Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT(1A) receptors

Article abstract of DOI:10.1021/jm9806906

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT(1A) receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl-methanone. Incorporation of a fluorine atom in the β-position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and long-lasting 5-HT(1A) agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT(1A) receptors (versus dopaminergic D₂ and adrenergic α₁ receptors) and displayed more potent 5-HT(1A) agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4- fluorophenyl-(4-fluoro-4{[(5-(H or CH₃)-6-R-pyridin-2-ylmethyl)-amino]- methyl}-piperidin-1-yl-methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT(1A) agonist properties. Thus, the 3- chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin-2- ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT(1A) receptor agonist in vitro and in vivo than its 5- unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT(1A) receptor agonists with marked antidepressant potential.

Full text of DOI:10.1021/jm9806906

1648
J . Med. Chem. 1999, 42, 1648-1660
Novel Der iva tives of 2-P yr id in em eth yla m in e a s Selective, P oten t, a n d Or a lly
Active Agon ists a t 5-HT1A Recep tor s
Bernard Vacher,*,† Bernard Bonnaud,† Philippe Funes,† Nathalie J ubault,† Wouter Koek,‡
Marie-Bernadette Assie´,‡ Cristina Cosi,‡ and Mark Kleven‡
Pierre Fabre Research Center, 17 avenue J ean Moulin, 81106 Castres Cedex, France
Received December 9, 1998
The aim of this work was to improve the oral bioavailability of a recently discovered, novel
structural class of 5-HT1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-
piperidin-1-yl-methanone. Incorporation of a fluorine atom in the â-position to the amino
function in the side chain led to analogues that exhibited, in general, enhanced and long-
lasting 5-HT1A agonist activity in rats after oral administration. Location of the fluorine atom
at the C-4 position of the piperidine ring was the most favorable, and among the various
substituents tested, the ability of the fluorine was unique in improving the oral activity of this
family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity
to 5-HT1A receptors (versus dopaminergic D2 and adrenergic R1 receptors) and displayed more
potent 5-HT1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To
examine the relationship between the conformation of the pharmacophore and the level of
agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-
fluoro-4{[(5-(H or CH3)-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone de-
rivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on
the pyridine ring synergistically affected their 5-HT1A agonist properties. Thus, the 3-chloro-
4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-pi-
peridin-1-yl-methanone 40 behaved as a more potent 5-HT1A receptor agonist in vitro and in
vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds
40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results
indicated that, after a single oral administration, these compounds inhibited immobility in
the FST more potently and more extensively than the clinically used antidepressant imipramine.
Thus, 40, 45, and 54 are potent, orally active 5-HT1A receptor agonists with marked
antidepressant potential.
In tr od u ction
5-HT1A receptors. Of primary interest, several members
of this series inhibited intracellular cAMP accumulation
in forskolin-stimulated HA7 cells more potently and
more extensively than the prototypical 5-HT1A agonist
(()-8-OH-DPAT. Unfortunately, despite their promising
in vitro profiles, these compounds exerted only weak
5-HT1A agonist activity in vivo,8 possibly because of low
bioavailability. Attempts to enhance the brain concen-
tration of these novel 5-HT1A agonists led to the design
of a series of aryl-(4-fluoro-4{[(6-R-pyridin-2-ylmethyl)-
amino]-methyl}-piperidin-1-yl-methanones that exhib-
ited very potent 5-HT1A agonist properties, not only in
vitro but also in vivo. Several of these compounds
demonstrated marked antidepressant-like effects in the
FST.9 Finally, this novel series provided further insight
into some of the structural determinants involved in the
activation of 5-HT1A receptors.
Many studies have focused on specific alterations of
monoaminergic neurotransmission in depression.1 The
role of central serotoninergic (5-HT) systems, and in
particular of 5-HT1A receptor subtype-mediated neu-
rotransmission, has attracted special interest over the
last two decades.2 However, the antidepressant effects
of 5-HT1A partial agonists, such as buspirone and
ipsapirone, do not exceed those of currently available
treatments, neither in terms of clinical efficacy3 nor in
terms of rapidity of onset.4 It is conceivable that their
limited clinical efficacy is related to their low level of
intrinsic activity at 5-HT1A receptors.5 Thus, our re-
search efforts are guided by the hypothesis that the
antidepressant efficacy of 5-HT1A agonists is a direct,
positive function of their intrinsic activity, and therefore,
aimed at discovering 5-HT1A agonists with a high level
of intrinsic activity.6
Ch em istr y
In a recent paper,7 we described a novel 5-HT1A
pharmacophore and reported a series of aryl-{[4-(6-R-
pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-meth-
anones that bind with high affinity and selectivity to
Compounds of the general formula 4 (Scheme 1, Table
7) were prepared from the appropriate pyridine-2-
carboxaldehydes 3 either by reductive amination with
primary amines of the type 1 (method A) or by an aza-
Wittig reaction with azides of the type 2 (method B).
The synthesis of amines 1a , as shown in Scheme 2,
began with acylation of the commercially available
4-piperidone-ethylene ketal by the appropriate aroyl
* To whom correspondence should be addressed. Fax: (33) 5-63-71-
42-99. E-mail: bernard.vacher@pierre-fabre.com.
† Division of Medicinal Chemistry I.
‡ Division of Neurobiology II.
10.1021/jm9806906 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/15/1999

Novel Derivatives 2-Pyridinemethylamine
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1649
Sch em e 1a
Sch em e 3a
a
Conditions: (a) LiBH4, THF, 20 °C; (b) (CF3SO2)2O, 2,4-
lutidine, CH2Cl2; (c) diethylene glycol, KF, 100 °C; (d) Raney Ni,
EtOH, NH4OH.
Sch em e 4a
a
Conditions: 1, toluene, 110 °C, then KBH4, MeOH, 20 °C
(method A), or 2, PPh3, MeOH, reflux, then KBH4, 20 °C (method
B).
Sch em e 2a
a
Conditions: (a) LDA, MeI, THF; (b) Raney Ni, EtOH, NH4OH.
Sch em e 5a
a
Conditions: (a) NaN3, NH4Cl, MeOH, H2O, reflux; (b) HNa,
MeI, THF.
Sch em e 6a
a
Conditions: (a) ArCOCl, TEA, CHCl3; (b) HCO2H, CuSO4, 80
°C; (c) trimethylsulfoxonium iodide, HNa, DMSO; (d) HF-pyri-
dine, CH2Cl2; (e) pTSCl, pyridine; (f) K-phthalimide, DMF, 150
°C; (g) NH2(CH2)2OH, 50 °C.
a
Conditions: (a) pTSCl, pyridine; (b) NaN3, Bu4NN3, DMSO,
100 °C.
chloride (NEt3, CH2Cl2, 0 °C). After removal of the C-4
carbonyl protecting group, the oxirane function was
installed by treatment of the piperidones 5 with di-
methyloxosulfonium methylide, as described by Fish-
man10 for the epoxidation of the N-benzyl-piperidone
analogue. The spiro derivatives 6 underwent a regiose-
lective ring-opening reaction with hydrogen fluoride-
pyridine complex11 to afford the fluoro alcohol 7. The
end of the synthesis was straightforward: the primary
alcohol 7 was activated as the tosylate 8, which was
then converted to the desired primary amine 1a via the
phthalimide 9 (Gabriel synthesis). The 4-cyano-1-(3,4-
dichloro-benzoyl)-piperidine-4-carboxylic acid ethyl es-
ter12 was used as the precursor to the amine 1b (Scheme
3). Thus, the ester function was first reduced to the
alcohol 10 and then transformed into the triflate 11.
Displacement of the triflate 11 by fluoride anion, under
Grieco conditions,13 provided the intermediate 12. Sub-
sequent hydrogenation of the cyano group over Raney
Ni gave the fluoromethylated amine 1b. The amine 1c
(Scheme 4) was prepared by C-methylation of the
lithium salt generated from 1-(3,4-dichloro-benzoyl)-
piperidine-4-carbonitrile14 (LDA, CH3I) followed by
hydrogenation of the cyano group.
Cl, CH3OH/H2O), attack of the nucleophile occurred at
the less substituted carbon exclusively. O-Methylation
of the resulting â-hydroxyazide 14 then yielded the azide
2a . The azide 2b could be derived from the intermediate
10 by the two-step sequence shown in Scheme 6.
The preparation of the 5-unsubstituted-6-substituted-
pyridine-2-carboxaldehydes used in this work has been
reported previously.7 The synthesis of the novel 5-meth-
yl-6-substituted-2-pyridinecarboxaldehydes was carried
out as depicted in Scheme 7. The ester 16, obtained by
the method of Hoornaert,15 was reduced to the alcohol
17. Treatment of the latter with a large excess of methyl,
ethyl, or dimethylamine under harsh reaction conditions
led to the 6-alkylamino-5-methyl-2-pyridinemethanol
derivatives 18a -c in moderate yields. Displacement of
the 6-chlorine atom by amines was much more difficult
than in the 5-unsubstituted series, demonstrating that
the 5-methyl group has a pronounced effect on the
reactivity of the pyridine ring. As a consequence, the
derivative 18d , bearing a more hindered 6-diethylamino
group, was best prepared from the intermediate 19,
according to a variant also developed by Hoornaert.16
Thus, treatment of the amidine 19 with DBU and
ethanol (lactone cleavage and aromatization) gave the
6-diethylamino-5-methyl-pyridine-2-carboxylic acid eth-
yl ester (not shown in Scheme 7) which was reduced as
The azide 2a was obtained by ring-opening of epoxide
6 by NaN3 (Scheme 5). Under standard conditions (NH4-

