Design and synthesis of a series of 6-substituted-2- pyridinylmethylamine derivatives as novel, high-affinity, selective agonists at 5-HT(1A) receptors

Article abstract of DOI:10.1021/jm9804329

A search for novel, selective agonists with high intrinsic activity at the 5-HT(1A) subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6- substituted-2-pyridinylmethylamine as a potential 5-HT(1A) pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT(1A), α₁-adrenergic, and D₂- dopaminergic receptors. Compounds with high affinity for 5-HT(1A) receptors (pK(i) ≥ 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT(1A) receptor gene and expressing the h5-HT(1A) receptor protein). Several compounds of the type aryl{4-[(6- substituted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT(1A) binding sites and were more than 500-fold selective with respect to α₁ and D₂ sites. Importantly, their 5-HT(1A) agonist properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP accumulation. In particular, (3,4- dichlorophenyl){4-[(6-oxazol-5-ylpyridin-2-ylmethylamino)methyl]piperidin- 1-yl}methanone (70) and (3,4-dichlorophenyl){4-[(6-azetidinopyridin-2- ylmethylamino)methyl]piperidin-1-yl}methanone (36) appeared to be more potent than, and at least as efficacious as, the prototypical 5-HT(1A) agonist (±)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT(1A) receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT(1A) binding sites.

Full text of DOI:10.1021/jm9804329

5070
J . Med. Chem. 1998, 41, 5070-5083
Design a n d Syn th esis of a Ser ies of 6-Su bstitu ted -2-p yr id in ylm eth yla m in e
Der iva tives a s Novel, High -Affin ity, Selective Agon ists a t 5-HT1A Recep tor s
Bernard Vacher,*,† Bernard Bonnaud,† Philippe Funes,† Nathalie J ubault,† Wouter Koek,‡
Marie-Bernadette Assie´,‡ and Cristina Cosi‡
Pierre Fabre Research Center, 17 avenue J ean Moulin, 81106 Castres Cedex, France
Received J uly 24, 1998
A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of
serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations
led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore.
Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested
for their affinity at 5-HT1A, R1-adrenergic, and D2-dopaminergic receptors. Compounds with
high affinity for 5-HT1A receptors (pKi g 8) were examined for agonist properties by measuring
their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells
permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor
protein). Several compounds of the type aryl{4-[(6-substituted-pyridin-2-ylmethylamino)-
methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT1A binding sites and were
more than 500-fold selective with respect to R1 and D2 sites. Importantly, their 5-HT1A agonist
properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP
accumulation. In particular, (3,4-dichlorophenyl){4-[(6-oxazol-5-ylpyridin-2-ylmethylamino)-
methyl]piperidin-1-yl}methanone (70) and (3,4-dichlorophenyl){4-[(6-azetidinopyridin-2-yl-
methylamino)methyl]piperidin-1-yl}methanone (36) appeared to be more potent than, and at
least as efficacious as, the prototypical 5-HT1A agonist (()-8-OH-DPAT. SAR studies revealed
that the pyridine nitrogen atom and the nature and the position of the substituents on the
pyridine ring were critically involved in the ability of the compounds to recognize and activate
5-HT1A receptors. Structural modifications of the nonpharmacophoric part of the molecule
showed, however, that the entire structure was required for affinity at 5-HT1A binding sites.
In tr od u ction
with an improved profile. Here, we describe the design,
synthesis, and preliminary pharmacological character-
ization of a series of 6-substituted-pyridin-2-ylmethyl-
amine derivatives. Affinity of members of this class for
5-HT1A binding sites was compared with their affinity
for R1-adrenergic and D2-dopaminergic sites. Further-
more, their agonist activity at 5-HT1A receptors was
examined in vitro by measuring their ability to inhibit
forskolin-stimulated cAMP production in HA7 cells.
Several of the compounds had an affinity for, and a
selectivity at, 5-HT1A receptors at least as high as the
prototypical 5-HT1A agonist (()-8-OH-DPAT. Finally,
several compounds appeared to have greater intrinsic
activity at 5-HT1A receptors than (()-8-OH-DPAT.
Serotonin (5-HT) recognizes several, distinct cell-
surface receptors.1 Among these, 5-HT1A receptors, at
which 5-HT has high affinity, have been implicated in
many psychiatric and neurological disorders.2 Clinical
evidence of a link between 5-HT1A receptor function and,
for example, depression is now becoming available.3
However, to represent a significant advance in antide-
pressant therapy, 5-HT1A receptor ligands must achieve
two objectives not yet met by currently available treat-
ments: (1) a fast onset of action and (2) a low percentage
of “non-responders”.4
Our research program in the 5-HT1A area is guided
by the hypothesis that very few, if any, of the ligands
reported so far possess the high level of intrinsic activity
needed to exert rapid and robust antidepressant effects.
Thus, we postulate that a 5-HT1A agonist with an
optimized level of intrinsic activity may offer a more
rapid and effective antidepressant treatment than exist-
ing drugs, including 5-HT1A partial agonists.5 Numer-
ous ligands at 5-HT1A receptors have been identified.6
They can be divided, however, into a small number of
chemical classes. Our effort is aimed at discovering a
structurally novel family of 5-HT1A ligands, assuming
this to be the best approach to obtain 5-HT1A agonists
Ch em istr y
Products of general formula 4 were prepared accord-
ing to the methods depicted in Scheme 1. The Schiff
base 1, obtained by condensation of the commercially
available 4-(aminomethyl)piperidine with the appropri-
ate carboxaldehydes, enabled the secondary amino
group to be selectively acylated. Reduction of the crude
imine 2 with KBH4 in methanol afforded the desired
derivatives 4 (method A). Pyridine-type compounds 4
(X ) N), containing an N-bound 6-substituent (i.e.,
6-alkylamino, 6-dialkylamino, 6-cycloalkylamino, 6-pyr-
rol-1-yl, or 6-imidazol-1-yl), were conveniently prepared
from the 6-halogeno derivative 3 and the appropriate
amine or sodium salt of the amine, via a SNAr at the
last step of the synthesis (method B). The homologues
* Corresponding author. 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/jm9804329 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/07/1998

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5071
Sch em e 1a
Sch em e 4a
a
Conditions: (a) SEMCl, DIEA, CH2Cl2; (b) BzOH, HNa, DMF,
a
Conditions: (a) toluene, 110 °C; (b) ArCOCl, THF, TEA; (c)
40 °C; (c) H2, Raney Ni, EtOH; (d) (CF3SO2)2O, pyridine; (e)
ArB(OH)2, Tl2CO3, Pd(PPh3)4; (f) nBu4NF, THF, HMPA; (g) MnO2,
CH2Cl2, 40 °C.
KBH4, CH3OH; (d) NH3, RNH2, RRNH, EtOH, 100 °C or nitrogen
heterocycles, HNa, DMF, 60 °C.
Sch em e 2a
Sch em e 5a
a
Conditions: (a) Swern oxidation; (b) 2-, 3-, or 4-pyridinylethyl-
amine, PhCH3, 110 °C; (c) KBH4, CH3OH.
Sch em e 3a
a
Conditions: (a) MeONa, MeOH, 25 °C; (b) NH2CH2CH2NH2‚
HCl, EtOH, 80 °C or NH2CH2CH2SH, 130 °C; (c) MeMgBr, THF;
(d) (Me)2NCH(OMe)2, 110 °C; (e) NH2NH2‚H2O, EtOH, 80 °C; (f)
BaMnO4 or NiO2, benzene, 80 °C; (g) HCO2H, H2O, 65 °C.
6-isopropyl-2-pyridinecarboxaldehyde,10 3-(dimethyl-
amino)benzaldehyde,11 and 3-(pyrrol-1-yl)benzalde-
hyde12 used as intermediates in the synthesis of com-
pounds 4, have been prepared as previously reported.
The synthesis of novel aldehydes 8 was carried out as
follows: the enamine formed by condensation of 6-fluoro-
2-picoline and tert-butoxy(dimethylamino)methane13 was
oxidatively cleaved14 by NaIO4 to give the 6-fluoro-2-
pyridinecarboxaldehyde (8a ) (Scheme 3). Protection of
a
Conditions: (a) tBuOCH(NMe2)2, 150 °C; (b) NaIO4, H2O, 25
°C; (c) HOCH2CH2OH, PTSA, PhCH3, 110 °C; (d) HNa, pyrazole,
DMF, 60 °C; (e) HCO2H, H2O, CuSO4, 65 °C.
6 were obtained by reductive amination of aldehydes 5
with the commercially available 2-(aminoethyl)pyridine
(Scheme 2).
Known aldehydes of the type 8 (Schemes 3-7), such
as 2-pyridinepropionaldehyde,7 6-methoxy-2-pyridine-
carboxaldehyde,8 6-phenyl-2-pyridinecarboxaldehyde,9

