylhydroxy-
lamine hydrochloride by method C in 52% and 14% overall yields,
respectively. 59a: mp 67-68 °C; 1H NMR (300 MHz, DMSO-d6)
δ 2.45 (m, 6H), 2.93 (t, J ) 7 Hz, 2H), 3.42 (t, J ) 4.5 Hz, 4H),
3.93 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9 Hz,
1H), 7.50 (m, 3H), 7.68 (m, 2H), 8.10 (m, 1H); MS (DCI/NH3)
(E)-1-(2,4-Dichlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one O-Methyloxime (63a) and (Z)-1-(2,4-Dichlorophen-
yl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime
(63b). Compounds were prepared from 1-(2,4-dichlorophenyl)-
ethanone, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine
hydrochloride by method A in 14% and 20% overall yields,
respectively. 63a: oil, 1H NMR (300 MHz, DMSO-d6) δ 2.45 (m,
6H), 2.92 (t, J ) 7 Hz, 2H), 3.37 (m, 4H), 3.90 (s, 3H), 6.61 (m,
1H), 6.78 (d, J ) 9 Hz, 1H), 7.50 (m, 3H), 7.71 (s, 1H), 8.10 (m,
1H); MS (DCI/NH3) m/z 393 (M + H)+. Anal. Calcd (C19H22-
Cl2N4O‚0.25H2O): C, H, N. 63b: oil, 1H NMR (300 MHz, DMSO-
d6) δ 2.40 (m, 6H), 2.66 (t, J ) 7 Hz, 2H), 3.40 (t, J ) 4.5 Hz,
4H), 3.70 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9
Hz, 1H), 7.39 (d, J ) 9 Hz, 1H), 7.50 (m, 2H), 7.67 (d, J ) 3 Hz,
1H), 8.10 (m, 1H); MS (DCI/NH3) m/z 393 (M + H)+. Anal. Calcd
(C19H22Cl2N4O): C, H, N.
1
m/z 359 (M + H)+. 59a maleate salt: mp 164-165 °C; H NMR
(300 MHz, DMSO-d6) δ 3.20 (m, 12H), 3.98 (s, 3H), 6.08 (s, 2H),
6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.50 (m,
2H), 7.60 (m, 1H), 7.73 (m, 2H), 8.16 (m, 1H); MS (DCI/NH3)
m/z 359 (M + H)+. Anal. Calcd (C19H23ClN4O‚C4H4O4): C, H,
1
N. 59b: mp 61-64 °C; H NMR (300 MHz, DMSO-d6) δ 2.40
(m, 6H), 2.70 (t, J ) 7 Hz, 2H), 3.42 (t, J ) 4.5 Hz, 4H), 3.72 (s,
3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9 Hz, 1H), 7.45
(m, 5H), 8.10 (m, 1H); MS (DCI/NH3) m/z 359 (M + H)+. 59b
maleate salt: mp 150-151 °C; 1H NMR (300 MHz, DMSO-d6) δ
3.30 (m, 12H), 3.79 (s, 3H), 6.08 (s, 2H), 6.74 (dd, J ) 7 and 4
Hz, 1H), 6,94 (d, J ) 9 Hz, 1H), 7.46 (m, 3H), 7.58 (m, 2H), 8.16
(m, 1H); MS (DCI/NH3) m/z 359 (M + H)+. Anal. Calcd (C19H23-
ClN4O‚C4H4O4‚0.4H2O): C, H, N.
(E)-1-(3-Chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-
1-yl)propan-1-one O-Methyloxime (64a) and (Z)-1-(3-Chloro-
4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-
Methyloxime (64b). Compounds were prepared from 1-(3-chloro-
4-fluorophenyl-ethanone, 1(pyridin-2-ylpiperazine and O-methyl-
hydroxylamine hydrochloride by method A in 28% and 12% overall
yields, respectively. 64a maleate salt: mp 161-162 °C; 1H NMR
(300 MHz, DMSO-d6) δ 3.18 (m, 12H), 3.97 (s, 3H), 6.06 (s, 2H),
6.74 (dd, J ) 7 and 4 Hz, 1H), 6.94 (d, J ) 9 Hz, 1H), 7.52 (t, J
) 9 Hz, 1H), 7.60 (m, 1H), 7.71 (m, 1H), 7.87 (dd, J ) 7 and 3
Hz, 1H), 8.16 (m, 1H); MS (DCI/NH3) m/z 377 (M + H)+. Anal.
Calcd (C19H22FClN4O‚C4H4O4): C, H, N. 64b maleate salt: mp
(E)-1-(4-Bromophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)pro-
pan-1-one O-Methyloxime (60a) and (Z)-1-(4-Bromophenyl)-3-
(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime (60b).
Compounds were prepared from 1-(4-bromophenyl)ethanone, 1-(py-
ridin-2-yl)piperazine, and O-methylhydroxylamine hydrochloride
by method A in 35% and 24% overall yields, respectively. 60a:
1
1
143-144 °C; H NMR (300 MHz, DMSO-d6) δ 3.22 (m, 12H),
oil, H NMR (300 MHz, DMSO-d6) δ 2.45 (m, 6H), 2.92 (t, J )
3.80 (s, 3H), 6.06 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.94 (d,
J ) 9 Hz, 1H), 7.58 (m, 3H), 7.77 (m, 1H), 8.16 (m, 1H); MS
(DCI/NH3) m/z 377 (M + H)+. Anal. Calcd (C19H22FClN4O‚
C4H4O4‚0.2H2O): C, H, N.