1650 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Vacher et al.
Sch em e 7a
performed in triplicate) for all compounds, except (()-
8-OH-DPAT whose values represent the mean of five
determinations.
The methods used to examine the ability of com-
pounds to produce lower lip retraction (LLR) in rats
were the same as those described previously.20 Rats
were observed at two time points, centered at 15 and
60 min after the injection and each lasting 10 min.
During a 10 min period, an animal was observed once
every minute for 10 s and the presence (1) or absence
(0) of LLR was recorded. Because an animal was
observed 10 times during a 10 min period, the incidence
of LLR could vary from 0 to 10. Dose-response functions
were determined from the percentage of rats (n at least
2 per dose) showing LLR scores of 1 or more. This
criterion was based on the incidence of LLR observed
in control animals treated with saline, fewer than 5%
of which had an LLR score of 1 or more; drugs were
therefore considered to produce an effect in an indi-
vidual animal when scores higher than zero were
obtained. ED50 estimates are obtained by linear inter-
polation. Because the pharmacological studies were
conducted using doses differing by factor 4, the range
of doses which encompassed the interpolated ED50
values could not exceed this factor. Further, the coef-
ficient of dispersion (i.e, ED50 × 100/range) varied from
43 to 138%.
The forced swimming test was conducted in a manner
similar to that described by Porsolt:21 the procedure
involved placing a rat in a cylinder (height: 45 cm,
diameter: 20 cm) containing 17 cm water (25 °C) for
15 min on the first day of the experiment and again in
the cylinder 24 h later for 5 min. The duration of
immobility during the 5 min period was measured by
an observer who was unaware of the treatment condi-
tions. Each animal was treated (volume: 10 mL/kg) with
vehicle after the session on day 1 and, on day 2, with a
particular dose of a test compound (n ) 10 per dose) or
its vehicle control, given p.o. 60 min before placement
in the cylinder. For each dose, the percentage inhibition
of immobility was calculated by expressing the differ-
ence between the median immobility times of vehicle
controls (i.e., 204 s) and of drug-treated animals as a
percentage of the median immobility time of vehicle
controls. In addition, dose-response functions were
determined from the percentage of rats with an im-
mobility time less than 138 s. Immobility times shorter
than this criterion value occurred in less than 5% of the
vehicle controls and were therefore considered signifi-
cant. ED50 estimates are obtained by linear interpola-
tion.
a
Conditions: (a) DBU, EtOH, THF; (b) NaBH4, EtOH; (c)
R1R2NH, EtOH, 100 °C, 72 h; (d) MnO2, CHCl3, reflux; (e)
(CH2OH)2, pTSA, PhCH3, 110 °C; (f) HNa, pyrazole, DMF, 60 °C;
(g) HCO2H, H2O, CuSO4, 65 °C.
described above (16 f 17) to afford the expected
6-diethylamino-5-methyl-2-pyridinemethanol 18d in mod-
est overall yield. The primary alcohols 18a -d were
subsequently oxidized to the target pyridine-2-carbox-
aldehydes 3a -d (MnO2/CHCl3).17
The synthetic sequence had to be modified slightly
for the synthesis of the 6-pyrazol-1-yl-5-methyl-2-py-
ridinecarboxaldehyde 3e. Thus, the alcohol 17 was first
oxidized and then the aldehyde function protected as
the dioxolane 20.18 Reaction of 20 with the sodium salt
of pyrazole yielded the intermediate 21, which upon
removal of the protecting group, afforded the desired
6-pyrazolo-5-methyl-pyridine-2-carboxaldehyde deriva-
tive 3e.
P h a r m a cology
Binding affinities for the different receptors were
determined by means of ligand competition assays using
the conditions summarized in the Experimental Section
(Table 8). All experiments were performed in triplicate.
IC50 values were determined using nonlinear regression.
Ki values were calculated using the equation Ki ) IC50/1
+ [C]/KD, and the results are expressed as mean pKi
values ( SEM of three independent determinations.
The HeLa cell line permanently transfected with the
human 5-HT1A receptor gene and permanently express-
ing the 5-HT1A receptor protein (HA7) as described by
Fargin19 was obtained commercially (Duke University,
Durham, NC). Concentration-effect relationships are
expressed as -log [M] of the test compound versus the
cAMP content expressed as a percentage of forskolin-
stimulated cAMP control values. IC50 values for com-
pounds were estimated by linear interpolation between
the logarithms of the concentrations that inhibited
forskolin-stimulated cAMP with amounts bordering 50%
of the maximal inhibition observed with the compound.
The potency and maximal inhibition values represent
the mean of 2-4 independent determinations (each
Resu lts a n d Discu ssion
Oxidative N-debenzylation is known to be a major
biotransformation pathway for biogenic amines and
nitrogen-containing xenobiotics.22 Thus, we assumed
that the pyridin-2-yl-methylamine fragment in struc-
tures such as 4 (Scheme 1; R2 ) H) may be a likely
target for redox active enzymes (cytochrome P 450’s,
MAO’s ...). This assumption was supported by the
finding that electron rich pyridine derivatives, even
though being more potent to inhibit adenyl-cyclase in
vitro than their electron deficient pyridine counterparts,
displayed, in general, much weaker 5-HT1A agonist

Novel Derivatives 2-Pyridinemethylamine
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1651
and (2) those having a five-membered heteroaromatic
ring in this position. Within the first group (23-25, 39,
46, 52), fluorine incorporation enhanced 5-HT1A recep-
tors binding whereas the affinity for D2 and R1 receptors
remained in the micromolar range. The selectivity of the
fluorinated ligands for 5-HT1A binding sites (versus D2
and R1), therefore, improved over that of the desfluoro
analogues.28a In addition, the fluoro derivatives were,
in general, more potent (39 and 46), and at least as
efficacious at inhibiting forskolin-stimulated cAMP ac-
cumulation in HA7 cells than their desfluoro counter-
parts (23 and 24, respectively). Of particular interest,
they showed clear superiority over their desfluoro
analogues in terms of their ability to induce LLR in rats
after i.p or p.o administration (39, 46, 52 compared with
23, 24, 25). In the second group (53-57, 26-30, 61),
the selectivity of the fluorinated ligands also improved,
but mainly because of further decreases of their D2 and
R1 affinity.28b Although the influence of the C-4 fluorine
on the oral performance of the compounds shared the
positive trend seen in the first group, there were marked
differences among members of this group in terms of
their in vitro potency (pEC50). Thus, depending on the
type of the heterocycle in the 6-position, the presence
of the C-4 fluorine was either deleterious (56 and 57
versus 29 and 30), neutral (53 and 55 versus 26 and
27), or advantageous (61 versus 28). Such broad varia-
tions in potency data (over more than 1 log unit)
suggested that the pattern of interactions used by these
molecules to activate 5-HT1A receptors may not overlap,
notwithstanding they are structurally closely related.
F igu r e 1.
Ta ble 1. Effects of a Fluorine Atom and Its Position on 5-HT1A
Affinity and on 5-HT1A Agonist Activity in Vivo
5-HT1A agonist activity
e
LLR,d ED50
5-HT1A
compd
X
X1
affinity pKib,c
i.p. 15 min
p.o. 60 min
22a
32
33
H
H
F
H
F
H
7.58 (0.15)
8.29 (0.10)
7.82 (0.08)
0.89
0.11
0.62
5.0
1.3
5.0
a
Derivative described in ref 7 whose appropriate pharmacologi-
b
cal data have been completed. See Experimental Section for
details. c Each value is the mean ( SEM of three determinations.
d
LLR ) lower lip retraction. e ED50 (mg/kg) values were obtained
by linear interpolation.
The LLR activity of the desfluoro derivatives listed
in Table 2, except for 24, was sustained at 60 min after
i.p. injection. Moreover, the ED50’s to produce LLR were
not, in general, dependent on the route of administra-
tion (26, 27, 29, and 30). Given these results, we
assumed that low brain exposure was the major factor
limiting the central activity of the C-4 desfluoro ago-
nists. In this regard, ligands displaying comparable in
vitro profiles but different in vivo activities, irrespec-
tively of the nature of the C-4 substituent (H or F), told
us about the pharmacokinetic input of the C-4 fluorine
atom (e.g., 25 compared with 52, 28 versus 61, 26 versus
53, and 27 versus 55). Thus, it became clear that a C-4
fluorine has the ability to enhance concentration of the
compound into the brain. Improved pharmacokinetics
would be also one of the features that would, qualita-
tively, account for the greater in vivo effects produced
in the more hydrophilic 6-amino ligands (e.g., 23, 24,
25 compared with 39, 46, 52, respectively). As discussed
below, the contribution of the C-4 fluorine to the
pharmacological profile of the ligand is, however, prob-
ably multifactorial. At present, even the possibility of
specific metabolic activation of the fluorinated com-
pounds cannot be ruled out.29
activity in vivo.23 The mechanism postulated for the
benzylic C-N bond cleavage in compounds of type 4,
catalyzed by oxido-reductases, involved a nitrogen radi-
cal cation in the first step (Figure 1). Thus, we reasoned
that an electronegative fluorine atom24 in the â-position
to the benzylic amino function should (1) retard the
oxidation-dependent processes by raising the redox
••
+•
potential of the secondary amino function (EN
/
) and
N
(2) facilitate absorption by reducing the pKa of the
secondary amine25 and increasing the lipophilicity of the
ligand.26
There were two options available for introducing a
fluorine atom in a suitable position relative to the
secondary amino function: either at the C-4 of the
piperidine ring or, in a vinylogous fashion, at C-3 of the
pyridine nucleus. We examined the influence of fluorine
incorporation in either of these positions.27
The binding affinities of compounds 32 and 33 were
only marginally improved by incorporation of a fluorine
atom in either position (compared with 22 in Table 1).
In contrast, 5-HT1A agonist potency in vivo (ED50 to
induce LLR) increased markedly after i.p. and p.o.
administration of the fluorinated derivative 32 as
compared with the desfluoro compound 22. In particu-
lar, fluorine substitution for hydrogen at the Csp3-4 of
the piperidine ring (32) provided a clear advantage in
terms of in vivo activity (LLR, i.p. and p.o.) over its
Csp2-3 location (33). These findings prompted us to
extend the Csp3-4 replacement of hydrogen by fluorine
to other ligands of this family.7
Having identified several orally active 5-HT1A ago-
nists, we investigated various substituents at C-4 posi-
tion to refine our understanding of the role of the
fluorine atom. Depending on the nature of the R group
at C-4, the affinity and the potency of compounds varied
over 1 order of magnitude (Table 3). Various C-4
substitutents led to ligands with substantial affinity for,
and agonist potency at, 5-HT1A receptors (e.g., 31, 58,
65, 67, 68, and 69). Among them, however, only a
The compounds shown in Table 2 could be separated
into two groups: (1) derivatives bearing an aliphatic
amino substituent in the 6-position of the pyridine ring

