N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A novel, exceptionally selective, potent δ opioid receptor agonist with oral bioavailability and its analogues

Article abstract of DOI:10.1021/jm000229p

The design, synthesis, and pharmacological evaluation of a novel class of δ opioid receptor agonists, N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by repl

Full text of DOI:10.1021/jm000229p

J . Med. Chem. 2000, 43, 3895-3905
3895
N,N-Dieth yl-4-(p h en ylp ip er id in -4-ylid en em eth yl)ben za m id e: A Novel,
Excep tion a lly Selective, P oten t δ Op ioid Recep tor Agon ist w ith Or a l
Bioa va ila bility a n d Its An a logu es
Zhong-Yong Wei,* William Brown, Bryan Takasaki, Niklas Plobeck, Daniel Delorme,§ Fei Zhou, Hua Yang,
Paul J ones, Lars Gawell, Helene Gagnon, Ralf Schmidt, Shi-Yi Yue, Chris Walpole, Kemal Payza,#
Stephane St-Onge,# Maryse Labarre,# Claude Godbout,# Andrea J akob,# J oanne Butterworth,#
Augustus Kamassah,# Pierre-Emmanuel Morin,# Denis Projean,# J ulie Ducharme,# and Edward Roberts†
Departments of Chemistry and Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting,
Saint-Laurent, Quebec, Canada H4S 1Z9
Received May 30, 2000
The design, synthesis, and pharmacological evaluation of a novel class of δ opioid receptor
agonists, N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a ) and its analogues,
are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine
ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to
bind with high affinity and exhibit excellent selectivity for the δ opioid receptor as full agonists.
6a , the simplest structure in the class, exhibited an IC50 ) 0.87 nM for the δ opioid receptors
and extremely high selectivity over the µ receptors (µ/δ ) 4370) and the κ receptors (κ/δ )
8590). Rat liver microsome studies on a selected number of compounds show these olefinic
piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of
compounds appear to interact with δ opioid receptors in a similar way to SNC-80 since they
demonstrate similar SAR. Two general approaches have been established for the synthesis of
these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions
of vinyl bromide (8), and are herewith reported.
In tr od u ction
Studies have indicated the existence of three main
opioid receptor subtypes, µ, δ, and κ, that all appear to
be present in both the central and peripheral nervous
systems of many species including humans.1-3 Agonists
of all three receptor subtypes have been shown to
produce analgesia.4 Recently, increasing evidence5-10
has accumulated to support the hypothesis that a
selective δ opioid agonist will be an effective analgesic
devoid of the side-effect liability associated with µ opioid
agonists such as morphine (e.g., respiratory depression,
dependence liability, and inhibition of gastrointestinal
F igu r e 1. Structures of compounds 1-3.
Due to the presence of three asymmetric carbon
atoms, (+)-4-[(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-pip-
erazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-
80, 2) has seven possible stereoisomers, which should
exhibit different pharmacological profiles. As described
in the first paper in the series,14 we aimed to find a
simple substructure of SNC-80 that retains δ receptor
agonist activity and improves the selectivity of δ against
µ or κ. Initial SAR studies15 around SNC-80 indicated
that the 4-N,N-diethylaminocarbonyl group is a key
structural feature, but neither the methoxy group, the
allyl group, nor the two methyl groups on the piperazine
were essential for high affinity at the δ opioid receptor
or for selectivity over the µ or κ opioid receptors.
Compared to SNC-80, compound 4 displayed a limited
decrease in δ binding affinity but improved selectivity.
These observations are consistent with recent reports
by Calderon et al.16-18 and Cottney et al.19 Further
studies also indicated that nitrogen N1 of the piperazine
was not involved in binding to the δ opioid receptor. For
motility) or the clinically limiting side effects from κ
opioid agonists such as CI977 (e.g., dysphoria, diuresis,
and locomotor impairment). This has provided the
impetus for the development of selective nonpeptide δ
opioid agonists. Two major advances in the area of
δ-selective agonists were the discoveries of diarylpiper-
azine derivative (()-BW373U86 (1)11 and morphinan
derivative (-)-TAN-67 (3) (Figure 1).12 Both compounds
exhibit a high affinity for the δ opioid receptor with
moderate selectivity with respect to the µ opioid recep-
tor. An analogue of (+)-BW373U86, SNC-80 (2),13
demonstrated an improved selectivity while retaining
potent δ receptor agonist activity.
* To whom correspondence should be addressed. Tel: 514-832-3200,
ext 2402. Fax: 514-832-3232. E-mail: john.wei@astrazeneca.com.
#
Department of Pharmacology.
§ Present address: Methylgene Inc., 7220 Frederick-Banting, Saint-
Laurent, Quebec, Canada H4S 2A1.
† Present address: F. Hoffmann-La Roche Ltd., Pharmaceuticals
Division, PRBC, Bldg 015/203, CH-4070 Basel, Switzerland.
10.1021/jm000229p CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

3896 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Wei et al.
Sch em e 1a
F igu r e 2. Structures of compounds 4, 5, and 6a .
example, piperidine derivative 5 (IC50 ) 8.8 nM) exhib-
ited an almost identical δ binding affinity to compound
4 (IC50 ) 11.3 nM) (Figure 2).
Introduction of conformational constraints in biologi-
cally active compounds is a well-established approach
for enhancing receptor binding affinity and selectivity.
On the basis of the above assumption, incorporation of
an exocyclic carbon-carbon double bond into the piper-
idine ring of 5 became the most logical modification20
on SNC-80. The resulting compound, 6a , has displayed
a 9-fold increase in binding affinity for the δ receptor
(IC50 ) 0.87 nM) and extremely high selectivity over
the µ receptor (µ/δ ) 4370) and the κ receptor (κ/δ )
8590). In this paper, we investigate the δ receptor
binding effects of the substitution pattern on the
aromatic ring of 6a and the effect of N-substitution of
the piperidine. All compounds were examined for their
affinity for all three human opioid receptor subtypes,
and their δ agonist activity was determined using the
GTP[γ-35S] binding assay.
a
Reagents: (a) Boc2O; (b) 4-iodo-N,N-diethylbenzamide/BuLi,
-78 °C; (c) TFA.
in THF at -78 °C followed by the addition of 10a , to
furnish compound 7a in 94% yield. Subsequent dehy-
dration of the benzhydryl alcohol 7a was performed in
methylene chloride in the presence of trifluoroacetic acid
to provide compound 6a in 91% yield. Similarly com-
pounds 6b and 6c were prepared from commercially
available 4-benzoylpiperidines 9b and 9c.
A more efficient strategy based on the dehydration
approach would react 10d with a number of different
arylmagnesium halides or aryllithiums. Thus as shown
in Scheme 2, 4-(4′-N,N-diethylaminocarbonyl)benzoyl-
piperidine was prepared from ethyl isonipecotate (11)
in 28% yield by a three-step procedure. Benzhydryl
alcohols 7d -7g were then obtained from reacting 10d
with a variety of aryllithium reagents. Dehydration
under the same conditions as for 6a provided the desired
compounds 6d -6g.
The synthetic approach based on Suzuki coupling
reaction is shown in Scheme 3. The key intermediate 8
was prepared in five steps from compound 13. Thus,
methyl 4-(bromomethyl)benzoate was refluxed for 5 h
in trimethyl phosphite to provide compound 14 in
quantitative yield. Wittig-Horner olefination of N-tert-
butoxycarbonyl-4-piperidone with compound 14 was
performed in the presence of LDA. Addition of bromine
to a solution of 15 in dichloromethane afforded com-
pound 16 in 78% yield, which was then treated with
aqueous NaOH in methanol at 40 °C to provide com-
pound 17. N,N-Diethylbenzamide (8) was then prepared
in 73% yield from 17 by the mixed anhydride approach.
The Suzuki coupling reaction of vinyl bromide 8 with a
variety of arylboronic acids was performed in the
Ch em istr y
Diarylmethylenepiperidines have been well-known as
antihistamine drugs in the treatment of allergic dis-
eases. The synthesis of these compounds has been
achieved by several approaches such as Wittig-Horner
reaction21 and McMurry coupling reaction.22 In our
opinion, however, more efficient procedures were re-
quired to prepare compounds 6 with modified aromatic
groups (Figure 3). Thus, novel approaches have been
explored, including the methodology based on the Su-
zuki coupling reaction of compound 8 with different
arylboronic acids and the procedure based on dehydra-
tion of compounds 7, which were easily prepared by
reacting a 4-benzoylpiperidine with an aryllithium or
an arylmagnesium halide.
Synthesis of compounds 6a-6c is described in Scheme
1. Thus 4-benzoylpiperidine hydrochloride (9a ) was
transformed to its N-Boc derivative 10a in 98% yield
under basic conditions. 4-Iodo-N,N-diethylbenzamide23
was subjected to metal-halogen exchange with t-BuLi
F igu r e 3. Reactions to prepare compound 6.