5072 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Vacher et al.
Sch em e 6a
P h a r m a cology
Binding affinities for the different receptors were
determined by ligand displacement assays using the
conditions summarized in the Experimental Section. 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,
where [C] is the concentration of the radioligand. The
results are expressed as mean pKi values ( SEM of 2-3
independent determinations, each performed in tripli-
cate.
a
Conditions: (a) TOSMIC, K2CO3, MeOH, 65 °C; (b) HCO2H,
H2O, 65 °C.
Sch em e 7a
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
Fargin,24 was commercially obtained from Duke Uni-
versity (Durham, NC). Concentration-effect relation-
ships 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 compounds 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 independent determina-
tions (each performed in triplicate) for all compounds,
except (()-8-OH-DPAT whose values represent the
mean of 5 determinations.
a
Conditions: (a) Na, nBuOH, 100 °C; (b) NaSMe, DMF, 100
°C; (c) NaIO4, MeOH; (d) HCO2H, H2O, 65 °C.
the aldehyde 8a as a dioxolane 7a followed by displace-
ment of the 6-fluoro substituent by the sodium salt of
pyrazole gave 7b. Hydrolysis of the acetal group under
acidic conditions furnished the aldehyde 8b.
The preparation of the 6-heteroaryl-2-pyridinecarbox-
aldehydes 8c-e (Scheme 4) began by protection of the
6-chloro-2-pyridinemethanol15 (9) as a (trimethylsi-
lyl)ethoxymethyl ether 10. Replacement of the 6-chloro
substituent by a hydroxyl group was performed by the
method of Sieburth16 (i.e., formation of the benzyl ether
11 and then hydrogenolysis of the benzyl group leading
to the pyridol 12). Conversion of 12 into the triflate 13
and then Suzuki cross-coupling reaction with the bo-
ronic acid of the appropriate heteroaryl derivatives
yielded compounds 14. Cleavage of the SEM group17
and oxidation of the resulting primary alcohol 15, under
mild conditions (MnO2/CH2Cl2), provided the 6-het-
eroaryl-2-pyridinecarboxaldehydes 8c-e.
The 6-(1,3-dioxolan-2-yl)-2-pyridinecarbonitrile (7f)
(Scheme 5), derived from the known 6-cyano-2-pyridine-
carboxaldehyde,18 was the common starting material in
the synthesis of aldehydes 8h ,k ,l. At first, the nitrile
function of 7f was activated as an imidoyl ether (not
shown in Scheme 5) which, by reaction with ethylene-
diamine or cysteamine, afforded the imidazoline 7i and
thiazoline 7j, respectively. Oxidation of 7i,j19,20 and
cleavage of the acetal group produced the aldehydes
8k ,l. Addition of CH3MgBr on the nitrile 7f gave the
methyl ketone 7g which was converted to the pyrazole
7h using known chemistry.21 Deprotection of the car-
bonyl function of 7h generated the 6-(pyrazol-3-yl)-2-
pyridinecarboxaldehyde (8h ).
Resu lts a n d Discu ssion
(a ) Design of th e P h a r m a cop h or e. At the outset
of the project, we wondered about the role of the indole
nitrogen lone pair of 5-HT in its ability to activate
5-HT1A receptors. However, because of the inaccuracy
in homology modeling methods25 and the lack of knowl-
edge about the conformational landscape of ligand-
receptor complexes,26 we took an approach that avoided
speculations about the protein residues involved and
about the nature of the interactions engaged in the
complex. On the basis of the model of 5-HT1A receptor
activation developed by Weinstein,27 we reasoned that
the intrinsic activity of a 5-HT1A ligand may be related
to the ability of its pharmacophore to stabilize a positive
charge generated on the receptor protein upon agonist
binding. Hence, one way of increasing the intrinsic
activity of a 5-HT1A agonist may be to enhance the
ability of its pharmacophore to stabilize a positive
charge.
According to Weinstein’s model, the protein cation
involved is a soft nitrogen cation derived from a basic
amino acid (i.e., ammonium, imidazolium, or guani-
dinium ion). Since soft nitrogen cations are soluble in
pyridine, which means that enthalpically favorable
interactions occur within N+-pyridine pairs,28 we sug-
gested that a pharmacophore containing a pyridine core
could efficiently stabilize the positive charge generated
on the protein side. Thus, a pyridine appropriately
located in the active site of the receptor could shift the
equilibrium toward its G-protein-coupled state(s).
Having selected pyridine as the core component of the
pharmacophore, our next concern was to find its optimal
position relative to a stronger basic amino function that
could serve as the prime anchoring point of the ligand
inside the receptor protein.27,29 At first, we looked at
Condensation of TOSMIC on the known aldehyde
7m 22 (Scheme 6) gave the derivative 7n .23 Removal of
the protecting group led to the expected aldehyde 8n .
Finally, acetals 7o,p (Scheme 7) were prepared via a
SNAr between the 6-fluoro derivative 7a and the sodium
salt of the appropriate alcohol or thiol. Acetal cleavage
furnished the aldehydes 8o,p . The aldehyde 8q was
obtained by a chemoselective oxidation at the sulfur
atom before the deprotection of the latent aldehyde
function.

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5073
Ta ble 1. Effects of the Py-NH Linker Length and the Chain Orientation on 5-HT1A Affinity
a
See Experimental Section for details. The compound with a pKi value indicated with a smaller than sign (<) has no binding affinity
b
at the given concentration. Each value is the mean ( SEM of three determinations. Two determinations only.
the distance between the pyridine and the secondary
nitrogen atoms in (3,4-dichlorophenyl){[pyridinyl(n-
alkylamino)methyl]piperidin-1-yl}methanones. The
choice of such side chains was motivated by the avail-
ability in our laboratory of the 1-(3,4-dichlorobenzoyl)-
piperidine-4-methanol precursor30 and by its successful
use with various other types of pharmacophores.30,31
From displacement data shown in Table 1, it appears
that unsubstituted 2-pyridinylmethyl, ethyl, and pro-
pylamino derivatives of (3,4-dichlorophenyl)(4-meth-
ylpiperidin-1-yl)methanone (16-18) have affinity for
5-HT1A receptors. When the pyridine is monosubsti-
tuted (R ) H), a two-methylene linkage is the optimum
distance between the pyridine ring and the secondary
amino group (17 compared with 16, 18). However, in
disubstituted pyridine, the nature of the R substituent
influenced affinity only with ligands having a mono-
methylene linker between the pyridine ring and the
amino group. Affinity varied over 1.2 log units for
compounds of the 2-pyridinylmethylamine type (16, 22,
58) and only over 0.4 log unit for ethyl homologues (17,
23, 61). Assuming that for agonists, the elements of
the pharmacophore involved in binding are also involved
in the control of intrinsic activity, a positive relationship
between the affinity and the intrinsic activity is ex-
pected for compounds whose pattern of interactions with
the receptor is homogeneous.32,33 Thus, a 6-substituted-
pyridin-2-ylmethylamine seemed a more suited motif
than a 6-substituted-pyridin-2-ylethylamine to examine
structure-intrinsic activity relationships and was there-
fore used subsequently. Another interesting feature of
a
6-substituted-pyridin-2-ylmethylamine pharmaco-
phore is that the distance between the pyridine nucleus
and the side-chain amino group is less than the distance
required for recognition as predicted by steric models
of 5-HT1A receptors.29 The 2-pyridinylethyl and 2-pyr-
idinylpropylamine homologues (17 and 18, respectively)
of compound 16 can be viewed as open-chain analogues
of aminotetralins or partial ergots.
Apparently, the range of substituents accommodated
in the 6-position of the pyridine ring (25, 34, 58) is much
wider than that in the 4-position (24, 33, 45), even
though C-4 and C-6 may be regarded as isoelectronic.
The 5-HT1A binding affinity of the benzene derivatives
72-74 was significantly lower than that of the pyridine
counterparts 22, 34, and 43 (Table 2) and decreased

