3-(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: Potent, non-peptidic agonists of both the μ and δ opioid receptors

Article abstract of DOI:10.1021/jm020395s

Opioid analgesics with both μ and δ opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to μ agonism, with a reduced side effect profile resulting from δ agonism. Replacing the p-diethylamide of the known potent δ opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the μ and δ opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the μ and δ opioid receptors have been identified, including (+)-3-((αR)-α ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N-(4-flourophenyl)-N-methylbenzamide (23), which has EC₅₀ values of 0.67 and 1.1 nM at the μ (guinea pig ileum assay) and δ (mouse vas deferens assay) opioid receptors, respectively.

Full text of DOI:10.1021/jm020395s

J . Med. Chem. 2003, 46, 623-633
623
3-(rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zin yl)-3-h yd r oxyben zyl)-
N-a lk yl-N-a r ylben za m id es: P oten t, Non -P ep tid ic Agon ists of Both th e µ a n d δ
Op ioid Recep tor s
Michael J . Bishop,*,† Dulce M. Garrido,† G. Evan Boswell,† Mark A. Collins,† Philip A. Harris,†
Robert W. McNutt,‡ Scott J . O’Neill,‡ Ke Wei,‡ and Kwen-J en Chang‡
GlaxoSmithKline Research and Development, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, North Carolina 27709,
and Ardent Pharmaceuticals, Inc., 631 United Drive, Suite 200, Durham, North Carolina 27713
Received September 11, 2002
Opioid analgesics with both µ and δ opioid receptor activation represent a new approach to
the treatment of severe pain with an improved safety profile. Compounds with this profile
may exhibit strong analgesic properties due to µ agonism, with a reduced side effect profile
resulting from δ agonism. Replacing the p-diethylamide of the known potent δ opioid receptor
selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity
at both the µ and δ opioid receptors. Modifying the amide to an N-methyl-N-phenylamide
increased agonist potency at both receptors. A series of 3-(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the
structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent
agonists of both the µ and δ opioid receptors have been identified, including (+)-3-((RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylben-
zamide (23), which has EC50 values of 0.67 and 1.1 nM at the µ (guinea pig ileum assay) and
δ (mouse vas deferens assay) opioid receptors, respectively.
In tr od u ction
The clinical treatment of moderate to severe pain
relies on traditional opioid analgesics, such as morphine
(1) and fentanyl (2) (Figure 1).1 These powerful anal-
gesics relieve pain primarily through agonism of µ opioid
receptors. While µ opioid agonists produce profound
analgesia, their use is also associated with some del-
eterious physiological effects, such as respiratory de-
F igu r e 1.
pression, muscle rigidity, emesis, constipation, and
physical dependence.2 The search for potent analgesics
discovery of the δ opioid receptor antagonist naltrindole,
with reduced side effects continues because of the
suboptimal pharmacological profile of current µ opioid
analgesics.
the first reported δ selective non-peptide opioid ligand.7
Over the past decade, non-peptidic δ opioid receptor
selective agonists have also been discovered. Selective
δ opioid receptor agonists have been disclosed in several
The existence of at least two other opioid receptors
structural classes, including morphinans,8 octahydroiso-
quinolines,9 phenoxyethylpiperidines,10 and benzhy-
drylpiperazines.11 These small-molecule agonists have
been valuable tools in evaluating the role of the δ opioid
receptor in nociception and other physiological events.
While there are δ opioid receptor agonists in preclini-
cal development, there are no current marketed opioid
analgesics that interact primarily with the δ opioid
receptor. The proposed therapeutic application for δ
agonists in development is typically treatment of hype-
ralgesia, not operative or postoperative analgesia. In our
evaluation of BW373U86 (3) (Figure 2), a potent,
selective δ opioid receptor agonist in the benzhydrylpip-
erazine series, the analgesic efficacy and potency of this
compound did not meet our expectations for treatment
of severe pain, and proconvulsant activity precluded
further development.12 However, BW373U86 did not
cause respiratory depression in laboratory animals and
may in fact reverse or block typical µ opioid agonist
induced respiratory depression.13
(µ, δ, and κ opioid receptors have been cloned, expressed,
and sequenced),3 and evidence for various subtypes4
have led to new avenues of opioid research. Agonism,
partial agonism, or even antagonism at one of these
receptors or subtypes could lead to a therapeutically
useful agent for pain, drug addiction, and urological or
gastrointestinal disorders possibly lacking the side
effects associated with µ opioid receptor agonism. Early
research in these labs and many others focused on
exploring the therapeutic potential of δ opioid receptor
specific agonists.
To evaluate the physiological effects of δ opioid
receptor activation, selective agonists and antagonists
have been explored.5 Small peptides provided early
examples of δ opioid receptor selective ligands.6 An
important breakthrough in the field was Portoghese’s
* To whom correspondence should be addressed. Phone: (919) 483-
9581. Fax: (919) 315-0430. E-mail: michael.j.bishop@gsk.com.
† GlaxoSmithKline Research and Development.
‡ Ardent Pharmaceuticals, Inc.
10.1021/jm020395s CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/21/2003

624 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4
Bishop et al.
F igu r e 3.
Ta ble 1. δ and µ Opioid Activitya
F igu r e 2.
EC50 (nM)
Ki (nM)
δ agonism
µ agonism
(GPI)
δ binding
µ binding
This exciting result added to the evidence that δ
opioid receptor agonists modulate and/or potentiate µ
opioid effects.14 Recent work in rats has shown that
hypercapnia induced by the highly µ selective opioid
agonist alfentanil can be reversed by a number of δ
selective agents in addition to BW373U86, including
naltrindole, cyclic [D-Pen2,5]enkephalin, deltorphin II,
and H-Tyr-Tic(ψ)[CH2NH]Phe-Phe-OH.15 However, the
δ selective agents did not lessen the analgesic effect of
the µ selective agonist. In this study, both traditional δ
receptor agonists and antagonists reversed the respira-
tory effects of alfentanil. However, a new δ antagonist,
DPI-2505 (Figure 2), blocked the effects of all of these
agents on alfentanil-induced hypercapnia. This suggests
that in this study, δ antagonists naltrindole and H-Tyr-
Tic(ψ)[CH2NH]Phe-Phe-OH behave like δ agonists with
low but sufficient intrinsic activities to reverse alfen-
tanil-induced hypercapnia in rats. In another study,13
when BW373U86 and fentanyl were coadministered to
mice, BW373U86 convulsive activity was attenuated by
fentanyl in a dose-dependent manner and the fentanyl-
induced Straub tail effect (indicative of muscle rigidity)
was also attenuated by BW373U86, again in a dose-
dependent manner. However, hot-plate analgesic activ-
ity was additive between the two compounds.
compd
(MVD)
(RBM)
(RBM)
morphine
fentanyl
19700 ( 170 51 ( 4
490 ( 15 4.5 ( 1.4
150 ( 7
90
400
1.8
1
1.5
15
BW373U86 0.2 ( 0.21
4
5
5.85 ( 0.40 4.35 ( 0.71 2.1
3.2
0.47 ( 0.30 1.22 ( 0.15 1.06 ( 0.04 1.55 ( 0.09
1.70 ( 0.25 59.5 ( 8.81 1.37 ( 0.28 1.06 ( 0.47
0.96 ( 0.06 0.94 ( 0.14 2.17 ( 0.30 3.39 ( 0.03
14
15
16
17
18
19
20
21
23
24
25
26
27
28
29
30
31
32
2.40 ( 0.07 18
1.42 ( 0.13 1.23 ( 0.24 1.92 ( 0.14 2.37 ( 0.50
1.70 ( 0.2 41 9.20 ( 0.03 8.88 ( 0.57
1.05 ( 0.15 11.5 ( 1.85 1.18 ( 0.06 2.55 ( 0.49
5.60 ( 0.3 6.07 ( 0.54 1.88 ( 0.27 2.16 ( 0.08
0.34 ( 0.07 6.6 ( 1.25 1.75 ( 0.23 2.19 ( 0.5
1.26 ( 0.20 1.82 ( 0.10
1.10 ( 0.2
0.67
1.40 ( 0.06 1.49 ( 0.03
0.18 ( 0.03 0.46 ( 0.08
0.79 ( 0.54 3.4 ( 1.6
0.69 ( 0.1
2.60 ( 0.6
4.1 ( 0.52 1.69 ( 0.17 1.58 ( 0.32
4.9
2.73 ( 0.92 3.46 ( 0.41
0.95 ( 0.15 5.6 ( 1.14 2.31 ( 0.15 2.74 ( 0.46
0.36 ( 0.04 1.1 ( 0.10 2.01 ( 0.33 2.35 ( 0.17
2.30 ( 0.32 4.1 ( 0.52 2.41 ( 0.48 2.78 ( 1.06
1.40 ( 0.1
0.68 ( 0.09 1053
25.3 ( 3.2 1800
4
6.95 ( 1.27 7.08 ( 1.32
2.75 ( 0.58 7.06 ( 0.49
11.39 ( 0.10 7.56 ( 1.17
a
Each value is an average of at least three runs ( SEM. MVD
) mouse vas deferens; GPI ) guinea pig ileum; RBM ) rat brain
membranes. [3H]Deltorphin II and [3H]DAMGO were used for the
δ and µ receptor binding studies, respectively. See Experimental
Section for full descriptions of the assays.
Our recent goal has been to exploit the exciting
intermodulatory effects of µ and δ opioid receptor
activation to develop useful therapeutic agents. Re-
search efforts in the benzhydrylpiperazine series have
shifted from the development of δ selective compounds
to identifying non-peptidic mixed δ/µ agonists that will
show strong analgesic properties due to µ agonism, with
a reduced side effect profile resulting from δ agonism.16
If one wishes to extend the message-address concept
that Portoghese developed for δ opioids to benzhydryl-
piperazines, the phenol/piperazine region of BW373U86
could correspond to the tyrosine residue found in
enkephalins, the putative opioid “message” domain
essential for receptor activation.17 The diethylamide is
appropriately positioned as the δ opioid “address”
region, the part of the molecule that confers opioid
receptor-type selectivity. Dondio and co-workers have
previously stated this hypothesis and have published
an elegant application of the diethylamide as a nonaro-
matic δ opioid address (Figure 3).18 Our results support
this hypothesis, since the location of the amide on
BW373U86 and related structures has a profound
influence on δ/µ opioid receptor selectivity (Figure 4).
Movement of the diethylamide from the para position
of BW373U86 to the meta position of the phenyl ring
(4) produced a 30-fold increase in µ activity and a 30-
fold decrease in δ activity. Changing the m-diethylamide
to a m-N-methylanilide (5) resulted in both a 12-fold
increase in δ agonism and a 3-fold increase in µ agonist
activity (see Table 1).19
The biological activity of 5 represented a break-
through in the search for potent mixed δ/µ opioid
agonists. Changes to the m-N-methylanilide were made
to probe the structural limitations of this phenomenon.