1652 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Vacher et al.
Ta ble 2. Fluorinated and Nonfluorinated Derivatives: Comparisons of Their Receptor Binding Profiles and Their Potencies at
5-HT1A Receptors in Vitro (cAMP) and in Vivo (LLR)
5-HT1A agonist activity
ED50 (mg/kg) to produce LLRe
receptor affinity (pKi)b,c
i.p
p.o
compd
A
X
Y
5-HT1A
D2
R1
cAMPd pEC50
15 min
60 min
60 min
23a
39
CH3NH
CH3NH
(CH3)2N
(CH3)2N
H
F
H
F
H
F
H
F
F
H
F
H
F
H
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
8.76 (0.06)
9.67 (0.15)
8.85 (0.11)
9.61 (0.07)
9.43 (0.05)
9.70 (0.12)
9.14 (0.06)
8.98 (0.04)
9.55 (0.04)
8.86 (0.04)
8.91 (0.04)
9.27 (0.10)
9.52 (0.07)
9.03 (0.01)
9.33 (0.14)
9.46 (0.08)
9.10 (0.08)
5.51 (0.05)
6.40 (0.18)
6.28 (0.04)
6.48 (0.22)
6.22 (0.13)
6.51 (0.09)
6.34 (0.08)
5.92 (0.07)
5.65 (0.13)
6.54 (0.07)
6.34 (0.08)
6.01 (0.03)
5.39 (0.17)
6.06 (0.04)
5.65 (0.14)
5.47 (0.07)
5.47 (0.23)
6.87 (0.04)
6.92 (0.03)
6.92 (0.03)
6.76 (0.04)
6.64 (0.04)
6.35 (0.05)
6.71 (0.07)
6.39 (0.04)
6.12 (0.05)
6.76 (0.05)
6.72 (0.07)
6.66 (0.07)
6.10 (0.04)
6.55 (0.02)
5.90 (0.03)
6.75 (0.02)
6.26 (0.07)
7.66 (0.12)
8.18 (0.06)
7.69 (0.14)
8.53 (0.09)
8.15 (0.02)
7.97 (0.14)
8.28 (0.35)
8.58 (0.07)
8.46 (0.05)
8.24 (0.06)
7.92 (0.25)
8.52 (0.11)
8.95 (0.08)
8.70 (0.01)
8.05 (0.01)
8.30 (0.13)
7.64 (0.14)
5.0
5.0
0.23
7.0
>10
0.32
5.0
0.32
>10
0.45
1.30
0.32
0.32
5.0
1.30
>10
1.30
1.30
1.30
5.0
0.11
0.08
0.62
1.30
0.32
1.30
0.16
0.08
1.30
0.32
5.0
0.32
0.45
0.32
0.32
0.45
24a
46
0.45
3.60
0.45
1.30
0.23
0.11
1.30
0.32
5.0
0.32
0.89
0.32
1.30
0.89
25a
52
azetidino
azetidino
furan-2-yl
furan-2-yl
furan-2-yl
thien-2-yl
thien-2-yl
pyrazol-3-yl
pyrazol-3-yl
oxazol-5-yl
oxazol-5-yl
thiazol-2-yl
thiazol-2-yl
26a
53
54
27a
55
28a
61
29a
56
30a
57
H
F
1.30
d
a-c See footnotes of Table 1. Forskolin-stimulated cAMP levels in HA7 cells were inhibited by (()-8-OH-DPAT (pEC50 ) 7.60 (0.17),
Emax ) 71% ( 4.3%) and to a greater extent (Emax > 80%) by all compounds reported in the table (data not shown). e LLR ) lower lip
retraction.
Ta ble 3. Effect of the Nature of the C-4 Piperidine Substituent
on Affinity, and Agonist Potency at 5-HT1A Receptors in Vitro
(cAMP) and in Vivo (LLR)
neous set of compounds shown in Table 3, reflects the
differences in the relative populations of molecules
achieving active conformation(s), then it appears that
the C-4 fluorine atom is able to select conformer(s)
energetically close to the bioactive conformation(s) of the
ligand. When R is small (R ) H; 31), or not sterically
too demanding and inducing a strong permanent dipole
moment (R ) F; 58), it tends to be axially oriented on
5-HT1A agonist activity
the piperidine.30 As a result, the piperidine ring is locked
5-HT1A
LLRe ED50
(mg/kg)f
in (a) conformation(s) where the C-4 methylamino chain
d
compd
R
affinity pKib,c
cAMP pEC50
occupies an equatorial position.31
31a
58
64
65
66
67
68
69
H
F
8.78 (0.09)
8.77 (0.09)
7.43 (0.06)
8.16 (0.10)
7.52 (0.07)
8.79 (0.03)
8.04 (0.05)
8.22 (0.16)
7.51 (0.09)
7.55 (0.12)
NT
5.0
1.30
NT
Apparently, an intramolecular hydrogen bond be-
tween the fluorine atom and one of the vicinal am-
monium protons did not participate in binding when the
fluorine is directly attached to C-4 of the piperidine32
(58 compared with 31). On the other hand, there may
be some entropic contributions to binding of such a
hydrogen bond in the higher homologue 68 (compared
with 64).
CH3
CN
OCH3
OH
6.79 (0.40)
NT
>10
NT
7.40 (0.02)
6.51 (0.18)
6.57 (0.15)
>10
>10
>10
CH2F
See footnotes of Table 2. e LLR ) lower lip retraction. NT
a-d
) not tested.
The synergy seen in the desfluoro series,7 between a
few combinations of meta-para benzamide substitu-
ents, no longer occurred in the fluorinated series (Table
4). Nonetheless, a 3-chloro, 4-fluoro-benzamide group
(45) still had the best overall profile, in vitro and in vivo.
fluorine atom was able to confer an in vivo activity to
the compound exceeding that of the corresponding C-4
unsubstituted derivative (LLR of 58 versus 31). More-
over, changing the piperidine moiety by a tetrahydro-
pyridine (69) was detrimental for recognition and
activation of 5-HT1A receptors, despite the fact that a
Csp2-4 produced minimal steric hindrance, and gener-
ated a negative electrostatic potential around the C-4
region of the molecule which could mimic that of a
fluorine atom. The contribution of the R group to 5-HT1A
binding is, therefore, best understood in terms of con-
formational distribution effects rather than in terms of
specific interactions of the C-4 substituent with the
receptor protein. Thus, if we assume that the variation
of the affinity constants (Ki), throughout the homoge-
To examine the relationship between the conforma-
tion of the pharmacophore and the level of agonist
activity, we prepared 5-methylated congeners of several
6-alkylamino and 6-heteroaromatic derivatives (Table
5). It was expected that, because of the presence of the
5-methyl group, the size of the 6-substituent would
control the degree of planarity of the 6-substituent-
pyridine system: a n-π or p-π overlap should be allowed
if the 6-substituents are small, but should become less
favored as the size of the 6-substituents increases.
Incorporation of a 5-methyl substituent in the 6-pyrazol-

Novel Derivatives 2-Pyridinemethylamine
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1653
Ta ble 4. Effect of the Nature of the Para Substituent on Receptor Affinity Profile and on 5-HT1A Agonist Activity in Vitro (cAMP)
and in Vivo (LLR)
5-HT1A agonist activity
ED50 (mg/kg)e to produce LLRf
receptor affinity (pKi)b,c
i.p.
p.o.
compd
R
5-HT1A
D2
R1
cAMPd pEC50
15 min
60 min
60 min
43
44
45
46
H
CH3
F
10.01 (0.04)
9.57 (0.05)
9.92 (0.09)
9.61 (0.07)
6.21 (0.04)
6.89 (0.15)
6.56 (0.06)
6.48 (0.22)
6.81 (0.03)
6.86 (0.06)
6.68 (0.09)
6.76 (0.04)
8.00 (0.45)
8.24 (0.22)
8.44 (0.09)
8.53 (0.09)
0.08
0.08
0.29
0.62
0.11
0.08
0.11
0.45
0.32
0.32
0.16
0.32
Cl
b-d
See footnotes of Table 2. e ED50 values were obtained by linear interpolation. f LLR ) lower lip retraction.
Ta ble 5. 5-Unsubstituted and -Substituted Derivatives: Comparisons of Their Affinity and Agonist Activity at 5-HT1A Receptors in
Vitro (cAMP) and in Vivo (LLR)
5-HT1A agonist activity
LLR, ED50 (mg/kg)e
receptor affinity
compd
R
R1
X
5-HT1A pKib,c
cAMPd pEC50
i.p. (15 min)
p.o. (60 min)
34
35
36
37
38
40
41
42
45
47
48
49
50
51
59
60
62
63
5-CH3
H
H
H
H
Cl
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
9.24 (0.07)
9.07 (0.05)
8.05 (0.10)
7.45 (0.05)
9.69 (0.05)
10.12 (0.11)
9.73 (0.06)
9.83 (0.01)
9.92 (0.09)
9.33 (0.03)
9.25 (0.05)
9.50 (0.09)
8.94 (0.01)
8.86 (0.07)
9.31 (0.06)
9.35 (0.06)
9.34 (0.12)
8.66 (0.04)
7.68 (0.13)
7.59 (0.04)
6.39 (0.25)
NT
NT
0.62
0.11
1.80
NT
0.32
0.08
0.32
0.45
0.16
1.30
0.89
0.08
1.0
5-CH3
5-CH2CH3
5-CH(CH3)2
H
5-CH3
H
5-CH3
H
3-CH3
4-CH3
5-CH3
H
0.08
1.30
NT
CH3NH
CH3NH
CH3CH2NH
CH3CH2NH
(CH3)2N
(CH3)2N
(CH3)2N
(CH3)2N
(CH3CH2)2N
(CH3CH2)2N
pyrazol-1-yl
pyrazol-1-yl
pyrazol-3-yl
pyrazol-3-yl
7.90 (0.38)
8.67 (0.02)
7.88 (0.02)
8.08 (0.24)
8.44 (0.09)
7.32 (0.12)
7.48 (0.03)
8.43 (0.15)
7.83 (0.10)
7.54 (0.08)
7.91 (0.04)
7.83 (0.09)
9.14 (0.18)
8.56 (0.01)
0.11
0.02
0.11
0.08
0.29
0.63
0.32
0.04
0.11
0.32
0.32
0.32
0.32
0.32
5-CH3
H
5-CH3
H
0.11
1.30
1.30
0.32
0.89
5-CH3
b-d
See footnotes of Table 2. e LLR ) lower lip retraction; ED50 values were obtained by linear interpolation.
3-yl-pyridine derivative 63 significantly decreased its
5-HT1A affinity and potency (compared with 62). In
contrast, the N-bound isomer 60 showed a pharmaco-
logical profile very similar to that of the 5-unsubstituted
control 59. Thus, intriguingly, either the conformation
of the pharmacophore plays a different role in C-bound
(63) than in N-bound (60) aromatic 6-substituted ligands
or the 5-methyl group reduces the steric tolerance in
the region occupied by the 6-substituent only in C-bound
6-substituted derivatives. In all cases, the binding mode
of the C-versus N-bound aromatic 6-substituted ligands
at 5-HT1A receptors is likely to be different.
When the methyl group was moved around the
pyridine ring, affinity for 5-HT1A receptors was retained
but potency and in vivo activity were reduced markedly
(47 and 48 compared with 49). In addition, in the
6-dialkylamino series, incorporation of a 5-methyl group
did not seem to affect the in vitro responses of the
corresponding ligands (49 and 51 compared with 45 and
50, respectively). This suggests that, in the 5,6-disub-
stituted series, the gain in free energy of stabilization
of the receptor-ligand complex, provided by the 5-meth-
yl effects, is partially offset by a less favorable contribu-
tion of the 6-substituents as compared to the 6-mono-
substituted series, possibly for steric reasons.
The impact of an additional 5-methyl group in the
nonaromatic 6-substituted series was more encouraging.
For instance, the 5-methylated derivative 34 (Table 5)
had 10 times higher affinity than its 5-unsubstituted
congener 32 (Table 1). Thus, clearly, the methyl group
in the 5-position on the pyridine nucleus interacts with
the receptor protein through hydrophobic effects.
Evidence in favor of such a scheme came from the
5-methyl-6-methylamino pyridine derivative 40. In this
compound the 5- and the 6-substituents act synergisti-
cally, as shown by the substantial improvement of all
the 5-HT1A parameters over those of the 5-unsubstituted
and the 6-dimethyl congeners (38 and 49, respectively).