5074 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Vacher et al.
Ta ble 2. Comparison of Effects of a Pyridyl versus a Phenyl
Group on 5-HT1A Affinity
The comparison of binding data of compounds 46-
48 (Table 4) indicates that the lipophilicity of the
carbonyl amide substituent is an important property of
that group. On the other hand, the 10-fold gain in
affinity observed with monosubstituted benzamides 50,
53, and 54, compared with the unsubstituted derivative
48, suggested that an accessory hydrophobic effect
occurred between the group in the meta position and
the receptor protein. Moreover, examination of the
benzamide monosubstitution pattern revealed that this
interaction was subjected to strict directional and size
requirements. Substitution in the meta position was
the only one allowed (50 compared to 49, 51), and the
size of the group should be between that of a fluorine
(52) and that of an ethoxy group (55). Finally, it seemed
that there was no electrostatic component contributing
to the meta effect (56). Taking into account the delete-
rious consequences on binding of a para substituent
alone (51), it was puzzling that some meta-para sub-
stituent combinations on the benzamide ring could act
synergistically (58, Table 1, compared to 50). This
synergistic effect was only observed when the substitu-
ent in the para position was not larger than a methyl
group (58, 63, 64 compared to 65, 66). With the
backbone of the ligand now roughly in place, we at-
tempted to refine our understanding of the contribution
of the substituent in the 6-position of the pyridine ring.
a
See footnotes of Table 1.
markedly as the R substituent became larger (72-74).
These results suggest that the pyridine ring contributes
to the binding of the ligand to 5-HT1A receptors.
Moreover, the nitrogen atom of the pyridine may be a
major site of interactions of the pharmacophore with the
receptor protein because the only tolerated orientation
for the side chain was the 2-position of the pyridine (16
and 17 compared to 19 and 20, 21, respectively, Table
1).
(b) In flu en ces of th e Ch a in a n d of th e Ter m in a l
Am id e F u n ction a l Gr ou p . To explore the influence
on binding of the nonpharmacophoric part of the mol-
ecule (i.e., the part other than the 6-R-pyridin-2-ylmeth-
ylamino fragment), we tested diverse representative
chains attached to the 6-(pyrazol-1-yl)-2-pyridinylmeth-
ylamine moiety. Usually, known classes of 5-HT1A
pharmacophores can accommodate various chains with
only minor consequences for their in vitro biological
activities. However, results summarized in Table 3
demonstrate the opposite for derivatives built around
(c) Mod u la tion of th e Su bstitu en t in th e 6-P osi-
tion of th e P yr id in e. Data summarized in Table 5
showed that the R substituent modulated affinity values
over more than 2 orders of magnitude. In general,
electron-withdrawing groups bound poorly to the recep-
tor (22, 31, 38, 39), whereas electron-releasing groups
(n-donors: 28, 30, 32, 34, 36, 37) and particularly
π-donors, such as five-membered heteroaromatic rings
C-bound to pyridine (41, 42, 67, 70, 71), had high
affinity for 5-HT1A sites.34 Qualitatively, the effect of
the R substituent is consistent with what would be
expected if the pharmacophore was acting by stabiliza-
tion of a positive charge on the protein. We assumed
that derivative 27 may combine favorable inductive
donor and steric effects. The size range of the R
substituent was well-delineated, extending from an
upper exclusion limit of four contiguous atoms (29, 35)
to a lower one of two atoms, below which some favorable
hydrophobic interactions may be lost (16, 25, 26).
a
6-substituted-2-pyridinylmethylamine pharmaco-
phore. Besides compound 58 (Table 1), only derivatives
78 and 82 (Table 3) achieved significant affinity for
5-HT1A receptors. In addition, the drop in binding
observed with the open-chain acetylenic derivative 83
and the piperidine regioisomer 85 illustrates the tight
geometric constraints imposed on that part of the
molecule. Compared with the conformationally re-
stricted piperidine (48, 53 in Table 4 and 58 in Table
1), the open-chain molecules 81-83 showed only weak
affinity for the 5-HT1A receptors, indicating they cannot
adopt suitable conformation(s) for optimal binding to the
receptors. In line with these findings, changing the
amide to a sulfonamide group or reducing the carbonyl
oxygen atom of the amide function suppressed binding
affinity (60 and 59, respectively, Table 4). Hence, the
amide function represents a compromise between steric
and conformational factors: the sulfone group being too
sterically hindered, whereas the reduced amide might
suffer a loss of entropic binding energy.
Fortunately, the most active compounds were among
the most selective toward R1 and D2 receptors, the
degree of selectivity being, in general, similar to that of
(()-8-OH-DPAT. Selectivity is important because in-
teractions with other receptors, in particular R1 and D2,
are known to influence the in vivo expression of 5-HT1A
agonist activity.35,36
Derivatives shown in Table 5 displayed pEC50 values
to inhibition of forskolin-stimulated cAMP that differed
by more than 2 log units, reminiscent of the trend seen
with affinity values. Moreover, derivatives having
nanomolar affinity for the receptor also inhibited the
accumulation of cAMP with greater efficacy (Emax) than
(()-8-OH-DPAT (Table 5, footnote). Hence, common
elements of the pharmacophore may participate in
recognition and activation of the 5-HT1A receptor.
Again, compounds containing a C-bound five-membered

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5075
Ta ble 3. Effects of the Nature of the Chain on 5-HT1A Affinity
a,b
d
See footnotes of Table 1. c Experimental Section. Oxalate. e Fumarate. f Maleate.
heteroaromatic ring substituent emerged as especially
potent (pEC50): 41, 42, 67, 70, and 71. Interestingly,
the two exceptions in this subset were the 6-pyrrol-2-yl
and the 6-imidazol-2-yl derivatives 44 and 69, respec-
tively. Their modest in vitro profiles compared with
that of the close analogue 67 suggest that the hydrogen-
bonding ability of the group in the 2′-position of the five-
membered ring pyridine substituent may be one of the
factors influencing the affinity and the potency of
compounds belonging to this subset. This group was a
hydrogen-bond donor in 44 and 69 but a hydrogen-bond
acceptor in 67.37
Taken together, the in vitro results pointed to a
C-bound five-membered heteroaromatic ring as the
6-substituent of choice for pyridine, although some
6-amino derivatives also deserve consideration (32, 34,
36). However, it still remains unclear which properties
of the 6-substituted-2-pyridinylmethylamine system
(e.g., hydrogen-bonding ability, charge-transfer or chelat-
ing potentials, etc.) determine intrinsic activity.
The novel 5-HT1A ligands described here were found
to have high intrinsic activity, and because of the
hypothesized importance of intrinsic activity in the
antidepressant effect of 5-HT1A agonists, future studies
will examine their effects in vivo.
Con clu sion s
In this paper, we summarized briefly the pharmaco-
logical rationale that prompted the search for novel,
potent, and efficacious 5-HT1A agonists. We then de-
scribed the basic concept that guided the design of a
structurally novel 5-HT1A pharmacophore. Importantly,
the approach adopted did not rely on assumptions
concerning the geometry of the receptor protein. Fi-
nally, we reported the preparation of various novel
compounds and discussed their preliminary in vitro
pharmacological properties.
Taken together, the results show that this novel class
of ligands is characterized by a high binding affinity for
5-HT1A receptors and a high selectivity versus R1 and

