Synthesis and evaluation of a set of para-substituted 4-phenylpiperidines and 4-phenylpiperazines as monoamine oxidase (MAO) inhibitors

Article abstract of DOI:10.1021/jm201692d

A series of para-substituted 4-phenylpiperidines/piperazines have been synthesized and their affinity to recombinant rat cerebral cortex monoamine oxidases A (MAO A) and B (MAO B) determined. Para-substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para-substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum.

Full text of DOI:10.1021/jm201692d

Article
pubs.acs.org/jmc
Synthesis and Evaluation of a Set of Para-Substituted
4-Phenylpiperidines and 4-Phenylpiperazines as Monoamine
Oxidase (MAO) Inhibitors
Fredrik Pettersson,* Peder Svensson, Susanna Waters, Nicholas Waters, and Clas Sonesson
NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, S-413 46 Goteborg, Sweden
̈
S
* Supporting Information
ABSTRACT: A series of para-substituted 4-phenylpiperidines/piperazines
have been synthesized and their affinity to recombinant rat cerebral cortex
monoamine oxidases A (MAO A) and B (MAO B) determined. Para-
substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded
compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para-
substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds
were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was
demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and
3-methoxytyramine (3-MT) in the striatum.
potentiate the effect of MAO A on DOPAC.17 It is therefore
INTRODUCTION
■
crucial to take into consideration the plasma concentrations of
different inhibitors when testing them in vivo, since most MAO
inhibitors are only selective up to a certain concentration.
MAO inhibitors can bind either reversibly (e.g., moclobemide)
or irreversibly (e.g., clorgyline and selegiline) (Figure 1).18−20
Flavin containing monoamine oxidases (MAOs) constitute a
heterogeneous family of enzymes that are present in mammals,
plants, and microorganisms. In addition to metabolizing foods
and pharmaceutical compounds, they are also responsible for the
degradation of amine neurotransmitters. There are two distinct
types of MAOs, MAO A and MAO B, which share 70% amino
acid sequence homology.1−5 Even though the two isomers have
a number of structural similarities and are both bound to the
outer mitochondrial membrane,6 they have different functions
in the brain. MAO A catalyzes the oxidative deamination of
serotonin (5-hydroxytryptamine, 5-HT), and the therapeutic use
of inhibitors of MAO A is primarily in the treatment of
depression.7,8 On the other hand, MAO B is responsible for the
degradation of benzylamine and α-phenethylamine, and MAO B
inhibitors are used to treat neurodegenerative disorders such as
Parkinson’s disease.9 Dopamine (DA), adrenaline (A), and
noradrenaline (NA) are metabolized by both isoforms, albeit
more efficiently by MAO A.10,11
Both MAO A and MAO B are present in the rat brain.5,12
MAO A is the isoform found primarily within dopaminergic
nerve terminals,13 whereas MAO B is found mainly in striatal
neurons and glial cells.14 Furthermore, it has been shown that
MAO A has a predominant effect on dopamine catabolism,
leading to production of the metabolite DOPAC (3,4-
dihydroxyphenylacetic acid), and that MAO A inhibitors (e.g.,
clorgyline) therefore reduce striatal DOPAC levels.6,15 In
addition, since more synaptic DA is metabolized by COMT
(catechol-O-methyltransferase) to 3-MT (3-methoxytyramine)
and less 3-MT is metabolized to HVA (homovanillic acid) by
MAO, a concomitant increase in 3-MT levels is observed.
Because of the location of MAO B, specific inhibition of
this isoform with, for example, selegeline has no effect or only
mild effects on DOPAC and 3-MT concentrations.16 However,
in the presence of a MAO A inhibitor, MAO B inhibitors
Figure 1. Examples of MAO A (moclobemide and clorgyline) and
MAO B (selegiline and rasagiline) inhibitors.