7 Hz, 2H), 3.42 (t, J ) 4.5 Hz, 4H), 3.93 (s, 3H), 6.62 (dd, J ) 7
and 4 Hz, 1H), 6.80 (d, J ) 9 Hz, 1H), 7.50 (m, 1H), 7.71 (s, 4H),
8.10 (m, 1H); MS (DCI/NH3) m/z 403 (M + H)+. Anal. Calcd
1
(C19H23BrN4O): C, H, N. 60b: oil, H NMR (300 MHz, DMSO-
d6) δ 2.40 (m, 6H), 2.70 (t, J ) 7 Hz, 2H), 3.40 (t, J ) 4.5 Hz,
4H), 3.70 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9
Hz, 1H), 7.39 (d, J ) 9 Hz, 2H), 7.50 (m, 1H), 7.61 (d, J ) 9 Hz,
2H), 8.10 (m, 1H); MS (DCI/NH3) m/z 403 (M + H)+. Anal. Calcd
(C19H23BrN4O): C, H, N.
(E)-1-(3,4-Dichlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one O-Methyloxime (65a) and (Z)-1-(3,4-Dichlorophen-
yl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime
(65b). Compounds were prepared from 1-(3,4-dichlorophenyl)-
ethanone, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine
hydrochloride by method A in 41% and 16% overall yields,
(E)-1-(3,5-Difluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one O-Methyloxime (61a) and (Z)-1-(3,5-Difluorophen-
yl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime
(61b). Compounds were prepared from 1-(3,5-difluorophenyl)-
ethanone, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine
hydrochloride by method A in 42% and 23% overall yields,
respectively. 61a: mp 70-73 °C; 1H NMR (300 MHz, DMSO-d6)
δ 2.45 (m, 6H), 2.92 (t, J ) 7 Hz, 2H), 3.40 (t, J ) 4 Hz, 4H),
3.94 (s, 3H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9 Hz,
1H), 7.33 (m, 3H), 7.50 (m, 1H), 8.09 (m, 1H); MS (DCI/NH3)
m/z 361 (M + H)+. Anal. Calcd (C19H22F2N4O‚0.3H2O): C, H, N.
61b maleate salt: mp 137-138 °C; 1H NMR (300 MHz, DMSO-
d6) δ 3.00 (m, 2H), 3.23 (m, 10H), 3.80 (s, 3H), 6.07 (s, 2H), 6.73
(dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.30 (m, 3H),
7.60 (m, 1H), 8.16 (m, 1H); (DCI/NH3) m/z 361 (M + H)+. Anal.
Calcd (C19H22F2N4O‚C4H4O4): C, H, N.
1
respectively. 65a maleate salt: mp 182-183 °C; H NMR (300
MHz, DMSO-d6) δ 3.27 (m, 12H), 3.98 (s, 3H), 6.07 (s, 2H), 6.73
(dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.60 (m, 1H),
7.70 (m, 2H), 7.90 (d, J ) 3 Hz, 1H), 8.16 (m, 1H); MS (DCI/
NH3) m/z 393 (M + H)+. Anal. Calcd (C19H22Cl2N4O‚C4H4O4):
C, H, N. 65b maleate salt: mp 140-142 °C; 1H NMR (300 MHz,
DMSO-d6) δ 3.00 (m, 2H), 3.30 (m, 10H), 3.80 (s, 3H), 6.06 (s,
2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.50
(m, 1H), 7.60 (m, 1H), 7.75 (d, J ) 9 Hz, 1H), 7.80 (d, J ) 3 Hz,
1H), 8.16 (m, 1H); MS (DCI/NH3) m/z 393 (M + H)+. Anal. Calcd
(C19H22Cl2N4O‚C4H4O4‚0.5H2O): C, H, N.
(E)-1-(4-Chloro-3-methylphenyl)-3-(4-pyridin-2-ylpiperazin-
1-yl)propan-1-one O-Methyloxime (66a) and (Z)-1-(4-Chloro-
3-methylphenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one
O-Methyloxime (66b). Compounds were prepared from 1-(4-
chloro-3-methylphenyl)ethanone, 1-pyridin-2-ylpiperazine, and O-
methylhydroxylamine hydrochloride by method A in 47% and 16%
overall yields, respectively. 66a maleate salt: mp 177-178 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.25 (m, 12H),
3.96 (s, 3H), 6.06 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d,
J ) 9 Hz, 1H), 7.60 (m, 4H), 8.16 (m, 1H); MS (DCI/NH3) m/z
373 (M + H)+. Anal. Calcd (C20H25ClN4O‚C4H4O4‚0.6H2O): C,
(E)-1-(3,5-Dimethylphenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one O-Methyloxime (62a) and (Z)-1-(3,5-Dimethylphen-
yl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime
(62b). Compounds were prepared from 1-(3,5-dimethylphenyl)-
ethanone, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine
hydrochloride by method A in 42% and 8% overall yields,
1
respectively. 62a maleate salt: mp 167-168 °C; H NMR (300
1
H, N. 66b maleate salt: mp 136-137 °C; H NMR (300 MHz,
MHz, DMSO-d6) δ 2.30 (s, 6H), 3.20 (m, 12H), 3.95 (s, 3H), 6.07
(s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H),
7.08 (m, 1H), 7.28 (m, 2H), 7.60 (m, 1H), 8.16 (m, 1H); MS (DCI/
NH3) m/z 353 (M + H)+. Anal. Calcd (C21H28N4O‚C4H4O4‚
DMSO-d6) δ 2.37 (s, 3H), 3.00 (m, 2H), 3.30 (m, 10H), 3.80 (s,
3H), 6.06 (s, 2H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9
Hz, 1H), 7.36 (m, 1H), 7.50 (m, 2H), 7.60 (m, 1H), 8.16 (m, 1H);
MS (DCI/NH3) m/z 373 (M + H)+. Anal. Calcd (C20H25ClN4O‚
C4H4O4‚0.6H2O): C, H, N.
1
0.6H2O): C, H, N. 62b maleate salt: mp 131-133 °C; H NMR
(300 MHz, DMSO-d6) δ 2.30 (s, 6H), 2.96 (m, 2H), 3.30 (m, 10H),
3.77 (s, 3H), 6.07 (s, 3H), 6.75 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d,
J ) 9 Hz, 1H), 7.08 (m, 3H), 7.28 (m, 2H), 7.60 (m, 1H), 8.16 (m,
1H); (DCI/NH3) m/z 353 (M + H)+. Anal. Calcd (C21H28N4O‚
1.5C4H4O4): C, H, N.