δ Opioid Receptor Agonists: Oral Bioavailability
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3897
Sch em e 2a
Sch em e 4a
a
Reagents: (a) R′-X, K2CO3; (b) R1R2CdO, NaBH4; or (c) Ph-
Br, Pd(dba)2, BINAP, NaO-t-Bu.
cyclohexanone. Finally the N-phenyl analogue 19g was
obtained by palladium catalyzed N-arylation24 of 6a .
Resu lts a n d Discu ssion
In Vitr o P h a r m a cology. The binding affinities
(IC50) of all compounds were determined using cloned
human δ, µ, and κ opioid receptors, and the δ agonist
potency (EC50) was measured with the GTP[γ-35S]
binding assay.
a
Reagents: (a) Boc2O; (b) Me(MeO)NH, i-PrMgCl; (c) 4-iodo-
The opioid receptor binding affinity, selectivity, and
agonist potency of the target compounds 6 are listed in
Table 1, and those of SNC-80, diarylmethylpiperazine
4, and diarylmethylpiperidine 5 are also included for
comparison. As compared to SNC-80 [δ IC50 ) 1.31 nM;
µ/δ ) 245; κ/δ ) 1890 (Ki ) 4 nM; µ/δ ) 990 on rat brain
membranes)18], compound 6f displayed similar binding
affinity [IC50 ) 1.56 nM (Ki ) 5 nM; µ/δ > 1200 on rat
brain membranes)18] on δ receptors but an improved
selectivity over µ and κ receptors (µ/δ ) 3370; κ/δ >
6410). 6a , a derivative of 6f without the 3-MeO group
on the phenyl ring, even further increased selectivity
as a result of improved δ-affinity (IC50 ) 0.87 nM;
µ/δ ) 4370; κ/δ ) 8590). Considerable variation is
possible in the nature of the substitution on the phenyl
ring, and this can lead to some highly potent δ agonists.
For example, compounds 6e (EC50 ) 4.6 nM) and 6h
(EC50 ) 3.18 nM) exhibited improved agonist activities
at δ receptors compared to the “parent” structure (6a ,
EC50 ) 7.2 nM). The position of a substituent on the
phenyl ring is important for both binding affinity and
agonist activity. Substitution at the para-position of the
phenyl ring appeared to be detrimental (6b vs 6e, 6l;
6p vs 6f, 6q), presumably reflecting steric constraints
in this region. The 2,6-dimethylphenyl analogue 6g
exhibited a dramatically reduced δ binding affinity as
compared to the parent compound 6a , suggesting that
the steric constraints imposed by the two methyl groups
may alter the conformation of the dimethylphenyl ring
in a manner which is deleterious to activity. On the
other hand, the phenyl group can be replaced by
heteroaryl or other aryl groups. For example, 1-naphthyl
(6d ) and 2-thiophenyl (6m ) analogues still retain potent
δ affinity and high selectivity over µ and κ receptors.
In general, this entire series of compounds displayed
extremely high affinity to δ opioid receptors (low nano-
molar to subnanomolar range) and very high selectivity
over µ or κ opioid receptors (>1000 in most cases). All
compounds exhibited full δ agonism at the cloned
human δ receptor as determined in GTP[γ-35S] binding
assay.
N,N-diethylbenzamide/BuLi, -78 °C; (d) Ar-Li; (e) TFA.
Sch em e 3a
a
Reagents: (a) P(OMe)3; (b) LDA, N-tert-butoxycarbonyl-4-
piperidone; (c) Br2; (d) NaOH; (e) (COCl)2/Et3N, Et2NH; (f) Ar-
B(OH)2, Pd(PPh3)4, Na2CO3; (g) 4 N HCl.
presence of tetrakis(triphenylphosphine)palladium (0)
using 2 M Na2CO3 as base. Subsequent cleavage of the
Boc group was achieved with 4 N HCl in dioxane
providing the final compounds 6h -6q.
Compounds 19a -19g representing different N-sub-
stituted analogues of 6a were prepared as described in
Scheme 4. Compounds 19a -19e were obtained by
treatment of 6a with the corresponding alkyl halides
in the presence of potassium carbonate in acetonitrile
at room temperature. The N-cyclohexyl derivative 19f
was provided by reductive amination from 6a and
To examine the effect on biological activity of N-alkyl
substitution on the piperidine nitrogen of 6a , N-Me,

3898 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Ta ble 1. Binding Affinities and Agonist Activities of Compounds 6
Wei et al.

δ Opioid Receptor Agonists: Oral Bioavailability
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3899
Ta ble 2. Binding Affinities and Agonist Activities of 6a Analogues (19)
Ta ble 3. Microsomal Incubation Analysisa
N-allyl, N-3,3-dimethylallyl, N-cyclopropylmethyl, N-
butyl, N-cyclohexyl, and N-phenyl substituents were
introduced (Table 2). None of these compounds bind to
δ opioid receptors with as high affinity as the “parent”
compound 6a : compounds 19b and 19c with allyl
substituents, which are known to be tolerated in piper-
azine series such as SNC-80, exhibited slightly de-
creased affinities relative to 6a , while 19a and 19f
showed more than 30-fold decreased δ receptor affini-
ties. The N-phenyl derivative 19g almost completely lost
its ability to bind to the δ receptors, presumably because
of the decreased basicity of the nitrogen (calculated pKa
values are 5.32 for compound 19g and 9.68 for com-
pound 6a by ACD pKa from Advanced Chemistry
Development Inc., Toronto, Canada), which is an es-
sential pharmacophore point to have an electrostatic
interaction at an anionic receptor site. The butyl and
cyclopropylmethyl derivatives (19d , 19e) showed similar
binding affinity and identical agonist activity in the δ
receptor assay probably due to their similarity in size.
In general, the N-alkyl compounds are also comparably
weak ligands for µ and κ opioid receptors with respect
to the parent compound 6a , while 19f exhibited some-
what increased µ receptor affinity.
% parent remaining at
compd
10 µM
100 µM
SNC-80
6a
6e
6f
6h
6i
6k
6q
1 ( 1 (n ) 5)
77 ( 7 (n ) 7)
55 ( 14 (n ) 3)
1 (n ) 2)
75 ( 2 (n ) 3)
63 ( 17 (n ) 2)
80 ( 1 (n ) 2)
55 (n ) 2)
24 ( 6 (n ) 5)
95 ( 6 (n ) 7)
94 ( 6 (n ) 3)
58 ( 3 (n ) 2)
95 ( 3 (n ) 3)
91 ( 9 (n ) 3)
100 (n ) 2)
90 ( 1 (n ) 2)
a
After 1-h incubations in rat liver microsomes.
more stable. Major metabolites were N-deethylated
analogues (M - 28), while minor metabolites included
hydroxylated derivatives (M + 16).
In agreement with the metabolic profiling data ob-
tained for SNC-80 in rat liver microsomes,14 the meth-
oxy analogue 6f was less stable than other compounds,
being extensively metabolized into an O-demethylated
derivative. The olefin 6a is markedly more stable, being
virtually undegraded at 100 µM, in sharp contrast to
SNC-80. As could be predicted by the improved meta-
bolic stability of 6a , together with the low molecular
weight and conformity with Lipinski’s rules,25 6a has
exceptional oral bioavailability, approaching 100%.
P r op osed Com m on Bin d in g Mod e of 2 (SNC-80)
a n d 6a . The essential elements of the δ agonist phar-
macophore (described in more detail in the previous
paper in this series14) are the basic nitrogen, the ‘right-
In Vitr o Meta bolism . Selected compounds were
examined in rat liver microsomes (Table 3). While SNC-
80 is unstable in rat liver microsomes, most of the
compound being degraded in 1 h at both concentrations,
most olefinic analogues 6 were found to be significantly

3900 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Wei et al.
F igu r e 4. Superpositions of 64 conformers of SNC-80, gener-
ated from conformational search. Carbon atoms are in light
green, nitrogen atoms in blue, and oxygen atoms in red.
F igu r e 6. Superposition of the crystal structures between
SNC-80 (carbon atoms in light green) and compound 6a
(carbon atoms in gold).
of the piperidine ring in 6a and the piperazine ring of
SNC-80 do not overlay well in the superposition, the
basic N atoms are disposed very closely in space. The
same phenomenon was also observed in the conforma-
tional search, suggesting that this part of the ring
structure only serves as a spacer to connect the basic
nitrogen and the two aromatic rings containing the
other two pharmacophore groups. A recent publication26
also experimentally proved this observation. The su-
perposition of the amide carbonyl groups in the two
molecules is excellent, despite the different orientations
of the intervening phenyl rings. The ‘right-hand’ phenyl
ring is well-overlaid in the two structures.
F igu r e 5. Superpositions of 4 conformers of 6a , generated
from conformational search with the same color coding as in
Figure 4.