It is believed that the newer reversible agents are less prone to
induce tyramine potentiation, a common side effect of MAO
inhibitors, than the irreversible inhibitors.21−23
Most of the known MAO A inhibitors have an aromatic
moiety with basic nitrogen at two to four atoms distance from
the ring. While the irreversible inhibitors have a functional
group that enables covalent binding to the MAO enzyme (e.g.,
Received: December 15, 2011
Published: March 5, 2012
© 2012 American Chemical Society
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Article
alkyne), the reversible inhibitors lack such moiety.24 Studies on
para-substituted phenethylamines, benzylamines, and amphet-
amines have shown correlations between MAO affinity and
different physiochemical properties of the para-substituent.
Both size and electronic properties have been proposed to
correlate with MAO A affinity, while mainly the hydrophobicity
of the substituent seems to correlate with MAO B affinity.25−29
CoMFA (comparative molecular field analysis) of substituted
phenethylamines25 and determination of the crystal structures
of inhibitor-bound MAO A30−32 have led to a greater under-
standing of the structure−activity relationships (SARs) of MAO
A ligands.
Meta-substituted 4-phenylpiperidines have previously been
reported to have dopaminergic effects, which are mediated
primarily by the dopamine type 2 (DA D2) receptor. By modifi-
cation of a partial DA D2 agonist, a compound with
dopaminergic stabilizing properties was obtained (i.e., a
compound with functional DA D2 antagonism and fast kinetic
properties33,34). Neurochemical analysis of post-mortem brain
tissue from freely moving rats shows that dopaminergic
stabilizers induce an increase in the synthesis and release of
dopamine in the basal ganglia (e.g., the striatum), a hallmark of
DA D2 receptor antagonism. The effect can easily be followed
by measuring changes in DOPAC levels in the striatum (i.e., an
increase in levels).
further modification of the substituent to obtain the desired
structure. The unsubstituted 4-phenylpiperidine (1a) along with
the para-substituted chloro (1b), trifluoromethyl (1c), and
methoxy (1e) analogues were obtained via N-alkylation of the
corresponding 4-phenylpiperidines by reflux with iodopropane
and potassium carbonate in acetonitrile. The same treatment of
readily available starting materials generated the aniline (3) and
benzamide (5) intermediates. The morpholine compound (1d)
was synthesized from the 4-(1-propyl-4-piperidyl)aniline (3) by
reaction with bis(2-chloroethyl) ether in dimethylformamide
under microwave irradiation. The butoxy compound (1f) was
formed by treatment of the corresponding methoxy analogue
(1e) with 48% HBr, producing the phenol (4), followed by
O-alkylation with 1-butyl bromide. Treating the 4-(1-propyl-4-
piperidyl)benzamide (5) with phosphoryl chloride in dimethyl-
formamide produced the desired nitrile (1g) in a good yield
(Scheme 1).
a
Scheme 1
In an attempt to explore further the SARs for substituted
4-phenylpiperidines/piperazines, we investigated the corre-
sponding para-substituted analogues of the dopaminergic
stabilizer pridopidine. Changing the aromatic position of the
methylsulfone in pridopidine from meta to para (Figure 2) gave
a
Reagents and conditions: (a) PrI, K2CO3, CH3CN, Δ; (b) bis(2-
chloroethyl) ether, DMF, microwave; (c) HBr (48%), Δ; (d) 1-butyl
bromide, K2CO3, CH3CN, Δ; (e) POCl3, DMF, Δ.
4-(4-Methylsulfonylphenyl)-1-propylpiperidine (1h) was
synthesized from 1-bromo-4-methylsulfonylbenzene in three
steps via an initial Suzuki coupling to give the 4-phenylpyridine
6, followed by quaternization of the pyridine nitrogen by
heating in neat iodopropane and finally reduction of the
pyridine to the corresponding piperidine by catalytic hydro-
genation (PtO2) (Scheme 2).
Figure 2. Pridopidine and the generic structure of para-substituted 4-
phenylpiperidines/piperazines.
a compound devoid of effect on striatal DOPAC. However, by
replacement of the electron-withdrawing methylsulfone with an
electron-donating substituent (e.g., methoxy), a major decrease
in DOPAC levels was observed. This was in sharp contrast to
the effect of the ortho- or meta-substituted 4-phenylpiper-
idines/piperazines (Pettersson, manuscript in preparation).