A series of 3-(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-pip-
erazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides
have been synthesized and show potent µ and δ opioid
receptor agonism in vitro.
Ch em istr y
Convergent, stereoselective synthetic approaches to
BW373U86 have been reported.20 However, because the
main focus of this research effort was to establish the
specific structure-activity relationship surrounding the
amide portion of the 3-(RR)-R-((2S,5R)-4-allyl-2,5-dim-
ethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-aryl-
benzamides, a divergent approach was taken, with the
amides synthesized from a common late intermediate,
acid chloride 6 (Scheme 1). The general strategy for
formation of the benzhydrylpiperazine opioids was to
first assemble the benzhydryl portion from the two
separate aromatic fragments and then to attach the
functionalized piperazine ring.

Arylbenzamides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 625
F igu r e 4.
Sch em e 1
Sch em e 2
The aromatic ring that will eventually bear the amide
group was introduced into the synthesis via 3-bro-
mobenzaldehyde. The benzhydryl portion of the molec-
ular framework was formed by treating the tert-
butyldimethylsilyl ether of 3-bromophenol with n-butyl-
lithium at -78 °C and then adding the solution to
3-bromobenzaldehyde (Scheme 2). This produced a 50:
50 mixture of enantiomeric benzhydryl alcohols (7). The
racemic benzhydryl alcohol was converted to the ben-
zhydryl chloride 8 using thionyl chloride in dichlo-
romethane at room temperature. Without purification,
the benzhydryl chloride was treated with (-)-(2R,5S)-
1-allyl-2,5-dimethylpiperazine 9 and deprotected to give
benzhydrylpiperazine 10 as a mixture of epimers at the
benzhydryl position. The silyl protecting group was
removed to improve the efficiency of the silica gel
column chromatography, which yielded the two enan-
tiopure isomers. The absolute stereochemistry was
proven by transforming a single stereoisomer of 10 into
a crystalline analogue and determining the structure
by X-ray crystallography (for example, the X-ray struc-
ture of the 3-fluorophenyl-N-methyl analogue 24 was
determined).21
cyanide using cuprous cyanide in N-methylpyrrolidinone
(Scheme 1).24 The nitrile was hydrolyzed using aqueous
potassium hydroxide, and the resulting carboxylic acid
was converted to the acid chloride via the tert-butyldim-
ethylsilyl ester, using oxalyl chloride and catalytic DMF
(this transformation also reprotected the phenol as the
TBDMS ether).25
All of the substituted anilines used to make anilides
have been previously reported. However, some of these
were not commercially available and were prepared by
various literature procedures. N-Methyl compounds
were prepared by N-formylation of the appropriate
aniline using the mixed anhydride method (acetic/formic
anhydride), followed by borane/dimethyl sulfide reduc-
tion to the N-methylaniline.26 Similarly, N-ethyl, N-
propyl, and N-butyl compounds were prepared by
acylation of the aniline followed by borane reduction of
the amide.27 N-Cyclopropylaniline was prepared from
cyclopropylamine via adaptation of Barton’s phenylation
procedure using triphenylbismuth and copper acetate.28
All of these anilines reacted readily with acid chloride
6 in the presence of triethylamine to produce, after
deprotection of the phenol using tetraethylammonium
fluoride, the desired targets. The descarbonyl compound
32 was prepared via allane reduction of compound 24
using a literature procedure.29
(-)-(2R,5S)-1-Allyl-2,5-dimethylpiperazine 9 has been
prepared by direct enantiospecific synthesis19,22 and via
classical resolution of the racemic piperazine.23 Kiloscale
batches of (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine 9
have been prepared from nonchiral trans-2,5-dimeth-
ylpiperazine by a three-step monoallylation, followed by
a resolution using di-p-toluoyl-D-tartaric acid.
Resu lts a n d Discu ssion
The δ and µ opioid agonist activities of the 3-(RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy-
benzyl)-N-alkyl-N-arylbenzamides were evaluated using
the mouse vas deferens (MVD) and guinea pig ileum
The acid chloride was prepared via displacement of
the bromide of bromobenzhydrylpiperazine (+)-10 with

626 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4
Bishop et al.
(GPI) preparations, respectively (see Table 1).30 All new
compounds in this series described in this manuscript
were effective in inhibiting the electrically stimulated
twitch in both the MVD and GPI tissues, indicating that
they profiled as full agonists in this assay within the
limits of differentiation. δ and µ opioid agonist binding
affinities for these compounds are also found in Table
1. These were determined by measuring the displace-
ment of ligand from rat brain membranes, as described
in the Experimental Section. For most compounds in
this series, the binding affinity and agonist potency (and
thus the receptor selectivity) tracked reasonably well.
There are a few instances where compounds were
significantly less potent in the GPI tissue preparations
than in the µ receptor binding assay, and these discrep-
ancies will be highlighted in the discussion below. This
phenomenon has been observed for 7TM receptor ago-
nists, and potency discrepancies between opioid receptor
in vitro binding and functional assays have been previ-
ously discussed.31
To investigate the SAR of the m-N-alkyl-N-arylben-
zamide portion of this series, the following structural
modifications were made: (1) variation of the N-alkyl
chain; (2) placement of an alkyl linker between the
amide nitrogen and the N-aryl ring; (3) substitution on
the N-aryl ring; and (4) replacement of the amide
carbonyl with a methylene.
Synthesis of the des-N-methyl analogue of 5 resulted
in a compound (14) with significantly reduced µ agonist
activity (however, this compound retained its ability to
bind to µ receptors on rat brain membranes, since the
µ RBM Ki values for 14 and 5 are indistinguishable).
Lengthening the alkyl chain to N-ethyl (15) was well-
tolerated, but an order of magnitude drop in µ activity
was observed upon lengthening the chain from N-ethyl
to N-n-propyl (16). N-Cyclopropyl (17) was tolerated and
was roughly equipotent at the δ and µ receptors. N-n-
butyl (18) resulted in a further 2-fold decline in µ
activity beyond the N-n-propyl analogue 16.
ring. The p-fluoro (23), m-fluoro (24), and o-fluoro (25)
analogues of 5 were potent agonists at both the δ and µ
receptors. While there were small differences in potency
between the analogues with substituents on the phenyl
ring, no small substituent caused a significant loss of
either µ or δ opioid activity. Further examples include
the o-trifluoromethyl (27), p-methoxy (28), and p-ni-
troaniline (29) analogues, all of which were tolerated
by both receptors, with compound 28 slightly more
potent at δ and µ than 27 and 29.
Combining the p-fluoro feature that brought good
potency at both the δ and µ receptors in compound 23
with the acceptable alkyl chains ethyl (15) or propyl (16)
gave interesting results. The N-ethyl-p-fluorophenyl
compound (30) showed potency close to that of 23 and
15, with a slight (∼5-fold) drop in µ activity. However,
The N-propyl-p-fluorophenyl compound (31) showed δ
receptor potency close to that of 16 but lost a significant
amount of µ activity, dropping to an EC50 greater than
1000 nM. This makes it a δ receptor-selective agonist,
with receptor agonism selectivity similar to BW373U86.
Like BW373U86, the binding affinity selectivity is not
as great as the functional agonism selectivity because
of an apparent difference in the ability of compound 31
to activate µ receptors in guinea pig ileum smooth
muscle and its ability to bind to and displace [3H]-
DAMGO from rat CNS µ receptors. Several reasons for
these differences are possible, including possible species
or tissue differences in the pharmacology.31a
An analogue of the potent m-fluoro compound 24 was
also prepared that lacked the amide carbonyl (32). While
this molecule was still an agonist at both receptors, it
lost >30-fold potency at the δ receptor and >500-fold
in µ activity (this resulted in a tissue selectivity that
was not mirrored in the binding affinities). The presence
of the carbonyl is likely important in orienting the amide
N-alkyl and N-aryl substituents into a favorable con-
formation for receptor activation.
Con clu sion s
It is interesting that both removing the N-alkyl chain
and lengthening the chain (to n-propyl and n-butyl)
resulted in increases in δ vs µ activity selectivity. In
this series, when increased selectivity is observed, the
selectivity is due to a decrease in the ligand’s agonist
potency at the µ receptor, not to an increase in potency
at the δ receptor. Constraining the N-propylanilide as
the tetrahydroquinoline amide (19) resulted in a com-
pound that was slightly more potent at both δ and µ
receptors. It appears that the area of the µ receptor
where these molecules interact does not readily accom-
modate anything larger than a propyl group on the
amide for activation, but it is important to have a small
alkyl group there for potent µ receptor activation.
Insertion of a spacer between the anilide nitrogen and
the aromatic ring was explored. The N-benzyl-N-me-
thylamide (20) was an order of magnitude less potent
than compound 5 at the δ receptor and roughly 5-fold
less potent at the µ receptor. Curiously, the N-methyl-
N-phenethylamide (21) regained the δ receptor potency
without picking up µ activity.
To exploit the exciting intermodulatory effects of δ
and µ receptor ligands, our research efforts in the
benzhydrylpiperazine series have shifted from the de-
velopment of δ selective compounds to identifying non-
peptidic mixed δ/µ agonists that will show strong
analgesic properties due to µ agonism, with a reduced
side effect profile resulting from δ agonism. Mixed δ/µ
agonists were discovered in the benzhydrylpiperazine
series by moving the p-diethylamide δ address portion
of the molecule to the meta position of the phenyl where
it no longer conferred δ selectivity. Changing the
m-diethylamide to a m-N-methylanilide resulted in a
potency increase at both the δ and µ receptors, and a
series of 3-(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piper-
azinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have
been synthesized to explore the µ and δ opioid receptor
agonism SAR. A number of various 3-(RR)-R-((2S,5R)-
4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-
alkyl-N-arylbenzamides have been identified that show
significant opioid activity at the µ and δ receptors. Many
small functional groups are tolerated on the aryl ring.
Additionally, N-methyl through N-propyl substituents
can be placed on the amide nitrogen and retain activity.
Increasing the size of the substituents (and increasing
From exploration of the effect of substitution on the
anilide phenyl ring, it was discovered that most small
substituents were reasonably well-tolerated. Small halo-
gens were very good at all positions on the aromatic

Arylbenzamides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 627
Mem br an e P r epar ation an d Opioid Radioligan d Bin d-
in g Assa ys. The δ and µ opioid receptor binding affinities of
the 3-(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
droxybenzyl)-N-alkyl-N-arylbenzamides were evaluated using
rat brain membranes obtained from brain tissue of Sprague-
Dawley rats. The brain tissue was rinsed with ice-cold 50 mM
Tris-HCl buffer (pH 7.4, 25 °C) containing the following
protease inhibitors: 50 µg/mL soybean trypsin inhibitor, 0.1
mM phenylmethylsulfonyl fluoride (PMSF), 1 mM (ethylene-
dinitrilo)tetraacetic acid (EDTA), 10 µg/mL leupeptin, 200 µg/
mL bacitracin, and 0.5 µg/mL aprotinin. Brains were homog-
enized in 5-10 volumes per gram wet weight in ice-cold 50
mM Tris buffer containing protease inhibitors. The homo-
genate was prepared using a glass/Teflon homogenizer and
centrifuged at 6000g for 15 min at 4 °C. The resulting
supernatant was centrifuged at 41000g for 30 min at 4 °C.