Con clu sion
A novel class of exceptionally selective, potent δ opioid
receptor ligands was identified as a result of replacing
the piperazine N atom in the progenitor series of
agonists with an olefinic C atom, resulting in 6a , the
simplest structure in the series which exhibited an
IC50 ) 0.87 nM for δ opioid receptors and exceptional
selectivity over µ receptors (µ/δ ) 4370) and κ receptors
(κ/δ ) 8590). This compound and its analogues pre-
sented here have the highest selectivity in the human
opioid receptors assay of any comparator compounds we
have tested: 14 out of the 17 compounds showed δ
affinity less than 3 nM, while 5 of these compounds had
subnanomolar affinity. The majority of these compounds
displayed a ratio of >1000 with respect to µ or κ opioid
receptors. Furthermore evaluation of a number of
compounds in rat liver microsomes showed these com-
pounds (including 6a ) to be much more stable than the
parent compound SNC-80. 6a was subsequently found
to have excellent oral availability27 (F ) 90-100% in
the rat).
hand’ (oxygenated in the case of SNC-80, unsubstituted
in the case of 6a ) phenyl ring, and the diethylamide
carbonyl group. To compare the pharmacophore groups
in the two molecules, SNC-80 and 6a , an extensive
conformational search was performed and the cor-
respondence of these key groups (the carbonyl carbon
atom was taken to represent the amide pharmacophore
to reduce the complexity of the conformational search)
in low-energy conformers was examined (Figures 4 and
5). This comparison of the two compounds showed that
compound 6a only partially covers the conformational
space available to SNC-80, while key pharmacophores
are closely superimposed in 6a and a population of SNC-
80 conformers. The first interpretation of this confor-
mational comparison is that compound 6a can efficiently
bind to and activate the δ opioid receptor but has
improved selectivity compared to SNC-80, since it does
not intrude into conformational space which might be
attributed to recognition of the other opioid receptor
subtypes.
These N,N-diethyl-4-(piperidin-4-ylidenemethyl)benz-
amides are the most selective δ opioid receptor agonists
described so far. They do not contain any chiral centers
and can easily be prepared by established synthetic
approaches. These important chemical features coupled
with their excellent pharmacological profile and oral
bioavailability make these compounds ideal for further
investigation and development.
Figure 6 shows a superposition of the crystallographic
structures of SNC-80 and compound 6a . The three-
dimensional coordinates of SNC-80 were built according
to its absolute stereochemistry.13 The basic nitrogen, the
two centroid phenyl rings, and the carbon atom of the
carbonyl group were used for the superposition (rms )
0.36). It is interesting to notice that, while the C atoms

δ Opioid Receptor Agonists: Oral Bioavailability
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3901
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
4-ch lor oben zyl)-N,N-d ieth ylben za m id e (7c). Method as
described for 7a , but starting with 10c (1.62 g, 5.0 mmol) led
to 7c as a solid (1.58 g, 63%): mp 100-105 °C (CH2Cl2); IR
Exp er im en ta l Section
Syn th esis. Melting points were taken in a capillary tube
by using a Thomas-Hoover melting point apparatus and are
uncorrected. For the HCl salts of many final compounds,
melting points were not measured because they were not
crystalline due to the fractional amounts of HCl present from
combustion analyses. IR spectra were determined with a
Perkin-Elmer Pragon 100 FT-IR spectrometer. NMR spectra
were recorded on a Varian Unity Plus 400 MHz spectrometer;
chemical shifts were recorded in parts per million downfield
from Me4Si. Elemental analyses were performed by Canadian
Microanalytical Service Ltd., Delta, British Columbia. Flash
column chromatography was performed with silica gel 60 (70-
230 mesh). Dry THF was distilled from sodium benzophenone
prior to use. Other anhydrous solvents over molecular sieves
were obtained from Fluka.
(KBr) 3411, 1685, 1617 cm-1 1H NMR (CDCl3) δ 1.08 (brs,
;
3H), 1.20 (brs, 3H), 1.33 (m, 4H), 1.41 (s, 9H), 2.44 (m, 1H),
2.63 (brs, 2H), 3.22 (brs, 2H), 3.49 (brs, 2H), 3.99 (s, 1H), 4.05
(m, 2H), 7.20 (m, 4H), 7.39 (d, J ) 8.0 Hz, 2H), 7.44 (d, J )
8.0 Hz, 2H); 13C NMR (CDCl3) δ 12.5, 13.9, 25.9, 28.1, 39.0,
43.0, 44.1, 78.7, 79.0, 125.6, 126.0, 127.2, 127.8, 131.9, 134.8,
144.1, 146.6, 154.3, 170.7.
N,N-Dieth yl-4-(ph en ylpiper idin -4-yliden em eth yl)ben z-
a m id e (6a ). To a solution of 7a (932 mg, 2.0 mmol) in dry
dichloromethane (10 mL) was added trifluoroacetic acid (10.0
mL) at room temperature. The reaction mixture was stirred
overnight and then concentrated. The residue was then
dissolved in CH2Cl2 (100 mL), washed with 1 N NaOH, brine,
and dried over MgSO4. Removal of solvents gave a crude
product, which was purified by flash chromatography eluting
with MeOH-CH2Cl2 (20:80) to provide 6a (632 mg, 91%): 1H
NMR (CDCl3) δ 1.08 (brs, 3H), 1.17 (brs, 3H), 2.29 (m, 4H),
2.86 (m, 4H), 2.94 (brs, 1H), 3.24 (brs, 2H), 3.47 (brs, 2H), 7.09
(m, 4H), 7.15 (m, 1H), 7.24 (m, 4H); 13C NMR (CDCl3) δ 12.6,
14.1, 32.7, 32.8, 39.1, 43.2, 47.9, 126.0, 126.4, 127.9, 129.6,
134.9, 135.4, 135.9, 141.7, 143.2, 171.1. HCl salt: mp 110-
120 °C (CH2Cl2); IR (KBr) 3440, 1617. Anal. (C23H28N2O‚
2.1HCl) C, H, N.
4-Ben zoyl-N-ter t-bu toxyca r bon ylp ip er id in e (10a ). A
mixture of 9a (6.77 g, 30.0 mmol), di-tert-butyl dicarbonate
(7.2 g, 33.0 mmol) and Na2CO3 (6.36 g, 60 mmol) was refluxed
in H2O-THF (50/20 mL) for 1 h. The reaction mixture was
then cooled and extracted with ethyl acetate (2 × 100 mL).
The combined organic layers were washed with brine, dried
over MgSO4, and evaporated to give 10a (8.54 g, 98%): mp
95-96 °C (Et2O); 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.70 (m, 2H),
1.83 (m, 2H), 2.91 (m, 2H), 3.42 (m, 1H), 4.18 (brs, 2H), 7.46
(m, 2H), 7.56 (m, 1H), 7.93 (m, 2H).
N,N-Dieth yl-4-(4-flu or oph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6b). Method as described for 6a , but starting
with 7b led to 6b in quantitative yield: 1H NMR (CDCl3) δ
1.12 (brm, 3 H, CH3CH2-), 1.24 (brm, 3 H, CH3CH2-), 2.32 (m,
4 H, piperidine CH-), 2.54 (brm, 1 H, NH), 2.91 (m, 4 H,
piperidine CH-), 3.27 (brm, 2 H, CH2N-), 3.52 (brm, 2 H,
CH2N-), 7.00 (m, 2 H, ArH), 7.09 (m, 2 H, ArH), 7.11 (d, J )
4-(4-F lu or oben zoyl)-N-ter t-bu toxyca r bon ylp ip er id in e
(10b). Following the same method as used to prepare 10a but
starting with 9b (2.44 g, 10 mmol) led to 10b as a solid (2.27
g, 74%): mp 80-83 °C (CH2Cl2); IR (KBr) 1680, 1587 cm-1
;
1H NMR (CDCl3) δ 1.44 (s, 9H), 1.69 (m, 2H), 1.79 (m, 2H),
2.87 (m, 2H), 3.34 (m, 1H), 4.13 (brs, 2H), 7.12 (m, 2H), 7.95
(m, 2H); 13C NMR (CDCl3) δ 27.4, 28.4, 43.2, 43.4, 79.6, 115.8,
115.9, 130.8, 130.9, 132.2, 154.6, 164.4, 166.9, 200.4.
8.0 Hz, 2H, ArH), 7.29 (d, J ) 8.0 Hz, 2 H, ArH). Anal. (C23H27
FN2O‚1.5HCl) C, H, N.