(E)-1-(3,4-Dimethylphenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)-
propan-1-one O-Methyloxime (67a) and (Z)-1-(3,4-Dimethylphen-
yl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-Methyloxime
(67b). Compounds were prepared from 1-(3,4-dimethylphenyl)-

5106 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Kolasa et al.
ethanone, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine
2.61 (m, 1H), 2.92 (m, 4H), 3.92 (s, 3H,), 7.19 (dd, J ) 7.5 and 6
Hz, 1H), 7.26 (d, J ) 9 Hz, 1H), 7.47 (m, 2H), 7.69 (m, 3H), 8.48
(m, 1H); MS (DCI-NH3) m/z 358 (M + H)+. Anal. Calcd for 70a
maleate salt (foam) (C20H24ClN3O‚C4H4O4): C, H, N. 70b: oil;
1H NMR (300 MHz, DMSO-d6) δ 1.71 (m, 4H), 1.98 (m, 2H),
2.36 (t, J ) 7.5 Hz, 2H), 2.60 (m, 1H), 2.68 (t, J ) 7.5 Hz, 2H),
2.88 (m, 2H), 3.71 (s, 3H,), 7.19 (dd, J ) 7.5 and 6 Hz, 1H), 7.25
(d, J ) 9 Hz, 1H), 7.45 (m, 4H), 7.69 (m, 1H), 8.48 (m, 1H); MS
(DCI-NH3) m/z 358 (M + H)+. Anal. Calcd (C20H24ClN3O‚
0.1H2O): C, H, N.
(E)-1-(4-Chlorophenyl)-3-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-
[2,4′]bipyridinyl-1′-yl)propan-1-one O-Methyl-oxime (71a) and
(Z)-1-(4-chlorophenyl)-3-(1-oxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]-
bipyridinyl-1′-yl)propan-1-one O-Methyloxime (71b). Com-
pounds were synthesized from the hydrochloride salt of 1′,2′,3′,4′,5′,6′-
hexahydro-[2,4′]bipyridinyl 1-oxide,18 3-chloro-1-(4-chlorophenyl)-
propan-1-one, and O-methylhydroxylamine by method C in 41%
and 7% yields, respectively. 71a: 1H NMR (300 MHz, DMSO-d6)
δ 1.50 (m, 2H), 1.88 (m, 2H), 2.08 (t, J ) 7.5 Hz, 2H), 2.45 (t, J
) 7 Hz, 1H), 2.93 (m, 5H), 3.21 (m, 1H), 3.92 (s, 3H), 7.28 (m,
2H), 7.38 (m, 1H), 7.48 (d, J ) 9 Hz, 2H), 7.68 (d, J ) 9 Hz, 2H);
8.24 (m, 1H); MS (DCI/NH3) m/z 374 (M + H)+. Anal. Calcd for
71a maleate salt (foam) (C20H24ClN3O2‚C4H4O4): C, H, N. 71b:
1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 2H), 1.89 (m, 2H),
2.00 (t, J ) 7.5 Hz, 2H), 2.37 (t, J ) 7.5 Hz, 2H), 2.68 (t, J ) 7.5
Hz, 2H), 3.21 (m, 1H), 3.72 (s, 3H), 7.30 (m, 2H), 7.38 (m, 2H),
7.45 (d, J ) 4.5 Hz, 2H), 7.49 (m, 1H); 8.21 (m, 1H); MS (DCI/
NH3) m/z 374 (M + H)+. Anal. Calcd for 71b maleate salt (foam)
(C20H24ClN3O2‚C4H4O4): C, H, N.
hydrochloride by method A in 39% and 7% overall yields,
1
respectively. 67a maleate salt: mp 166-167 °C; H NMR (300
MHz, DMSO-d6) δ 2.23 and 2.26 (2s, 6H), 3.20 (m, 12H), 3.97 (s,
3H), 6.06 (s, 2H), 6.74 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9
Hz, 1H), 7.20 (d, J ) 9 Hz, 1H), 7.40 (m, 1H), 7.46 (m, 1H), 7.60
(m, 1H), 8.16 (m, 1H); MS (DCI/NH3) m/z 353 (M + H)+. Anal.
Calcd (C21H28N4O‚C4H4O4‚0.6H2O): C, H, N. 67b maleate salt:
1
mp 130-131 °C; H NMR (300 MHz, DMSO-d6) δ 2.23 (s, 6H),
3.12 (m, 12H), 3.76 (s, 3H), 6.06 (s, 2H), 6.74 (dd, J ) 7 and 4
Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.24 (m, 3H), 7.60 (m, 1H), 8.16
(m, 1H); MS (DCI/NH3) m/z 353 (M + H)+. Anal. Calcd
(C21H28N4O‚C4H4O4): C, H, N.
1-Pyridin-3-yl-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one
O-Methyloxime (68ab). Compound was prepared from 1-pyridin-
3-ylethanone, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine
hydrochloride by method A in 26% overall yield. 5:2 E:Z maleate
salt (foam): 1H NMR (300 MHz, DMSO-d6) δ 3.23 (m, 12H), 4.82
and 4.98 (2s, 2:5, 3H), 6.17 (s, 5H), 6.75 (m, 1H), 6.95 (d, J ) 7
Hz, 1H), 7.44 (m, 1H), 7.62 (m, 1H), 7.94 and 8.07 (2m, 2:5, 1H),
8.17 (m, 1H), 8.61 and 8.65 (2m, 2:5, 1H), 8.72 and 8.90 (2m, 2:5,
1H); MS (DCI/NH3) m/z 326 (M + H)+. Anal. Calcd (C18H23-
ClN5O‚2.5C4H4O4): C, H, N.