The pellet was suspended in 10 volumes per gram wet weight
of 10 mM Tris-sucrose buffer and sonicated with a Polytron
tissue grinder (10 s, low speed). The homogenate was then
centrifuged at 41000g for 30 min at 4 °C. The resulting
membrane pellet was resuspended in 50 mM Tris buffer with
protease inhibitors at a final protein concentration that ranged
from 40 to 50 µg/mL. The membrane preparation was frozen
under liquid N2 and stored at -80 °C prior to use in receptor
binding studies. Protein determination was determined by the
method described by Bradford.33 Membrane fractions were
incubated with 0.1 nM [3H]deltorphin II or 0.1 nM [3H]-
DAMGO in 2 mL of 10 mM Tris-HCl buffer containing 5 mM
MgCl2 and protease inhibitors in the presence or absence of
DPI-125. Incubation was carried out for 90 min at 25 °C. These
conditions permitted the complete equilibration of the radio-
ligand with opioid receptors. The reaction was terminated by
rapid filtration through Whatman GF/C glass fiber filters
using a cell harvester (model M-48R, Brandel Instruments,
Gaithersburg, MD) followed by three 3 mL rinses with ice-
cold 50 mM Tris buffer. Nonspecific binding was defined as
that radioligand bound in the presence of 1 × 10-6 M naloxone.
Filters were counted by liquid scintillation spectrometry at an
efficiency determined by external standards of 50-65%.
flexibility by removing the carbonyl) resulted in com-
pounds with increasing δ selectivity by reducing µ
agonist activity. These compounds may be putting a
lipophilic group back into part of the δ address region
that was occupied by the p-diethylamide.
The identification of several compounds that have in
vitro potencies in the 1-5 nM range at both the µ and
δ receptors, such as compounds 5, 15, 17, 23-26, and
28-30, has provided useful tools to test the pharmaco-
logical effects of mixed δ/µ opioid agonists. In vivo work
demonstrating that these opioid agonists exhibit a
promising therapeutic profile will be reported in due
course.
Exp er im en ta l Section
Melting points were determined with a Thomas-Hoover
apparatus and are uncorrected. All chemical reagents were
purchased from Aldrich Chemical Co., Milwaukee, WI, unless
otherwise specified. Commercial solvents were used without
further purification except tetrahydrofuran, which was dis-
tilled from potassium. Nuclear magnetic resonance (NMR)
spectra were obtained with Varian XL-200 and XL-300 spec-
trometers. HPLC analyses were performed with a Waters
liquid chromatography system equipped with a 700 satellite
WISP, 600E system controller, and a 991 photodiode array
detector, with a 4.6 mm × 250 mm Cyclobond I column
(Advanced Separations Technologies, Whippany, NJ ) at a flow
rate of 1 mL/min. Optical rotations were obtained with a
Perkin-Elmer 241 polarimeter. Mass spectra were performed
by Oneida Research Services, Whitesboro, NY. X-ray crystal-
lography and structural determination of compound 24 were
performed by Dr. Steven J . Geib at the University of Pitts-
burgh Chemistry X-Ray Diffraction Facility on a Siemens P3
single-crystal diffractometer. Analytical thin-layer chroma-
tography was performed on Analtech glass plates precoated
with silica gel GF (250 microns). Elemental analyses were
performed by Atlantic Microlab, Norcross, GA.
Receptor binding data were analyzed by a nonlinear regres-
sion of the one-site competition model to determine the IC50
and Ki values using a computer program, Prism (GraphPad
Software Inc., San Diego, CA). The apparent dissociation
constants, Ki values, were determined by the method of Cheng
and Prusoff.34
In Vitr o Bioa ssa ys. The δ and µ opioid agonist activities
of the 3-(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
hydroxybenzyl)-N-alkyl-N-arylbenzamides were evaluated us-
ing the mouse vas deferens (MVD) and guinea pig ileum (GPI)
preparations, respectively.30
Vas deferens were isolated from mice weighing 20-25 g
following cervical dislocation. Muscles were dissected and
suspended in individual organ baths containing Mg-free
Krebs-Henseleit solution (37 °C, aerated with O2/CO2, 95:5)
of the following composition (millimolar): NaCl, 117.5; KCl,
4.75; CaCl2, 2.6; KH2PO4, 1.2; NaHCO3, 24.5; glucose, 11.
The vas deferens segments were positioned between plati-
num electrodes and connected to a Grass FTO3 isometric force
transducer. Muscles were stimulated to contract by adminis-
tering 400 ms pulse trains (1 ms duration, supramaximal
voltage, 10 Hz) with a Grass S88 stimulator; resting tension
was 0.5 g.
3-Br om op h en yl ter t-Bu tyld im eth ylsilyl Eth er . A mix-
ture of 3-bromophenol (1400 g, 8.1 mol), tert-butylchlorodim-
ethylsilane (1218 g, 8.1 mol), and imidazole (1376 g, 20.2 mol)
in DMF was stirred at room temperature under nitrogen for
18 h. The reaction mixture was poured into pH 8 aqueous
buffer and extracted with Et2O. The ether extracts were
washed with water and brine and dried over sodium sulfate,
and the solvent was evaporated under vacuum to give 2314 g
of crude 3-bromophenyl tert-butyldimethylsilyl ether as an
orange oil. NMR (CDCl3, 200 MHz): δ 0.2 (s, 6H), 0.95 (s, 9H),
6.8 (m, 1H), 7.0-7.1 (m, 3H).
r-(3-Br om op h en yl)-3-(ter t-bu tyld im eth ylsilyloxy)ben -
zyl Alcoh ol (7). 3-Bromophenyl tert-butyldimethylsilyl ether
(1771 g, 6.17 mol) was dissolved in dry THF (4 L) under
nitrogen and cooled to -78 °C. n-Butyllithium (3.85 L of a 1.6
M solution in hexane) was added at a rate to keep the
temperature below -70 °C. Stirring was continued at -78 °C
for 2 h. A solution of 3-bromobenzaldehyde (1119 g, 6.05 mol)
in dry THF (600 mL) was added at a rate to keep the reaction
temperature below -70 °C. After the mixture was stirred for
2 h at -78 °C, the reaction was quenched with saturated
aqueous NH4Cl (1.4 L) and the mixture was warmed to room
temperature. The mixture was filtered to remove solids. The
organic phase was washed with brine, dried over sodium
sulfate, and evaporated to give 2.5 kg of crude R-(3-bromophe-
nyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol as a yellow oil.
Chromatography on silica gel of 1 kg of the crude product with
hexane/dichloromethane (gradient from 90:10 to 75:25, fol-
lowed by dichloromethane/ethyl acetate at a ratio of 90:10)
Intact ileums (about 3 cm in length) were removed from
guinea pig and suspended with 1 g of tension in a bath
chamber as described for the vasa deferentia. The modified
Krebs’s buffer also contained MgSO4 (1.20 mM). The ileums
were stimulated with electrical square-wave pulses of 0.1 Hz,
0.5 ms pulse duration at supramaximal voltage.
To establish cumulative concentration-response relation-
ships, the compound was added to organ baths and allowed
to produce maximal response before addition of the next higher
concentration. The percentage inhibition of the electrically
induced muscle contractions was determined for the com-
pounds at varying cumulative concentrations. The EC50 values
were extrapolated from curves showing the dose-concentra-
tion plotted against the response.32 Each reported value is the
average of at least three experiments, with average standard
error of the mean (SEM) values of (22% and (17% for the
MVD and GPI assay results, respectively.

628 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4
Bishop et al.
gave 692.3 g of R-(3-bromophenyl)-3-(tert-butyldimethylsilyl-
oxy)benzyl alcohol as a yellow oil. NMR (CDCl3, 200 MHz): δ
0.2 (s, 6H), 0.95 (s, 9H), 2.3 (br s, 1H), 5.7 (s, 1H), 6.75 (d, J )
8 Hz, 1H), 6.8 (s, 1H), 6.9 (d, J ) 8 Hz, 1H), 7.2 (m, 2H), 7.3
(d, J ) 8 Hz, 1H), 7.4 (d, J ) 8 Hz, 1H), 7.5 (s, 1H).
r-(3-Br om op h en yl)-3-(ter t-bu tyld im eth ylsilyloxy)ben -
zyl Ch lor id e (8). Thionyl chloride (38 mL, 0.51 mol) was
added dropwise to a solution of benzhydryl alcohol 7 (160 g,
0.41 mol) in 1 L of CH2Cl2, and the mixture was stirred
overnight at room temperature. The solvent was removed
under vacuum, the residue was dissolved in toluene, and the
solvent was again removed under vacuum to give crude R-(3-
bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl chloride as
a brown oil. The benzhydryl chloride was used without further
purification. NMR (CDCl3, 200 MHz): δ 0.2 (s, 6H), 0.95 (s,
9H), 6.0 (s, 1H), 6.8-7.0 (m, 3H), 7.2-7.6 (m, 5H).
a previous small-scale resolution) and cooled to room temper-
ature over 2-3 h. The solution was slowly stirred for 2 days
at room temperature. The resulting salt was collected by
filtration, washed twice with 95% EtOH, and dried under
vacuum to give 826.5 g of a white solid (47%). The process
was repeated with a second batch of the di-p-toluoyl-D-tartaric
acid and racemic trans-1-allyl-2,5-dimethylpiperazine to give
869 g (50%).
The total of 1695 g of salt was divided into three batches,
and each batch was recrystallized twice from 95% ethanol. The
total amount recovered was 1151 g. The salt was dissolved in
3 L of 2 M aqueous NaOH, and the aqueous solution was
extracted with four 1 L portions of CH2Cl2. The organic
extracts were combined and dried over sodium sulfate, and
the solvent was removed by rotary evaporation (temperature
less than 20 °C) to give 293 g (29% based on racemic weight)
of (2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil. [R]20
D
(-)-(2R,5S)-1-Allyl-2,5-d im eth ylp ip er a zin e (9). A 12 L,
three-necked round-bottom flask was charged with trans-2,5-
dimethylpiperazine (767 g, 6.72 mol). The flask was cooled in
an ice bath, and a solution of methanesulfonic acid (1290 g,
13.4 mol) in 600 mL of water was added slowly, maintaining
the temperature below 40 °C. The solution was cooled to 20
°C, and 800 mL of ethanol was added. The pH was adjusted
to 4.0 with 60% aqueous potassium acetate, then ethyl
chloroformate (642 mL, 6.71 mol in 360 mL of THF) and
potassium acetate solutions were simultaneously added drop-
wise with adjustment of rate to maintain the reaction solution
at pH 4.0 ( 0.1, with cooling to maintain temperature at 25
°C. After the mixture was stirred an additional hour, the
organic solvents were removed and the remaining aqueous
solution was washed with ethyl acetate. The ethyl acetate
wash was extracted with two 500 mL portions of 1 M HCl to
recover the desired product. The acid extracts were combined
with the original aqueous solution, and the pH was adjusted
to 11 by addition of 10 M NaOH, with cooling to maintain
temperature below 40 °C. The aqueous solution was extracted
with ethyl acetate, the combined extracts were dried over
magnesium sulfate, and the solvent was removed to give 927
g (74%) of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate as
a yellow oil.