-
4-(4-Ch lor oben zoyl)-N-ter t-bu toxyca r bon ylp ip er id in e
(10c). Following the same method as used to prepare 10a but
starting with 9c (2.60 g, 10 mmol) led to 10c as a solid (2.75
N,N-Dieth yl-4-(4-ch lor oph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6c). Method as described for 6a , but starting
with 7c led to 6c in quantitative yield: 1H NMR (CDCl3) δ
1.13 (brm, 3 H, CH3CH2-), 1.22 (brm, 3 H, CH3CH2-), 2.02 (brm,
1 H, NH), 2.30 (m, 4 H, piperidine CH-), 2.90 (m, 4 H,
piperidine CH-), 3.28 (brm, 2 H, CH2N-), 3.53 (brm, 2 H,
CH2N-), 7.04 (d, J ) 8.0 Hz, 2 H, ArH), 7.11 (d, J ) 8.0 Hz, 2
H, ArH), 7.25 (d, J ) 8.0 Hz, 2 H, ArH), 7.30 (d, J ) 8.0 Hz,
2 H, ArH). HCl salt: mp 115-120 °C (CH2Cl2); IR (KBr) 3337,
1618 cm-1. Anal. (C23H27ClN2O‚1.6HCl) C, H, N.
N-ter t-Bu toxyca r bon yl-N′-m eth yl-N′-m eth oxyison ip e-
cota m id e (12). Method as described for 10a , but starting with
ethyl isonipecotate (11; 4.71 g, 30.0 mmol) led to N-tert-
butoxylcarbonyl ethyl isonipecotate (7.67 g): 1H NMR (CDCl3)
δ 1.25 (t, J ) 7.2 Hz, 3H), 1.45 (s, 9H), 1.62 (m, 2H), 1.87 (m,
2H), 2.43 (m, 1H), 2.84 (m, 2H), 4.02 (m, 2H), 4.13 (q, J ) 7.2
Hz, 2H); 13C NMR (CDCl3) δ 14.0, 27.8, 28.2, 40.9, 42.9, 60.2,
79.2, 154.4, 174.2.
To a mixture of the above product and NHMe(OMe) HCl
(4.39 g, 45.0 mmol) in dry THF was added i-PrMgCl (2.0 M in
THF, 45 mL, 90 mmol) at -20 °C. The resulting solution was
stirred for 1 h at -5 °C, then quenched with aqueous NH4Cl
solution and extracted with ethyl acetate (2 × 100 mL). The
combined organic layers were washed with brine and dried
over MgSO4. Removal of solvents gave 12 (8.0 g, 98%): 1H
NMR (CDCl3) δ 1.30 (s, 9H), 1.54 (m, 4H), 2.65 (m, 3H), 3.02
(s, 3H), 3.56 (s, 3H), 3.99 (brs, 2H); 13C NMR (CDCl3) δ 27.7,
28.1, 32.0, 37.8, 43.1, 61.3, 79.1, 154.4, 176.0.
4-(4′-N′,N′-Diet h yla m in oca r b on ylb en zoyl)-N-ter t-b u -
toxyca r bon ylp ip er id in e (10d ). To a solution of 4-iodo-N,N-
diethylbenzamide (9.09 g, 30.0 mmol) and TMEDA (6.96 g, 60.0
mmol) in dry THF (60 mL) was added tert-butyllithium (35.0
mL, 1.7 M, 60.0 mmol) at -78 °C. After 30 min, 12 (8.0 g,
29.4 mmol) in THF (10 mL) was dropwise added. The reaction
mixture was warmed to room temperature, then quenched
with aqueous NH4Cl solution, acidified with hydrochloric acid
(concentrated, 20 mL) at 0 °C, and extracted with ethyl acetate
(2 × 100 mL). The combined organic layers were washed with
g, 85%): mp 122-125 °C (CH2Cl2); IR (KBr) 1680, 1582 cm-1
;
1H NMR (CDCl3) δ 1.47(s, 9H), 1.69 (m, 2H), 1.81 (m, 2H),
2.90 (m, 2H), 3.36 (m, 1H), 4.18 (brs, 2H), 7.44 (m, 2H), 7.88
(m, 2H); 13C NMR (CDCl3) δ 28.3, 28.4, 43.2, 43.4, 79.6, 129.0,
129.6, 134.1, 139.4, 154.6, 200.7.
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
ben zyl)-N,N-d ieth ylben za m id e (7a ). To a solution of 4-iodo-
N,N-diethylbenzamide (6.67 g, 22.0 mmol) in dry THF (70 mL)
was added tert-butyllithium (18.0 mL, 2.5 M, 45.0 mmol) at
-78 °C. After 10 min, 10a (4.34 g, 15.0 mmol) in THF (5 mL)
was dropwise added. The reaction mixture was warmed to
room temperature and then quenched with aqueous NH4Cl
solution and extracted with ethyl acetate (2 × 100 mL). The
combined organic layers were washed with brine and dried
over MgSO4. Removal of solvents gave a crude product, which
was purified by flash chromatography eluting with MeOH-
CH2Cl2 (0:100 f 5:95) to provide 7a (6.56 g, 94%): mp 100-
103 °C (CH2Cl2); IR (KBr) 3426, 1687, 1618 cm-1 1H NMR
;
(CDCl3) δ 1.08 (brs, 3H), 1.20 (brs, 3H), 1.30 (m, 4H), 1.41 (s,
9H), 2.50 (t, J ) 11.2 Hz, 1H), 2.66 (m, 2H), 2.86 (s, OH), 3.22
(brs, 2H), 3.50 (brs, 2H), 4.09 (brs, 2H), 7.18 (m, 1H), 7.26 (m,
4H), 7.45 (m, 4H); 13C NMR (CDCl3) δ 12.8, 14.1, 26.2, 28.3,
39.1, 43.2, 44.3, 53.3, 79.2, 79.4, 125.75, 125.79, 126.2, 126.6,
128.1, 135.1, 145.3, 146.8, 154.6, 171.0.
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
4-flu or oben zyl)-N,N-d ieth ylben za m id e (7b). Method as
described for 7a , but starting with 10b (1.54 g, 5.0 mmol) led
to 7b as a solid (1.14 g, 47%): mp 84-86 °C (CH2Cl2); IR (KBr)
3421, 1685, 1612 cm-1; 1H NMR (CDCl3) δ 1.13 (brs, 3H), 1.23
(brs, 3H), 1.32 (m, 4H), 1.44 (s, 9H), 2.48 (m, 1H), 2.68 (brs,
2H), 3.26 (brs, 2H), 3.54 (brs, 2H), 3.57 (s, 1H), 4.11 (brs, 2H),
6.96 (m, 2H), 7.27 (d, J ) 8.0 Hz, 2H), 7.44 (m, 2H), 7.47 (d,
J ) 8.0 Hz, 2H); 13C NMR (CDCl3) δ 12.9, 14.0, 26.2, 28.2,
39.1, 43.2, 43.6, 44.3, 78.9, 79.1, 114.5, 114.7, 125.7, 126.1,
127.5, 127.6, 135.0, 141.2, 146.9, 154.5, 160.0, 162.5, 170.9.

3902 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Wei et al.
brine and dried over MgSO4. Removal of solvents gave a crude
product, which was purified by flash chromatography eluting
with MeOH-CH2Cl2 (2:98) to provide 10d (3.15 g, 28%): 1H
NMR (CDCl3) δ 1.08 (brs, 3H), 1.23 (brs, 3H), 1.43 (s, 9H), 1.61
(m, 2H), 1.80 (m, 2H), 2.89 (m, 2H), 3.20 (brs, 2H), 3.40 (m,
1H), 3.53 (brs, 2H), 4.11 (brs, 2H), 7.44 (d, J ) 8.0 Hz, 2H),
7.94 (d, J ) 8.0 Hz, 2H).
N,N-Dieth yl-4-(3-flu or oph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6e). Method as described for 6a , but starting
with 7e (242 mg, 0.5 mmol) led to 6e (159 mg, 87%): 1H NMR
(CDCl3) δ 1.08 (br, 3 H, CH3CH2N-), 1.19 (br, 3 H, CH3CH2-
N-), 2.09 (s, 1 H, NH), 2.25 (m, 4 H, piperidine CH-), 2.84 (br,
4 H, piperidine CH-), 3.23 (br, 2 H, CH3CH2N-), 3.47 (br, 2 H,
CH3CH2N-), 6.74 (m, 1 H, ArH), 6.86 (m, 2 H, ArH), 7.06 (d,
J ) 8.0 Hz, 2 H, ArH), 7.18 (m, 1 H, ArH), 7.24 (d, J ) 8.0 Hz,
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
r-(1-n a p h th yl)m eth yl)-N,N-d ieth ylben za m id e (7d ). To a
solution of 1-bromonaphthalene (0.52 g, 2.5 mmol) in dry THF
(10 mL) was added n-butyllithium (1.1 mL, 2.5 M, 2.75 mmol)
at -78 °C. After 30 min, 10d (776 mg, 2.0 mmol) in THF (2
mL) was dropwise added. The reaction mixture was warmed
to room temperature, quenched with aqueous NH4Cl solution,
and extracted with ethyl acetate (2 × 50 mL). The combined
organic layers were washed with brine and dried over MgSO4.