(E)-1-(4-Chlorophenyl)-3-(2-methyl-4-pyridin-2-ylpiperazin-
1-yl)propan-1-one O-Methyloxime (69a) and (Z)-1-(4-Chlo-
rophenyl)-3-(2-methyl-4-pyridin-2-ylpiperazin-1-yl)propan-1-
one O-Methyloxime (69b). A solution of 2-methylpiperazine (0.50
g, 5.0 mmol) and 2-bromopyridine (5.0 mL, 50 mmol) was heated
at 120 °C for 18 h. The mixture was cooled to 22 °C, diluted with
water, and extracted with ethyl acetate. The organic phase was
extracted with dilute aqueous HCl (2×), and the combined aqueous
layers were concentrated under reduced pressure. The resulting oil
was triturated with Et2O and the solid residue was dissolved in
MeOH and codistilled with dry toluene (2×) to produce 1.23 g
(96%) of the desired 3-methyl-1-pyridin-2-ylpiperazine hydrobro-
mide,14: 1H NMR (300 MHz, DMSO-d6) δ 1.30 (d, J ) 6 Hz,
3H), 3.17 (m, 2H), 3.41 (m, 3H), 4.36 (m, 2H), 6.93 (t, J ) 6 Hz,
1H), 7.28 (d, J ) 9 Hz, 1H), 7.90 (t, J ) 8 Hz, 1H), 8.13 (dd, J )
6 and 1.5 Hz, 1H), 9.17 (br s, 1H), 9.35 (br s, 1H); MS (DCI/NH3)
m/e 178 (M + H)+.
(E)-1-(4-Chlorophenyl)-3-(3′,4′,5′,6′-tetrahydro-2′H-[2,3′]bi-
pyridinyl-1′-yl)propan-1-one O-Methyloxime (72a). Compound
72a was synthesized from tert-butyl-3-oxo-1-piperidinecarboxy-
late36,37 by the process described for the synthesis of 70a: 1H NMR
(300 MHz, CDCl3) δ 1.63 (m, 3H), 1.79 (m, 1H), 1.97 (m, 1H),
2.15 (m, 1H), 2.26 (t, J ) 7.5 Hz, 1H), 2.59 (m, 2H), 2.95 (m,
3H), 3.12 (m, 1H), 3.97 (s, 3H), 7.13 (m, 2H), 7.35 (d, J ) 9 Hz,
2H), 7.58 (d, J ) 9 Hz, 2H), 7.63 (m, 1H), 8.57 (m, 1H); MS
(DCI/NH3) m/z 358 (M + H)+. Anal. Calcd (C20H24ClN3O‚
0.25H2O): C, H, N.
(E)-1-(4-Fluorophenyl)-2-(4-pyridin-2-yl)ethanone Oxime (73a)
and (Z)-1-(4-Fluorophenyl)-2-(4-pyridin-2-yl)ethanone Oxime
(73b). Compounds were prepared from 2-chloro-1-(4-fluorophenyl)-
ethanone, 1-pyridin-2-ylpiperazine, and hydroxylamine hydrochlo-
ride by method D in 34% and 4% overall yields, respectively.
The title E- and Z-isomers were prepared from 3-chloro-1-(4-
chlorophenyl)propan-1-one, 3-methyl-1-(pyridin-2-yl)piperazine,
and O-methylhydroxylamine hydrochloride by method C in 45%
and 14% overall yields, respectively. 69a: oil; 1H NMR (300 MHz,
CDCl3) δ 1.11 (d, J ) 6 Hz, 3H), 2.57 (m, 2H), 2.72 (m, 2H), 2.90
(m, 4H), 3.09 (m, 1H), 3.95 (m, 1H), 3.98 (s, 3H), 3.99 (m, 1H),
6.60 (m, 1H), 6.64 (d, J ) 9 Hz, 1H), 7.34 (m, 2H), 7.47 (m, 1H),
7.59 (m, 2H), 8.18 (m, 1H); MS (DCI/NH3) m/z 373 (M + H)+.
1
73a: mp 136-137 °C; H NMR (300 MHz, DMSO-d6) δ 2.46
(m, 4H), 3.38 (m, 6H), 6.60 (dd, J ) 7 and 4 Hz, 1H), 6.76 (d, J
) 9 Hz, 1H), 7.20 (t, J ) 9 Hz, 2H), 7.50 (m, 1H), 7.62 (m, 2H),
8.09 (m, 1H), 11.05 (s, 1H); MS (DCI/NH3) m/z 315 (M + H)+.
1
1
73b: mp 136-138 °C; H NMR (300 MHz, DMSO-d6) δ 2.50
69a maleate salt: mp 140-141 °C; H NMR (300 MHz, DMSO-
(m, 4H), 3.60 (t, J ) 4 Hz, 4H), 3.66 (s, 2H), 6.62 (dd, J ) 7 and
4 Hz, 1H), 6.77 (d, J ) 9 Hz, 1H), 7.20 (t, J ) 9 Hz, 1H), 7.50 (m,
1H), 7.62 (m, 2H), 8.09 (m, 1H), 11.45 (s, 1H); MS (DCI/NH3)
m/z 315 (M + H)+. Anal. Calcd (C17H19FN4O‚0.3H2O): C, H, N.