-55.1° (c 1.2, absolute ethanol). The trifluoroacetamide of the
product was prepared with trifluoroacetic anhydride and
analyzed by chiral capillary gas chromatography (Chiraldex
B-PH column, 20 m × 0.32 mm, Advanced Separation Tech-
nologies Inc., Whippany, NJ , 120 °C) indicating an enantio-
purity of >99% ee (retention time of desired enantiomer, 11.7
min; other enantiomer, 10.7 min).
3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zin yl)-
3-br om oben zyl)p h en ol (10). A mixture of benzhydryl chlo-
ride 8 and (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine 9 (137.6
g, 0.89 mol) in 1500 mL of acetonitrile was heated at reflux
for 48 h and concentrated in vacuo, and the residue was
dissolved in ethyl acetate. The mixture was washed with 0.25
M aqueous NaOH, dried over sodium sulfate, and concentrated
in vacuo to give 202.6 g of dark oil, which was dissolved in
acetonitrile (1 L) and treated with tetraethylammonium
fluoride dihydrate (88.9 g, 0.48 mol). After the mixture was
stirred at room temperature overnight, the solvent was
removed under vacuum. The residue was dissolved in CH2Cl2
(2 L), washed with pH 8 aqueous buffer solution, dried over
sodium sulfate, and concentrated to give 163 g of a dark solid.
A portion (11 g) of this solid was purified by chromatography
on silica gel with ethanol (0-2.5%) in CH2Cl2. An amount of
2.2 g of (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazi-
nyl)-3-bromobenzyl)phenol, the second spot to elute, was
obtained as a white solid. NMR (DMSO-d6, 200 MHz): δ 0.95
(d, J ) 6 Hz, 3H), 1.03 (d, J ) 6 Hz, 3H), 1.8 (dd, J 1 ) 6 Hz,
J 2 ) 10 Hz, 1H), 2.1 (dd, J 1 ) 6 Hz, J 2 ) 10 Hz, 1H), 2.4-2.6
(m, 3H), 2.7 (d, J ) 11 Hz, 1H), 2.8 (dd, J 1 ) 7 Hz, J 2 ) 14 Hz,
1H), 3.2 (dd, J 1 ) 6 Hz, J 2 ) 13 Hz, 1H), 4.9 (s, 1H), 5.1 (d, J
) 10 Hz, 1H), 5.2 (d, J ) 18 Hz, 1H), 5.7-5.9 (m, 1H), 6.6-
6.8 (m, 3H), 7.0-7.4 (m, 4H), 7.55 (s, 1H), 9.35 (s, 1H).
A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxy-
late (643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and
sodium carbonate (440 g, 4.15 mol) in 2.5 L of CH3CN was
heated at reflux for 1.5 h. The reaction mixture was cooled to
room temperature and filtered, and the solvent was removed
under vacuum. The residue was dissolved in 4 L of CH2Cl2,
washed with 1 M NaOH, and dried over magnesium sulfate,
and the solvent was removed to give 630 g (81%) of ethyl trans-
4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.
Acid Ch lor id e (6) P r ep a r a tion . (+)-3-((rR)-r-((2S,5R)-
4-Allyl-2,5-dim eth yl-1-piper azin yl)-3-h ydr oxyben zyl)ben -
zon itr ile. Compound (+)-10 (147.3 g, 0.355 mol) was dissolved
in 1 L of N-methyl-2-pyrrolidinone with cuprous cyanide (63.6
g, 0.71 mol), and the reaction mixture was heated at 170 °C
for 30 h.24 The reaction mixture was cooled to room temper-
ature and poured into 7 L of aqueous 14% sodium cyanide.
The mixture was stirred overnight and extracted with ethyl
acetate. The ethyl acetate extracts were combined, washed
with water, dried over sodium sulfate, and concentrated in
vacuo to give 133.3 g of a brown solid. Chromatography on
silica gel with ethanol (2-7%) in CH2Cl2 gave 97.8 g of crude
(+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
droxybenzyl) benzonitrile. Recrystallization from acetonitrile
gave 74.2 g (58%) of (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-hydroxybenzyl)benzonitrile as a white solid.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)ben zoic Acid . (+)-3-((RR)-R-((2S,5R)-
4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoni-
trile (78.8 g, 0.22 mol) was combined with 60 g of NaOH pellets
in 1 L of 95% EtOH and heated at reflux for 72 h. The mixture
was concentrated in vacuo and dissolved in water, and the
resulting solution was adjusted to pH 5 with concentrated HCl.
The solvent was removed in vacuo to give 138.8 g of the
3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630
g, 2.78 mol) was added to a solution of 87% potassium
hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol,
and the mixture was heated at reflux for 1.5 h. The reaction
mixture was cooled below reflux temperature, and 2 L of
toluene was carefully added. Ethanol was removed by azeo-
tropic distillation at 105 °C while adding an additional 4 L of
toluene to the reaction flask during the course of the distilla-
tion. After collection of 9 L of distillate, the reaction mixture
was cooled to 100 °C and 1 L of toluene was added. The
solution was slowly cooled to 5 °C and maintained at 5 °C for
30 min. The solution was filtered, and the filter cake was
washed with an additional 1.5 L of toluene. The filtrate was
washed with 1 L of water and dried over magnesium sulfate,
and the solvent was removed to give 296 g (69%) of trans-1-
allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,
DMSO-d6): δ 0.87 (d, J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.3 Hz,
3H), 1.63 (t, J ) 11 Hz, 1H), 2.05 (m, 1H), 2.30 (t, J ) 11 Hz,
1H), 2.6-2.8 (m, 4H), 3.33 (dd, J 1 ) 5 Hz, J 2 ) 14 Hz, 1H),
5.09 (d, J ) 8.7 Hz, 1H), 5.13 (d, J ) 14 Hz, 1H), 5.8 (m, 1H).
Di-p-toluoyl-D-tartaric acid (1.25 kg, 3.2 mol) was dissolved
in hot 95% EtOH (16 L), and racemic trans-1-allyl-2,5-
dimethylpiperazine (500 g, 3.2 mol) was added in several
portions (caution: exothermic). The hot solution was seeded
with crystals of the stereoisomerically pure salt (obtained from

Arylbenzamides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 629
droxybenzyl)benzoic acid as a mixture with sodium chloride.
A portion (5.0 g) of the crude acid was stirred with 50 mL of
water. The resulting slurry was filtered and the solid in the
filter was washed three times with water and then dried under
vacuum for 3 h to give 2.02 g of (+)-3-((RR)-R-((2S,5R)-4-allyl-
2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid as a
light-beige solid. NMR (DMSO-d6, 200 MHz): δ 0.95 (d, J ) 6
Hz, 3H), 1.1 (d, J ) 6 Hz, 3H), 1.9 (ddd, J 1 ) 3 Hz, J 2 ) 7 Hz,
J 3 ) 10 Hz, 1H), 2.1 (dd, J 1 ) 8 Hz, J 2 ) 10 Hz, 1H), 2.5 (m,
2H), 2.7-2.9 (m, 2H), 3.2 (m, 2H), 5.05 (d, J ) 12 Hz, 1H), 5.2
(d, J ) 18 Hz, 1H), 5.8 (m, 1H), 6.7 (m, 3H), 7.1 (t, J ) 8 Hz,
1H), 7.4 (t, J ) 8 Hz, 1H), 7.65 (d, J ) 8 Hz, 1H), 7.8 (d, J )
Hz, 1H), 5.70-5.82 (m, 1H), 6.41 (d, J ) 7.4 Hz, 1H), 6.54 (s,
1H), 6.64 (d, J ) 8.0 Hz, 1H), 7.05-7.26 (m, 10H), 9.31 (s,
1H). Mass spectrum (CI - CH4) m/e: 470 (M + 1, 100%), 376
(81%), 316 (45%), 153 (97%). [R]20D +12.3° (c 1.2, ethanol). The
free amine (0.339 g) was dissolved in ethanol and titrated with
ethanolic hydrogen chloride to pH 3.0 followed by precipitation
with diethyl ether from dichloromethane to give 0.321 g (88%
recovery) of the monohydrochloride salt as a hygroscopic light-
yellow powder. Anal. (C30H35N3O2‚HCl‚H2O) C, H, N, Cl.
Gen er a l N-Meth yla n ilin e F or m a tion Meth od . N-Meth -
yl-4-flu or oa n ilin e (22). Following a general literature pro-
cedure for reductive alkylation, acetic-formic anhydride was
prepared by slowly adding formic acid (7.5 mL) to acetic
anhydride at 0 °C.26 After being stirred for 5 min at 0 °C, the
mixture was heated at 55 °C for 1.75 h. The mixture was cooled
to 0 °C and used without purification. 4-Fluoroaniline (3.1 mL,
32.8 mmol) in THF (10 mL) was added to acetic-formic
anhydride (12.5 mL, 88 mmol) at 0 °C. The reaction mixture
was stirred for 25 min, and the volatiles were removed under
vacuum to provide the formamide as a brown solid. A portion
of the crude solid (2.39 g, 17.2 mmol) was dissolved in THF (8
mL) and cooled to 0 °C. Borane in THF (40 mL of a 1.0 M
solution) was added dropwise. After the addition, the solution
was heated to reflux and maintained for 3 h. The solution was
cooled to 0 °C, and methanol (10 mL) was added carefully.
After the mixture was stirred for 10 min, ethanolic HCl (7 mL
of a 7.1 M solution) was added and the reaction was stirred
overnight. After removal of all volatiles in vacuo, crude
N-methyl-4-fluoroaniline was obtained as a light-purple solid.
NMR (200 MHz, DMSO-d6): δ 2.65 (s, 3H), 5.54 (s, 1H), 6.51
8 Hz, 1H), 8.0 (s, 1H), 9.4 (s, 1H). [R]20 +4.1° (c 1.09, 0.1 M
D
aqueous sodium hydroxide). Mass spectrum (CI - CH4) m/e:
381 (M + 1, 35%), 380 (M, 2%), 227 (28%), 155 (100%), 153
(83%). Anal. (C23H28N2O3‚0.75H2O) C, H, N.