Additionally, the levels of 3-MT increased significantly in the
striatum, as well as in limbic regions and in the prefrontal
cortex. On the basis of these effects, we hypothesized that para-
substituted 4-phenylpiperidines could act as MAO inhibitors.
In order to test this hypothesis, these compounds were further
characterized in vitro with respect to their affinity for MAO A
and MAO B. Moreover, a series of new para-substituted
4-phenylpiperidines/piperazines (Figure 2) were synthesized
and tested in vitro and in vivo to further investigate the SARs of
these compounds. The results from these studies are presented
in this article.
a
Scheme 2
a
Reagents and conditions: (a) pyridine-4-boronic acid, Pd2dba3, PPh3,
K3PO4, toluene, EtOH, Δ; (b) PrI, Δ; (c) PtO2, H2, MeOH.
1-Phenyl-4-propylpiperazine (2a) and 1-(4-methoxyphenyl)-
4-propylpiperazine (2b) were obtained by N-alkylation of the
corresponding secondary amines. Treatment of 2b with 48%
HBr yielded 4-(4-propylpiperazin-1-yl)phenol which was
further modified to the corresponding triflate (2c) by addition
of triflic chloride in a suspension of dichloromethane and
triethylamine (Scheme 3).
CHEMISTRY
■
Most of the para-substituted 4-phenylpiperidines/piperazines
were obtained from readily available starting materials that were
N-alkylated with iodopropane. A few compounds required
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a
Scheme 3
a
Reagents and conditions: (a) PrI, K2CO3, CH3CN, Δ; (b) HBr
(48%), Δ; (c) TfCl, TEA, CH2Cl2, Δ
Figure 3. Relationship between negative logarithm of MAO A binding
affinities (rat cerebral cortex cells with [3H]Ro 41-1049 as ligand)
(pKi) and group dipole moment (μR) of the aromatic para-substituent.
The compounds with no para-substituent (1a and 2a) were excluded.
RESULTS AND DISCUSSION
■
In Vitro Pharmacology. The apparent Ki of the tested
compounds to MAO A and MAO B was determined (Table 1
Scorza et al. have previously published the effect of different
aromatic substituents on MAO affinity in the amphetamine-
like compound series (Figure 5), and they also found that the
most potent MAO A inhibitors were para-substituted with
electron-donating groups like methoxy, ethoxy, or thioalkyls.28
In addition, Nandigama et al. have published an extensive SAR
analysis for the oxidation of para-substituted phenethylamines
by MAO A. They showed that while there was a strong
correlation between substrate propensity for the MAO A
enzyme and steric effects of the para-substituent, it was mainly
electronic parameters that determined binding affinity to MAO
A (shown as Kd in Table 1 of ref 27).
Table 1. Generic Structures and Binding Affinities at MAO A
and MAO B Enzymes of 1a−h, 2a−c, and Reference
Compounds and the Dipole Moments of the Para-
Susbtituents
a
a
c
compd
X
R
pKi (MAO A) pKi (MAO B)
μR
1a
1b
1c
1d
1e
1f
CH
CH
CH
CH
CH
CH
CH
CH
N
H
5.01
5.82
5.16
5.92
6.62
6.43
4.03
3.23
4.33
5.85
4.77
4.93
5.92
NT
0
Cl
4.42
4.89
4.89
3.66
5.80
3.23
3.23
NT
−1.59
−2.61
−0.58
−1.30
−1.19
−4.08
−4.75
0
CF3
morpholine
OMe
Scorza et al. also showed that amphetamines para-substituted
with thioalkyl groups containing more than two carbons gave a
decrease in affinity to MAO A.28 However, the three-carbon
thioalkyl group in that series was i-PrS and Gallardo-Godoy
et al.25 later showed that the branched thioalkyls gave lower
affinity to MAO A than unbranched p-thioalkylamphetamines
which had affinity in the order n-PrS > n-BuS > EtS > MeS >
n-PeS.25 In comparison, the alkoxy compounds in our series
had a slightly different order, where n-butoxy (1f) gave lower
affinity than methoxy (1e) (pKi of 6.43 and 6.62, respectively;
Table 1). Molecular modeling, based on the X-ray crystal
structure of MAO A irreversibly bound to the MAO A selective
inhibitor clorgyline, described by Gallardo-Godoy et al.25
showed a hydrophobic pocket at the location of the para-
substituent as well as an interaction between CYS323 and the
oxygen/sulfur of the alkoxy/thioalkyl groups in this position.