5076 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Vacher et al.
Ta ble 4. Effects of the Nature of the N-Piperidine Substituent on 5-HT1A Affinity
a,b
See footnotes of Table 1.
D2 receptors. Several members of this class behave in
vitro as more potent inhibitors of forskolin-induced
cAMP accumulation than the prototypical agonist (()-
8-OH-DPAT. From a structural standpoint, the 6-sub-
stituted-2-pyridinylmethylamine motif was used in an
effort to obtain a novel 5-HT1A pharmacophore. The
importance of the 6-substituent on the pyridine nucleus
in the recognition and activation of 5-HT1A receptors
was established. In addition, examples were given of
the unexpected sensitivity of 5-HT1A binding to the
structural integrity of the entire molecule. The very
interesting in vitro profile of the most active derivatives
warrants a further examination of their properties in
biochemical and behavioral studies. Already, these
derivatives and their analogues may provide innovative
tools that could contribute to the further characteriza-
tion of 5-HT1A receptors and, perhaps, to a better
understanding of their functional roles and therapeutic
significance.
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 spectropho-
tometer. 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. (3,4-Dich lor op h en yl)(4-{[(6-flu or op yr id in -
2-ylm eth yl)am in o]m eth yl}piper idin -1-yl)m eth an on e (22).
A solution of 8a (0.58 g, 4.62 mmol), 4-(aminomethyl)piperidine
(0.53 g, 4.62 mmol), and toluene (25 mL) was heated under
reflux for 2 h with water separation by a Dean-Stark trap.
The solvent was removed under vacuum, and the residue was
taken up in THF (10 mL) and TEA (0.68 mL, 4.9 mmol). To

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5077
Ta ble 5. Receptor Binding Profile and Agonist Activity of Compounds of the Type
(3,4-Dichlorophenyl)(4-{[(6-substituted-pyridin-2-ylmethyl)amino]methyl}piperidin-1-yl)methanone
a,b
See footnotes of Table 1. c See Experimental Section for details. Each value is the mean ( SEM of two independent determinations,
d
each performed in triplicate. Mean ( SEM of five determinations. NT, not tested. Forskolin-stimulated cAMP levels in HA7 cells were
inhibited by (()-8-OH-DPAT (Emax ) 71 ( 4.3%) and to a greater extent (Emax > 80%) by all the other compounds (data not shown).

5078 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Vacher et al.
Ta ble 6. Physical Data of Substituted-4-[(pyridinylalkylamino)methyl]piperidines

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5079
Ta ble 6 (Continued)
a
b
d
The analyses for all compounds were within 0.4% of the theoretical value for C, H, and N. Maleate. c Oxalate. Fumarate.
Ta ble 7. Experimental Details for Each of the Binding Assays
[3H]ligand
tissue (rat)
incubation
nonspecific binding
drug concn (µM) buffer
binding site
KD (nM)
concn (nM)
0.2
type
concn (mg/mL) time (min) temp (°C)
b
5-HT1A
8-OH-DPAT
(3.1)
cortex
10
1
30
60
30
23
23
23
5-HT
10
A
B
C
c
D2
YM-09151-2
(0.036)
prazosin
(0.063)
0.05
0.1
striatum
cortex
(+)-butaclamol
1
b
R1
5
phentolamine
50
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 40. c Reference 41.
b