3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zin yl)-
3-(ter t-bu tyld im eth ylsilyloxy)ben zyl)ben zoyl Ch lor id e
(6). 3-((RR)-R-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-
hydroxybenzyl)benzoic acid (25.9 g of a 50 wt % mixture with
sodium chloride, 34.0 mmol) was dissolved in 40 mL of DMF
with 12.8 g (84.9 mmol) of tert-butylchlorodimethylsilane and
11.5 g (169.1 mmol) of imidazole, and the mixture was stirred
overnight at room temperature. The reaction solution was
poured into 500 mL of ice/water and extracted with 500 mL
of Et2O. The extract was washed twice with 250 mL of water
and then with 125 mL of brine. The ether solution was dried
over sodium sulfate, and the solvent was removed to give 20.8
g of crude tert-butyldimethylsilyl 3-((RR)-R-((2S,5R)-4-allyl-2,5-
dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-
benzoate.
The crude silyl ether/silyl ester (20.7 g, e33.9 mmol based
on the previous reaction) was dissolved in 60 mL of dichlo-
romethane and cooled to 0 °C under nitrogen. Oxalyl chloride
(3.7 mL, 42.4 mmol) was added dropwise. While the bath
temperature was maintained at 0 °C, catalytic DMF (10 drops)
was added slowly. The bath temperature was maintained at
0 °C for 30 min and then allowed to warm to room tempera-
ture. The solution was stirred at room temperature for 24 h.
All of the volatiles were removed by evaporation under reduced
pressure to give 29.76 g of crude 3-((RR)-R-((2S,5R)-4-allyl-
2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)ben-
zyl)benzoyl chloride as a yellow-brown solid. The crude acid
chloride was used without purification.
(dd, J 1 ) 4.7 Hz, J 2 ) 8.8 Hz, 2H), 6.93 (dd, J 1 ) 8.9 Hz, J 2
8.8 Hz, 2H).
)
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-(4-flu or op h en yl)-N-m eth ylben -
za m id e (23). 23 was prepared from 3-((RR)-R-((2S,5R)-4-
a llyl-2,5-dim et h yl-1-piper a zin yl)-3-(ter t-bu t yldim et h yl-
silyloxy)benzyl)benzoyl chloride and 4-fluoro-N-methylaniline
as described above. (+)-3-((RR)-R-((2S,5R)-4-Allyl-2,5-dimethyl-
1-piperazinyl)-3-(hydroxybenzyl)-N-(4-fluorophenyl)-N-meth-
ylbenzamide was obtained as a yellow powder. NMR (300
MHz, DMSO-d6): δ 0.88 (d, J ) 6.0 Hz,3H), 0.96 (d, J ) 6.0
Hz, 3H), 1.68 (dd, J 1 ) 7.7 Hz, J 2 ) 10.8 Hz, 1H), 2.02 (dd, J 1
) 7.1 Hz, J 2 ) 10.7 Hz, 1H), 2.28 (br d, J ) 10.7 Hz, 1H),
2.35-2.52 (m, 2H), 2.66 (br d, J ) 10.6 Hz, 1H), 2.82 (dd, J 1
)
Gen er a l Ben za m id e F or m a t ion Met h od . (+)-3-
((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zin yl)-3-(h y-
d r oxyben zyl)-N-m eth yl-N-p h en ylben za m id e (5). 3-((RR)-
R-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldim-
ethylsilyloxy)benzyl)benzoyl chloride (2.33 g of crude, approx-
imately 1.44 g of actual compound, 2.81 mmol based on 3-((RR)-
R-((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxyben-
zyl)benzoic acid) was dissolved in 12 mL of dichloromethane
at room temperature under nitrogen. Triethylamine (0.5 mL)
was added to the solution. N-Methylaniline (0.46 mL, 4.3
mmol) was added dropwise to the solution, and the reaction
mixture was stirred overnight at room temperature. All
volatiles were removed by evaporation under reduced pressure
to provide a gummy brown solid. This crude solid was dissolved
in acetonitrile (8 mL) under nitrogen at room temperature.
Tetraethylammonium fluoride dihydrate (1.19 g, 6.42 mmol)
was added, and the solution was stirred for 1 h at room
temperature. After removal of solvent, the residue was purified
by chromatography on silica gel with 0.5-2% ethanol in
dichloromethane to give 0.368 g (28% over four steps from
3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy-
droxybenzyl)benzoic acid) of (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-
dimethyl-1-piperazinyl)-3-(hydroxybenzyl)-N-methyl-N-phe-
nylbenzamide as a light-yellow solid. NMR (300 MHz, DMSO-
d6): δ 0.89 (d, J ) 6.0 Hz, 3H), 0.96 (d, J ) 6.0 Hz, 3H), 1.66
(dd, J 1 ) 7.3 Hz, J 2 ) 11.4 Hz, 1H), 2.01 (dd, J 1 ) 7.8 Hz, J 2
) 10.6 Hz, 1H), 2.26 (br d, J ) 10.6 Hz, 1H), 2.37-2.54 (m,
7.4 Hz, J 2 ) 13.9 Hz, 1H), 3.16 (dd, J 1 ) 4.6 Hz, J 2 ) 14.0 Hz,
1H), 3.32 (s, 3H), 4.77 (s, 1H), 5.10 (d, J ) 10.3 Hz, 1H), 5.16
(d, J ) 17.3 Hz, 1H), 5.70-5.84 (m, 1H), 6.43 (d, J ) 7.4 Hz,
1H), 6.56 (s, 1H), 6.64 (d, J ) 8.0 Hz, 1H), 7.02-7.22 (m, 9H),
9.31 (s, 1H). Mass spectrum (CI - CH4) m/e: 488 (M + 1,-
100%), 334 (11%), 153 (68%). [R]20D +6.9° (c 1.6, ethanol). The
monohydrochloride salt was formed as described above to give
a hygroscopic light-yellow powder. Anal. (C30H34N3O2F‚HCl‚
H2O) C, H, N, F, Cl.
(-)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h ydr oxyben zyl)-N-ph en ylben zam ide (14). This com-
pound was obtained as a light-yellow powder from aniline and
3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-
butyl-dimethylsilyloxy)benzyl)benzoyl chloride as described
above. NMR (200 MHz, DMSO-d6): δ 0.99 (d, J ) 5.7 Hz, 3H),
1.10 (d, J ) 5.8 Hz, 3H), 1.91 (dd, J 1 ) 7.0 Hz, J 2 ) 10.5 Hz,
1H), 2.14 (dd, J 1 ) 6.0 Hz, J 2 ) 10.4 Hz, 1H), 2.51-2.81 (m,
4H), 2.88 (dd, J 1 ) 6.8 Hz, J 2 ) 13.9 Hz, 1H), 3.18 (dd, J 1
)
5.4 Hz, J 2 ) 13.8 Hz, 1H), 5.06 (d, J ) 15.6 Hz, 1H), 5.14 (s,
1H), 5.19 (d, J ) 18.1 Hz, 1H), 5.75 (m, 1H), 6.73 (m, 3H),
7.10 (d, J ) 7.8 Hz, 1H), 7.17 (d, J ) 8.0 Hz, 1H), 7.30-7.59
(m, 3H), 7.65 (d, J ) 7.6 Hz, 1H), 7.71-7.83 (m, 3H), 7.93 (s,
1H), 9.37 (s, 1H), 10.21 (s, 1H). Mass spectrum (CI - CH4)
m/e: 456 (M + 1,100%), 302 (41%), 153 (77%). [R]20D -4.44° (c
1.4, ethanol). The monohydrochloride salt was prepared to give
a hygroscopic light-yellow powder. Anal. (C29H33N3O2‚HCl‚
0.75H2O) C, H, N, Cl.
2H), 2.66 (br d, J ) 11.0 Hz, 1H), 2.82 (dd, J 1 ) 7.0 Hz, J 2
)
13.9 Hz, 1H), 3.17 (dd, J 1 ) 4.8 Hz, J 2 ) 13.9 Hz, 1H), 3.34 (s,
3H), 4.77 (s, 1H), 5.10 (d, J ) 10.1 Hz, 1H), 5.16 (d, J ) 17.3
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-eth yl-N-p h en ylben za m id e (15).

630 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4
Bishop et al.
15 was prepared from 3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chlo-
ride and N-ethylaniline as described above. (+)-3-((RR)-R-
((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-ethyl-N-phenylbenzamide was obtained as a white solid.
NMR (300 MHz, DMSO-d6): δ 0.89 (d, J ) 6.1 Hz, 3H), 0.96
(d, J ) 6.1 Hz, 3H), 1.07 (t, J ) 7.0 Hz, 3H), 1.67 (dd, J 1 ) 7.4
Hz, J 2 ) 10.4 Hz, 1H), 2.02 (dd, J 1 ) 7.4 Hz, J 2 ) 10.6 Hz,
1H), 2.27 (dd, J 1 ) 1.4 Hz, J 2 ) 10.6 Hz, 1H), 2.36-2.52 (m,
was dissolved in ethanol and titrated with ethanolic hydrogen
chloride to pH 3.95 followed by precipitation with diethyl ether
from dichloromethane to give the monohydrochloride salt as
a hygroscopic orange powder. Anal. (C32H37N3O2‚HCl‚1.50H2O)
C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h ydr oxyben zyl)-N-n -bu tyl-N-ph en ylben zam ide (18).
N-Butylaniline was coupled with 3-((RR)-R-((2S,5R)-4-allyl-2,5-
dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-
benzoyl chloride, deprotected, and purified by the methods
described to give (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-(hydroxybenzyl)-N-n-butyl-N-phenylbenza-
mide as an off-white solid. NMR (200 MHz, DMSO-d6): δ 0.87
(t, J ) 7.2 Hz, 3H), 0.92 (d, J ) 6.3 Hz, 3H), 0.98 (d, J ) 6.1
Hz, 3H), 1.29 (m, 2H), 1.48 (m, 2H), 1.70 (dd, J 1 ) 7.4 Hz, J 2
) 10.9 Hz, 1H), 2.05 (dd, J 1 ) 7.3 Hz, J 2 ) 10.6 Hz, 1H), 2.30
(d, J ) 10.1 Hz, 1H), 2.39-2.54 (m, 2H), 2.67 (br d, J ) 10.6
Hz, 1H), 2.86 (dd, J 1 ) 7.4 Hz, J 2 ) 13.7 Hz, 1H), 3.19 (dd, J 1
) 5.1 Hz, J 2 ) 13.7 Hz, 1H), 3.83 (t, J ) 7.4 Hz, 2H), 4.78 (s,
1H), 5.13 (d, J ) 9.9 Hz, 1H), 5.19 (d, J ) 16.0 Hz, 1H), 5.71-
5.86 (m, 1H), 6.43 (d, J ) 7.5 Hz, 1H), 6.57 (s, 1H), 6.65 (d, J
) 8.0 Hz, 1H), 7.03-7.33 (m, 10H), 9.34 (s, 1H). MS (CI -
CH4) m/e: 512 (M + 1,30%), 358 (5%), 153 (40%) 79 (100%).