We have adopted a similar approach, based on the more recent
high resolution X-ray crystal complex of MAO A and the
reversible inhibitor harmine (PDB entry 2Z5X),37 and manually
docked compound 1e. Harmine and two crystal waters close
to the pyridine was replaced by 1e followed by relaxation of
ligand, binding pocket amino acid side chains, and crystal
waters close to the ligand, using the MMFF94x38,39 force field
and Born solvation40 implemented in the MOE software.41
The resulting binding pose of 1e indicated a CYS323−oxygen
interaction and a hydrophobic pocket perpendicular to the
aromatic ring where the para-substituent is located (Figure 4).
The flexibility of the substituent is therefore likely a determining
factor for the fit. Thus, unbranched groups would give higher
affinity than branched, which is a possible explanation for the
lower than predicted affinity of the morpholine derivative 1d
b
O-n-Bu
CN
b
b
b
b
1g
1h
2a
2b
2c
SO2Me
H
b
d
N
OMe
3.23
7.48
−1.30
−2.99
N
OSO2CF3
d
e
moclobemide
selegiline
<4.0
e
8.15
a
Negative logarithm of binding affinities (apparent Ki) to MAO in rat
cerebral cortex cells with [3H]Ro 41-1049as ligand for MAO A and Ro
16-6491 for MAO B. NT: not tested. IC50 higher than 1 mM is
b
c
equivalent to Ki higher than 0.58 mM. Group dipole moment for the
aromatic para-substituent. pKi from Di Santo et al.35 pIC50 from
d
e
Sterling et al.36
and Table S2, Supporting Information). There was a general
preference for MAO A in the data set. Strong correlation was
observed between the affinity to MAO A and two estimates of
electronic properties of the aromatic para-substituent, namely,
the group dipole moment μR and the Hammett’s σ parameters
(Figure 3 and Table S1, Supporting Information) (for μR, R2 =
0.88 (see Figure 3); for σp, R2 = 0.78). Compounds containing
substituents with low dipole moment, such as methoxy, had a
high affinity for MAO A, while groups with high dipole moment,
such as cyano, yielded compounds with no or only weak MAO
A affinity. Replacing the piperidine ring with a piperazine
resulted in a slight decrease in affinity toward MAO A, both for
the unsubstituted compounds (1a and 2a) and the methoxy-
substituted derivatives (1e and 2b, Table 1).
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Figure 4. Binding pose of compound 1e in the active site of human MAO A (2Z5X) is shown. The protein is represented by the Connolly
surface42,43 of the binding site amino acids color coded by lipophilic potential.44 Lipophilic areas are coded as green and hydrophilic areas as purple.
Side chains of the key residues from the Gallardo-Godoy et al. paper25 are included. Part of FAD close to 1e is shown with carbon atoms in white.
Water molecules close to the ligand is included. The hydrogen bonds between the basic nitrogen in 1e and Gln215 and one of the water molecules
are shown. The hydrophobic pocket perpendicular to the aromatic ring in the area of the para-substituent is indicated by the opening in the
molecular surface.
(pKi = 5.92, Table 1 and Figure 3). Yet in the complete set of
para-substituted phenylpiperidines/piperazines, no correlation
between the size of the substituent and MAO A affinity was
observed (R2 = 0.01, Table S1, Supporting Information).