1654 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Vacher et al.
Ta ble 6. Effects of 40, 45, 54, and the Reference Compound
Imipramine in the Rat Forced Swimming Test
ing factors, rather than increased agonist properties of
the fluorinated ligand at 5-HT1A receptors. From a
conformational standpoint, we proposed that the chain
linked at C-4 on the piperidine ring assumed an equato-
rial or a pseudoequatorial orientation in the bioactive
conformation(s) of the ligand.
The outstanding in vitro and in vivo profile of several
compounds in this series, together with the novelty of
their structures, warrants a further examination of their
properties in other preclinical models. Already, these
derivatives and analogues will provide innovative tools
that could contribute to a better understanding of the
therapeutic significance of 5-HT1A receptors.
immobilityb inhibition
ED50 (mg/kg)
inhibitionc
max (%)
compda
40
45
54
0.05
0.16
0.09
80
>80
>80
>80
31
imipramine
a
b
Compounds given orally 60 min before test. Potency to
produce a significant inhibition of immobility in 50% of the animals
tested. c Estimated maximum inhibition of immobility, expressed
as a percentage of immobility observed in vehicle controls.
Hence, not only do the 5- and the 6-substituents in 40
(fully) cooperate in the stabilization of the receptor-
ligand complex (i.e., gain in affinity) but, of prime
interest, they seem to cooperate in the stabilization of
a G-protein coupled state(s) of the receptor (i.e., gain in
efficacy). Also consistent with the scheme proposed
above, the steric constraints imposed on each component
of the 5,6-pair are very tight. Thus, the synergistic effect
between the 5- and the 6-groups vanished when the size
of one of them was larger than a 5-methyl or a
6-methylamino group: the derivatives 36, 37, and 42
suffered marked losses in affinity and potency at 5-HT1A
receptors.
Compounds 40, 45 (Table 5), and 54 (Table 2), which
emerged as the most active derivatives in each group,
were then assessed in the FST. As summarized in Table
6, all three compounds potently decreased immobility
after a single administration, and maximal effects were
greater than that of the tricyclic antidepressant imi-
pramine. These novel 5-HT1A receptor agonists have,
therefore, the potential to exert antidepressant effects
in humans.33
Exp er im en ta l Section
Melting points were determined on a Bu¨chi 530 melting
point apparatus and were not corrected. 1H NMR spectra were
recorded on a Bruker AC200 (200 MHz) instrument. Chemical
shifts are reported in δ value (ppm) relative to an internal
standard of tetramethylsilane in CDCl3 or DMSO-d6. Infrared
(IR) spectra were obtained on a Nicolet FT 510 P spectra
photometer. Microanalyses were obtained on a Fison EA 1108/
CHN analyzer, and the results obtained were (0.4% of the
theoretical values. Analytical thin-layer chromatography was
carried out on precoated plates (silica gel, 60 F 254 Merck).
SDS silica gel (0.040-0.063 mm) was used for flash chroma-
tography. Organic extracts were dried over MgSO4 unless
otherwise noted.
Meth od A. N-(3-Ch lor o-4-flu or oben zoyl)-4-flu or o-4-[(5-
m eth yl-6-d im eth yla m in op yr id yl-2)-m eth yla m in o-m eth -
yl]-p ip er id in e (49). A solution of amine 1a a (1.43 g, 4.95
mmol), aldehyde 3c (0.68 g, 4.14 mmol), and toluene (50 mL)
was heated under reflux for 2 h with water separation by a
Dean-Stark trap. The solvent was removed under reduced
pressure, the residue was taken up in MeOH (25 mL) and
cooled to 0-5 °C, and KBH4 (0.45 g, 8.28 mmol) was added
portionwise. Stirring was continued at room temperature for
18 h. The mixture was concentrated, extracted with CH2Cl2,
washed with water and brine, and then dried and filtered.
Evaporation of the solvent gave a pale yellow oil which was
purified by flash chromatography, MeOH-CH2Cl2 (1:9), to
afford 1.56 g of 49 (86%) as a pale yellow oil. The oxalate salt
of 49 was crystallized from MeOH-Et2O to give 1.46 g of a
Currently, these compounds, and others within this
series, are being evaluated further in various preclinical
models.
Con clu sion
1
white solid: mp 204-206 °C; H NMR (DMSO-d6) δ 1.75 (m,
The present study is part of an effort to improve the
in vivo properties of a recently described, novel class of
5-HT1A receptor agonists. Here, we reported the prepa-
ration of, and discussed pharmacological results ob-
tained with, a series of aryl-[4-fluoro-4-({[5-H or CH3,
6-substituted-pyridin-2-ylmethyl]-amino}-methyl)-pip-
eridin-1-yl]-methanones. These compounds have, in
general, high affinity for and selectivity at 5-HT1A
receptors (versus D2 and R1). Among them, several
inhibited forskolin-stimulated cAMP accumulation in
HA7 cells more potently than the prototypical agonist
(()8-OH-DPAT. Importantly, their 5-HT1A agonist ac-
tivity, when administered i.p. and p.o. to rats, was
superior to that of the aryl-[4-({[5-H or CH3, 6-substi-
tuted-pyridin-2-ylmethyl]-amino}-methyl)-piperidin-1-
yl]-methanone analogues. Furthermore, their ability to
reduce immobility in the FST after a single oral
administration, compared with that of imipramine
(tricyclic antidepressant), suggests that they have marked
antidepressant potential.
1H), 1.84 (m, 2H), 1.99 (m, 1H), 2.25 (s, 2H), 2.82 (s, 6H), 3.07
(m, 1H), 3.18 (d, 2H), 3.25 (m, 1H), 3.44 (m, 1H), 4.08 (s, 2H),
4.30 (m, 1H), 6.89 (d, 1H), 7.46 (m, 3H), 7.66 (dd, 1H); Anal.
(C22H27ClF2N4O‚C2H2O4) C, H, N, and Cl.
N-(3-Ch lor o-4-flu or oben zoyl)-p ip er id in e-4-on e (5a ). To
a cooled solution of piperidin-4-one ethyleneketal (82.05 g,
0.573 mol), TEA (160 mL, 1.15 mol), and chloroform (300 mL)
was added dropwise a solution of 3-chloro-4-fluorobenzoyl
chloride (110.6 g, 0.573 mol) in anhydrous chloroform (100 mL).
After stirring for 17 h at room temperature, the solution was
washed successively with 1 N HCl, H2O, aqueous NaHCO3,
and brine then dried and filtered. The solvent was evaporated
under vacuum to give 172 g of the protected amide (quantita-
tive) as an oil which was treated with 80% formic acid (500
mL) containing CuSO4 (2 g) at 80 °C for 16 h. Formic acid was
eliminated by azeotropic distillation with toluene, and the oily
residue obtained was neutralized with aqueous K2CO3. The
mixture was extracted twice with CH2Cl2, dried, and filtered,
and the solvent was evaporated to give an oil which crystal-
lized on standing. Recrystallization from CH2Cl2-diisopropyl
ether afforded 105 g of 5a (71.6%): mp 118-120 °C; 1H NMR
(CDCl3) δ 2.50 (s, 4H), 3.86 (s, 4H), 7.20 (t, 1H), 7.37 (m, 1H),
7.55 (dd, 1H); IR (KBr, cm-1) 1635 and 1710. Anal. (C12H11
ClFNO2) C, H, N, and Cl.
-
From a structural standpoint, a Csp3-4 fluorine atom
proved unique in its ability to enhance the central
5-HT1A activity of the ligands when administered orally.
This effect may result from improved pharmacokinetics,
possibly combined with some stereoelectronic contribut-
N-(3-Ch lor o-4-m eth ylben zoyl)-piper idin -4-on e (5b). This
compound was prepared in 64% yield as described for 5a using
3-chloro-4-methylbenzoyl chloride as starting material. 5b was
1
obtained as a white solid: mp 74-75 °C; H NMR (CDCl3) δ