5080 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Vacher et al.
this cooled solution (ice bath) was added 3,4-dichlorobenzoyl
chloride (0.68 g, 4.62 mmol) in THF (2 mL), and stirring was
continued at room temperature for 2 h. Methanol (10 mL) was
added followed by KBH4 (0.50 g, 9.27 mmol), and stirring was
continued at room temperature for 4 h. The mixture was
concentrated, taken up in CH2Cl2, washed with water and
brine, dried, and concentrated. Purification by flash chroma-
tography (5% MeOH-CH2Cl2) gave 0.73 g (40%) of 22 as a
pale-yellow solid: mp 77-79 °C. The oxalate salt of 22 was
crystallized from MeOH-EtOAc to afford a white solid (0.65
g): mp 182-184 °C; 1H NMR (DMSO-d6) δ 1.19 (m, 2H), 1.90
(m, 3H), 2.85 (m, 3H), 3.04 (m,1H), 3.47 (s, 1H), 4.24 (s, 2H),
4.39 (m, 1H), 7.20 (dd, 1H), 7.36 (dd, 1H), 7.48 (dd, 1H), 7.70
(m, 2H), 8.05 (dd, 1H), 8.15 (s, broad, 2H). Anal. (C19H20Cl2-
FN3O‚C2H2O4) C, H, N.
tion of the amide 58 (0.70 g, 1.57 mmol) in THF (5 mL) was
added over 15 min to a suspension of LiAlH4 (90 mg, 2.37
mmol) in THF (10 mL) maintained at 0 °C. Stirring was
continued for 18 h at room temperature; then the reaction was
quenched by addition of H2O and 1 N NaOH. The mixture
was filtered through Celite and the solid washed with THF.
The filtrate was evaporated to dryness and then the residue
taken up in CH2Cl2, dried, and concentrated. The product was
purified by flash chromatography (10% MeOH-CH2Cl2) to give
0.30 g (44%) of 59 as a pale-yellow oil. The fumarate salt was
crystallized from EtOH to afford a white solid (0.33 g): mp
201-203 °C; 1H NMR (DMSO-d6) δ 1.23 (m, 2H), 1.77 (m, 3H),
1.99 (t, 2H), 2.76 (m, 4H), 3.50 (s, 2H), 4.22 (s, 2H), 6.52 (s,
2H), 6.57 (t, 1H), 7.27 (dd, 1H), 7.38 (d, 1H), 7.53 (m, 2H), 7.83
(d, 2H), 7.99 (t, 1H), 8.82 (d, 1H). Anal. (C22H25Cl2N5‚
2C4H4O4) C, H, N.
Met h od B1. (3,4-Dich lor op h en yl)(4-{[(6-a zet id in -1-
ylpyr idin -2-ylm eth yl)am in o]m eth yl}piper idin -1-yl)m eth -
a n on e (36). A solution of 22 (0.70 g, 1.77 mmol), THF (10
mL), and azetidine (0.20 g, 3.54 mmol) was heated at 100 °C
for 17 h. After cooling to room temperature, the mixture was
concentrated under vacuum, and water was added. The
product was extracted with CH2Cl2, washed with water and
brine, dried, filtered, and evaporated under reduced pressure.
The residue was purified by flash chromatography (10%
MeOH-CH2Cl2) to give 0.40 g (52%) of 36 as a pale-yellow
oil. The oxalate salt of 36 was crystallized from EtOH-EtOAc
to give a white solid (0.35 g): mp 219-221 °C; 1H NMR
(DMSO-d6) δ 1.19 (m, 2H), 1.80 (m, 2H) 2.00 (m, 1H), 3.35 (m,
2H), 2.75 (m, 1H), 2.88 (d, 2H), 3.04 (m, 1H), 3.49 (m, 1H),
3.95 (t, 4H), 4.09 (s, 2H), 4.39 (m, 1H), 6.31 (d, 1H), 6.68 (d,
1H), 7.35 (dd, 1H), 7.53 (t, 1H), 7.65 (d, 1H), 7.70 (d, 1H). Anal.
(C22H26Cl2N4O‚C2H2O4) C, H, N.
Meth od E. [1-(3,4-Dich lor op h en ylsu lfon yl)p ip er id in -
4-ylm eth yl](6-p yr a zol-1-ylp yr id in -2-ylm eth yl)a m in e (60).
This product was prepared from aldehyde 8b, 4-(aminometh-
yl)piperidine, and 3,4-dichlorobenzenesulfonyl chloride as
described for compound 22. Purification by flash chromatog-
raphy (5% MeOH-CH2Cl2) followed by salt formation with
fumaric acid gave the fumarate salt of 60 as a white solid
1
(35%): mp 199-201 °C; H NMR (DMSO-d6) δ 1.18 (m, 2H),
1.57 (m, 1H), 1.80 (d, 2H), 2.32 (t, 2H), 2.55 (d, 2H), 3.63 (d,
2H), 3.96 (s, 2H), 6.55 (s, 2H), 6.57 (d, 1H), 7.35 (d, 1H), 7.69
(dd, 1H), 7.77 (m, 2H), 7.94 (m, 3H), 8.70 (d, 1H). Anal.
(C21H23Cl2N5O2S‚C4H4O4) C, H, N.
1-(3,4-Dich lor oben zoyl)p ip er id in e-4-ca r boxa ld eh yd e
(5). To a solution of oxalyl chloride (2.72 mL, 31 mmol) in
CH2Cl2 (50 mL), cooled to -70 °C, was added DMSO (4.1 mL,
58 mmol) dropwise. Stirring was continued at -60 °C for 10
min followed by addition of a solution of (3,4-dichlorophenyl)[4-
(hydroxymethyl)piperidin-1-yl]methanone30 (7.50 g, 26 mmol)
in CH2Cl2 (20 mL). The reaction mixture was stirred for 1 h
at -60 °C; then DIEA (18 mL, 104 mmol) was added dropwise
and the temperature allowed to reach to room temperature.
Water was added, and the organic layer was washed with 1 N
HCl, water, and brine, dried, filtered, and concentrated.
Purification by flash chromatography (30% EtOAc-CH2Cl2)
Meth od B2. (3,4-Dich lor op h en yl)(4-{[(6-p yr r ol-1-yl-
p yr id in -2-ylm eth yl)a m in o]m eth yl}p ip er id in -1-yl)m eth -
a n on e (43). To a solution of pyrrole (0.45 g, 6.70 mmol) in
anhydrous DMF (5 mL), under a nitrogen atmosphere, was
added NaH (60% oil dispersion, 0.27 g, 6.75 mmol). After the
mixture stirred at room temperature for 1 h, a solution of 22
(1.32 g, 3.33 mmol) in DMF (2 mL) was added, and the mixture
was stirred at 60 °C for 2 h. The cooled solution was poured
into ice-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 (5% MeOH-CH2Cl2) gave an oily residue
which on trituration with Et2O gave 43 as a pale-yellow solid
(0.85 g; 57%): mp 108-110 °C. The hemifumarate salt of 43
was crystallized from EtOH-EtOAc to give a white solid: mp
1
gave 5.65 g (76%) of 5 as a white solid: mp 101-103 °C; H
NMR (CDCl3) δ 1.65 (m, 2H), 1.95 (m, 2H), 2.54 (m, 1H), 3.13
(m, 2H), 3.68 (m, 1H), 4.35 (m, 1H), 7.18 (dd, 1H), 7.46 (m,
2H), 9.66 (s, 1H); IR (KBr, cm-1) 1640, 1732. Anal. (C13H13
Cl2NO2) C, H, N.
-
6-F lu or o-2-p yr id in eca r boxa ld eh yd e (8a ). A solution of
6-fluoro-2-picoline (20 g, 0.18 mol) and tert-butoxybis(dimeth-
ylamino)methane (47 g, 0.27 mol) was heated, under a nitrogen
atmosphere, at 140 °C for 24 h. The cooled reaction mixture
was diluted with THF (100 mL), and a solution of NaIO4 (77
g, 0.36 mol) in water (400 mL) was added. The mixture was
stirred overnight at room temperature; then the precipitate
was filtered off. THF was removed under vacuum, and the
product was extracted with CH2Cl2. The organic layer was
washed with brine, dried, and filtered. The solution was
carefully concentrated (the boiling point of the product is low),
and the residual brown oil was submitted to distillation to give
7.40 g (33%) of 8a as a pale-yellow oil: bp 65-70 °C (80 mb);
1H NMR (CDCl3) δ 7.16 (dd, 1H), 7.82 (dd, 1H), 7.96 (m, 1H),
9.90 (s, 1H); IR (film, cm-1) 1713.
6-F lu or o-2-(1,3-d ioxola n -2-yl)p yr id in e (7a ). A solution
of 8a (7.40 g, 59 mmol), ethanediol (11.2 mL, 180 mmol), and
p-toluenesulfonic acid monohydrate (0.25 g) in benzene (80 mL)
was heated under reflux for 18 h with water separation by a
Dean-Stark trap. The solvent was removed under vacuum
and the residue taken up in Et2O and washed with 10%
NaHCO3 solution and then brine. The organic layer was dried
and filtered, and the solvent was removed under reduced
pressure. The oily residue was distilled to give 8 g (80%) of
7a as a pale-yellow oil: bp 75-80 °C (0.1 mb); 1H NMR (CDCl3)
δ 4.05 (m, 2H), 4.16 (m, 2H), 5.77 (s, 1H), 6.90 (dd, 1H), 7.39
(dd, 1H), 7.79 (dd, 1H).
1
174-176 °C; H NMR (CDCl3) δ 1.12 (m, 2H), 1.81 (m, 3H),
2.60 (m, 2H), 2.94 (s, 1H), 3.60 (m, 2H), 3.95 (s, 2H), 4.59 (s,
1H), 6.25 (t, 2H), 6.65 (s, 1H), 7.01 (d, 1H), 7.14 (m, 2H), 7.39
(m, 4H), 7.64 (t, 1H). Anal. (C23H24Cl2N4O‚0.5C4H4O4) C, H,
N.
Meth od C. (3,4-Dich lor op h en yl){4-[(2-p yr id in -4-yleth -
yla m in o)m eth yl]p ip er id in -1-yl}m eth a n on e (21). A solu-
tion of 5 (0.80 g, 2.80 mmol), 4-(2-aminoethyl)pyridine (0.34
g, 2.80 mmol), and toluene (30 mL) was heated under reflux
for 2 h with water separation by a Dean-Stark trap. The
solvent was removed under vacuum and then the residue
taken up in MeOH (30 mL) and cooled to 0-5 °C, and KBH4
(0.30 g, 5.6 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, dried, filtered, and concentrated under vacuum to give
a yellow oil. Purification by flash chromatography (10%
MeOH-CH2Cl2) afforded 0.64 g (58%) of 21 as a pale-yellow
oil. The fumarate salt of 21 was crystallized from EtOH-
EtOAc to give a white solid (0.55 g): mp 149-151 °C; 1H NMR
(DMSO-d6) δ 1.34 (m, 2H), 1.75 (m, 1H), 1.95 (m, 1H), 2.14
(m, 1H), 2.90-3.25 (m, 4H), 2.33-3.54 (m, 4H), 3.74 (m, 1H),
4.53 (m, 1H), 6.60 (s, 3H), 7.32 (dd, 1H), 7.60 (d, 1H), 7.64 (d,
1H), 7.95 (d, 2H), 8.71 (d, 2H). Anal. (C20H23Cl2N3O‚
1.5C4H4O4) C, H, N.
Meth od D. [1-(3,4-Dich lor oben zyl)p ip er id in -4-ylm eth -
6-P yr a zolo-2-(1,3-d ioxola n -2-yl)p yr id in e (7b). To a sus-
yl](6-p yr a zol-1-ylp yr id in -2-ylm eth yl)a m in e (59). A solu-
pension of HNa (60% dispersion in mineral oil, 7 g, 0.174 mol)