2H), 2.66 (br d, J ) 10.4 Hz, 1H), 2.82 (dd, J 1 ) 7.8 Hz, J 2
)
13.5 Hz, 1H), 3.16 (dd, J 1 ) 4.0 Hz, J 2 ) 13.9 Hz, 1H), 3.83 (q,
J ) 7.0 Hz, 2H), 4.75 (s, 1H), 5.09 (d, J ) 9.9 Hz, 1H), 5.16 (d,
J ) 17.2 Hz, 1H), 5.70-5.84 (m, 1H), 6.41 (d, J ) 7.6 Hz, 1H),
6.54 (s, 1H), 6.63 (d, J ) 8.2 Hz, 1H), 7.03-7.29 (m, 10H),
9.30 (s, 1H). Mass spectrum (CI - CH4) m/e: 484 (M + 1,-
100%), 330 (57%), 153 (66%). [R]20D +10.4° (c 1.2, ethanol). The
monohydrochloride salt was prepared to give a hygroscopic
white powder. Anal. (C27H37N3O2‚HCl‚H2O): C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h ydr oxyben zyl)-N-ph en yl-N-pr opylben zam ide (16).
N-Propylaniline (Pfaltz & Bauer, Inc., 172 E. Aurora Street,
Waterbury, CT 06708) was coupled with 3-((RR)-R-((2S,5R)-
4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-
benzyl)benzoyl chloride, deprotected, and purified by the
methods described above to give (+)-3-((RR)-R-((2S,5R)-4-allyl-
2,5-dimethyl-1-piperazinyl)-3-(hydroxybenzyl)-N-phenyl-N-pro-
pylbenzamide as a light-yellow solid. NMR (200 MHz, DMSO-
d6): δ 0.87 (t, J ) 7.4 Hz, 3H), 0.91 (d, J ) 5.9 Hz, 3H), 0.98
[R]20 +9.5° (c 1.0, ethanol). The free amine was dissolved in
D
ethanol and titrated with ethanolic hydrogen chloride to pH
4.0 followed by precipitation with diethyl ether from dichlo-
romethane to give the monohydrochloride salt as a hygroscopic
beige powder. Anal. (C33H41N3O2‚HCl‚1.25H2O) C, H, N, Cl.
(d, J ) 6.0 Hz, 3H), 1.51 (m, 2H), 1.69 (dd, J 1 ) 7.2 Hz, J 2
)
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)p h en yl 1,2,3,4-tetr a h yd r o-1-qu in o-
lin yl Keton e (19). 1,2,3,4-Tetrahydroquinoline was coupled
with 3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotect-
ed, and purified by the methods described to give an off-white
powder. NMR (200 MHz, DMSO-d6): δ 0.87 (d, J ) 6.1 Hz,
3H), 0.99 (d, J ) 6.0 Hz, 3H), 1.65 (dd, J 1 ) 7.3 Hz, J 2 ) 10.0
Hz, 1H), 1.86-2.14 (m, 3H), 2.26 (d, J ) 11.6 Hz, 1H), 2.28-
2.39 (m, 1H), 2.45-2.54 (m, 1H), 2.65 (d, J ) 10.9 Hz, 1H),
2.78 (t, J ) 6.3 Hz, 2H), 2.83 (m, 1H), 3.17 (dd, J 1 ) 4.4 Hz, J 2
) 9.2 Hz, 1H), 3.73 (t, J ) 6.1 Hz, 2H), 4.89 (s, 1H), 5.10 (d, J
) 8.4 Hz, 1H), 5.16 (d, J ) 18.3 Hz, 1H), 5.66-5.82 (m, 1H),
6.43 (d, J ) 8.5 Hz, 1H), 6.56 (s, 1H), 6.62-6.71 (m, 2H), 6.86
(t, J ) 7.5 Hz, 1H), 7.00 (t, J ) 7.4 Hz, 1H), 7.07 (t, J ) 7.8
Hz, 1H), 7.20 (d, J ) 7.7 Hz, 1H), 7.25-7.34 (m, 4H), 9.31 (s,
1H). MS (CI - CH4) m/e: 496 (M + 1,100%), 342 (22%), 153
10.9 Hz, 1H), 2.06 (dd, J 1 ) 7.0 Hz, J 2 ) 10.5 Hz, 1H), 2.30 (d,
J ) 10.3 Hz, 1H), 2.39-2.54 (m, 2H), 2.65 (br d, J ) 10.3 Hz,
1H), 2.85 (dd, J 1 ) 7.4 Hz, J 2 ) 14.5 Hz, 1H), 3.16 (dd, J 1
)
5.1 Hz, J 2 ) 14.2 Hz, 1H), 3.79 (t, J ) 7.6 Hz, 2H), 4.77 (s,
1H), 5.12 (d, J ) 10.2 Hz, 1H), 5.18 (d, J ) 16.0 Hz, 1H), 5.71-
5.84 (m, 1H), 6.43 (d, J ) 7.6 Hz, 1H), 6.57 (s, 1H), 6.64 (d, J
) 8.0 Hz, 1H), 7.02-7.33 (m, 10H), 9.32 (s, 1H). Mass spectrum
(CI - CH4) m/e: 498 (M + 1, 100%), 344 (23%), 153 (80%).
[R]20 +8.9° (c 1.1, ethanol). The free amine (0.585 g) was
D
dissolved in ethanol and titrated with ethanolic hydrogen
chloride to pH 4.0 followed by precipitation with diethyl ether
from dichloromethane to give 0.479 g of the monohydrochloride
salt as a hygroscopic off-white powder. Anal. (C32H39N3O2‚HCl‚
0.75H2O) C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyb en zyl)-N-cyclop r op yl-N-p h en ylb en za -
m id e (17). N-Cyclopropylaniline was prepared via the Barton
approach for arylation of amines.28 Cyclopropylamine (1.0 g,
17.5 mmol) was added to triphenylbismuth (9.25 g, 21.0 mmol)
and cupric acetate (1.6 g, 8.75 mmol) in CH2Cl2 (30 mL) at
room temperature under nitrogen. The mixture was stirred
for 18 h, filtered over a short plug of Celite, and purified by
chromatography on a silica gel column using hexane/ethyl
acetate (95:5) for elution. The fraction containing the desired
product was stripped of all volatiles under vacuum to yield
N-cyclopropylaniline (0.8 g). NMR (200 MHz, DMSO-d6): δ
0.37 (m, 2H), 0.68 (m, 2H), 2.30 (m, 1H), 6.03 (br s, 1H), 6.56
(t, J ) 7.4 Hz, 1H), 6.70 (d, J ) 8.2 Hz, 2H), 7.09 (t, J ) 7.8
Hz, 2H).
N-Cyclopropylaniline was then coupled with 3-((RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldim-
ethylsilyloxy)benzyl)benzoyl chloride, deprotected, and purified
by the methods described to give 3-((RR)-R-((2S,5R)-4-allyl-
2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-cyclopropyl-N-
phenylbenzamide as a yellow powder. NMR (200 MHz, DMSO-
d6): δ 0.44 (m, 2H), 0.70 (m, 2H), 0.93 (d, J ) 6.1 Hz, 3H),
1.01 (d, J ) 5.7 Hz, 3H), 1.74 (dd, J 1 ) 7.7 Hz, J 2 ) 11.8 Hz,
1H), 2.05 (dd, J 1 ) 6.8 Hz, J 2 ) 11.1 Hz, 1H), 2.39 (br d, J )
10.5 Hz, 1H), 2.41-2.54 (m, 2H), 2.69 (br d, J ) 11.8 Hz, 1H),
2.83 (dd, J 1 ) 6.6 Hz, J 2 ) 13.6 Hz, 1H), 3.05-3.36 (m, 2H),
4.83 (s, 1H), 5.10 (d, J ) 9.8 Hz, 1H), 5.17 (d, J ) 17.4 Hz,
1H), 5.70-5.86 (m, 1H), 6.57 (d, J ) 7.1 Hz, 1H), 6.63 (s, 1H),
6.65 (d, J ) 8.2 Hz, 1H), 7.03-7.38 (m, 10H), 9.34 (s, 1H).
Mass spectrum (CI - CH4) m/e: 496 (M + 1, 100%), 342 (45%),
153 (90%). [R]20D +7.1° (c 1.1, absolute ethanol). The free amine
(33%). [R]20 +23.2° (c 1.2, absolute ethanol). The free amine
D
was dissolved in ethanol and titrated with ethanolic hydrogen
chloride to pH 4.0 followed by precipitation with diethyl ether
from dichloromethane to give the monohydrochloride salt as
a hygroscopic light-brown powder. Anal. (C32H37N3O2‚HCl‚
0.75H2O) C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h ydr oxyben zyl)-N-ben zyl-N-m eth ylben zam ide (20).
This compound was prepared from 3-((RR)-R-((2S,5R)-4-allyl-
2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)ben-
zyl)benzoyl chloride and N-benzyl-N-methylamine as de-
scribed. NMR (300 MHz, DMSO-d6, 121 °C): δ 0.93 (d, J )
6.2 Hz, 3H), 1.06 (d, J ) 6.2 Hz, 3H), 1.96 (dd, J 1 ) 6.7 Hz, J 2
) 11.0 Hz, 1H), 2.12 (dd, J 1 ) 7.0 Hz, J 2 ) 11.0 Hz, 1H), 2.58
(dd, J 1 ) 2.9 Hz, J 2 ) 11.4 Hz, 1H), 2.67-2.84 (m, 3H), 2.86
(s, 3H), 2.89 (dd, J 1 ) 6.6 Hz, J 2 ) 13.5 Hz, 1H), 3.18 (dd, J 1
) 4.0 Hz, J 2 ) 14.1 Hz, 1H), 4.58 (s, 2H), 4.98 (s, 1H), 5.08 (d,
J ) 10.2 Hz, 1H), 5.16 (d, J ) 17.3 Hz, 1H), 5.74-5.89 (m,
1H), 6.62-6.74 (m, 3H), 7.10 (t, J ) 7.8 Hz, 1H), 7.21-7.50
(m, 9H), 8.76 (s, 1H). Mass spectrum (CI - CH4) m/e: 484 (M
+ 1,88%), 330 (33%), 153 (100%). [R]20D +14.3° (c 1.25, ethanol).
The free amine was dissolved in ethanol and titrated with
ethanolic hydrogen chloride to pH 3.4 followed by precipitation
with diethyl ether from dichloromethane to give (+)-3-((RR)-
R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-benzyl-N-methylbenzamide monohydrochloride as a hygro-
scopic light-yellow powder. Anal. (C31H37N3O2‚HCl‚0.75H2O)
C, H, N, Cl.