Novel Derivatives 2-Pyridinemethylamine
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1655
Ta ble 7. Physical Data of Pyridin-2-ylmethylamino Derivatives
compd
R
R1
R2
R3
R4
Cl
Cl
Cl
F
F
F
F
Cl
F
F
F
H
CH3
F
Cl
Cl
F
F
F
method
% yield
formulaa
mp (°C)
b
b
b
b
b
b
b
b
d
c
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69e
H
H
H
H
H
H
H
F
H
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
Cd
A
A
60
78
51
49
47
37
78
71
91
57
79
45
61
67
58
65
51
86
77
69
52
49
75
43
75
62
39
75
81
51
48
58
70
42
62
56
53
54
C
C
19H20Cl2FN3O‚C4H4O4
19H20Cl2FN3O‚C4H4O4
161-163
155-157
162-164
156-158
153-155
155-157
164-166
167-169
162-164
173-175
130-132
152-154
166-168
158-160
173-175
169-171
140-142
204-206
198-200
140-142
215-216
142-144
158-160
171-173
182-184
146-148
138-140
173-175
171-173
150-152
165-167
172-174
131-133
178-180
187-189
191-193
208-210
120-125
3-F
5-CH3
5-CH3
5-C2H5
C20H22Cl2FN3O‚C4H4O4
C20H22ClF2N3O‚C4H4O4
C21H24ClF2N3O‚C4H4O4
C22H26ClF2N3O‚C4H4O4
C20H23ClF2N4O‚C4H4O4
C20H23Cl2FN4O‚C4H4O4
C21H25ClF2N4O‚C4H4O4
C21H25ClF2N4O‚C2H2O4
C22H27ClF2N4O‚C4H4O4
5-iC3H7
CH3NH
CH3NH
CH3NH
C2H5NH
C2H5NH
(CH3)2N
(CH3)2N
(CH3)2N
(CH3)2N
(CH3)2N
(CH3)2N
(CH3)2N
(C2H5)2N
(C2H5)2N
6-azetidin-1-yl
6-furan-2-yl
6-furan-2-yl
6-thien-2-yl
6-oxazol-5-yl
6-thiazol-2-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
6-pyrazol-3-yl
6-pyrazol-3-yl
6-pyrazol-3-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
6-pyrazol-1-yl
H
H
5-CH3
H
b
5-CH3
b
H
H
H
H
C21H26ClFN4O‚C4H4O4
C22H28ClFN4O‚C4H4O4
b
b
b
c
b
c
c
b
c
C21H25ClF2N4O‚C4H4O4
C21H25Cl2FN4O‚C4H4O4
C22H27Cl2FN4O‚C2H2O4
C22H27ClF2N4O‚C4H4O4
C22H27ClF2N4O‚C2H2O4
C23H29ClF2N4O‚C2H2O4
C24H31ClF2N4O‚C4H4O4
3-CH3
4-CH3
5-CH3
H
5-CH3
F
H
H
H
H
H
H
H
H
Cl
Cl
F
Cl
Cl
Cl
Cl
F
C
C
C
C
C
C
C
C
22H25Cl2FN4O‚C2H2O4
b
b
23H22Cl2FN3O2‚0.5C4H4O4
23H22ClF2N3O2‚0.5C4H4O4
b
23H22Cl2FN3OS‚0.5C4H4O4
c
22H21Cl2FN4O2‚C2H2O4
b
22H21Cl2FN4OS‚C4H4O4
b
22H22Cl2FN5O‚0.5C4H4O4
b
22H22ClF2N5O‚C4H4O4
b
5-CH3
F
Cl
F
C23H24ClF2N5O‚C4H4O4
c
c
b
H
H
C
C
22H22Cl2FN5O‚C2H2O4
22H22ClF2N5O‚C2H2O4
5-CH3
F
C23H24ClF2N5O‚C4H4O4
b
H
H
H
H
H
H
CH3
CN
OCH3
OH
Cl
Cl
Cl
Cl
Cl
Cl
C23H25Cl2N5O‚1.5C4H4O4
c
C
23H22Cl2N6O‚C2H2O4
c
C23H25Cl2N5O2‚C2H2O4
b
C22H23Cl2N5O2‚1.5C4H4O4
c
CH2F
C23H24Cl2N5O‚C2H2O4
b
C22H21Cl2N5O‚C4H4O4
a
b
d
Analyses for all compounds were within 0.4% of the theoretical value for C, H, and N. Fumarate. c Oxalate. Method C involved a
reductive amination between the 6-(pyrazol-1-yl)-2-pyridinecarboxaldehyde7 and the N-(3,4-dichlorobenzoyl)-4-hydroxy-4-aminometh-
ylpiperidine in the same experimental conditions used for method A. e The piperidine ring is replaced by a 1,2,5,6-tetrahydropyridine.
2.42 (s, 3H), 2.51 (s, 4H), 3.87 (s, 4H), 7.25 (d, 1H), 7.28 (d,
was washed with water and brine and then dried and
concentrated. The residue was purified by a short flash
chromatography on silica gel, eluting with CHCl3-EtOAc (9:
1), to give 7.68 g of 6a (79%) as an oil which crystallized on
standing: mp 75-77 °C; 1H NMR (CDCl3) δ 1.50 (m, 2H), 1.92
(m, 2H), 2.74 (s, 2H), 3.52 (m, 2H), 3.87 (m, 1H), 4.19 (m, 1H),
7.18 (t, 1H), 7.32 (m, 1H), 7.51 (dd, 1H); IR (KBr, cm-1) 1620.
Anal. (C13H13ClFNO2) C, H, N, and Cl.
N-(3-Ch lor o-4-m et h ylb en zoyl)-1-oxa -6-a za sp ir o[2,5]-
octa n e (6b). This compound was prepared in 60% yield as
described for 6a starting from 5b. Compound 6b was obtained
as a white solid: mp 104-105 °C; 1H NMR (CDCl3) δ 1.48 (m,
2H), 1.92 (m, 2H), 2.40 (s, 3H), 2.74 (s, 2H), 3.54 (m, 2H), 3.63
(m, 1H), 4.24 (m, 1H), 7.21 (dd, 1H), 7.27 (d, 1H), 7.42 (d, 1H);
IR (KBr, cm-1) 1628. Anal. (C14H16ClNO2) C, H, N, and Cl.
N-(3,4-Dich lor ob en zoyl)-1-oxa -6-a za sp ir o[2,5]oct a n e
(6c). This compound was prepared in 72% yield as described
for 6a starting from 5c. Compound 6c was obtained as a white
solid: mp 95-97 °C; 1H NMR (CDCl3) δ 1.45 (m, 2H), 1.88
(m, 2H), 2.71 (s, 2H), 3.50 (m, 3H), 4.19 (m, 1H), 7.22 (dd, 1H),
7.49 (m, 2H); IR (KBr, cm-1) 1625. Anal. (C13H13Cl2NO2) C,
H, N, and Cl.
1H), 7.47 (s, 1H); IR (KBr, cm-1) 1626 and 1714. Anal. (C13H14
ClNO2) C, H, N, and Cl.
-
N-(3,4-Dich lor oben zoyl)-p ip er id in -4-on e (5c). This com-
pound was prepared in 76% yield as described for 5a using
3,4-dichlorobenzoyl chloride as starting material. Compound
1
5c was obtained as a white solid: mp 115-117 °C; H NMR
(CDCl3) δ 2.51 (s, 4H), 3.86 (s, 4H), 7.30 (dd, 1H), 7.52 (d, 1H),
7.57 (d, 1H); IR (KBr, cm-1) 1645 and 1721. Anal. (C12H11Cl2-
NO2) C, H, N, and Cl.
N-(3-Ch lor oben zoyl)-p ip er id in -4-on e (5d ). This com-
pound was prepared in 67% yield as described for 5a using
3-chlorobenzoyl chloride as starting material. Compound 5d
was obtained as a white solid: mp 62-64 °C; 1H NMR (CDCl3)
δ 2.51 (m, 4H), 3.87 (m, 4H), 7.34-7.47 (m, 4H); IR (KBr, cm-1
1638 and 1721. Anal. (C12H12ClNO2) C, H, N, and Cl.
)
N-(3-Ch lor o-4-flu or ob e n zoyl)-1-oxa -6-a za sp ir o[2,5]-
octa n e (6a ). A solution of dimethylsulfoxonium methylide was
prepared, under nitrogen, from sodium hydride (1.52 g of a
60% dispersion in mineral oil, 37.8 mmol) and trimethylsul-
foxonium iodide (8.32 g, 37.8 mmol) in anhydrous DMSO (20
mL). A solution of 5a (9.21 g, 36 mmol) in DMSO (20 mL) was
added in 30 min and stirring was continued at 60 °C for 3.5 h.
The cooled reaction mixture was poured into ice-water and
extracted twice with ethyl acetate. The combined organic layer
N-(3-Ch lor oben zoyl)-1-oxa -6-a za sp ir o[2,5]octa n e (6d ).
This compound was prepared in 56% yield as described for 6a
starting from 5d . Compound 6d was obtained as a pale yellow