Furthermore, Scorza et al. concluded that the amphetamine-like
compounds in their series were reversible MAO A inhibitors.28
The structural similarity to the amphetamines and a lack of
functional groups that enable covalent binding indicate that
the MAO A ligands in our series (Table 1) also bind reversibly
(not tested). Another structure analogue to our compounds is
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Figure 5),
be essential for MPTP's substrate propensity to MAO,49,50 and
it is therefore unlikely that the compounds in Table 1 are
substrates for the MAO enzymes (not tested).
In contrast to the properties yielding high MAO A affinity,
the compound with the highest affinity for MAO B had a bulky
and hydrophobic para-substituent (i.e., triflate). MAO B affinity
was modeled against five physicochemical descriptors for the
para-substituent and clogP for the whole molecule (Table S1,
Supporting Information), using orthogonal partial least squares
(OPLS) regression.51 A (1 + 1) model with a R2Y of 0.89 and a
Q2 of 0.70 was obtained in which all six descriptors correlated
positively with the response. Hydrophobicity (π), clogP, and
volume were the most important descriptors (Figure 6). This is
Figure 5. Para-substituted amphetamines/phenylpiperidines and the
neurotoxin MPTP.
a neurotoxin that is known to be both a substrate and an
inhibitor of the MAOs (preferably substrate to MAO B and
inhibitor of MAO A).45,46 However, specific modifications of the
MPTP structure, such as saturation of the 1,2,3,6-tetrahydropyr-
idine ring or increasing the length of the N-alkyl, generated
compounds that were not MAO B substrates.47,48 The
unsaturated 1,2,3,6-tetrahydropyridine ring has been claimed to
Figure 6. Loading plot of the predictive component of the OPLS model
of pKi (MAO B) versus physicochemical descriptors (values listed in
Table S1 in Supporting Information) for compounds 1b−h and 2b,c.
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in line with previous studies, where docking of harmine and
analogues showed a larger hydrophobic cavity at this specific
location in the MAO B structure compared to MAO A.52 The
positive correlation with hydrophobicity is also in line with
earlier work on para-substituted benzylamines reported by
Walker et al.29 However, in contrast to our observations, in the
benzylamine series the volume of the para-substituent was
negatively correlated with MAO B affinity.
In Vivo Pharmacology. The synthesized compounds in
Table 1 and known MAO A and MAO B ligands
(moclobemide and selegiline, respectively) were tested in
freely moving rats. Post-mortem brain tissue neurochemistry
was measured, and the levels of each monoamine and its re-
spective metabolites were quantified (Table 2) using the method
described in Supporting Information.
Figure 7. Relationship between DOPAC levels and pKi (MAO A).
Compound 1h, which has Ki(MAO A) > 0.58 mM (IC50 > 1 mM), is
excluded.
Table 2. Levels of DOPAC and 3-MT in Post-Mortem
Neurochemistry
a
a
compd
DOPAC
3-MT
One of the most potent MAO A ligands within this series
(1f) was administered to unrestrained rats, and the levels of
striatal dopamine metabolites were subsequently measured
using microdialysis. A sharp increase of 3-MT along with a
significant decrease in both DOPAC and HVA was detected
(Figure 8). These results are in line with previously published
1a
1b
1c
1d
1e
1f
130
68
100
130
100
160
260
150
115
100
100
135
120
400
110
145
86
38
22
40
1g
1h
2a
2b
2c
105
100
180
71
121
18
moclobemide
selegeline low
selegeline high
83
37
a
Levels of DOPAC and 3-MT in the striatum are expressed as
percentage compared with saline control (n = 4 per dose). Doses are
as follows: 1a−h and 2a−c, 100 μmol/kg; moclobemide, 37 μmol/kg;
selegeline, 5.3 μmol/kg (low) and 53 μmol/kg (high).1
Moclobemide, a reversible and selective inhibitor of MAO A,
produced a potent decrease in striatal DOPAC and an increase
of 3-MT levels. Furthermore, the para-substituted 4-phenyl-
piperidines/piperazines displaying high affinity for MAO A
had neurochemical profiles that were similar to that of
moclobemide, whereas compounds with low or no affinity
where devoid of these effects (a few of the compounds with low
affinity to MAO A actually produced increases in striatal
DOPAC, probably associated with weak DA D2 antagonism).