(E)-1-(4-Fluorophenyl)-2-(4-pyridin-2-yl)ethanone O-Methyl-
oxime (74a) and (Z)-1-(4-Fluorophenyl)-2-(4-pyridin-2-yl)etha-
none O-Methyloxime (74b). Compounds were prepared from
2-chloro-1-(4-fluorophenyl)ethanone, 1-pyridin-2-ylpiperazine, and
O-methylhydroxylamine hydrochloride by method D in 17% and
6% overall yields, respectively. 74a dimaleate salt: mp 152-153
°C; 1H NMR (300 MHz, DMSO-d6) δ 3.30 (m, 10H), 3.86 (s, 3H),
6.20 (s, 4H), 6.70 (dd, J ) 7 and 4 Hz, 1H), 6.88 (d, J ) 9 Hz,
1H), 7.30 (t, J ) 9 Hz, 2H), 7.60 (m, 1H), 7.68 (m, 2H), 8.12 (m,
1H); MS (DCI/NH3) m/z 329 (M + H)+. Anal. Calcd (C18H21FN4O‚
2.0C4H4O4‚1.2H2O): C, H, N. 74b dimaleate salt: mp 144-145
°C; 1H NMR (300 MHz, DMSO-d6) δ 3.30 (m, 10H), 3.97 (s, 3H),
6.20 (s, 4H), 6.70 (dd, J ) 7 and 4 Hz, 1H), 6.87 (d, J ) 9 Hz,
1H), 7.30 (t, J ) 9 Hz, 2H), 7.58 (m, 1H), 7.85 (m, 2H), 8.13 (m,
1H); MS (DCI/NH3) m/z 329 (M + H)+. Anal. Calcd (C18H21FN4O‚
2.0C4H4O4): C, H, N.
d6) δ 1.25 (d, J ) 6 Hz, 3H), 4.00 (m, 11H), 3.97 (s, 3H), 6.08 (s,
2H), 6.72 (dd, J ) 7.0 and 5 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.50
(m, 2H), 7.59 (m, 1H), 7.72 (m, 2H), 8.14 (dd, J ) 5 and 1.5 Hz,
1
1H); Anal. Calcd (C20H25ClN4O‚C4H4O4): C, H, N. 69b: oil; H
NMR (300 MHz, DMSO-d6) δ 0.85 (d, J ) 6 Hz, 3H), 2.22 (m,
1H), 2.33 (m, 2H), 2.68 (m, 4H), 2.83 (m, 1H), 2.96 (m, 1H), 3.72
(s, 3H), 3.85 (d, J ) 12 Hz, 2H), 6.61 (d, J ) 7 Hz, 1H), 6.79 (d,
J ) 9 Hz, 1H), 7.48 (m, 5H), 8.1 (m, 1H); MS (DCI/NH3) m/z 373
(M + H)+. 69b maleate salt: foam; 1H NMR (300 MHz, DMSO-
d6) δ 1.28 (d, J ) 6 Hz, 3H), 3.69 (m, 11H), 3.80 (s, 3H), 6.09 (s,
2.4H), 6.73 (dd, J ) 7 and 5 Hz, 1H), 6.95 (d, J ) 9 Hz, 1H), 7.58
(m, 5H), 8.15 (dd, J ) 5 and 1.5 Hz, 1H); Anal. Calcd (C20H25-
ClN4O‚1.2C4H4O4): C, H, N.
(E)-1-(4-Chlorophenyl)-3-(3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bi-
pyridinyl-1′-yl)propan-1-one O-Methyloxime (70a) and (Z)-1-
(4-Chlorophenyl)-3-(3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-
1′-yl)propan-1-one O-Methyloxime (70b). The title E- and
Z-isomers were prepared from 3-chloro-1-(4-chlorophenyl)propan-
1-one, 1′,2′,3′,4′,5′,6′-hexahydro[2,4′]bipiridinyl hydrochloride,18,35,36
and O-methylhydroxylamine hydrochloride by method C in 21%
and 7% overall yields, respectively. 70a: oil; 1H NMR (300 MHz,
DMSO-d6) δ 1.71 (m, 4H), 2.05 (m, 2H), 2.45 (t, J ) 7.5 Hz, 2H),
(E)-1-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-1-yl)butan-
1-one Oxime (75a) and (Z)-1-(4-Fluorophenyl)-4-(4-pyridin-2-

Dopamine D4 Receptor Agonists for Treatment of ED
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17 5107
ylpiperazin-1-yl)butan-1-one Oxime (75b). Compounds were
prepared from 4-chloro-1-(4-fluorophenyl)butan-1-one, 1-pyridin-
2-ylpiperazine, and hydroxylamine hydrochloride by method D in
35% and 4% overall yields, respectively. 75a: mp 158-159 °C;
1H NMR (300 MHz, DMSO-d6) δ 1.65 (m, 2H), 2.32 (t, J ) 7 Hz,
2H), 2.40 (m, 4H), 2.75 (t, J ) 7 Hz, 2H), 3.43 (m, 4H), 6.61 (dd,
J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9 Hz, 1H), 7.22 (t, J ) 9 Hz,
2H), 7.51 (m, 1H), 7.72 (dd, J ) 9 and 4 Hz, 2H), 8.10 (m, 1H),
11.07 (s, 1H); MS (DCI/NH3) m/z 343 (M + H)+. Anal. Calcd
MHz, DMSO-d6) δ 3.30 (m, 10H), 3.78 (s, 3H), 4.85 (m, 1H),
6.06 (s, 2H), 6.72 (dd, J ) 7 and 4.5 Hz, 1H), 6.91 (d, J ) 7 Hz,
1H), 7.44 (d, J ) 9 Hz, 2H), 7.52 (d, J ) 9 Hz, 1H), 7.60 (m, 1H),
8.15 (m, 1H); MS (DCI/NH3) m/z 375 (M + H)+. Anal. Calcd
(C19H23ClN4O2‚C4H4O4): C, H, N. 77b maleate salt: mp 167-
169 °C; 1H NMR (300 MHz, DMSO-d6) δ 3.30 (m, 10H), 3.95 (s,
3H), 4.35 (m, 1H), 5.56 (br d, J ) 7 Hz, 1H), 6.11 (s, 3H), 6.74
(dd, J ) 7 and 4.5 Hz, 1H), 6.93 (d, J ) 7 Hz, 1H), 7.48 (d, J )
9 Hz, 2H), 7.60 (m, 1H), 7.70 (d, J ) 9 Hz, 1H), 8.15 (m, 1H);
MS (DCI/NH3) m/z 375 (M + H)+. Anal. Calcd (C19H23ClN4O2‚
1.5C4H4O4): C, H, N.