Arylbenzamides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 631
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyb e n zyl)-N -m e t h yl-N -p h e n e t h ylb e n za -
m ide (21). N-Methylphenethylamine was coupled with 3-((RR)-
R-((2S ,5R)-4-a llyl-2,5-dim et h yl-1-piper a zin yl)-3-(ter t-
butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected,
and purified by the methods described above to give (+)-3-
((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy-
benzyl)-N-methyl-N-phenethylbenzamide as a light-yellow
powder. NMR (300 MHz, DMSO-d6, 80 °C): δ 0.91 (d, J ) 5.5
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-(4-ch lor op h en yl)-N-m eth ylben -
za m id e (26). 26 was prepared from 3-((RR)-R-((2S,5R)-4-
a llyl-2,5-dim et h yl-1-piper a zin yl)-3-(ter t-bu t yldim et h yl-
silyloxy)benzyl)benzoyl chloride and 4-chloro-N-methylaniline
as described above. (+)-3-((RR)-R-((2S,5R)-4-Allyl-2,5-dimethyl-
1-piperazinyl)-3-hydroxybenzyl)-N-(4-chlorophenyl)-N-methyl-
benzamide was obtained as a light-yellow powder. NMR (300
MHz, DMSO-d6): δ 0.89 (d, J ) 6.2 Hz, 3H), 0.96 (d, J ) 6.1
Hz, 3H), 1.65 (dd, J 1 ) 7.6 Hz, J 2 ) 10.8 Hz, 1H), 2.01 (dd, J 1
) 7.6 Hz, J 2 ) 10.4 Hz, 1H), 2.27 (dd, J 1 ) 1.5 Hz, J 2 ) 11.4
Hz, 1H), 2.35-2.52 (m, 2H), 2.65 (br d, J ) 10.8 Hz, 1H), 2.82
(dd, J 1 ) 7.6 Hz, J 2 ) 13.5 Hz, 1H), 3.16 (dd, J 1 ) 4.5 Hz, J 2
) 14.6 Hz, 1H), 3.33 (s, 3H), 4.77 (s, 1H), 5.10 (d, J ) 10.2 Hz,
1H), 5.16 (d, J ) 17.2 Hz, 1H), 5.70-5.86 (m, 1H), 6.42 (d, J
) 8.1 Hz, 1H), 6.56 (s, 1H), 6.64 (d, J ) 7.5 Hz, 1H), 7.04-
7.25 (m, 5H), 7.13 (d, J ) 8.5 Hz, 2H), 7.29 (d, J ) 8.5 Hz,
2H), 9.31 (s, 1H). Mass spectrum (CI - CH4) m/e: 504 (35Cl,
Hz, 3H), 1.08 (d, J ) 6.3 Hz, 3H), 1.87 (dd, J 1 ) 7.1 Hz, J 2
)
11.2 Hz, 1H), 2.09 (dd, J 1 ) 7.1 Hz, J 2 ) 11.0 Hz, 1H), 2.58 (d,
J ) 11.3 Hz, 1H), 2.67 (m, 1H), 2.76 (dd, J 1 ) 6.2 Hz, J 2
13.2 Hz, 1H), 2.77-2.87 (m, 4H), 2.89 (s, 3H), 3.18 (dd, J 1
)
)
5.5 Hz, J 2 ) 14.2 Hz, 1H), 3.55 (br s, 2H), 4.97 (s, 1H), 5.10 (d,
J ) 10.2 Hz, 1H), 5.16 (d, J ) 17.3 Hz, 1H), 5.74-5.89 (m,
1H), 6.65-6.73 (m, 3H), 7.07-7.41 (m, 9H), 7.43 (d, J ) 7.9
Hz, 1H), 9.07 (s, 1H). Mass spectrum (CI - CH4) m/e: 498 (M
+ 1, 88%), 344 (22%), 153 (100%). [R]20D +3.8° (c 1.25, ethanol).
The free amine (0.232 g) was dissolved in ethanol and titrated
with ethanolic hydrogen chloride to pH 3.9 followed by
precipitation with diethyl ether from dichloromethane to give
0.205 g of the monohydrochloride salt as a hygroscopic light-
yellow powder. Anal. (C32H39N3O2‚HCl‚H2O) C, H, N, Cl.
M + 1, 86%), 350 (28%), 153 (100%). [R]20 +10.2° (c 1.6). The
D
monohydrochloride salt was prepared as described above to
give a hygroscopic light-yellow powder. Anal. (C30H34N3O2Cl‚
HCl‚0.75H2O) C, H, N, Cl.
(-)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-m eth yl-N-(2-(tr iflu or om eth yl)-
p h en yl)b en za m id e (27). N-Methyl-2-(trifluoromethyl)-
aniline35 [NMR (200 MHz, DMSO-d6): δ 2.75 (s, 3H), 3.40 (s,
1H), 6.70 (t, J ) 8.0 Hz, 1H), 6.94-7.16 (br m, 2H), 7.38 (d, J
) 7.3 Hz, 1H)] was coupled with 3-((RR)-R-((2S,5R)-4-allyl-2,5-
dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-
benzoyl chloride, deprotected, and purified by the methods
described to give (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2-(trifluorometh-
yl)phenyl)benzamide as a yellow powder. NMR (200 MHz,
DMSO-d6): δ 0.90 (d, J ) 6.0 Hz, 3H), 0.97 (d, J ) 6.0 Hz,
3H), 1.64 (m, 1H), 2.05 (m, 1H), 2.27 (br d, J ) 10.5 Hz, 1H),
2.40-2.84 (m, 4H), 3.18 (br d, J ) 13.5 Hz, 1H), 3.29 (s, 3H),
4.79 (s, 1H), 5.11 (d, J ) 10.2 Hz, 1H), 5.18 (d, J ) 17.0 Hz,
1H), 5.70-5.82 (m, 1H), 6.42 (d, J ) 7.6 Hz, 1H), 6.65 (d, J )
7.7 Hz, 1H), 6.67 (s, 1H), 7.04-7.83 (m, 9H), 9.32 (s, 1H). Mass
spectrum (CI - CH4) m/e: 538 (M + 1, 82%), 384 (13%), 153
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-(3-flu or op h en yl)-N-m eth ylben -
za m id e (24). 3-Fluoro-N-methylaniline [NMR (200 MHz,
DMSO-d6): δ 2.76 (s, 3H), 3.42 (s, 1H), 6.51-6.92 (m, 3H),
7.28 (dt, J 1 ) 7.3 Hz, J 2 ) 8.0 Hz, 1H)] was prepared from
3-fluoroaniline, coupled with 3-((RR)-R-((2S,5R)-4-allyl-2,5-
dimethyl-1-piperazinyl)-3-(tert-butyldimethyl-silyloxy)benzyl)-
benzoyl chloride, deprotected, and purified by the methods
described to give (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methyl-
benzamide as a light-yellow powder. NMR (200 MHz, DMSO-
d6): δ 0.84 (d, J ) 6.0 Hz, 3H), 0.97 (d, J ) 5.9 Hz, 3H), 1.69
(dd, J 1 ) 7.7 Hz, J 2 ) 10.7 Hz, 1H), 2.01 (dd, J 1 ) 7.4 Hz, J 2
) 10.7 Hz, 1H), 2.28 (br d, J ) 8.3 Hz, 1H), 2.40-2.52 (m,
2H), 2.67 (br d, J ) 10.5 Hz, 1H), 2.82 (dd, J 1 ) 7.6 Hz, J 2
)
13.2 Hz, 1H), 3.17 (br d, J ) 14.0 Hz, 1H), 3.34 (s, 3H), 4.80
(s, 1H), 5.10 (d, J ) 10.1 Hz, 1H), 5.17 (d, J ) 17.3 Hz, 1H),
5.70-5.84 (m, 1H), 6.42 (d, J ) 7.1 Hz, 1H), 6.56 (s, 1H), 6.65
(d, J ) 8.3 Hz, 1H), 6.90-7.32 (m, 9H), 9.31 (s, 1H). Mass
spectrum (CI - CH4) m/e: 488 (M + 1, 100%), 334 (39%), 153
(100%). [R]20 -1.8° (c 1.0, ethanol). The free amine was
D
dissolved in ethanol and titrated with ethanolic hydrogen
chloride to pH 3.7 followed by precipitation with diethyl ether
from dichloromethane to give the monohydrochloride salt as
a hygroscopic beige powder. Anal. (C31H34N3O2F3‚HCl‚0.75H2O)
C, H, N, Cl.
(87%). [R]20 +4.9° (c 1.2, ethanol). The free amine (0.091 g)
D
was dissolved in ethanol and titrated with ethanolic hydrogen
chloride to pH 3.7 followed by precipitation with diethyl ether
from dichloromethane to give 0.072 g (74% recovery) of the
monohydrochloride salt as a hygroscopic light-yellow powder.
Anal. (C30H34N3O2F‚HCl‚1.25H2O) C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyb en zyl)-N-(4-m et h oxyp h en yl)-N-m et h yl-
ben za m id e (28). 4-Methoxy-N-methylaniline was coupled
with 3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotect-
ed, and purified by the methods described to give 3-((RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-(4-methoxyphenyl)-N-methylbenzamide as a light-purple
powder. NMR (200 MHz, DMSO-d6): δ 0.89 (d, J ) 6.0 Hz,
3H), 0.96 (d, J ) 6.1 Hz, 3H), 1.66 (dd, J 1 ) 6.5 Hz, J 2 ) 11.0
Hz, 1H), 2.00 (dd, J 1 ) 7.1 Hz, J 2 ) 10.4 Hz, 1H), 2.27 (br d,
J ) 11.4 Hz, 1H), 2.36-2.54 (m, 2H), 2.64 (d, J ) 11.6 Hz,
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-(2-flu or op h en yl)-N-m eth ylben -
za m id e (25). 2-Fluoro-N-methylaniline [NMR (200 MHz,
DMSO-d6): δ 2.89 (s, 3H), 3.87 (br s, 1H), 6.59-6.78 (m, 2H),
6.91-7.10 (m, 2H)] was prepared from 2-fluoroaniline, coupled
with 3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotect-
ed, and purified by the methods described to give 3-((RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-(2-fluorophenyl)-N-methylbenzamide as an off-white powder.
NMR (200 MHz, DMSO-d6): δ 0.92 (d, J ) 6.1 Hz, 3H), 0.99
(d, J ) 6.1 Hz, 3H), 1.69 (dd, J 1 ) 6.7 Hz, J 2 ) 10.8 Hz, 1H),
2.05 (dd, J 1 ) 7.6 Hz, J 2 ) 11.1 Hz, 1H), 2.30 (br d, J ) 11.5
Hz, 1H), 2.41-2.52 (m, 2H), 2.68 (br d, J ) 10.4 Hz, 1H), 2.83
(dd, J 1 ) 7.2 Hz, J 2 ) 13.8 Hz, 1H), 3.20 (dd, J 1 ) 6.1 Hz, J 2
) 14.2 Hz, 1H), 3.30 (s, 3H), 4.82 (s, 1H), 5.12 (d, J ) 9.7 Hz,
1H), 5.18 (d, J ) 15.8 Hz, 1H), 5.72-5.86 (m, 1H), 6.45 (d, J
) 7.4 Hz, 1H), 6.56 (s, 1H), 6.66 (d, J ) 8.0 Hz, 1H), 7.05-
7.38 (m, 9H), 9.33 (s, 1H). Mass spectrum (CI - CH4) m/e: 488
1H), 2.82 (dd, J 1 ) 6.9 Hz, J 2 ) 13.6 Hz, 1H), 3.18 (dd, J 1
)
5.4 Hz, J 2 ) 12.8 Hz, 1H), 3.30 (s, 3H), 3.68 (s, 3H), 4.76 (s,
1H), 5.11 (d, J ) 10.6 Hz, 1H), 5.18 (d, J ) 17.1 Hz, 1H), 5.66-
5.88 (m, 1H), 6.42 (d, J ) 7.1 Hz, 1H), 6.58 (s, 1H), 6.63 (d, J
) 7.4 Hz, 1H), 6.78 (d, J ) 8.8 Hz, 2H), 6.97-7.24 (m, 7H),
9.34 (s, 1H). Mass spectrum (CI - CH4) m/e: 500 (M + 1, 79%),
346 (49%), 153 (100%). [R]20 +9.6° (c 1.0, absolute ethanol).