Removal of solvents gave a crude product, which was puri-
fied by flash chromatography eluting with MeOH-CH2Cl2 (0.5:
99.5 f 5:95) to provide 7d (760 mg, 74%): mp 121-124 °C
(CH2Cl2); IR (KBr) 3402, 1685, 1626 cm-1; 1H NMR (CDCl3) δ
1.03 (brs, 3H), 1.16 (brs, 3H), 1.18-1.35 (m, 3H), 1.95 (m, 1H),
2.60 (m, 2H), 2.75 (brs, 2H), 3.15 (brs, 2H), 3.42 (brs, 2H), 4.10
2 H, ArH). HCl salt: mp g 70 °C dec; IR (NaCl) 1605 cm-1
Anal. (C23H27FN2O‚2.2HCl) C, H, N.
.
N,N-Dieth yl-4-(3-m eth oxyp h en ylp ip er id in -4-ylid en e-
m eth yl)ben za m id e (6f). Method as described for 6a , but
starting with 7f (199 mg, 0.4 mmol) led to 6f18 (148 mg, 98%).
Anal. (C24H30N2O2‚1.8HCl) C, H, N.
N,N-Dieth yl-4-(2,6-dim eth ylph en ylpiper idin -4-yliden e-
m eth yl)ben za m id e (6 g). Method as described for 6a , but
starting with 7g (495 mg, 1.0 mmol) led to 6g (301 mg, 80%):
1H NMR (CDCl3) δ 1.10 (brs, 3H), 1.21 (brs, 3H), 2.08 (m, 4H),
2.21 (s, 6H), 2.84 (m, 2H), 3.00 (m, 2H), 3.20 (brs, 1H), 3.25
(brs, 2H), 3.46 (brs, 2H), 6.94 (m, 1H), 7.00 (m, 2H), 7.04 (d,
J ) 8.0 Hz, 2H), 7.16 (d, J ) 8.0 Hz, 2H). HCl salt: dec g 115
°C (CH2Cl2); IR (KBr) 1590 cm-1. Anal. (C25H32N2O‚2.2HCl)
C, H, N.
(brs, 2H), 7.10-7.50 (m, 7H), 7.75 (m, 3H), 8.27 (brs, 1H); 13
C
4-(4-Met h oxyca r b on ylb en zylid en e)p ip er id in e-1-ca r -
boxylic Acid ter t-Bu tyl Ester (15). A mixture of 13 (11.2 g,
49 mmol) and trimethyl phosphite (25 mL) was refluxed under
N2 for 5 h. Excess trimethyl phosphite was removed by
codistillation with toluene to give 14 in quantitative yield: 1H
NMR (CDCl3) δ 3.20 (d, 2H, J ) 22 Hz), 3.68 (d, 3H, 10.8 Hz),
3.78 (d, 3H, 11.2 Hz), 3.91 (s, 3H), 7.38 (m, 2H), 8.00 (d, 2H,
J ) 8 Hz).
To a solution of the above product (14) in dry THF (200 mL)
was added dropwise lithium diisopropylamide (32.7 mL 1.5
M in hexanes, 49 mmol) at -78 °C. The reaction mixture was
then allowed to warm to room temperature prior to addition
of N-tert-butoxycarbonyl-4-piperidone (9.76 g, 49 mmol in 100
mL dry THF). After 12 h, the reaction mixture was quenched
with water (300 mL) and extracted with ethyl acetate (3 ×
300 mL). The combined organic phases were dried over MgSO4
and evaporated to give a crude product, which was purified
by flash chromatography (0-33% ethyl acetate in hexanes) to
provide 15 as a white solid (5.64 g, 35%): IR (NaC1) 1718,
1688, 1606 cm-1; 1H NMR (CDCl3) δ 1.44 (s, 1H), 2.31 (t, J )
5.5 Hz, 2H), 2.42 (t, J ) 5.5 Hz, 2H), 3.37 (t, J ) 5.5 Hz, 2H),
3.48 (t, J ) 5.5 Hz, 2H), 3.87 (s, 3H), 6.33 (s, 1H), 7.20 (d J )
6.7 Hz, 2H), 7.94 (d, J ) 6.7 Hz, 2H); 13C NMR (CDCl3) δ 28.3,
29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6,
166.8. Anal. (C19H25NO4) C, H, N.
4-Br om o-4-[br om o(4-m eth oxyca r bon ylp h en yl)m eth yl]-
p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (16). To a
mixture of 15 (5.2 g, 16 mmol) and K2CO3 (1.0 g) in dry
dichloromethane (200 mL) was added a solution of bromine
(2.9 g, 18 mmol) in 30 mL CH2Cl2 at 0 °C. after 1.5 h at room
temperature, the solution after filtration of K2CO3 was con-
centrated. The residue was then dissolved in ethyl acetate (200
mL), washed with water (200 mL), 0.5 M HC1 (200 mL) and
brine (200 mL), and dried over MgSO4. Removal of solvents
provided a crude product, which was recrystallized from
methanol to give 16 as a white solid (6.07 g, 78%): IR (NaC1)
1725, 1669 cm-1; 1H NMR (CDCl3) δ 1.28 (s, 9H), 1.75 (m, 2H),
1.90 (m, 2H), 2.1 (m, 4H), 3.08 (br, 4H), 3.90 (s, 3H), 4.08 (br,
4H), 5.14 (s, 1H), 7.57 (d, J ) 8.4 Hz, 2H) 7.98 (d, J ) 8.4 Hz,
2H); 13C NMR (CDCl3) δ 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9,
129.0, 130.3, 130.4, 141.9, 154.4, 166.3. Anal. (C19H25Br2NO4)
C, H, N.
4-[Br om o(4-ca r b oxyp h en yl)m et h ylen e]p ip er id in e-1-
ca r boxylic Acid ter t-Bu tyl Ester (17). A solution of 16 (5.4
g 11 mmol) in methanol (300 mL) and 2.0 M NaOH (100 mL)
was heated at 40 °C for 3 h. The solid was collected by filtration
and dried overnight under vacuum. The dry salt was dissolved
in 40% acetonitrile/water and was adjusted to pH 2 using
concentrated HCl. The desired product (17; 3.8 g, 87%) was
isolated as a white powder by filtration: 1H NMR (CDCl3) δ
1.45 (s, 9H), 2.22 (dd, J ) 5.5 Hz, 6.1 Hz, 2H), 2.64 (dd, J )
NMR (CDCl3) δ 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4,
79.3, 80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128.8, 129.2,
131.4, 135.0, 135.2, 139.4, 146.5, 154.6, 171.0. Anal. (C32H40N2O4‚
0.5H2O) C, H, N.
N,N-Dieth yl-4-[(N-ter t-bu toxyca r bon ylp ip er id in -4-yl)-
3-flu or op h en ylh yd r oxym et h yl]ben za m id e (7e). Method
as for 7d using 3-bromofluorobenzene provided 7e (262 mg,
27%): 1H NMR (CDCl3) δ 1.03 (br, 3 H, CH3CH2N-), 1.15 (br,
3 H, CH3CH2N-), 1.19-1.29 (m, 4 H, piperidine CH-), 1.35 (s,
9 H, CH3C), 2.39 (m, 1 H, piperidine CH-), 2.59 (br, 2 H,
piperidine CH-), 3.17 (br, 2 H, CH3CH2N-), 3.28 (s, 1 H, OH),
3.45 (br, 2 H, CH3CH2N-), 4.02 (br, 2 H, piperidine CH-), 6.80
(m, 1 H, ArH), 7.15 (m, 3 H, ArH), 7.18 (d, J ) 8.0 Hz, 2 H,
ArH), 7.39 (d, J ) 8.0 Hz, 2 H, ArH).
N,N-Dieth yl-4-[(N-ter t-bu toxyca r bon ylp ip er id in -4-yl)-
3-m eth oxyp h en ylh yd r oxym eth yl]ben za m id e (7f). Method
as for 7d using 3-bromoanisole provided 7f (228 mg, 23%): mp
95-103 °C (CH2Cl2); IR (NaCl) 3422, 1684, 1614 cm-1; 1H NMR
(CDCl3) δ 1.07 (br, 3 H, CH3CH2N-), 1.19 (br, 3 H, CH3CH2N-
), 1.31 (m, 4 H, piperidine CH-), 1.41 (s, 9 H, CH3C), 2.46 (m,
1 H, piperidine CH-), 2.64 (br, 2 H, piperidine CH-), 3.22 (br,
2 H, CH3CH2N-), 3.49 (br, 2 H, CH3CH2N-), 3.65 (s, 1 H, OH),
3.72 (s, 3 H, OCH3), 4.06 (br, 2 H, piperidine CH-), 6.69 (m, 1
H, ArH), 7.01 (d, J ) 7.6 Hz, 1 H, ArH), 7.08 (s, 1 H, ArH),
7.17 (d, J ) 8.0 Hz, 1 H, ArH), 7.21 (d, J ) 8.0 Hz, 2 H, ArH),
7.48 (d, J ) 8.0 Hz, 2 H, ArH). Anal. (C29H40N2O5‚0.6H2O) C,
H, N.