1656 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Vacher et al.
oil: 1H NMR (CDCl3) δ 1.48 (m, 2H), 1.89 (m, 2H), 2.62 (s,
2H), 3.54 (m, 2H), 3.72 (m, 1H), 4.26 (m, 1H), 7.26-7.46 (m,
4H).
pared in 85% yield as described for 8a starting from alcohol
7d . Compound 8d was obtained as a pale yellow oil: 1H NMR
(CDCl3) δ 1.63 (m, 2H), 1.89 (m, 2H), 2.46 (s, 3H), 3.12 (m,
1H), 3.34 (m, 1H), 3.63 (m, 1H), 4.02 (d, 2H), 4.56 (m, 1H),
7.25 (d, 1H), 7.37 (m, 5H), 7.79 (d, 2H).
N-(3-Ch lor o-4-flu or oben zoyl)-4-flu or o-4-h yd r oxym eth -
ylp ip er id in e (7a ). To a solution of the epoxide 6a (11.90 g,
44.1 mmol) and anhydrous CH2Cl2 (20 mL), stirred at -10 °C,
was added dropwise 70% poly(hydrogenfluoride)-pyridine (12.60
g, 441 mmol). The solution was stirred at -10 °C for 15 min
and then at room temperature for 16 h. The dark-red solution
was poured into ice-water and carefully neutralized with K2-
CO3, and the product was extracted three times with CH2Cl2.
The combined organic layer was washed with water, 1 N HCl,
and brine and dried, and the solvent was evaporated off. The
solid obtained was recrystallized from ethanol-ethyl acetate
to give 6.40 g of 7a (50%) as a white solid: mp 188-190 °C;
1H NMR (CDCl3) δ 1.50 (m, 1H), 1.63 (s, 1H exchangeable),
1.70 (m, 1H), 1.99 (m, 2H), 3.30 (m, 3H), 3.61 (dd, 2H), 4.53
(m, 1H), 7.16 (t, 1H), 7.29 (m, 1H), 7.46 (dd, 1H); IR (KBr,
cm-1) 3328 and 1612. Anal. (C13H14ClF2NO2) C, H, N, and Cl.
N -(3-Ch lor o-4-m e t h ylb e n zoyl)-4-flu or o-4-h yd r oxy-
m eth ylp ip er id in e (7b). This compound was prepared in 48%
yield as described for 7a starting from 6b. Compound 7b was
N-(3-Ch lor o-4-flu or oben zoyl)-4-flu or o-4-p h th a lim id o-
m eth ylp ip er id in e (9a ). The mixture of 8a (60 g, 0.0135 mol),
K-phthalimide (32.4 g, 0.175 mol), and anhydrous DMF (500
mL) was stirred at 150 °C for 7 h. The cooled suspension was
poured into ice-water and extracted twice with CH2Cl2. The
combined organic layer was washed with brine, dried, and
filtered through a pad of silica. Evaporation of the solvent gave
an oil which crystallized upon addition of a mixture of
diisopropyl ether-cyclohexane. Filtration of the solid gave
1
49.32 g of 9a (87%): mp 123-125 °C; H NMR (CDCl3) 1.85
(m, 4H), 3.16 (m, 1H), 3.34 (m, 1H), 3.65 (m, 1H), 3.91 (d, 2H),
4.56 (m, 1H), 7.18 (t, 1H), 7.29 (m, 1H), 7.49 (dd, 1H), 7.76 (m,
2H), 7.88 (m, 2H); IR (KBr, cm-1) 1776, 1720 and 1623. Anal.
(C21H17ClF2N2O3) C, H, N, and Cl.
N-(3-Ch lor o-4-m et h ylb en zoyl)-4-flu or o-4-p h t h a lim i-
d om eth ylp ip er id in e (9b). This compound was prepared in
85% yield as described for 9a starting from 8b. Compound 9b
was obtained as a white solid: mp 149-151 °C; 1H NMR
(CDCl3) δ 1.62-1.95 (m, 4H), 2.39 (s, 3H), 3.13 (m, 1H), 3.32
(m, 1H), 3.63 (m, 1H), 3.90 (d, 2H), 4.56 (m, 1H), 7.18 (m, 1H),
7.25 (d, 1H), 7.39 (s, 1H), 7.76 (m, 2H), 7.88 (m, 2H); IR (KBr,
cm-1) 1777, 1720, and 1625; Anal. (C22H20ClFN2O3) C, H, N,
and Cl.
1
obtained as a white solid: mp 148-150 °C; H NMR (CDCl3)
δ 1.63 (m, 1H), 1.83 (s, 1H, exchangeable), 1.96 (m, 1H), 2.40
(s, 3H), 3.27 (m, 2H), 3.62 (d, 1H), 3.68 (m, 1H), 4.55 (m, 1H),
7.19 (d, 1H), 7.27 (d, 1H), 7.40 (s, 1H); IR (KBr, cm-1) 3370
and 1617. Anal. (C14H17ClFNO2) C, H, N, and Cl.
N-(3,4-Dich lor oben zoyl)-4-flu or o-4-h yd r oxym eth ylp i-
p er id in e (7c). This compound was prepared in 46% yield as
described for 7a starting from 6c. Compound 7c was obtained
as a white solid: mp 178-180 °C; 1H NMR (DMSO d6) δ 1.46-
1.61 (m, 4H), 3.04 (m, 2H), 3.31 (s, 1H, exchangeable), 3.38
(dd, 2H), 4.18 (m, 1H), 4.99 (t, 1H), 7.36 (dd, 1H), 7.67 (m,
2H). Anal. (C13H14Cl2FNO2) C, H, N, and Cl.
N-(3,4-Dich lor oben zoyl)-4-flu or o-4-p h th a lim id om eth -
ylp ip er id in e (9c). This compound was prepared in 83% yield
as described for 9a starting from 8c. Compound 9c was
1
obtained as a white solid: mp 152-154 °C; H NMR (CDCl3)
δ 1.60-1.90 (m, 4H), 3.22 (m, 2H), 3.62 (m, 1H), 3.90 (d, 2H),
4.58 (m, 1H), 7.25 (dd, 1H), 7.50 (m, 2H), 7.75 (m, 2H), 7.88
(m, 2H); IR (KBr, cm-1) 1776, 1723, and 1635. Anal. (C21H17
Cl2FN2O3) C, H, N, and Cl.
-
N-(3-Ch lor oben zoyl)-4-flu or o-4-h yd r oxym eth ylp ip er i-
d in e (7d ). This compound was prepared in 35% yield as
described for 7a starting from 6d . Compound 7d was obtained
as a white solid: mp 130-132 °C; 1H NMR (CDCl3) δ 1.62 (m,
2H), 1.93 (s, 1H exchangeable), 2.05 (m, 2H), 3.28 (m, 2H),
3.63 (m, 3H), 4.57 (m, 1H), 7.27 (m, 1H), 7.37 (m, 2H); IR (KBr,
cm-1) 3365 and 1613. Anal. (C13H15ClFNO2) C, H, N, and Cl.
N-(3-Ch lor o-4-flu or oben zoyl)-4-flu or o-4-(4-m eth ylph en -
ylsu lfon yloxym eth yl)-p ip er id in e (8a ). To a solution of 7a
(47.65 g, 0.164 mol) in anhydrous pyridine (235 mL), cooled
to 0-5 °C, was added dropwise p-toluenesulfonyl chloride
(34.32 g, 0.18 mol), and the solution was stirred at room
temperature overnight. The suspension was poured into ice-
water and extracted twice with CH2Cl2. The combined organic
layer was washed successively with 1 N HCl, water, and brine,
dried, filtered, and concentrated under vacuum. Crystallization
from diisopropyl ether afforded 64.40 g of 8a (83%) as a white
solid: mp 90-92 °C; 1H NMR (CDCl3) δ 1.58 (m, 1H), 1.71
(m, 1H), 1.86 (m, 2H), 2.43 (s, 3H), 3.23 (m, 2H), 3.64 (m, 1H),
3.97 (d, 2H), 4.46 (m, 1H), 7.15 (t, 1H), 7.25 (m, 1H), 7.34 (d,
2H), 7.44 (dd, 1H), 7.76 (d, 2H); IR (KBr, cm-1) 1622. Anal.
(C20H20ClF2NO4S) C, H, N, and Cl.
N-(3-Ch lor o-4-m eth ylben zoyl)-4-flu or o-4(4-m eth ylph en -
ylsu lfon yloxym eth yl)-p ip er id in e (8b). This compound was
prepared in 78% yield as described for 8a starting from alcohol
7b. Compound 8b was obtained as a white solid: mp 122-
123 °C; 1H RMN (CDCl3) δ 1.62 (m, 1H), 1.88 (m, 1H), 2.40 (s,
3H), 2.46 (s, 3H), 3.13 (m, 1H), 3.31 (m, 1H), 3.64 (m, 1H),
4.01 (d, 2H), 4.54 (m, 1H), 7.16 (d, 1H), 7.26 (d, 1H), 7.38 (m,
3H), 7.79 (d, 2H); IR (KBr, cm-1) 1618. Anal. (C21H23ClFNO4S)
C, H, N, and Cl.
N-(3-Ch lor oben zoyl)-4-flu or o-4-p h th a lim id om eth ylp i-
p er id in e (9d ). This compound was prepared in 80% yield as
described for 9a starting from 8d . Compound 9d was obtained
1
as a white solid: mp 126-127 °C; H NMR (CDCl3) δ 1.62-
1.99 (m, 4H), 3.13 (m, 1H), 3.34 (m, 1H), 3.63 (m, 1H), 3.90 (d,
2H), 4.59 (m, 1H), 7.26 (d, 1H), 7.36 (m, 2H), 7.76 (dd, 2H),
7.89 (dd, 2H). Anal. (C21H18ClFN2O3) C, H, N, and Cl.
N-(3-Ch lor o-4-flu or ob en zoyl)-4-flu or o-4-a m in om et h -
ylp ip er id in e (1a a ). A mixture of 9a (2.60 g, 6.20 mmol) and
ethanolamine (8 mL) was stirred at 60 °C for 2 h. The cooled
solution was poured into ice-water and extracted twice with
CH2Cl2. The organic layers were washed with brine, dried, and
concentrated to give 1.50 g of 1a a (87%) as a pale yellow oil:
1H NMR (CDCl3) δ 1.37 (s broad, exchangeable), 1.63 (m, 2H),
1.91 (m, 2H), 2.79 (d, 2H), 3.22 (m, 2H), 3.62 (m, 1H), 4.49 (m,
1H), 7.15 (t, 1H), 7.26 (m, 1H), 7.45 (dd, 1H).
N-(3-Ch lor o-4-m eth ylben zoyl)-4-flu or o-4-a m in om eth -
ylp ip er id in e (1a b). This compound was prepared from 9b
(90%) using the same procedure as described for the prepara-
tion of 1a a . Compound 1a b was obtained as a pale yellow oil:
1H NMR (CDCl3) δ 1.23 (s broad, exchangeable), 1.59 (m, 2H),
1.95 (m, 2H), 2.40 (s, 3H), 2.83 (d, 2H), 3.14 (m, 1H), 3.37 (m,
1H), 3.64 (m, 1H), 4.56 (m, 1H), 7.19 (d, 1H), 7.26 (m, 1H),
7.39 (d, 1H).
N-(3,4-Dich lor oben zoyl)-4-flu or o-4-a m in om eth ylp ip e-
r id in e (1a c). This compound was prepared from 9c (82%)
using the same procedure as described for the preparation of
1a a . Compound 1a c was obtained as a pale yellow oil: 1H
NMR (CDCl3) δ 1.32 (s broad, exchangeable), 1.64 (m, 2H),
1.94 (m, 2H), 2.81 (d, 2H), 3.27 (m, 2H), 3.59 (m, 1H), 4.52 (m,
1H), 7.26 (m, 1H), 7.48 (m, 2H).
N-(3-Ch lor ob en zoyl)-4-flu or o-4-a m in om et h ylp ip er i-
d in e (1a d ). This compound was prepared from 9d (87%) using
the same procedure as described for the preparation of 1a a .
Compound 1a d was obtained as a pale yellow oil: 1H NMR
(CDCl3) δ 1.35 (s broad, exchangeable), 1.61 (m, 2H), 1.93 (m,
2H), 2.80 (d, 2H), 3.25 (m, 2H), 3.65 (m, 1H), 4.54 (m, 1H),
7.28 (d, 1H), 7.39 (m, 3H).
N-(3,4-Dich lor ob en zoyl)-4-flu or o-4-(4-m et h ylp h en yl-
su lfon yloxym eth yl)-p ip er id in e (8c). This compound was
prepared in 81% yield as described for 8a starting from alcohol
7c. Compound 8c was obtained as a white solid: mp 142-
144 °C; 1H NMR (CDCl3) δ 1.61 (m, 2H), 1.85 (m, 2H), 2.45 (s,
3H), 3.26 (m, 2H), 3.60 (m, 1H), 4.01 (d, 2H), 4.51 (m, 1H),
7.20 (dd, 1H), 7.35 (d, 2H), 7.48 (m, 2H), 7.78 (d, 2H).
N-(3-Ch lor oben zoyl)-4-flu or o-4-(4-m eth ylp h en ylsu lfo-
n yloxym eth yl)-p ip er id in e (8d ). This compound was pre-