(E)-1-(4-Chlorophenyl)-2-methoxy-3-(4-pyridin-2-ylpiperazin-
1-yl)propanon-1-one O-Methyloxime (78a) and (Z)-1-(4-Chlo-
rophenyl)-2-methoxy-3-(4-pyridin-2-ylpiperazin-1-yl)propanon-
1-one O-Methyloxime (78b). Compounds were isolated as side
products of process for the synthesis of 77a and 77b in 2% and
3% yields, respectively. 78a: oil; 1H NMR (300 MHz, DMSO-d6)
δ 2.56 (m, 5H), 2.80 (dd, J ) 12 and 6 Hz, 1H), 3.14 (s, 3H), 3.42
(t, J ) 6 Hz, 4H), 3.94 (s, 3H), 5.05 (dd, J ) 7 and 4.5 Hz, 1H),
6.62 (dd, J ) 7 and 4.5 Hz, 1H), 6.80 (d, J ) 7 Hz, 1H), 7.50 (m,
3H), 7.68 (d, J ) 9 Hz, 1H), 8.08 (m, 1H); MS (DCI/NH3) m/z
389 (M + H)+. Anal. Calcd (C20H25ClN4O2): C, H, N. 78b: oil;
1H NMR (300 MHz, DMSO-d6) δ 2.30 (m, 4H), 2.40 (dd, J ) 12
and 6 Hz, 1H), 2.55 (m, 1H), 3.35 (s, 3H), 3.42 (m, 4H), 3.76 (s,
3H), 4.17 (t, J ) 7 Hz, 1H), 6.62 (dd, J ) 7 and 4.5 Hz, 1H), 6.80
(d, J ) 7 Hz, 1H), 7.34 (d, J ) 9 Hz, 2H), 7.50 (m, 3H), 8.10 (m,
1H); MS (DCI/NH3) m/z 389 (M + H)+. Anal. Calcd (C20H25-
ClN4O2): C, H, N.
1
(C19H23FN4O‚0.5H2O): C, H, N. 75b: oil; H NMR (300 MHz,
DMSO-d6) δ 1.55 (m, 2H), 2.30 (t, J ) 7 Hz, 2H), 2.35 (t, J ) 4.5
Hz, 4H), 2.53 (m, 2H), 3.42 (t, J ) 4.5 Hz, 4H), 6.61 (dd, J ) 7
and 4 Hz, 1H), 6.79 (d, J ) 9 Hz, 1H), 7.22 (t, J ) 9 Hz, 2H),
7.52 (m, 3H), 8.09 (m, 1H), 10.64 (s, 1H); MS (DCI/NH3) m/z 343
(M + H)+.
(E)-1-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-1-yl)butan-
1-one O-Methyloxime (76a) and (Z)-1-(4-Fluorophenyl)-4-(4-
pyridin-2-ylpiperazin-1-yl)butan-1-one O-Methyloxime (76b).
Compounds were prepared from 4-chloro-1-(4-fluorophenyl)butan-
1-one, 1-pyridin-2-ylpiperazine, and O-methylhydroxylamine hy-
drochloride by method D in 43% and 18% overall yields,
respectively. 76a: mp 55-56 °C, 1H NMR (300 MHz, DMSO-d6)
δ 1.63 (m, 2H), 2.32 (t, J ) 7 Hz, 2H), 2.38 (t, J ) 4.5 Hz, 4H),
2.75 (t, J ) 7 Hz, 2H), 3.42 (t, J ) 4.5 Hz, 4H), 3.91 (s, 3H), 6.61
(dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 9 Hz, 1H), 7.22 (t, J ) 9
Hz, 2H), 7.51 (m, 1H), 7.72 (dd, J ) 9 and 4 Hz, 2H), 8.10 (m,
1H); MS (DCI/NH3) m/z 357 (M + H)+. Anal. Calcd (C20H25-
FN4O): C, H, N. 76b: oil, 1H NMR (300 MHz, DMSO-d6) δ 1.55
(quintet, J ) 7 Hz, 2H), 2.30 (t, J ) 7 Hz, 2H), 2.37 (t, J ) 4.5
Hz, 4H), 2.55 (m, 2H), 3.42 (t, J ) 4.5 Hz, 4H), 3.72 (s, 3H), 6.61
(dd, J ) 7 and 4 Hz, 1H), 6.79 (d, J ) 9 Hz, 1H), 7.22 (t, J ) 9
Hz, 2H), 7.50 (m, 3H), 8.09 (m, 1H); MS (DCI/NH3) m/z 357 (M
+ H)+.
(E)-2-Hydroxy-3-(4-pyridin-2-ylpiperazin-1-yl)-1-(m-tolyl)-
propan-1-one Oxime (79a) and (Z)-2-Hydroxy-3-(4-pyridin-2-
ylpiperazin-1-yl)-1-(m-tolyl)propan-1-one Oxime (79b). Com-
pounds 79a and 79b were prepared from 3-(4-pyridin-2-ylpiperazin-
1-yl)-1-(m-tolyl)propan-1-one by the process described for the
synthesis of 77a and 77b in 10% and 8% overall yields, respec-
(E)-1-(4-Chlorophenyl)-2-hydroxy-3-(4-pyridin-2-ylpiperazin-
1-yl)propanon-1-one O-Methyloxime (77a) and (Z)-1-(4-Chlo-
rophenyl)-2-hydroxy-3-(4-pyridin-2-ylpiperazin-1-yl)propanon-
1-one O-Methyloxime (77b). 1-(4-Chlorophenyl)-3-(4-pyridin-2-
ylpiperazin-1-yl)propan-1-one (522 mg, 1.6 mmol) and iodobenzene
diacetate [PhI(OAc)2, 547 mg, 1.7 mmol) were combined in
methanol (25 mL), and a solution of KOH (297 mg, 5.3 mmol) in
MeOH (5 mL) was added dropwise. The reaction was continued
at room temperature for 5 h and then was concentrated under
reduced pressure. The residue was treated with ethyl acetate and
water, and the organic layer was separated, washed with brine, dried
over anhydrous MgSO4, and concentrated under reduced pressure
to afford 570 mg of crude 1-(4-chlorophenyl)-1,1-dimethoxy-3-(4-
1
tively. 79a: mp 198-200 °C; H NMR (300 MHz, DMSO-d6) δ
2.34 (s + m, 7H), 2.52 (m, 2H), 3.42 (m, 4H), 4.52 (m, 1H), 5.20
(d, J ) 4 Hz, 1H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 7
Hz, 1H), 7.16 (m, 3H), 7.22 (t, J ) 7 Hz, 1H), 7.50 (m, 1H), 8.10
(m, 1H), 10.60 (s, 1H); MS (ESI+) m/z 341 (M + H)+; MS (ESI-)
m/z 339 (M - H)-. Anal. Calcd (C19H24N4O2): C, H, N. 79b: mp
157-159 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 2.55
(m, 5H), 2.66 (dd, J ) 12 and 7 Hz, 1H), 3.44 (m, 4H), 5.18 (m,
1H), 5.44 (m, 1H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 7
Hz, 1H), 7.14 (m, 1H), 7.22 (t, J ) 7 Hz, 1H), 7.45 (m, 2H), 7.51
(m, 1H), 8.10 (m, 1H), 11.20 (s, 1H); MS (ESI+) m/z 341 (M +
H)+; MS (ESI-) m/z 339 (M - H)-. Anal. Calcd (C19H24N4O2):
C, H, N.