Thus, we confirmed findings from previous studies showing that
MAO A affinity is well correlated with the release and turnover
of striatal dopamine (i.e., levels of DOPAC, Figure 7).6,13,53 The
same correlation, however, is not observed between the affinity
for MAO B and DOPAC levels (R2 = 0.05), supporting the
general view that MAO B ligands have no or only a limited
effect on striatal DOPAC levels.6,54 We found that selegeline, an
MAO B ligand with an approximately 100-fold selectivity for
MAO B over MAO A, produced no significant effect on striatal
DOPAC levels at the lower dose tested (1.1 mg/kg), while at
the highest dose tested (10 mg/kg) a significant decrease in
DOPAC was observed. This supports previous data suggesting
that selegiline loses selectivity when administered in high doses
and that MAO B affinity can potentiate the effect MAO A has
on DOPAC levels.17
Figure 8. Striatal levels of 3-MT, DOPAC, and HVA, measured by
microdialysis in freely moving rats (n = 2) and expressed as percentage
of saline control, after administration of 1f (50 μmol/kg) at 0 min.
microdialysis studies of known MAO A inhibitors,15 indicating
that the high-affinity MAO A compounds in Table 1 also act as
inhibitors.
CONCLUSION
■
A set of para-substituted 4-phenylpiperidines/piperazines have
been synthesized and evaluated both in vitro and in vivo. A
clear correlation between the group dipole moment (i.e., μR) of
the para-substituent and MAO A affinity was observed
(R2 = 0.88, Figure 3). Substituents with low dipole moment
yielded compounds with a high MAO A affinity, whereas sub-
stituents with high dipole moment produced compounds that
had no or only low affinity to MAO A. In contrast, the pro-
perties of para-substituents that correlated with MAO B affinity
were mainly hydrophobicity and bulk. Large hydrophobic
groups yielded compounds that had a high affinity to MAO B,
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Anal. (C14H20ClN·HCl·0.25H2O) C, H, N. MS m/z (relative intensity,
70 eV) 237 (M+, 7), 210 (34), 209 (15), 208 (bp), 70 (34). 1H NMR
(300 MHz, CDCl3) δ 0.92 (t, J = 7.4 Hz, 3H), 1.43−1.66 (m, J = 15.3,
7.62, 7.5, 7.5 Hz, 2H), 1.68−1.90 (m, 4H), 2.01 (td, J = 11.4, 3.2 Hz,
2H), 2.31 (d, J = 8.1 Hz, 2H), 2.46 (td, J = 10.8, 5.9 Hz, 1H), 3.05
(d, J = 11.1 Hz, 2H), 7.11−7.20 (m, 2H), 7.25 (d, J = 8.6 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 12.0, 20.2, 33.5, 42.3, 54.3, 61.1, 128.2,
128.4, 131.6, 144.9.
whereas compounds with small and/or polar groups were
devoid of any affinity.
The effect of these compounds on rat post-mortem
neurochemistry was also examined. Striatal DOPAC and 3-MT
levels correlated well with MAO A affinity (R2 of 0.79 (Figure 7)
and 0.60 (data not shown), respectively) where high affinity
compounds produced a decrease in DOPAC and an increase
in 3-MT. The same profile was observed in microdialysis experi-
ments, and these results, together with previous publications in
the field, support our view that the high-affinity MAO A ligands
in this class act as inhibitors. Furthermore, absence of functional
groups required for irreversible bonding to MAO and structural
similarities to known reversible inhibitors suggests that the
inhibition is reversible. In contrast to the MAO A ligands,
we found no correlation between affinity to MAO B and the
levels of DOPAC or 3-MT, and the compound with the highest
affinity to MAO B (2c) had only weak effects on post-mortem
neurochemistry.
Within the structural class presented herein, we have
determined correlations between the physicochemical proper-
ties of the para-substituent and affinity to MAO A and MAO B,
respectively. In addition, we have shown that affinity to MAO
A, but not MAO B, correlates well with the levels of striatal
DOPAC and 3-MT in post-mortem neurochemistry and that
the compounds displaying affinity to MAO A act as inhibitors.