4-(r-Hyd r oxy-r-(4-N-ter t-bu toxyca r bon ylp ip er id in yl)-
2,6-d im eth ylben zyl)-N,N-d ieth ylben za m id e (7g). Method
as described for 7d , but using 2-bromo-m-xylene led to 7g (752
mg, 76%): mp 92-96 °C (CH2Cl2); IR (KBr) 3451, 1690, 1631
1
cm-1; H NMR (CDCl3) δ 1.10 (brs, 3H), 1.21 (brs, 3H), 1.32
(m, 2H), 1.43 (s, 9H), 1.69 (m, 1H), 1.77 (m, 1H), 2.32 (s, 6H),
2.47 (s, 1H), 2.75 (m, 3H), 3.25 (brs, 2H), 3.51 (brs, 2H), 4.13
(brs, 2H), 6.91 (m, 2H), 7.00 (m, 1H), 7.26 (d, J ) 8.4 Hz, 2H),
7.39 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ 12.6, 14.0, 25.0,
27.7, 28.2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3,
127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7. Anal.
(C30H42N2O4‚0.5H2O) C, H, N.
N,N-Dieth yl-4-(1-n a p h th ylp ip er id in -4-ylid en em eth yl)-
ben za m id e (6d ). Method as described for 6a , but starting
with 7d (517 mg, 1.0 mmol) led to 6d (283 mg, 71%): mp 80-
1
85 °C (CH2Cl2); IR (KBr) 1628 cm-1; H NMR (CDCl3) δ 1.06
(brs, 3H), 1.16 (brs, 3H), 2.00 (m, 2H), 2.53 (m, 2H), 2.64 (brs,
NH), 2.77 (m, 2H), 2.97 (m, 2H), 3.20 (brs, 2H), 3.47 (brs, 2H),
7.26 (m, 5H), 7.43 (m, 3H), 7.74 (m, 2H), 8.0 (m, 1H); 13C NMR
(CDCl3) δ 12.8, 14.1, 32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5,
125.7, 125.8, 126.1, 127.1, 127.2, 129.1, 131.9, 132.5, 133.8,
135.1, 138.3, 139.8, 142.6, 171.1. Anal. (C27H30N2O‚0.4HCl) C,
H, N.

δ Opioid Receptor Agonists: Oral Bioavailability
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3903
5.5 Hz, 6.1 Hz, 2H), 3.34 (dd, J ) 5.5 Hz, 6.1 Hz, 2H), 3.54
(dd, J ) 5.5 Hz, 6.1 Hz, 2H), 7.35 (d, J ) 6.7 Hz, 2H), 8.08 (d,
J ) 6.7 Hz, 2H); 13C NMR (CDCl3) δ 28.3, 31.5, 34.2, 44.0,
115.3, 128.7, 129.4, 130.2, 137.7, 145.2, 154.6, 170.3. Anal.
(C18H22BrNO4) C, H, N.
2.27 (t, J ) 5.2 Hz, 2H), 2.83(m, 4H), 3.20 (br, 2H), 3.45 (br,
2H), 6.94-7.03 (m, 3H), 7.10-7.23 (m, 5H). Anal. (C23H27FN2O‚
1.5HCl) C, H, N.
N,N-Dieth yl-4-(2-th iop h en ylp ip er id in -4-ylid en em eth -
yl)ben za m id e (6m ). Method as for 6h but using 2-thiophen-
ylboronic acid provided 6m in quantitative yield: 1H NMR
(CDCl3) δ 1.12 (br, 3H), 1.20 (br, 3H), 2.24 (t, J ) 5.2 Hz, 2H),
2.50 (t, J ) 5.2 Hz, 2H), 2.85 (t, J ) 5.6 Hz, 2H), 2.92 (t, J )
5.6 Hz, 2H), 3.27 (br, 2H), 3.51 (br, 2H), 6.75 (d, J ) 3.6 Hz,
1H), 6.93 (t, J ) 3.6 Hz, 1H), 7.16 (d, J ) 7.2 Hz, 2H), 7.21 (d,
J ) 3.6 Hz, 1H), 7.30 (d, J ) 7.2 Hz, 2H). Anal. (C21H26N2OS‚
1.5HCl) C, H, N.
4-[Br om o(4-dieth ylcar bam oylph en yl)m eth ylen e]piper -
id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (8). To a solution
of 17 (1.0 g, 2.5 mmol) in dry dichloromethane (10 mL) at -
20 °C was added isobutyl chloroformate (450 mg, 3.3 mmol).
After 20 min at -20 °C diethylamine (4 mL) was added and
the reaction was allowed to warm to room temperature. After
1.5 h the solvents were evaporated and the residue was
partitioned between ethyl acetate and water. The organic
phase was washed with brine and dried over MgSO4. Removal
of solvents provided a crude product, which was purified by
flash chromatography (0-60% ethyl acetate in heptanes) to
give 8 as white needles (800 mg, 73%): 1H NMR (CDCl3) δ
1.13 (br, 3H), 1.22 (br, 3H), 1.44 (s, 9H), 2.22 (t, J ) 5.5 Hz,
2H), 2.62 (t, J ) 5.5 Hz, 2H), 3.31 (t, J ) 5.5 Hz, 2H), 3.52 (t,
J ) 5.5 Hz, 2H), 7.27 (d, J ) 7.9 Hz, 2H), 7.33 (d, J ) 7.9 Hz,
2H); 13C NMR (CDCl3) δ 12.71, 14.13, 28.3, 31.5, 34.2, 39.1,
43.2, 79.7, 115.9, 126.3, 129.3, 136.8, 137.1, 140.6, 154.6, 170.5.
Anal. (C22H31BrN2O3) C, H, N.
N,N-Diet h yl-4-[p ip er id in -4-ylid en e(3-t r iflu or om et h -
ylp h en yl)m eth yl]ben za m id e (6h ). A mixture of 8 (500 mg,
1.1 mmol), 3-trifluoromethylphenylboronic acid (500 mg, 2.6
mmol), 2 M Na2CO3 (3 mL), and tetrakis(triphenylphosphine)-
palladium(0) (20 mg) in toluene (degassed, 5 mL) and ethanol
(degassed, 5 mL) was refluxed at 85 °C for 5 h under N2. The
reaction mixture was then cooled to room temperature and
extracted with ethyl acetate (2 × 100 mL). The combined
organic phases were dried over MgSO4 and evaporated to give
a crude product (18a ).
The above product (18a ) was treated with 4.0 M HC1 in
dioxane at room temperature for 2 h. After evaporation, the
residue was dissolved in 1 M HCl (100 mL) and impurities
were extracted with diethyl ether (3 × 100 mL). The aqueous
phase was basified with NH4OH and extracted with dichlo-
romethane (3 × 100 mL). The combined organic phases were
washed with brine, dried over MgSO4 and evaporated to give
6h (291 mg, 64%): 1H NMR (CDCl3) δ 1.13 (brm, 3 H, CH3-
CH2-), 1.22 (brm, 3 H, CH3CH2-), 1.96 (s, 1 H, NH), 2.28 (m, 2
H, piperidine CH-), 2.33 (m, 2 H, piperidine CH-), 2.92 (m, 4
H, piperidine CH-), 3.29 (brm, 2 H, CH3CH2N-), 3.54 (brm, 2
H, CH3CH2N-), 7.13 (d, J ) 8.0 Hz, 2 H, ArH), 7.28-7.48 (m,
6 H, ArH). HCl salt: mp > 85 °C dec; IR (NaCl) 3409, 1620
cm-1. Anal. (C24H27 F3N2O‚1.3HCl) C, H, N.
N,N-Dieth yl-4-(4-m eth ylth ioph en ylpiper idin -4-yliden e-
m eth yl)ben za m id e (6n ). Method as for 6h but using 4-meth-
ylthiophenylboronic acid provided 6n in quantitative yield: 1H
NMR (CDCl3) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.32-2.75 (m, 4H),
2.45 (s, 3H), 2.90-2.87 (m, 4H), 3.26 (br, 2H), 3.51 (br, 2H),
7.01 (d, J ) 6.0 Hz, 2H), 7,10 (d, J ) 6.0 Hz, 2H), 7.15 (d, J )
6.8 Hz, 2H), 7.27 (d, J ) 6.8 Hz, 2H). Anal. (C24H30N2OS‚
2.5HCl) C, H, N.