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5081
in anhydrous DMF (50 mL) under a nitrogen atmosphere was
added dropwise a solution of pyrazole (11.85 g, 0.174 mol) in
DMF (55 mL). After 2 h, 7a (9.81 g, 0.058 mol) was added
dropwise, and the mixture was stirred at 80 °C for 3 h. 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
vacuum. The product was purified by flash chromatography
(20% EtOAc-hexane) to give 9.50 g (75%) of 7b as a pale-
yellow oil: 1H NMR (CDCl3) δ 4.10 (m, 2H), 4.22 (m, 2H), 5.87
(s, 1H), 6.45 (dd, 1H), 7.43 (dd, 1H), 7.73 (d, 1H), 7.86 (t, 1H),
7.98 (dd, 1H), 8.62 (d, 1H).
(CH2Cl2) gave 4.30 g (75%) of 13 as a colorless oil: 1H NMR
(CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H), 3.66 (t, 2H), 4.68 (s, 2H),
4.80 (s, 2H), 7.05 (d, 1H), 7.52 (d, 1H), 7.87 (t, 1H).
2-[6-[2-(Tr im eth ylsila n yl)eth oxym eth oxym eth yl]p yr -
idin -2-yl]pyr r ole-1-car boxylic Acid ter t-Bu tyl Ester (14c).
To a degassed solution of 13 (4 g, 10.3 mmol) in benzene (40
mL) were added Tl2CO3 (9.68 g, 20.6 mmol), Pd [P(C6H5)3]4 (1
g, 0.86 mmol), and [1-(tert-butoxycarbonyl)pyrrol-2-yl]boronic
acid38 (2.45 g, 11.6 mmol). After stirring at room temperature
for 23 h, the mixture was filtered and the filtrate concentrated
under reduced pressure. The oily residue was purified by flash
chromatography (1% EtOAc-CH2Cl2) to give 3.75 g (90%) of
14c as a pale-yellow oil: 1H NMR (CDCl3) δ 0.00 (s, 9H), 0.94
(t, 2H), 1.32 (s, 9H), 3.67 (t, 2H), 4.73 (s, 2H), 4.82 (s, 2H),
6.21 (t, 1H), 6.37 (m, 1H), 7.27 (d, 1H), 7.32 (m, 1H), 7.34 (d,
1H), 7.68 (t, 1H).
6-P yr a zol-1-ylp yr id in e-2-ca r boxa ld eh yd e (8b). A mix-
ture of 7b (9.50 g, 43.7 mmol), CuSO4‚5H2O (1.09 g, 4.37
mmol), formic acid (80 mL), and water (20 mL) was stirred at
65 °C for 5 h. The solution was concentrated under vacuum,
and the residual formic acid was eliminated by azeotropric
distillation with toluene. The oil was taken up in ice-water
and made basic with excess K2CO3. The product was extracted
with EtOAc, washed with diluted NH4OH and brine, dried,
and concentrated under vacuum. The product was isolated
by flash chromatography (10% EtOAc-CH2Cl2) to give 6 g
(79%) of 8b as a pale-yellow solid: mp 75-76 °C; 1H NMR
(CDCl3) δ 6.52 (dd, 1H), 7.78 (s, 1H), 7.84 (dd, 1H), 7.99 (t,
6-(1H-P yr r ol-2-yl)p yr id in e-2-m eth a n ol (15c). To a solu-
tion of (nC4H9)4NF (1.10 M THF solution, 3 mL), anhydrous
THF (45 mL), HMPA (5 mL), and 4-Å molecular sieves (10 g)
was added 14c (3 g, 7.41 mmol). The mixture was stirred at
room temperature under argon for 8 h. Insoluble materials
were filtered off, and the solvent was removed under vacuum.
Purification by flash chromatography (1% EtOAc-CH2Cl2)
1
gave 0.51 g (39%) of 15c as a white solid: mp 73-75 °C; H
1H), 8.23 (dd, 1H), 8.67 (d, 1H), 10.04 (s, 1H); IR (KBr, cm-1
1701. Anal. (C9H7N3O) C, H, N.
)
NMR (CDCl3) δ 3.61 (s, 1H), 4.74 (s, 2H), 6.30 (dd, 1H), 6.75
(m, 1H), 6.92 (m, 1H), 6.98 (d, 1H), 7.45 (d, 1H), 7.62 (t, 1H),
9.56 (s, 1H). Anal. (C10H10N2O) C, H, N.
2-Ch lor o-6-[2-(tr im eth ylsila n yl)eth oxym eth oxym eth -
yl]p yr id in e (10). To a solution of 6-chloro-2-pyridinemeth-
anol15 (2.50 g, 17.4 mmol), DIEA (3.30 mL, 19.1 mmol). and
CH2Cl2 (20 mL), under nitrogen atmosphere and cooled to 0
°C, was added (trimethylsilyl)ethoxychloromethyl ether (3.20
mL, 18.2 mmol). Stirring was continued at room temperature
for 3 h. The solvent was evaporated and the oil extracted with
Et2O, washed with water, dried, filtered, and evaporated to
dryness. The product was purified by flash chromatography
(CH2Cl2) to give 3.65 g (76.6%) of 10 as a colorless oil: 1H NMR
(CDCl3) δ 0.00 (s, 9H), 0.95 (t, 2H), 3.68 (t, 2H), 4.67 (s, 2H),
4.80 (s, 2H), 7.24 (d, 1H), 7.35 (d, 1H), 7.64 (t, 1H).
2-(Ben zyloxy)-6-[2-(tr im eth ylsila n yl)eth oxym eth oxy-
m eth yl]p yr id in e (11). To a suspension of HNa (60% disper-
sion in mineral oil, 0.91 g, 22.6 mmol) in DMF (20 mL) at 0
°C and under a nitrogen atmosphere was added dropwise a
solution of benzyl alcohol (2.10 mL, 19.9 mmol) in DMF (3 mL).
Stirring was continued for 1.5 h at 0 °C, and a solution of 10
(3.65 g, 13.3 mmol) in DMF (3 mL) was added dropwise. The
reaction mixture was heated at 40 °C for 12 h, cooled to room