1-Propyl-4-[4-(trifluoromethyl)phenyl]piperidine (1c). The
compound was obtained in 77% yield. The amine was converted to
the HCl salt and recrystallized from ethanol/diethyl ether: mp 236−
237 °C. Anal. (C15H20F3N·1.5HCl) C, H, N. MS m/z (relative
intensity, 70 eV) 271 (M+, 5), 243 (15), 242 (bp), 159 (8), 70 (30). 1H
NMR (300 MHz, CDCl3) δ 0.95 (t, J = 7.4 Hz, 3H), 1.59 (dd, J = 15.7,
7.5 Hz, 2H), 1.78−1.94 (m, 4H), 1.99−2.16 (m, 2H), 2.38 (t, J = 2.7
Hz, 2H), 2.59 (t, J = 8.5 Hz, 1H), 3.11 (d, J = 11.9 Hz, 2H), 7.36 (d, J =
8.5 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
12.1, 20.2, 33.2, 42.7, 54.2, 61.1, 122.8−123.2 (m, 1C) 125.3, 125.3,
125.4, 125.4, 127.2, 127.9, 128.2−128.6 (m, 1C) 128.9, 150.4.
4-(4-Methoxyphenyl)-1-propylpiperidine (1e). The compound
was obtained in 89% yield. The amine was converted to the HCl salt
and recrystallized from ethanol/diethyl ether: mp 197−198 °C. Anal.
(C15H23NO·HCl) C, H, N. MS m/z (relative intensity, 70 eV) 233
(M+, 17), 205 (15), 204 (bp), 133 (16), 70 (20). 1H NMR (300 MHz,
CD3OD) δ 0.91 (t, J = 7.5 Hz, 3H), 1.54 (dd, J = 16.1, 7.6 Hz, 2H),
1.73 (dd, J = 7.6, 3.1 Hz, 4H), 2.04 (td, J = 11.5, 3.5 Hz, 2H), 2.31 (t,
J = 3.0 Hz, 2H), 2.42 (td, J = 10.7, 5.9 Hz, 1H), 3.01 (d, J = 11.9 Hz,
2H), 3.71 (s, 3H), 6.81 (q, J = 5.1 Hz, 2H), 7.11 (q, J = 5.1 Hz, 2H);
13C NMR (75 MHz, CD3OD) δ 11.1 19.4, 33.0, 41.4, 54.0, 54.3, 60.7
113.5, 127.3, 138.0, 158.2.
EXPERIMENTAL SECTION
■
1
Chemistry. General. H and 13C NMR spectra were recorded in
1-Phenyl-4-propylpiperazine (2a). The compound was obtained
in 21% yield. The amine was converted to the HCl salt and
recrystallized from EtOH/diethyl ether: mp 210−211 °C. Anal.
(C13H20N2·HCl) C, H, N. MS m/z (rel intensity, 70 eV) 204 (M+,
CD3OD or CDCl3 at 300 and 75 MHz, respectively, using a Varian XL
300 spectrometer, or at 400 and 100 MHz, respectively, using a Mercury
Plus 400 spectrometer. Chemical shifts are reported as δ values (ppm)
relative to an internal standard (tetramethylsilane). Low resolution mass
spectra were recorded on a HP 5970A instrument operating at an
ionization potential of 70 eV. The mass detector was interfaced with a
HP5700 gas chromatograph equipped with a fused silica column (11 m,
0.22 mm i.d.) coated with cross-linked SE-54 (film thickness 0.3 mm,
He gas, flow 40 cm/s). Elemental analysis was performed by MikroKemi
AB (Uppsala, Sweden) or Mikroanalytisk Laboratorium (Copenhagen,
Denmark). Melting points were determined with a point microscope
(Reichert Thermovar) and are uncorrected. For flash chromatography,
silica gel 60 (0.040−0.063 mm, VWR, no. 109385) was used. The amine
products were converted to the corresponding salts by dissolving the
free base in ethanol and adding 1−2 equiv of the acid (fumaric or oxalic)
or ethanolic HCl solution. The solvent was removed and azeotroped
with absolute ethanol in vacuo followed by recrystallization from
appropriate solvents. Purity of all target compounds was assessed as
greater than 95% by elemental analysis (C, H, N).