N,N-Dieth yl-4-(3-am in oph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6o). Method as for 6h but using 3-aminophen-
ylboronic acid provided 6o in quantitative yield: 1H NMR
(CDCl3) δ 1.11 (br, 3H), 1.20 (br, 3H), 2.27-2.33 (m, 4H), 2.86-
2.90 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.57 (br, 2H), 3.68
(s, 1H), 6.39 (s, 1H), 6.52 (dd, J ) 1.6 Hz, J ) 7.6 Hz, 2H),
7.06 (t, J ) 8.0 Hz, 1H), 7.12 (d, J ) 6.4 Hz, 2H), 7.26 (d, J )
6.4 Hz, 2H). Anal. (C23H29N3O‚1.2HCl) C, H, N.
N,N-Dieth yl-4-(4-m eth oxyp h en ylp ip er id in -4-ylid en e-
m eth yl)ben za m id e (6p ). Method as for 6h but using 4-meth-
oxyphenylboronic acid provided 6p in quantitative yield: 1H
NMR (CDCl3) δ 1.12 (br, 3H), 1.19 (br, 3H), 2.29 (m, 4H), 2.87
(m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.77 (s, 3H), 6.80 (m, 2H),
7.00 (m, 2H), 7.10 (d, J ) 8.4 Hz, 2H), 7.26 (d, J ) 8.4 Hz).
Anal. (C24H30N2O2‚1.95HCl) C, H, N.
N,N-Dieth yl-4-(2-m eth oxyp h en ylp ip er id in -4-ylid en e-
m eth yl)ben za m id e (6q). Method as for 6h but using 2-meth-
oxyphenylboronic acid provided 6q in quantitative yield: 1H
NMR (CDCl3) δ 1.09 (br, 3H), 1.18 (br, 3H), 2.10 (q, J ) 4.8
Hz, 2H), 2.31 (q, J ) 4.8 Hz, 2H), 2.8-2.9 (m, 4H), 3.25 (br,
2H), 3.50 (br, 2H), 3.68 (s, 3H), 6.83-6.90 (m, 2H), 7.0 (d, 1H),
7.15-7.25 (m, 5H). Anal. (C24H30N2O2‚1.5HCl) C, H, N.
N,N-Diet h yl-4-[(1-m et h ylp ip er id in -4-ylid en e)p h en yl-
m eth yl]ben za m id e (19a ). N,N-Diethyl-4-[(piperidin-4-yli-
dene)phenylmethyl]benzamide (6a ; 0.35 g, 1.0 mmol) was
dissolved in acetonitrile (5 mL). Potassium carbonate (0.14 g,
1.0 mmol) and methyl iodide (63 µL, 1.0 mmol) were added
with stirring at 25 °C. After 30 min, the reaction mixture was
evaporated and put onto silica gel for purification by chroma-
tography using 0 to 10% MeOH (10% NH4OH) in CH2Cl2 to
give 48 mg of the final product (28% of converted starting
material), which was converted to the hydrochloride salt by
treatment with HCl in ether: 1H NMR (CDCl3) δ 1.1 (m, 6H,
amide-Me), 2.40 (s, 3H, MeN), 2.49, 2.60 (2m, 8H, piperazine-
H), 3.40 (m, 4H, amide-CH2) 7.08-7.34 (m, 9H, Ar-H). HCl
salt: mp g 110 °C dec; IR (KBr) 1695 cm-1. Anal. (C24H30N2O‚
3.2HCl) C, H, N.
N,N-Dieth yl-4-(3,4-d ich lor op h en ylp ip er id in -4-ylid en e-
m eth yl)ben za m id e (6i). Method as for 6h using 8 (600 mg,
1.3 mmol) and 3,4-dichlorophenylboronic acid (500 mg, 2.6
mmol) provided 6i (437 mg, 79%): 1H NMR (CDCl3) δ 1.12
(br, 3H), 1.20 (br, 3H), 2.28 (t, J ) 5.6 Hz, 4H), 2.89 (m, 4H),
3.27 (br, 2H), 3.52 (br, 2H), 6.8-7.4 (m, 7H). Anal. (C23H26
Cl2N2O‚1.5HCl) C, H, N.
-
N,N-Dieth yl-4-(3-acetylph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6j). Method as for 6h using 8 (500 mg, 1.1
mmol) and 3-acetylphenylboronic acid (500 mg, 3.0 mmol)
provided 6j (401 mg, 93%): 1H NMR (CDCl3) δ 1.11 (br, 3H),
1.20 (br, 3H), 2.06 (brs, 1H), 2.28 (m, 2H), 2.34 (m, 2H), 2.55
(s, 3H), 2.92 (m, 4H), 3.26 (br, 2H), 3.51 (br, 2H), 7.15 (d, J )
8.0 Hz, 2H), 7.32 (d, J ) 8.0 Hz, 2H), 7.35 (d, J ) 7.2 Hz, 1H),
7.40 (t, J ) 8.0 Hz, 1H), 7.74 (s, 1H), 7.81 (d, J ) 7.2 Hz, 1H).
Anal. (C25H30N2O2‚1.8HCl) C, H, N.
N,N-Dieth yl-4-(3-n itr op h en ylp ip er id in -4-ylid en em eth -
yl)ben za m id e (6k ). Method as for 6h but using 3-nitrophen-
ylboronic acid provided 6k in quantitative yield: 1H NMR
(CDCl3) δ 1.11 (br, 3H), 1.21 (br, 3H), 2.27-2.34 (m, 4H), 2.92
(t, J ) 6.0 Hz, 4H), 3.26 (br, 2H), 3.52 (br, 2H), 7.10 (d, J )
8.4 Hz, 2H), 7.31 (d, J ) 8.4 Hz, 2H), 7.40-7.50 (m, 2H), 7.95-
8.08 (m, 2H). Anal. (C23H27N3O3‚1.4HCl) C, H, N.
N,N-Dieth yl-4-(ph en yl-N-allylpiper idin -4-yliden em eth -
yl)ben za m id e (19b). Method as described for compound 19a ,
using allyl bromide as the alkylating reagent provided 19b
(86%): 1H NMR (CDCl3) δ 1.12 (brs, 3H), 1.21 (brs, 3H), 2.43
(m, 4H), 2.55 (m, 4H), 3.08 (d, J ) 6.8 Hz, 2H), 3.25 (brs, 2H),
3.53 (brs, 2H), 5.18 (m, 2H), 5.86 (m, 1H), 7.12 (m, 4H), 7.20
(m, 1H), 7.27 (m, 4H). HCl salt: mp 85-95 °C (CH2Cl2); IR
(KBr) 1624 cm-1. Anal. (C26H32N2O‚1.6HCl) C, H, N.
N,N-Dieth yl-4-[N-(3-m eth yl-2-bu ten yl)ph en ylpiper idin -
4-ylid en em eth yl]ben za m id e (19c). Method as described for
compound 19a , using 1-bromo-3-methyl-2-butene as the al-
kylating reagent provided 19c (71%): 1H NMR (CDCl3) δ 1.10-
1.30 (br, 6 H, OCNCH2CH3), 1.64 (s, 3 H, dCCH3), 1.73 (s, 3
H, dCCH3), 2.40 (m, 4 H, NCH2CH2), 2.52 (m, 4 H, dCCH2),
3.0 (d, J ) 7.6 Hz, 2 H, NCH2CHdC), 3.20-3.60 (br, 4 H,
N,N-Dieth yl-4-(2-flu or oph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (6l). Method as for 6h but using 2-fluorophen-
ylboronic acid provided 6l in quantitative yield: 1H NMR
(CDCl3) δ 1.11 (br, 3H), 1.15 (br, 3H), 2.10 (t, J ) 5.2 Hz, 2H),

3904 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Wei et al.
OCNCH2CH3), 5.28 (m, 1 H, NCH2CHdC), 7.16-7.45(m, 9 H,
Ar). HCl salt: IR (NaCl) 1623 cm-1. Anal. (C28H36N2O‚1.8HCl)
C, H, N.
from 2-parameter logistic curve fits of percent specific binding
vs log(molar ligand), solving for IC50 and Hill slope.
3. GTP [γ-35S] Bin d in g Assa ys. Membranes expressing 10
pmol of hDOR/mg protein were combined with test compounds
and approximately 0.2 nM GTP[γ-35S] in 50 mM Hepes, 20
mM NaOH, pH 7.4, 5 mM MgCl2, 100 mM NaCl, 1 mM EDTA,
1 mM DTT, 0.1% BSA, 15 µM GDP. The bound radioactivity
was determined after 1 h by filtration. Control and stimulated
binding were determined in the absence and presence of 3 µM
SNC-80, respectively. Values of EC50 and Emax for ligands were
obtained from 3-parameter logistic curve fits of percent
stimulated GTP[γ-35S] binding vs log(molar ligand), solving for
N,N-Dieth yl-4-(N-bu tylph en ylpiper idin -4-yliden em eth -
yl)ben za m id e (19d ). Method as described for compound 19a ,
using 1-iodobutane as the alkylating reagent provided 19d
(85%): 1H NMR (CDCl3) δ 0.92 (t, J ) 7.2 Hz, 3 H, CH2CH3),
1.10-1.26 (br, 6 H, OCNCH2CH3), 1.32 (m, 2 H, CH2CH3), 1.53
(m, 2 H, CH2CH2CH2), 2.42 (m, 6 H, NCH2), 2.55 (m, 4 H, d
CCH2), 3.20-3.60 (br, 4 H, OCNCH2CH3), 7.10-7.31 (m, 9 H,
Ar). HCl salt: IR (NaCl) 1622 cm-1. Anal. (C27H36N2O‚1.9HCl)
C, H, N.