1
pyridin-2-ylpiperazin-1-yl)propan-2-ol: H NMR (300 MHz, DMSO-
d6) δ 2.42 (m, 4H), 3.13 (s, 3H), 3.20 (s, 3H), 3.41 (m, 6H), 4.05
(m, 1H), 4.78 (d, J ) 6 Hz, 1H), 6.60 (dd, J ) 7 and 4.5 Hz, 1H),
6.77 (d, J ) 9 Hz, 1H), 7.40 (s, 4H), 7.50 (m, 1H), 8.08 (m, 1H);
MS (DCI/NH3) m/z 392 (M + H)+.
The crude 1-(4-chlorophenyl)-1,1-dimethoxy-3-(4-pyridin-2-
ylpiperazin-1-yl)propan-2-ol (570 mg, ∼1.5 mmol) was dissolved
in chloroform (20 mL) and treated at room temperature with 5%
H2SO4 (15 mL) for 18 h. After a saturated solution of NaHCO3
was added, the organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure to
afford 345 mg of crude 1-[4-chloro-2-hydroxy-3-(4-pyridin-2-
ylpiperazin-1-yl)]propanon-1-one: MS (DCI/NH3) m/z 346 (M +
H)+.
Methoxylamine hydrochloride (410 mg, 5 mmol) and crude 1-[4-
chloro-2-hydroxy-3-(4-pyridin-2-ylpiperazin-1-yl)]propanon-1-one
(344 mg, ∼1 mmol) were combined in pyridine (10 mL) and the
reaction was left at room temperature for 14 h. The pyridine was
removed under reduced pressure, and the residue was treated with
a saturated solution of NaHCO3 and extracted with ethyl acetate.
The acetate layer was washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography (CH2Cl2/acetone 4:1 as eluent)
to provide 200 mg (53%) of E-isomer (77a) and 132 mg (35%) of
Z-isomer (77b). 77a maleate salt: mp 155-156 °C; 1H NMR (300
(E)-2-Methoxy-3-(4-pyridin-2-ylpiperazin-1-yl)-1-(m-tolyl)-
propan-1-one O-Methyloxime (80a) and (Z)-2-Methoxy-3-(4-
pyridin-2-ylpiperazin-1-yl)-1-(m-tolyl)propan-1-one O-Methyl-
oxime (80b). Compounds were isolated as side products of process
for the synthesis of 79a and 79b in 2% and 1% yields, respectively.
80a: oil, 1% overall yield; 1H NMR (300 MHz, DMSO-d6) δ 2.30
(s, 3H), 2.38 (m, 4H), 2.85 (s, 2H), 3.20 (s, 3H), 3.30 (m, 5H),
6.60 (dd, J ) 7 and 4 Hz, 1H), 6.74 (d, J ) 7 Hz, 1H), 7.10 (m,
1H), 7.20 (m, 3H), 7.46 (m, 1H), 8.05 (m, 1H), 11.10 (s, 1H); MS
(ESI+) m/z 355 (M + H)+; MS (ESI-) m/z 353 (M - H)-. 80b:
1
oil, 2% overall yield; H NMR (300 MHz, DMSO-d6) δ 2.32 (s,
3H), 2.53 (m, 5H), 2.80 (dd, J ) 12 and 7 Hz, 1H), 3.15 (s, 3H),
3.44 (m, 4H), 5.18 (q, J ) 3 Hz, 1H), 6.62 (dd, J ) 7 and 4 Hz,
1H), 6.80 (d, J ) 7 Hz, 1H), 7.14 (m, 1H), 7.22 (t, J ) 7 Hz, 1H),
7.45 (m, 2H), 7.51 (m, 1H), 8.10 (m, 1H), 11.44 (s, 1H); MS (ESI+)
m/z 355 (M + H)+; MS (ESI-) m/z 353 (M - H)-. Anal. Calcd
(C20H26N4O2‚0.15CH2Cl2): C, H, N.
1-(4-Chlorophenyl)-2-methyl-3-(4-pyridin-2-ylpiperazin-1-yl)-
propanon-1-one O-Methyloxime (81ab). Compound was prepared
from 1-(4-chlorophenyl)propan-1-one, 1-pyridin-2-ylpiperazine, and
O-methylhydroxylamine hydrochloride by method A in 18% overall
yield, as a 3:1 mixture of Z:E isomers: dimaleate salt, mp 152-
153 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.05 and 1.28 (2 d, 3:1,
J ) 7 Hz, 3H), 3.30 (m, 11H), 3.78 and 3.92 (2 s, 3:1, 3H), 6.18

5108 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 17
Kolasa et al.