temperature, poured in ice-water, and extracted with Et2O.
The combined extracts were washed with water, dried, and
filtered, and the solvent was evaporated to dryness. The crude
product was purified by flash chromatography (40% hexane-
CH2Cl2) to give 3 g (65%) of 11 as a colorless oil: 1H NMR
(CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H), 3.67 (t, 2H), 4.61 (s, 2H),
4.80 (s, 2H), 5.35 (s, 2H), 6.66 (d, 1H), 6.97 (d, 1H), 7.34 (m,
3H), 7,42 (m, 2H), 7.54 (t, 1H).
2-Hydr oxy-6-[2-(tr im eth ylsilan yl)eth oxym eth oxym eth -
yl]p yr id in e (12). To a solution of 11 (7 g, 20.26 mmol) in
EtOH saturated with hydrogen chloride (75 mL) was added
Raney nickel (7 g). The suspension was stirred at room
temperature under hydrogen atmosphere for 1.5 h. The
catalyst was filtered off through Celite and then the solvent
removed under vacuum. The product was isolated by flash
chromatography to give 4 g (76.8%) of 12 as a pale-yellow oil:
1H NMR (CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H), 3.61 (t, 2H), 4.50
(s, 1H), 4.75 (s, 2H), 6.21 (d, 1H), 6.47 (d, 1H), 7.36 (d, 1H),
7.41 (d, 1H), 12.28 (s, 1H).
Tr iflu or om eth a n esu lfon ic Acid 6-[2-(Tr im eth ylsila n -
yl)et h oxym et h oxym et h yl]p yr id in -2-yl E st er (13). To a
solution of 12 (3.80 g, 14.8 mmol) and DMAP (0.10 g, 0.82
mmol) in pyridine (35 mL) at 0 °C was added dropwise
(CF3SO2)2O (2.63 mL, 14.9 mmol). After stirring for 2 h at 0
°C, the mixture was poured into ice-water and extracted with
Et2O. The combined organic layers were washed with an
aqueous KHSO4 solution and water, dried, filtered, and
evaporated to dryness. Purification by flash chromatography
6-(Th ien -2-yl)p yr id in e-2-m eth a n ol (15d ). Prepared as
15c from 13 and commercially available thien-2-ylboronic acid.
Purification by flash chromatography (10% EtOAc-CH2Cl2)
gave 15d as a yellow oil (45%): 1H NMR (CDCl3) δ 3.7 (s, 1H),
4.65 (s, 2H), 7.10 (dd, 1H), 7.35 (m, 2H), 7.66 (m, 2H), 7.85
(m, 1H).
6-(F u r a n -2-yl)p yr id in e-2-m eth a n ol (15e). Prepared as
15c from 13 and commercially available furan-2-ylboronic acid.
Purification by flash chromatography (10% EtOAc-CH2Cl2)
gave 15e as a yellow oil (56%): 1H NMR (CDCl3) δ 3.99 (s,
1H), 4.74 (s, 2H), 6.50 (dd, 1H), 7.06 (m, 2H), 7.49 (d, 1H),
7.56 (d, 1H), 7.67 (t, 1H).
6-(1H-P yr r ol-2-yl)p yr id in e-2-ca r boxa ld eh yd e (8c). To
a solution of 15c (0.30 g, 1.72 mmol) and anhydrous CH2Cl2
(3 mL) was added MnO2 (0.75 g, 8.61 mmol), and the suspen-
sion was stirred under reflux for 1 h. Insoluble materials were
filtered, and the solvent was removed under vacuum. Puri-
fication by flash chromatography (CH2Cl2) afforded 0.20 g
(66%) of 8c as a white solid: mp 112-113 °C; 1H NMR (CDCl3)
δ 6.31 (dd, 1H), 6.77 (m, 1H), 6.95 (m, 1H), 7.63-7.81 (m, 3H),
9.67 (s, 1H), 10.03 (s, 1H); IR (KBr, cm-1) 1701. Anal.
(C10H8N2O) C, H, N.
6-(Th ien -2-yl)p yr id in e-2-ca r boxa ld eh yd e (8d ): mp 48-
1
50 °C; H NMR (CDCl3) δ 7.15 (dd, 1H), 7.46 (dd, 1H), 7.69
(dd, 1H), 7.78-7.88 (m, 3H), 10.16 (s, 1H); IR (KBr, cm-1) 1714.
Anal. (C10H7NOS) C, H, N.
6-(F u r a n -2-yl)p yr id in e-2-ca r boxa ld eh yd e (8e): mp 46-
1
48 °C; H NMR (CDCl3) δ 6.55 (q, 1H), 7.16 (d, 1H), 7.55 (d,
1H), 7.82 (m, 3H), 10.07 (s, 1H); IR (KBr, cm-1) 1717. Anal.
(C10H7NO2) C, H, N.
2-(4,5-Dih yd r ot h ia zol-2-yl)-6-(1,3-d ioxola n -2-yl)p yr i-
d in e (7i). A solution of 2-(1,3-dioxolan-2-yl)-6-cyanopyridine18
(2 g, 11.35 mmol), methanol (10 mL), and sodium methoxide
(0.20 g, 3.70 mmol) was stirred at room temperature for 24 h.
The solvent was distilled, and the residue was taken up in
EtOAc, washed with brine, dried, filtered, and concentrated
under vacuum. The crude imidate (1 g, 4.80 mmol) was mixed
with 2-aminoethanethiol (0.47 g, 6.10 mmol) and heated at
130 °C for 1.5 h. The cooled mixture was taken up in CH2Cl2,
washed with water, dried, filtered, and concentrated. Purifi-
cation by flash chromatography (2% MeOH-CH2Cl2) gave 1.10
1
g (97%) of 7i as a pale-yellow solid: mp 55-57 °C; H NMR
(CDCl3) δ 3.36 (t, 2H), 4.15 (m, 4H), 4.55 (t, 2H), 5.91 (s, 1H),
7.60 (dd, 1H), 7.81 (t, 1H), 8.03 (dd, 1H). Anal. (C11H12N2O2S)
C, H, N.
2-(1H-Im idazolin -2-yl)-6-(1,3-dioxolan -2-yl)pyr idin e (7j).
Prepared from 7f and ethylenediamine (55%): 1H NMR