1
10), 105 (31), 104 (32), 77 (58), 70 (bp). H NMR (300 MHz,
CD3OD) δ d 1.02 (t, 3H, J = 7.3 Hz), 1.50−1.62 (m, 2H), 2.35−2.39
(m, 2H), 2.63 (t, 4H), 3.23 (t, 4H), 6.83−6.90 (m, 1H), 6.92−6.96
(m, 2H), 7.26−7.31 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 10.9,
16.1, 20.7, 44.1, 56.2, 59.7, 61.1, 117.6, 122.1, 130.3, 150.9.
1-(4-Methoxyphenyl)-4-propylpiperazine (2b). The com-
pound was obtained in 61% yield. The amine was converted to the
HCl salt and recrystallized from EtOH/diethyl ether: mp 215−216 °C.
Anal. (C14H22N2O·2HCl) C, H, N. MS m/z 235 (M+ + 1, 16), 234
(M+, bp), 205 (73), 135 (16), 70 (15). 1H NMR (400 MHz, CDCl3) δ
0.95 (t, J = 7.4 Hz, 3H), 1.57 (dq, J = 15.3, 7.5 Hz, 2H), 2.38 (t, J = 2.3
Hz, 2H), 2.63 (d, J = 5.1 Hz, 4H), 3.12 (d, J = 5.1 Hz, 4H), 3.77 (s,
3H), 6.83−6.88 (m, 2H), 6.90−6.95 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 12.0, 20.1, 50.6, 53.4, 55.5, 60.7, 114.4, 118.1, 145.8, 153.7.
ASSOCIATED CONTENT
* Supporting Information
■
General Procedure for the Preparation of Compounds 1a−
c,e and 2a,b. A solution of the phenylpiperidine/piperazine
(1.0 equiv), 1-iodopropane (1.1 equiv), and potassium carbonate (3 equiv)
in acetonitrile was refluxed for 15 h. The mixture was allowed to cool
to ambient temperature. The solid was filtered off, and the solvent was
evaporated. The crude product was purified by flash chromatography
using ethyl acetate/methanol in appropriate ratios as eluent. The
amines were converted to the corresponding salts and recrystallized
from appropriate solvents.
S
Experimental details of the synthesis of 1a−1h and 2a−c as
well as biological methods and physiochemical descriptors. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Phone: +(46) 31 7727710. Fax: +(46) 31 7720601. E-mail:
fpe@neurosearch.se.
■
4-Phenyl-1-propylpiperidine (1a). The compound was obtained
in 81% yield. The amine was converted to the HCl salt and
recrystallized from EtOH/diethyl ether: mp 234−235 °C; MS m/z
(relative intensity, 70 eV) 203 (M+, 6), 174 (bp), 103 (11), 91 (11),
70 (34). Anal. (C14H21N·HCl) C, H, N. 1H NMR (400 MHz, DMSO-
d6) δ 1.04 (t, J = 7.4 Hz, 3H), 1.77−1.85 (m, 2H), 2.00 (d, J = 12.7
Hz, 2H), 2.06−2.13 (m, 2H), 2.88−2.96 (m, 1H), 3.08−3.17 (m, 4H),
3.65 (d, J = 12.2 Hz, 2H), 7.22−7.33 (m, 5H).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Anna Sandahl, Jonas Karlsson, and Mikael Andersson
for help with the synthetic chemistry and Elisabeth Ljung,
■
4-(4-Chlorophenyl)-1-propylpiperidine (1b). The compound
was obtained in 67% yield. The amine was converted to the HCl
salt and recrystallized from ethanol/diethyl ether: mp 219−220 °C.
́
Marianne Thorngren, Ingrid Berg, Katarina Ryden Markinhuhta,
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