(s, 4H), 6.73 (m, 1H), 6.93 (m, 1H), 7.50 (m, 5H), 8.16 (m, 1H);
MS (DCI/NH3) m/z 373 (M+H)+. Anal. Calcd (C20H25ClN4O‚
2.0C4H4O4): C, H, N.
injection. The number of penile erections was recorded by direct
observation for a period of 60 min after drug dosing, and the number
of animals exhibiting one or more erections was expressed as
incidence (percent).
1-(4-Chlorophenyl)-2-(methoxyaminomethyl)-3-(4-pyridin-2-
ylpiperazin-1-yl)propanon-1-one O-Methyloxime (82a). Com-
pound was prepared from 3-chloro-1-(4-chlorophenyl)propan-1-one,
1-pyridin-2-ylpiperazine, and O-methylhydroxylamine hydrochlo-
ride by method A in 25% overall yield, as a 1:1 mixture of Z:E
isomers: maleate salt, mp 118-121 °C; 1H NMR (300 MHz,
DMSO-d6) δ 3.20 (m + 2s, 13H), 3.70 (m + 2s, 6H), 6.18 (s,
3.5H), 6.75 (m, 1H), 6,95 (m, 1H), 7.50 (m, 3H), 7.60 (m, 1H),
7.75 (m, 1H), 8.16 (m, 1H); MS (DCI/NH3) m/z 418 (M + H)+.
Anal. Calcd (C21H28ClN5O2‚1.75C4H4O4): C, H; N calcd 11.28,
found 10.86.
(E) Emesis Model in Ferrets. Male Fitch ferrets (body weights
1.0-1.5 kg, Marshall Farms) were fasted overnight before experi-
mentation. Test compounds were administrated subcutaneously, and
animals were carefully placed in individual observation cages and
watched for any signs of drug-induced emesis and signs of nausea
for 90 min. Nausea was characterized by behaviors such as licking,
gagging, backing, head burying, and intense abdominal grooming.
When present, emesis was usually preceded by these behaviors and
was characterized by rhythmic abdominal contractions which were
associated with vomiting or retching movement.
1-(4-Chlorophenyl)-2-isopropoxymethyl-3-(4-pyridin-2-ylpi-
perazin-1-yl)propanon-1-one O-Methyloxime (83a). Compound
was prepared from 3-chloro-1-(4-chlorophenyl)propan-1-one, 1-py-
ridin-2-ylpiperazine, and O-methylhydroxylamine hydrochloride by
method A in 35% overall yield, as a 2:1 mixture of Z:E isomers:
Supporting Information Available: Elemental analysis data
for the compounds and X-ray crystallographic information for
compounds 22a, 25a, 39a, and 75a. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
dimaleate salt, mp 106-109 °C; H NMR (300 MHz, DMSO-d6)
References
δ 1.01 (m, 6H), 3.40 (m, 20H), 3.80 (s, 2H), 3.92 (s, 1H), 6.18 (s,
4H), 6.75 (m, 1H), 6,95 (m, 1H), 7.50 (m, 5H), 8.16 (m, 1H); MS
(DCI/NH3) m/z 431 (M + H)+. Anal. Calcd (C23H31ClN4O2‚
2.0C4H4O4): C, H, N.
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process described for the synthesis of 77a and 77b in 13% overall
yield as a 2:1 mixture of Z:E isomers: 1H NMR (300 MHz, DMSO-
d6) δ 2.32 (m, 2.5H), 2.55 (m, 3.2 H), 3.71 (dd, J ) 12 and 7 Hz,
0.3H), 3.42 (m, 4H), 3.75 (s, 2H), 3.92 (s, 1H), 4.57 (m, 0.66H),
5.36 (m, 0.34H), 5.52 (d, J ) 4 Hz, 0.34H), 5.60 (d, J ) 4 Hz,
0.66H), 6.62 (dd, J ) 7 and 4 Hz, 1H), 6.80 (d, J ) 7 Hz, 1H),
7.42 (m, 1H), 7.53 (m, 1H), 7.75 (dt, J ) 7 and 2 Hz, 0.66H), 8.04
(dt, J ) 7 and 2 Hz, 0.34H), 8.10 (m, 1H), 8.54 (m, 1.66H), 8.78
(m, 0.33H); MS (ESI+) m/z 342 (M + H)+. Anal. Calcd
(C18H23N5O2‚0.5H2O): C, H; N calcd 19.99, found 19.53.
2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-3,4-dihydro-2H-naph-
thalen-1-one O-Ethyloxime (85a). Compound was prepared from
3,4-dihydro-2H-naphthalen-1-one, 1-pyridin-2-ylpiperazine, and
O-ethylhydroxylamine hydrochloride by method A in 15% overall
yield: dimaleate salt, mp 146-147 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.30 (t, J ) 7 Hz, 3H), 1.87 (m, 1H), 2.10 (m, 1H),
2.73 (m, 1H), 3.25 (m, 11H), 3.97 (m, 1H), 4.22 (q, J ) 7 Hz,
2H), 6.15 (s, 4H), 6.73 (dd, J ) 7 and 4 Hz, 1H), 6.95 (d, J ) 9
Hz, 1H), 7.23 (m, 2H), 7.33 (m, 1H), 7.60 (m, 1H), 7.90 (d, J )
9 Hz, 1H), 8.16 (m, 1H); MS (DCI/NH3) m/z 365 (M + H)+. Anal.
Calcd (C22H28N4O‚2.0C4H4O4): C, H, N.
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Biological Procedures: (A) FLIPR Assay of Receptor Activa-
tion by Agonists. Test compounds were evaluated for their ability
to activate the human D4.4 receptor coexpressed with GRq05 in
HEK293 cells according to the method described by Moreland et
al.39
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(B) D4.4 Calcium Flux Assay (Antagonist Mode). Compounds
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continued for an additional 3 min. The data were normalized with
the response of 1 µM dopamine alone.39
(C) D2L and D4.4 Radioligand Binding Assays. Dopamine D2L
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