5082 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Vacher et al.
(CDCl3) δ 4.10 (m, 8H), 5.82 (s, 1H), 6.03 (s, 1H), 7.56 (dd,
6-(Meth ylth io)-2-(1,3-d ioxola n -2-yl)p yr id in e (7p ).
A
mixture of 7a (1.36 g, 5.91 mmol), NaSCH3 (0.83 g, 11.82
mmol), and DMF (4 mL) was heated at 100 °C for 18 h. The
cooled mixture was diluted with ice-water and extracted with
EtOAc. The combined organic layers were washed with 1 N
NaOH and water, dried, and filtered, and the solvent was
removed under vacuum to give 0.85 g (73%) of 7p as a yellow
oil: 1H NMR (CDCl3) δ 2.56 (s, 3H), 4.03-4.20 (m, 4H), 5.82
(s, 1H), 7.16 (t, 2H), 7.50 (t, 1H).
1H), 7.78 (t, 1H), 8.10 (dd, 1H).
2-(Th ia zol-2-yl)-6-(1,3-d ioxola n -2-yl)p yr id in e (7k ).
A
solution of 7i (1.33 g, 5.62 mmol) in benzene (50 mL) was
treated with NiO2 (hydrate, 10 g in 10 portions) while the
reaction mixture was heated under reflux for 20 h with
elimination of water with a Dean-Stark trap. The cooled
reaction mixture was filtered through Celite, and the filtrate
was concentrated under vacuum. The crude product was
purified by flash chromatography (15% EtOAc-CH2Cl2) to give
6-(Meth ylsu lfin yl)-2-(1,3-d ioxola n -2-yl)p yr id in e (7q).
To a solution of NaIO4 (0.72 g, 3.36 mmol) in water (15 mL)
and maintained at 0 °C was added dropwise a solution of 7p
(0.60 g, 3.04 mmol) in methanol (10 mL). The mixture was
allowed to stir at room temperature for 18 h. The methanol
was removed under vacuum; the residue was taken up in water
and extracted with CH2Cl2. The combined extracts were
washed with water and brine, dried, and filtered, and the
solvent was removed under vacuum. The product was purified
by flash chromatography (50% EtOAc-CH2Cl2) to give 0.48 g
(67%) of 7q as a pale-yellow oil: 1H NMR (CDCl3) δ 2.82 (s,
3H), 4.01-4.18 (m, 4H), 5.79 (s, 1H), 7.58 (dd, 1H), 7.97 (m,
2H).
6-(Meth ylth io)p yr id in e-2-ca r boxa ld eh yd e (8p ). Pre-
pared from 7p and obtained as a yellow oil (45%): 1H NMR
(CDCl3) δ 2.62 (s, 3H), 7.37 (dd, 1H), 7.60 (m, 2H), 9.99 (s,
1H); IR (film, cm-1) 1709.
6-(Meth ylsu lfin yl)pyr idin e-2-car boxaldeh yde (8q). Pre-
pared from 8q and obtained as a pale-yellow oil (60%): 1H
NMR (CDCl3) δ 2.92 (s, 3H), 8.02 (dd, 1H), 8.14 (t, 1H), 8.27
(dd, 1H), 10.03 (s, 1H); IR (film, cm-1) 1710.
1
0.42 g (31%) of 7k as a white solid: mp 70-72 °C; H NMR
(CDCl3) δ 4.16 (m, 4H), 5.91 (s, 1H), 7.42 (d, 1H), 7.54 (dd,
1H), 7.81 (d, 1H), 7.89 (t, 1H), 8.17 (dd, 1H).
2-(1H-Im id a zol-2-yl)-6-(1,3-d ioxola n -2-yl)p yr id in e (7l).
Prepared from 7j using BaMnO4 as oxidant to give after
purification by flash chromatography (5% MeOH-CH2Cl2) 7l
as a yellow gummy solid (68%): 1H NMR (CDCl3) δ 2.24 (s,
1H), 4.12 (m, 4H), 5.83 (s, 1H), 7.09 (s, 1H), 7.18 (s, 1H), 7.44
(dd, 1H), 7.78 (t, 1H), 8.11 (dd, 1H).
6-(Th ia zol-2-yl)p yr id in e-2-ca r boxa ld eh yd e (8k ). Pre-
pared from 7k and obtained as a white solid (78%): mp 90-
1
92 °C; H NMR (CDCl3) δ 7.48 (d, 1H), 7.96 (m, 3H), 8.38 (m,
1H), 10.09 (s, 1H); IR (KBr, cm-1) 1705. Anal. (C9H6N2OS)
C, H, N.
6-(1H -Im id a zol-2-yl)p yr id in e-2-ca r b oxa ld eh yd e (8l).
Prepared from 7l and obtained as a yellow solid (34%): mp
1
147-149 °C; H NMR (CDCl3) δ 7.23 (m, 2H), 7.89 (m, 2H),
8.37 (dd, 1H), 10.05 (s, 1H), 10.77 (s, 1H). Anal. (C9H7N3O)
C, H, N.
1-[6-(1,3-Dioxola n -2-yl)p yr id in -2-yl]eth a n on e (7g). To
a solution of 7f (0.88 g, 4.99 mmol) in anhydrous THF (10 mL),
under an argon atmosphere and cooled at -10 °C, was added
a solution of methylmagnesium bromide (3 M in Et2O, 3.5 mL,
10.5 mmol). After stirring at room temperature for 3 h, the
mixture was quenched with a saturated aqueous ammonium
chloride solution and vigorously stirred at room temperature
for 30 min. The mixture was extracted with EtOAc, washed
with brine, dried, and filtered, and the solvent was evaporated
under vacuum. Purification by flash chromatography (CH2Cl2)
gave 0.80 g (83%) of 7g as a yellow oil: 1H NMR (CDCl3) δ
2.72 (s, 3H), 4.15 (m, 4H), 5.89 (s, 1H), 7.70 (dd, 1H), 7.86 (t,
1H), 8.01 (dd, 1H); IR (film, cm-1) 1700.
2-(1H-P yr a zol-3-yl)-6-(1,3-d ioxola n -2-yl)p yr id in e (7h ).
A solution of 7g (0.80 g, 4.14 mmol) and DMF dimethyl acetal
(1 mL, 7.53 mmol) was heated under reflux for 12 h. Excess
DMF acetal was removed under vacuum, and the residual oil
was taken up in EtOH (5 mL). Hydrazine hydrate (0.80 mL,
25.7 mmol) was added, and the solution was heated under
reflux for 10 min. The solvent was evaporated, and water was
added. The mixture was extracted with EtOAc, washed with
water, dried, filtered, and distilled under vacuum. Purification
by flash chromatography (2% MeOH-CH2Cl2) gave 0.65 g
(72%) of 7h as a yellow gum: 1H NMR (CDCl3) δ 4.15 (m, 4H),
5.90 (s, 1H), 6.80 (d, 1H), 7.48 (dd, 1H), 7.65 (d, 1H), 7.76 (m,
2H), 11.23 (s, 1H).
6-n -Bu toxy-2-(1,3-d ioxola n -2-yl)p yr id in e (7o). To a so-
lution of Na (0.30 g, 0.013 atg) in n-butanol (3 mL) was added
7a (0.91 g, 5.39 mmol), and the mixture was heated at 100 °C
for 18 h. After cooling to room temperature, the mixture was
diluted with water and extracted with EtOAc. The organic
layer was washed with water and brine, dried, and filtered,
and the solvent was removed under vacuum. Residual n-
butanol was removed by azeotropic distillation with cyclohex-
ane to give 1.08 g (90%) of 7o as a yellow oil: 1H NMR (CDCl3)
δ 0.96 (t, 3H), 1.40-1.80 (m, 4H), 4.13 (m, 4H), 4.31 (t, 2H),
5.77 (s, 1H), 6.69 (d, 1H), 7.06 (d, 1H), 7.57 (dd, 1H).
6-n -Bu toxyp yr id in e-2-ca r boxa ld eh yd e (8o). Prepared
from 7o and obtained as a yellow oil (75%): 1H NMR (CDCl3)
δ 0.99 (t, 3H), 1.50 (m, 2H), 1.77 (m, 2H), 4.42 (m, 2H), 6.95
(dd, 1H), 7.54 (dd, 1H), 7.72 (t, 1H), 8.09 (s, 1H); IR (film, cm-1
1708.
)
P r ep a r a tion of 6-P yr a zol-1-yl-2-p yr id in ylm eth yla m in o
Der iva tives 75-85 (Ta ble 3). To a mixture of 8b and an
equimolar quantity of the corresponding amine39 in 1,2-
dichloroethane was added 1.4 equiv of sodium triacetoxyboro-
hydride. The mixture was stirred at room temperature for 24
h and then quenched by adding 1 N NaOH. The product was
extracted with EtOAc, purified by flash chromatography, and
converted to the appropriate salts.
Ra d ioliga n d Bin d in g. Binding affinities for the different
receptors were determined by means of ligand displacement
assays using the conditions summarized in Table 1. The
reactions were stopped by rapid filtration through Whatman
GF/B glass fiber filters, and the filters were washed with
appropriate buffer. The radioactivity retained on the filters
was measured by scintillation spectroscopy in 4 mL of scintil-
lation fluid (Emulsifier Safe, Packard).
Cyclic AMP in HA7 Cells. HA7 cells were grown in
Dulbecco’s modified Eagle’s medium (DMEM) (GIBCO) supple-
mented with 10% fetal calf serum, gentamicin (100 µg/mL),
Geneticin (G418) (400 µg/mL) in 5% CO2 at 37 °C in a water-
saturated atmosphere. The cells were plated in 6-well culture
plates and used in the experiments at a confluency of 80-
90%. Culturing medium [DMEM, 10% fetal calf serum,
gentamicin (100 µg/mL), G418 (400 µL/mL)] was replaced by
DMEM supplemented with 10% fetal calf serum without
antibiotics 24 h before experimentation.
6-(1H-P yr azol-3-yl)pyr idin e-2-car boxaldeh yde (8h ). Pre-
pared from 7h and obtained as an amorphous white solid
(60%): 1H NMR (DMSO-d6) δ 6.91 (d, 1H), 7.80 (m, 2H), 8.03
(t, 1H), 8.20 (d, 1H), 9.99 (s, 1H), 13.17 (s, 1H); IR (KBr, cm-1
1710.
)
2-(Oxa zol-5-yl)-6-(1,3-d ioxola n -2-yl)p yr id in e (7n ).
A
mixture of 7m (1 g, 5.58 mmol), tosylmethyl isocyanide (1.10
g, 5.63 mmol), K2CO3 (0.80 g, 5.79 mmol), and methanol (15
mL) was heated under reflux for 2 h. The solvent was
evaporated, and water was added. The product was extracted
with EtOAc, washed with brine, dried, filtered, and concen-
trated under vacuum. Purification by flash chromatography
(50% EtOAc-hexane) gave 1.13 g (96%) of 7n as a yellow oil:
1H NMR (CDCl3) δ 1.34 (d, 6H), 3.10 (m, 1H), 7.37 (m, 1H),
7.73 (d, 2H), 10.03 (s, 1H); IR (film, cm-1) 1712.
6-(Oxa zol-5-yl)p yr id in e-2-ca r boxa ld eh yd e (8n ). Pre-
pared from 7n and obtained as a pale-yellow solid (41%): mp
1
150-152 °C; H NMR (CDCl3) δ 7.81-8.01 (m, 5H), 10.08 (s,
Cells were preincubated with DMEM, 10 mM Hepes for 10
min at room temperature. Drugs, at concentrations ranging
1H); IR (KBr, cm-1) 1703. Anal. (C9H6N2O2) C, H, N.

6-Substituted-2-pyridinylmethylamine Derivatives
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5083
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