EC50, Hill slope, and %Emax
.
N,N-Dieth yl-4-(1-cyclop r op ylm eth ylp h en ylp ip er id in -
4-ylid en em eth yl)ben za m id e (19e). Method as described for
compound 19a , using compound 6 and cyclopropylmethyl
chloride provided 19e (86%): 1H NMR (CDCl3) δ 0.20 (m, 2H),
0.59 (m, 2H), 1.04 (m, 1H), 1.14 (brs, 3H), 1.24 (brs, 3H), 2.48
(d, J ) 6.4 Hz, 2H), 2.56 (brs, 4H), 2.80 (brs, 4H), 3.29 (brs,
2H), 3.53 (brs, 2H), 7.14 (m, 4H), 7.22 (m, 1H), 7.27 (m, 4H);
13C NMR (CDCl3) δ 4.18, 7.3, 12.8, 14.1, 30.3, 39.2, 43.2, 54.3,
62.7, 126.2, 126.6, 128.0, 129.5, 129.6, 134.1, 135.3, 136.3,
141.5, 142.9, 171.0. HCl salt: dec g 100 °C (CH2Cl2); IR (KBr)
1620 cm-1. Anal. (C27H34N2O‚2.3HCl) C, H, N.
4. In Vitr o Meta bolic Stu d ies. In cu ba tion con d ition s:
All incubations [rat liver microsomes (0.4 mg/mL proteins;
Xenotech LLC, Kansas City, KS), substrate at 10 or 100 nmol/
L, 1 mM NADPH, 100 mM phosphate buffer at pH 7.4] were
performed in duplicate in disposable 96-well plates on a gently
shaking platform maintained at 37 °C. Control incubations
were carried out by incubating the same substrate concentra-
tions in phosphate buffer without rat liver microsomes or
NADPH. The final assay volume was 500 µL, containing 1%
DMSO (test article stock solutions were prepared at 10 mM
in DMSO).
4-[(1-Cycloh exylp ip er id in -4-ylid en e)p h en ylm et h yl]-
N,N-d ieth ylben za m id e (19f). A mixture of 6a (100 mg, 0.29
mmol), cyclohexanone (36 ul, 0.35 mmol) and Ti(OPr-i)4 (0.17
mL, 0.58 mmol) was ultrasonicated for 1 h and then stirred
at room temperature overnight under a nitrogen atmosphere.
The mixture was diluted with ethanol (5 mL) followed by
addition of NaBH4 (33 mg, 0.87 mmol). The resulting mixture
was stirred for 12 h at room temperature. 2 N NH3‚H2O was
added to quench the reaction and the mixture filtered through
Celite. The filtrate was extracted with ethyl acetate several
times and the combined organic phases were washed with
water and brine and dried over Na2SO4. Concentration in
vacuo and MPLC purification (0:100 to 100:0 EtOAc:heptane
eluting on silca gel 60) gave the title compound 11f (24 mg,
20%): 1H NMR (CDCl3) δ 1.00-1.25 (m, 19H), 1.60 (m, 1H),
1.75 (1H, m), 1.80 (m, 1H), 2.30 (m, 3H), 2.60 (m, 2H), 3.20
(bs, 2H), 3.50 (bs, 2H), 7.00-7.30 (m, 9H); 13C NMR (CDCl3) δ
12.7, 14.1, 25.9, 28.7, 32.0, 39.1, 43.2, 50.7, 50.8, 63.6, 126.0,
126.3, 127.9, 129.7, 129.8, 134.7, 134.9, 136.9, 142.0, 143.4,
171.2; mp (HCl salt) 105-109 °C. Anal. (C29H38N2O‚2.0HCl)
C, H, N.
Incubations were started by the addition of NADPH (or
buffer for NADPH-free controls) and were stopped after 0 and
60 min by the addition of 500 µL of ice-cold acetonitrile. The
precipitated proteins were removed following a 10-min cen-
trifugation at 8500g and the supernatants were analyzed for
parent drug by a benchtop LC-MSD system.
An a lytica l con d ition s: Aliquots (5 µL) of the supernatants
were directly injected onto a Zorbax Eclipse XDB C18 column
(4.6 × 30 mm, 3.5-µm particles) using a micro plate sampler
(HP220, Hewlett-Packard, Kirkland, Quebec, Canada). The
mobile phase consisted of a mixture of acetonitrile, methanol
and 0.04% formic acid in water (60-80:0-15:15-30, v/v). The
flow rate was 1.0 mL/min. The LC system (HP1100, Hewlett-
Packard) was equipped with a quaternary pump (Hewlett-
Packard) and linked to a mass selective detector (MSD) with
an electrospray interface (Hewlett-Packard). The MSD was
operated in selected ion monitoring mode (the selected m/z
being that of the parent compound). Nebulizer pressure was
60 psi, while the drying gas (nitrogen) was delivered at 13
L/min. The capillary voltage was 3500 V, and the fragmentor
(collision-induced dissociation cell) was set at 70 eV.
4-[(1-P h en ylp ip er id in -4-ylid en e)p h en ylm et h yl]-N,N-
d ieth ylben za m id e (19g).A mixture of 6a (44 mg, 0.13 mmol),
phenyl bromide (20 uL, 0.19 mmol), Pd(dba)2 (1 mg, 0.0017
mmol), BINAP (2.5 mg, 0.004 mmol) and sodium tert-butoxide
(20 mg, 0.20 mmol) in 2 mL toluene was heated at 80-90 °C
for 12 h, under a nitrogen atmosphere. The solvent was
removed in vacuo and the residure purified by MPLC (0 to
100% of EtOAc in heptane on silica gel) to give the desired
title compound 19g (30 mg, 56%): 1H NMR (CDCl3) δ 1.0-1.4
5. Resu lts (p a r en t d r u g d isa p p ea r a n ce fr om th e in -
cu ba tion m ed iu m ). The parent drug peak area in the 0-min
incubation sample was considered to be the 100% value, and
parent drug levels were expressed as percent (%) parent
remaining.
6. Molecu la r Mod elin g Stu d ies. Models of compound 6a
and SNC-80 were constructed with standard parameters in
Sybyl 6.2 (Tripos Inc., 1699 South Hanley Rd., St. Louis, MO
63144) using a SGI workstation (Indigo 2). The random
conformational search and energy minimization were per-
formed using the Tripos force field. An energy window of 5
kcal/mol (Ei - Emin) was used to collect low-energy conformers.
The rotatable bonds with an interval of 30° were further used
to classify the low-energy conformers. There were 12 different
conformers for 6a and 159 for SNC-80. The representative
conformers were then compared between the two compounds.
The superposition of the conformers was carried out with the
piperazine ring (for SNC-80) or piperidine ring (for 6a ) and
the right-hand phenyl rings. The superposition of X-ray
structures of 6a and SNC-80 was carried out between five
points: the two nitrogen atoms of the piperazine ring, the
centroid points of the two phenyl rings, and the carbon atom
of the carbonyl group.
(m, 6H), 2.45 (m, 4H), 3.1-3.7 (m, 8H), 6.8-7.5 (m, 14H); 13
C
NMR (CDCl3) δ 12.77, 13.97, 31.29, 39.10, 43.21, 51.03, 116.23,
119.21, 126.12, 126.49, 127.98, 128.98, 129.66, 129.72, 135.13,
135.63, 135.73, 141.81, 143.15, 151.00, 171.09; IR (HCl salt)
1616 cm-1. Anal. (C29H32N2O‚1.7HCl) C, H, N.
Biologica l Assa ys. 1. Cell Cu ltu r e a n d Mem br a n e
P r ep a r a tion . Human HEK-293S cells were subject to stable
transfection with cDNA encoding the human µ, δ, and κ
receptors. Clones were chosen for high receptor expression and
grown in suspension culture. Cells were harvested and P2
membrane preparations were produced.
2. Recep tor Bin d in g Assa ys. Membranes were combined
with test compounds and approximately 0.07 nM of the
appropriate radioligand [125I][D-Ala2]deltorphin II (Kd ) 0.93
nM at δ), [125I]FK33824 (Kd ) 1.14 nM at µ), and [125I]-D-Pro10-
dynorphin A[1-11] (Kd ) 0.16 nM at κ) in 50 mM Tris, 3 mM
MgCl2, 1 mg/mL BSA, pH 7.4. The amounts of bound radio-
activity were determined at equilibrium by filtration. The
nonspecific (NS) binding was defined in the presence of 10 µM
naloxone. The IC50 values of test compounds were determined
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