Novel Derivatives 2-Pyridinemethylamine
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1657
N-(3,4-Dich lor oben zoyl)-4-cya n o, 4-h yd r oxym eth ylp i-
p er id in e (10). To a mixture of KBH4 (0.92 g, 17 mmol), LiCl
(0.73 g, 17.2 mmol), and anhydrous THF (30 mL) under a
nitrogen atmosphere was added dropwise at room temperature
a solution of N-(3,4-dichlorobenzoyl)-4-cyano, 4-ethoxycarbo-
nylpiperidine12 (5.48 g, 15.4 mmol) and THF (20 mL). Stirring
was continued at room temperature for 18 h. The mixture was
concentrated under vacuum, and water was added. The
product was extracted with EtOAc, washed with water and
brine, dried, and filtered, and the solvent was evaporated
under vacuum. The crude product was crystallized from
diisopropyl ether to give 3.19 g (66%) of 10 as a white solid:
mp 188-190 °C; 1H NMR (DMSO-d6) δ 1.51 (dt, 2H), 1.87 (m,
2H), 2.96 (m, 1H), 3.17 (m, 1H), 3.46 (d, 2H), 3.65 (m, 1H),
4.44 (m, 1H), 5.49 (t, 1H), 7.36 (d, 1H), 7.41 (d, 1H), 7.70 (dd,
1H). Anal. (C14H14Cl2N2O2) C, H, N.
N-(3,4-Dich lor oben zoyl)-4-cya n o, 4-Tr iflu or om eth yl-
su lfon yloxym eth ylpiper id in e (11). Trifluoromethanesulfon-
ic anhydride (1.08 mL, 6.4 mmol) was added dropwise to an
ice-cold mixture of 10 (1.60 g, 5.1 mmol), 2,6-dimethylpyridine
(1 mL, 8.6 mmol), DMAP (62 mg, 0.51 mmol), and anhydrous
CH2Cl2 (15 mL). Stirring was continued for 1 h at 0 °C and
for 3 h at room temperature. The suspension was successively
washed with water, aqueous citric acid solution, and water.
The organic layer was dried and filtered, and the solvent was
removed under vacuum to give 2.16 g (95%) of 11 as an oil
which crystallized on standing: mp 120-122 °C; 1H NMR
(CDCl3) δ 1.60 (m, 2H), 2.08 (m, 2H), 3.32 (m, 2H), 3.97 (m,
1H), 4.46 (s, 2H), 4.80 (m, 1H), 7.21 (d, 1H), 7.25 (d, 1H), 7.51
(m, 2H).
and obtained as a pale yellow oil: 1H NMR (CDCl3) δ 0.97 (s,
3H), 1.41 (m, 6H), 2.56 (m, 2H), 3.27 (m, 3H), 4.07 (m, 1H),
7.22 (m, 1H), 7.43 (m, 2H).
N-(3,4-Dich lor oben zoyl)-4-a zid om eth yl, 4-Hyd r oxyp i-
p er id in e (14). A suspension of 6 (0.50 g, 1.75 mmol), NaN3
(0.57 g, 8.7 mmol), NH4Cl (0.20 g, 3.7 mmol), MeOH (8 mL),
and H2O (1 mL) was refluxed under stirring for 5 h. The
solvent was removed under vacuum, water was added, and
the product was extracted with EtOAc. The organic layer was
washed with water and brine, dried, and filtered. The solvent
was distilled off to give an oil which crystallized on standing:
mp 115-117 °C; 1H NMR (CDCl3) δ 1.62 (m, 4H), 2.01 (m, 1H),
3.30 (s, 3H), 3.46 (m, 2H), 4.43 (m, 1H), 7.20 (dd, 1H), 7.46
(m, 2H). Anal. (C13H14Cl2N4O2) C, H, N.
N-(3,4-Dich lor oben zoyl)-4-a zid om eth yl, 4-Meth oxyp i-
p er id in e (2a ). A solution of 14 (2.0 g, 6.08 mmol) and
anhydrous THF (5 mL) was added dropwise to a suspension
of HNa (60% dispersion in mineral oil, 0.365 g, 9.1 mmol) and
THF (10 mL) under stirring and cooling in an ice-bath. Stirring
was continued for 15 min at 0 °C and for 1 h at room
temperature. ICH3 (0.57 mL, 9.1 mmol) was added dropwise,
and stirring was continued for 18 h at room temperature. The
reaction mixture was poured in ice-water and extracted with
EtOAc. The combined extracts were washed with water and
brine, dried, and filtered, and the solvent was removed under
vaccuum. The product was crystallized from hexane to give
1
1.50 g (72%) of 2a as a white solid: mp 83-85 °C; H NMR
(DMSO-d6) δ 1.44 (m, 2H), 1.71 (m, 2H), 3.0 (m, 1H), 3.17 (s,
3H), 3.26 (m, 2H), 3.37 (s, 2H), 4.13 (m, 1H), 7.35 (dd, 1H),
7.67 (m, 2H). Anal. (C14H16Cl2N4O2) C, H, N.
N-(3,4-Dich lor oben zoyl)-4-cya n o, 4-F lu or om eth ylp ip -
er id in e (12). The solution of 11 (2.05 g, 4.6 mmol), KF (2.9 g,
50 mmol), and diethyleneglycol (12 mL) was stirred at 100-
105 °C for 1 h. The cooled mixture was poured into water and
extracted with EtOAc. The organic layer was washed with
water and brine, dried, and filtered, and the solvent was
removed under vacuum. Purification by flash chromatography,
EtOAc-CH2Cl2 (1:9) gave an oil which was crystallized from
diisopropyl ether to afford 0.99 g (68%) of 12 as a white solid:
mp 135-137 °C; 1H NMR (CDCl3) δ 1.60 (m, 2H), 1.98 (m, 2H),
3.25 (m, 2H), 3.83 (m, 1H), 4.40 (d, 1H), 4.74 (m, 1H), 7.19
(dd, 1H), 7.49 (m, 1H). Anal. (C14H13Cl2FN2O) C, H, N.
N-(3,4-Dich lor oben zoyl)-4-cya n o, 4-p-Tolu en esu lfon yl-
oxym eth ylp ip er id in e (15). Compound 15 was obtained from
10 and purified by flash chromatography, MeOH-CHCl3 (1:
99), and then by crystallization from diisopropyl ether as a
white solid (75%): mp 169-171 °C; 1 NMR (CDCl3) δ 1.58 (m,
2H), 1.97 (m, 2H), 2.48 (s 3H), 3.27 (m, 2H), 3.84 (m, 1H), 4.02
(s 2H), 4.70 (m, 1H), 7.22 (dd, 1H), 7.39 (d, 2H), 7.50 (m, 2H),
7.82 (d, 2H).
N-(3,4-Dich lor oben zoyl)-4-a zid om eth yl, 4-Cya n op ip -
er id in e (2b). The suspension of 15 (2.03 g, 4.34 mmol), NaN3
(0.56 g, 8.6 mmol), n-tetrabutylammoniun azide (0.07 g, 0.25
mmol), and DMSO (6 mL) was stirred at 100-105 °C for 15 h.
The cooled reaction mixture was poured in ice-water and
extracted with EtOAc. The combined extracts were washed
with water and brine, dried, and filtered. The solvent was
removed under vacuum to give 1.4 g (95%) of 2b as a thick
pale yellow oil: 1H NMR (CDCl3) δ 1.52 (m, 2H), 2.01 (m, 2H),
3.25 (m, 2H), 3.50 (s 2H), 3.86 (m, 1H), 4.74 (m, 1H), 7.22 (dd,
1H), 7.49 (m, 2H).
Meth od B. N-(3,4-Dich lor oben zoyl)-4-m eth oxy-4-{[(6-
p yr a zol-1-yl-p yr id in -2-ylm et h yl)a m in o]m et h yl}-p ip er i-
d in e (66). The mixture of 2a (0.87 g, 2.53 mmol), 6-pyrazol-
1-ylpyridine-2-carboxaldehyde (0.44 g, 2.54 mmol), triphenyl-
phosphine (0.67 g, 2.55 mmol), and methanol (40 mL) was
refluxed under stirring for 3 h. After the mixture cooled to
room temperature, KBH4 (0.41 g, 7.59 mmol) was added, and
stirring was continued for 18 h. The solvent was distilled off,
and the residue was poured in ice-water and extracted with
CH2Cl2. The organic layer was washed with water and brine,
dried, and filtered. Purification by flash chromatography,
MeOH-EtOAc (1:9), gave 0.75 g (62%) of 58 as a pale yellow
oil. The oxalate salt was crystallized from EtOH-EtOAc to
afford a white solid (0.60 g): mp 187-189 °C; 1H NMR (DMSO-
d6) δ 1.55 (m, 2H), 1.90 (m, 2H), 2.90-3.30 (m, 8H), 4.08 (m,
1H), 4.31 (s, 2H), 6.59 (t, 1H), 7.35 (dd, 1H), 7.44 (d, 1H), 7.67
N-(3,4-Dich lor oben zoyl)-4-a m in om eth yl,
4-F lu or o-
m eth ylp ip er id in e (1b). To a solution of 12 (0.82 g, 2.6 mmol),
methanol (20 mL), and concentrated NH4OH (0.25 mL) was
added Raney nickel (1.50 g). The suspension was stirred under
hydrogen atmosphere for 4 h. The catalyst was filtered off
through Celite, and the solution was concentrated under
vacuum. The oily residue was taken up in chloroform and
washed with water and brine, dried, and filtered. The solvent
was removed in a vacuum to give 0.80 g (96%) of 1b as an
yellow oil: 1HNMR (CDCl3) δ 1.13 (m, 2H), 1.52 (m, 4H), 2.76
(s, 2H), 3.39 (m, 1H), 3.68 (m, 1H), 4.38 (d, 2H), 7.21 (dd, 1H),
7.48 (m, 2H).
N-(3,4-Dich lor oben zoyl)-4-cya n o, 4-Meth ylp ip er id in e
(13). LDA (2 mL, 3.9 mmol as a 2 M solution in heptane/THF/
ethylbenzene) was added to the solution of N-(3,4-dichloroben-
zoyl)-4-cyanopiperidine14 (1.0 g, 3.5 mmol), 1,3-dimethyl-2-
imidazolidinone (0.1 g), and anhydrous THF (30 mL) under
stirring and cooling at -15 °C. Stirring was continued for 30
min in the same conditions. ICH3 (0.25 mL, 3.9 mmol) was
added dropwise, and the mixture was stirred at room temper-
ature for 2 h. The solvents were removed under vacuum, and
the residue was taken up in CHCl3 and washed with water
and brine. The organic layer was dried and filtered, and the
solvent was removed under vacuum. Purification of the residue
by flash chromatography, EtOAc-CHCl3 (1:9), gave 0.70 g
(66%) of 13 which crystallized on standing: mp 116-118 °C;
1H NMR (CDCl3) δ 1.42 (s, 3H), 1.50 (m, 2H), 1.93 (m, 2H),
3.25 (m, 2H), 3.70 (m, 1H), 4.64 (m, 1H), 7.21 (dd, 1H), 7.47
(m, 2H). Anal. (C14H14Cl2N2O) C, H, N.
(m, 2H), 7.86 (m, 2H), 8.04 (t, 1H), 8.83 (d, 1H). Anal. (C23H25
-
Cl2N5O2‚C2H2O4) C, H, N.
5-Meth yl-6-ch lor o-2-p yr id in em eth a n ol (17). To a solu-
tion of 5-methyl-6-chloro-2-pyridinecarboxylic acid ethyl ester
1615 (8.80 g, 44 mmol) in ethanol (100 mL), maintained at room
temperature, was added portionwise NaBH4 (2.80 g, 74 mmol),
and the mixture was stirred overnight at room temperature.
The suspension was concentrated under vacuum, poured into
brine, and extracted twice with EtOAc. The organic layer was
N-(3,4-Dich lor oben zoyl)-4-a m in om eth yl, 4-Meth ylp i-
p er id in e (1c). Compound 1c was prepared in a quantitative
yield from 13 as described for the preparation of 1b from 12

1658 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9
Ta ble 8. Experimental Details for Each of the Binding Assaysa
Vacher et al.
[3H]ligand
tissue (rat)
concn (mg/mL)
incubation
binding
site
nonspecific
drug
KD (nM)
concn (nM)
type
time (min)
temp (°C)
b
5-HT1A
8-OH-DPAT (3.1)
YM-09151-2 (0.036)
prazosin (0.063)
0.2
0.05
0.1
cortex
striatum
cortex
10 mg/mL
1 mg/mL
5 mg/mL
30
60
30
23
23
23
5-HT
(+)-butaclamol
phentolamine
c
D2
b
R1
a
Buffers: (A) Tris HCl, 50 mM, pH 7.4; pargyline, 10 µM; CaCl2, 4 mM; ascorbic acid, 0.1%; (B) Tris HCl, 50 mM, pH 7.4; NaCl, 120
mM; KCl, 5 mM; (C) Tris HCl, 50 mM, pH 7.4. Reference 34. c Reference 35.
b
1
dried, filtered, and evaporated under vacuum to give 6.10 g of
17 (88%) as a pale yellow oil: 1H NMR (CDCl3) δ 2.38 (s, 3H),
3.10 (s, 1H, exchangeable), 4.71 (s, 2H), 7.16 (d, 1H), 7.55 (d,
1H).
obtained as a white solid: mp 68-70 °C; H NMR (CDCl3) δ
1.30 (t, 3H), 2.15 (s, 3H), 3.60 (q, 2H), 4.25 (s, 1H), 7.21 (d,
1H), 7.35 (d, 1H), 9.90 (s, 1H); IR (KBr, cm-1) 1698.
5-Met h yl-6-(d im et h yla m in o)-2-p yr id in eca r b oxa ld e-
h yd e (3c). This compound was prepared in 60% yield as
described for 3a starting from 18c. Compound 3c was obtained
as a yellow oil: 1H NMR (CDCl3) δ 2.37 (s, 3H), 2.93 (s, 6H),
7.44 (d, 1H), 7.49 (d, 1H), 9.93 (s, 1H); IR (KBr, cm-1) 1705.
5-Meth yl-6-m eth yla m in o-2-p yr id in em eth a n ol (18a ). A
solution of 17 (3.49 g, 22 mmol) and methylamine (33% in
ethanol, 27 mL), was heated at 100 °C in a closed vessel for
48 h. After the mixture cooled to room temperature, the solvent
was removed under vacuum and the residue extracted twice
with EtOAc. The organic layer was washed with water and
brine, dried, and filtered. The residue was purified by flash
chromatography on silica gel, eluent EtOAc-cyclohexane (6:
4), to give 1.68 g of 18a (50%) as an oil which crystallized on
standing: mp 86-88 °C; 1H NMR (CDCl3) δ 2.07 (s, 3H), 3.05
(d, 3H), 4.13 (s, 1H, exchangeable), 4.24 (s, 1H, exchangeable),
4.59 (s, 2H), 6.39 (d, 1H), 7.18 (d, 1H).
5-Meth yl-6-(eth ylam in o)-2-pyr idin em eth an ol (18b). This
compound was prepared in 63% yield as described for 18a
using ethylamine in place of methylamine. Compound 18b was
obtained as an oil: 1H NMR (CDCl3) δ 1.27 (t, 3H), 2.07 (s,
3H), 3.53 (dt, 2H), 4.14 (s, 2H, exchangeable), 4.58 (s, 2H), 6.37
(d, 1H), 7.18 (d, 1H).
5-Met h yl-6-d iet h yla m in o-2-p yr id in eca r b oxa ld eh yd e
(2d ). This compound was prepared in 53% yield as described
for 3a starting from 18d . Compound 3d was obtained as a
yellow oil: 1H NMR (CDCl3) δ 1.13 (ts, 6H), 2.33 (s, 3H), 3.28
(q, 4H), 7.44 (d, 1H), 7.50 (d, 1H), 9.95 (s, 1H); IR (KBr, cm-1
1708.
)
5-Met h yl-6-ch lor o-2-(1.3-d ioxola n -2-yl)-p yr id in e (20).
To a solution of 17 (5.49 g, 34.8 mmol) and anhydrous CHCl3
(200 mL) was added MnO2 (26 g, 300 mmol), and the suspen-
sion was stirred under reflux for 3 h. Insoluble materials were
filtered off, and then the compound was purified on a short
silica gel column. The solvent was removed under vacuum to
give 4.03 g of 5-methyl-6-chloro-2-pyridinecarboxaldehyde
(74%) as an oil which crystallized on standing: mp 70-72 °C;
1H NMR (CDCl3) δ 2.50 (s, 3H), 7.75 (d, 1H), 7.83 (d, 1H), 9.98
(s, 1H). A solution of this aldehyde (3.98 g, 25.6 mmol),
ethylene glycol (4.4 mL, 78.9 mmol), and p-toluenesulfonic acid
monohydrate (0.30 g) in toluene (150 mL) was heated under
reflux for 8 h with water separation by a Dean-Stark trap.
The solvent was evaporated off, and the residue was taken up
in EtOAc and washed with 10% NaHCO3 and then brine. The
combined organic layer was dried and filtered through a pad
of silica. The solvent was removed under reduced pressure to
5-Meth yl-6-(dim eth ylam in o)-2-pyr idin em eth an ol (18c).
This compound was prepared in 55% yield as described for
18a using dimethylamine in place of methylamine. Compound
18c was obtained as an oil: 1H NMR (CDCl3) δ 2.28 (s, 3H),
2.88 (s, 6H), 4.17 (s, 1H, D2O exchange), 4.62 (s, 2H), 6.65 (d,
1H), 7.34 (d, 1H).
5-Meth yl-6-d ieth yla m in o-2-p yr id in em eth a n ol (18d ). To
a solution of 4-chloro-6-diethylamino-1-methyl-2-oxa-5-aza-
bicyclo[2.2.2]oct-5-en-3-one 1916 (9.37 g, 39.6 mmol), DBU (22.4
mL, 159 mmol), and anhydrous THF (130 mL) at room
temperature was added ethanol (2.77 mL, 47.5 mmol), and the
mixture was heated under reflux for 24 h. The solvent was
distilled under vacuum and the residue was poured into water
and extracted twice with ethyl acetate. The combined organic
layer was washed with brine and water, dried, filtered, and
concentrated under vacuum. The crude product was purified
by flash chromatography on silica gel, eluent cyclobexane-
EtOAc (95:5), to afford 1.89 g of 5-methyl-6-diethylamino-2-
pyridinecarboxylic acid ethyl ester as an oil. This oil was taken
up in EtOH (25 mL), treated at room temperature with NaBH4
(875 mg, 23 mmol), and then heated at reflux for 2 h. The
solvent was distilled off, and the residue was taken up in ice-
water and then extracted twice with CH2Cl2. The organic
layers were dried, filtered, and concentrated under vacuum.
The residue was purified by flash chromatography on silica
gel, eluent CH2Cl2-EtOAc (95:5), to give 0.92 of 18d (12%) as
a pale yellow oil: 1H NMR (CDCl3) δ 1.10 (t, 6H), 2.25 (s, 3H),
3.25 (q, 4H), 4.21 (s, 1H, exchangeable), 4.62 (s, 2H), 6.63 (d,
1H), 7.35 (d, 1H).
5-Met h yl-6-m et h yla m in o-2-p yr id in eca r b oxa ld eh yd e
(3a ). To a solution of 18a (0.93 g, 6.11 mmol) and anhydrous
CHCl3 (20 mL) was added MnO2 (5 g, 57.5 mmol), and the
suspension was stirred vigorously under reflux for 2 h.
Insoluble material was filtered off, and then the compound was
purified on a short silica gel column eluting with CHCl3.
Removal of the solvent under vacuum gave 0.75 g of 3a (80%)
as an oil which crystallized on standing: mp 78-80 °C; 1H
NMR (CDCl3) δ 2.15 (s, 3H), 3.12 (d, 3H), 4.36 (m, 1H), 7.22
(d, 1H), 7.35 (d, 1H), 9.91 (s, 1H); IR (KBr, cm-1) 1701.
5-Met h yl-6-(et h yla m in o)-2-p yr id in eca r b oxa ld eh yd e
(3b). This compound was prepared in 50% yield as described
for 3a using 18b as starting material. The aldehyde 3b was
1
give 3.90 g of 20 (76%) as a pale yellow oil; H NMR (CDCl3)
δ 2.39 (s, 3H), 4.06 (m, 2H), 4.15 (m, 2H), 5.79 (s, 1H), 7.39 (d,
1H), 7.59 (d, 1H).
5-Me t h yl-6-(p yr a zol-1-yl)-2(1.3-d ioxola n -2-yl)-p yr i-
d in e (21). To a suspension of HNa (0.60 g, 60% dispersion in
mineral oil, 15 mmol) in anhydrous N-methypyrrolidone (4 mL)
under a nitrogen atmosphere, was added dropwise a solution
of pyrazole (1 g, 15 mmol) in N-methylpyrrolidone (2 mL). After
30 min at room temperature, 20 (0.95 g, 5.10 mmol) was added
and the mixture was stirred at 100 °C for 5.5 h. The cooled
reaction mixture was poured into ice-water and extracted
twice with EtOAc. The combined organic layers were washed
with water and brine, dried, and filtered, and the solvent was
removed under vacuum. The product was purified by flash
chromatography, eluent cyclohexanes-EtOAc (70:30), to give
0.61 g of 21 (76%) as a pale yellow oil: 1H NMR (CDCl3) δ
2.58 (s, 3H), 4.10 (m, 2H), 4.18 (m, 2H), 5.84 (s, 1H), 6.43 (t,
1H), 7.42 (d, 1H), 7.72 (m, 2H), 8.29 (d, 1H).
5-Met h yl-6-(p yr a zol-2-yl)-2-p yr id in eca r b oxa ld eh yd e
(3e). A suspension of 21 (0.60 g, 2.73 mmol), formic acid (4
mL), H2O (1 mL), and CuSO4 (0.03 g) was stirred at 65 °C for
2.5 h. The solution was concentrated under vacuum, and then
the residual formic acid was eliminated by azeotropical distil-
lation with toluene. The residue was taken up in ice-water,
and an excess of K2CO3 was added. The product was extracted
twice with EtOAc, washed with diluted NH4OH and brine,
dried, and concentrated under vacuum. The product was
purified by flash chromatography, eluent hexanes-EtOAc (80:
20), to give 0.29 g of 3e (55%) as a pale yellow oil which
crystallized on standing: mp 46-48 °C; 1H NMR (CDCl3) δ
2.70 (s, 3H), 6.50 (t, 1H), 7.26 (s, 1H), 7.78 (d, 1H), 7.85 (s,
2H), 8.39 (d, 1H), 10.02 (s, 1H); IR (KBr, cm-1) 1713.

Novel Derivatives 2-Pyridinemethylamine
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1659
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receptors were determined by means of ligand competition
assays using the conditions summarized in Table 8. The
reactions were stopped by rapid filtration through Whatman
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All animals were housed in environmentally controlled
rooms (21 ( 1 °C, relative humidity: 55 ( 5%) under a 12 h
light-dark cycle (lights on at 7:00 a.m.), both during quaran-
tine and during the experiments. The experimental procedures
were in accordance with the European Communities Counsel
Directive of November 24, 1986 (86/609/EEC) and the National
Institutes of Health Guide for the Care and Use of Laboratory
Animals (NIH publication No. 85-23, revised 1985) and were
approved by the institutional Protocol Review Committee.
Compounds were dissolved in distilled water. Compounds
not soluble in distilled water were suspended in distilled water
by adding Tween 80 (2 drops/10 mL). Doses are expressed as
the weight of the free base.
Ack n ow led gm en t. We thank Dr. J . P. Ribet for
analytical chemistry support. Mr L. Petitpas’ assistance
with bibliographic searches was also very much appreci-
ated.
Su p p or tin g In for m a tion Ava ila ble: Additional physical
data (1H NMR and elemental analyses) on final compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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