D
The free amine was dissolved in ethanol and titrated with
ethanolic hydrogen chloride to pH 4.0 followed by precipitation
with diethyl ether from dichloromethane to give the monohy-
drochloride salt as a hygroscopic light-purple powder. Anal.
(C31H37N3O3‚HCl‚H2O) C, H, N, Cl.
(M + 1, 100%), 334 (45%), 153 (86%). [R]20 +2.02° (c 1.1,
D
absolute ethanol). The free amine was dissolved in ethanol and
titrated with ethanolic hydrogen chloride to pH 4.0 followed
by precipitation with diethyl ether from dichloromethane to
give the monohydrochloride salt as a hygroscopic beige powder.
Anal. (C30H34N3O2F‚HCl‚0.75H2O) C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyb en zyl)-N-m et h yl-N-(4-n it r op h en yl)b en -
zam ide (29). N-Methyl-4-nitroaniline was coupled with 3-((RR)-
R-((2S ,5R)-4-a llyl-2,5-dim et h yl-1-piper a zin yl)-3-(ter t-

632 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4
Bishop et al.
butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected,
and purified by the methods described to give 3-((RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-methyl-N-(4-nitrophenyl)benzamide as a light-yellow pow-
der. NMR (200 MHz, DMSO-d6): δ 0.88 (d, J ) 6.0 Hz, 3H),
0.94 (d, J ) 6.0 Hz, 3H), 1.66 (dd, J 1 ) 7.3 Hz, J 2 ) 11.1 Hz,
1H), 1.98 (dd, J 1 ) 7.7 Hz, J 2 ) 10.9 Hz, 1H), 2.27 (br d, J )
After 1 h, with slow warming to room temperature, the
reaction was quenched with 155 µL of 33% H2O in THF
(CAUTION: gas evolution), then with 77 µL of 30% aqueous
NaOH, and finally with 77 µL of H2O. After 1 h of stirring, all
solids were filtered off. After the mixture was dried with Na2-
SO4, all volatiles were removed under vacuum to give 111 mg
of (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-
hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzylamine as a
fluffy white solid. [R]20D +25.0° (c 1.4, ethanol). The free amine
(0.085 g) was dissolved in ethanol and treated with ethanolic
HCl, followed by precipitation with diethyl ether from dichlo-
romethane to give 0.059 g of the monohydrochloride salt as a
hygroscopic off-white powder. Mass spectrum (CI - CH4) m/e:
474 (M + 1, 100). Anal. (C30H36N3O2F‚HCl‚1.25H2O) C, H, N,
Cl.
11.5 Hz, 1H), 2.36-2.56 (m, 2H), 2.65 (dd, J 1 ) 2.5 Hz, J 2
)
8.4 Hz, 1H), 2.82 (dd, J 1 ) 7.4 Hz, J 2 ) 14.5 Hz, 1H), 3.17 (dd,
J 1 ) 5.5 Hz, J 2 ) 14.1 Hz, 1H), 3.45 (s, 3H), 4.79 (s, 1H), 5.12
(d, J ) 8.8 Hz, 1H), 5.17 (d, J ) 15.2 Hz, 1H), 5.67-5.89 (m,
1H), 6.41 (d, J ) 7.4 Hz, 1H), 6.50 (s, 1H), 6.62 (d, J ) 6.5 Hz,
1H), 7.03 (t, J ) 7.6 Hz, 1H), 7.09-7.42 (m, 6H), 8.11 (d, J )
9.0 Hz, 2H), 9.32 (s, 1H). MS (CI - CH4) m/e: 515 (M + 1,
76%), 361 (26%), 153 (100%). [R]20 +5.9° (c 1.3, absolute
D
ethanol). The free amine was dissolved in ethanol and titrated
with ethanolic hydrogen chloride to pH 4.0 followed by
precipitation with diethyl ether from dichloromethane to give
the monohydrochloride salt as a hygroscopic light-yellow
powder. Anal. (C30H34N4O4‚HCl‚0.5H2O) C, H, N, Cl.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N,N-d ieth ylben za m id e (4). By use
of diethylamine and the methods described above, (+)-3-((RR)-
R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N,N-diethylbenzamide was prepared and isolated as an off-
white solid. [R]20 +20° (c 2, methanol). NMR (400 MHz,
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-eth yl-N-(4-flu or op h en yl)ben za -
m id e (30). 4-Fluoro-N-ethylaniline [NMR (200 MHz, DMSO-
d6): δ 1.25 (t, J ) 7.1 Hz, 3H), 3.12 (q, J ) 7.1 Hz, 2H), 3.24
(br s, 1H), 6.57 (dd, J 1 ) 4.5 Hz, J 2 ) 9.0 Hz, 2H), 6.90 (t, J )
8.9 Hz, 2H)] was coupled with 3-((RR)-R-((2S,5R)-4-allyl-2,5-
dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-
benzoyl chloride, deprotected, and purified by the methods
described to give (+)-3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-
1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)-
benzamide as an off-white powder. NMR (200 MHz, DMSO-
d6): δ 0.91 (d, J ) 6.1 Hz, 3H), 0.98 (d, J ) 6.0 Hz, 3H), 1.08
(t, J ) 7.0 Hz, 3H), 1.71 (dd, J 1 ) 7.0 Hz, J 2 ) 11.3 Hz, 1H),
2.05 (dd, J 1 ) 7.2 Hz, J 2 ) 10.8 Hz, 1H), 2.31 (d, J ) 11.4 Hz,
1H), 2.36-2.57 (m, 2H), 2.69 (dd, J 1 ) 2.2 Hz, J 2 ) 10.7 Hz,
D
DMSO-d6): δ 0.91 (d, J ) 6.2 Hz, 3H), 0.99 (br s, 3H), 1.05 (d,
J ) 6.2 Hz, 3H), 1.09 (br s, 3H), 1.84 (dd, J 1 ) 7.3 Hz, J 2
)
10.9 Hz, 1H), 2.06 (dd, J 1 ) 7.3 Hz, J 2 ) 10.9 Hz, 1H), 2.48
(m, 1H), 2.51 (dd, J 1 ) 2.7 Hz, J 2 ) 10.9 Hz, 1H), 2.58 (br s,
1H), 2.70 (dd, J 1 ) 2.7 Hz, J 2 ) 10.9 Hz, 1H), 2.81 (dd, J 1
)
7.0 Hz, J 2 ) 13.9 Hz, 1H), 3.12 (br s, 2H), 3.15 (dd, J 1 ) 5.1
Hz, J 2 ) 13.9 Hz, 1H), 3.38 (br s, 2H), 4.97 (br s, 1H), 5.07 (d,
J ) 10.2 Hz, 1H), 5.14 (d, J ) 16.9 Hz, 1H), 5.70-5.82 (m,
1H), 6.64 (dd, J 1 ) 2.1 Hz, J 2 ) 8.0 Hz, 1H), 6.65 (s, 1H), 6.68
(d, J ) 7.7 Hz, 1H), 7.11 (t, J ) 8.0 Hz, 1H), 7.14 (d, J ) 7.6
Hz, 1H), 7.30 (s, 1H), 7.33 (t, J ) 7.6 Hz, 1H), 7.39 (d, J ) 8.0
Hz, 1H), 9.31 (s, 1H). Mass spectrum (CI - CH4) m/e: 436 (M
+ 1, 53%). The free amine was dissolved in absolute ethanol
and titrated with ethanolic hydrogen chloride (7 and 1 M) to
a pH of 3.95. The solvent was removed, and the residue was
redissolved in dichloromethane. Diethyl ether was added with
vigorous stirring to precipitate a gummy product that solidified
upon stirring overnight under nitrogen. The product was
collected by filtration and dried under vacuum at 55 °C to give
the monohydrochloride salt. Anal. (C27H37N3O2‚HCl‚H2O) C,
H, N, Cl.
1H), 2.85 (dd, J 1 ) 7.0 Hz, J 2 ) 13.9 Hz, 1H), 3.18 (dd, J 1
)
5.3 Hz, J 2 ) 13.9 Hz, 1H), 3.84 (q, J ) 7.0 Hz, 2H), 4.78 (s,
1H), 5.11 (d, J ) 10.0 Hz, 1H), 5.18 (d, J ) 16.4 Hz, 1H), 5.65-
5.88 (m, 1H), 6.46 (d, J ) 7.4 Hz, 1H), 6.58 (s, 1H), 6.65 (d, J
) 8.1 Hz, 1H), 7.01-7.27 (m, 9H), 9.33 (s, 1H). Mass spectrum
(CI - CH4) m/e: 502 (M + 1, 90%), 348 (15%), 153 (100%).
[R]20 + 6.30° (c 1.1, absolute ethanol). The free amine (0.313
D
g) was dissolved in ethanol and titrated with ethanolic
hydrogen chloride to pH 3.95 followed by precipitation with
diethyl ether from dichloromethane to give 0.263 g of the
monohydrochloride salt as a hygroscopic white powder. Anal.
(C31H36N3O2F‚HCl‚H2O) C, H, N, Cl.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data, atomic coordinates and isotropic displacement param-
eters, bond lengths and bond angles, anisotropic displacement
parameters, and hydrogen coordinates of 24. This material is
available free of charge via the Internet at http://pubs.acs.org.
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-(4-flu or op h en yl)-N-p r op ylben -
za m id e (31). 4-Fluoro-N-propylaniline was coupled with
3-((RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-
butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected,
and purified by the methods described to give (+)-3-((R-R)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-(4-fluorophenyl)-N-propylbenzamide as a light-beige solid.
NMR (200 MHz, DMSO-d6): δ 0.87 (t, J ) 7.4 Hz, 3H), 0.92
(d, J ) 6.0 Hz, 3H), 0.99 (d, J ) 6.1 Hz, 3H), 1.50 (m, 2H),
1.69 (dd, J 1 ) 7.3 Hz, J 2 ) 10.7 Hz, 1H), 2.04 (dd, J 1 ) 6.6 Hz,
J 2 ) 10.3 Hz, 1H), 2.31 (d, J ) 10.2 Hz, 1H), 2.39-2.53 (m,
Refer en ces
(1) (a) Parrot, T. Using opioid analgesics to manage chronic non-
cancer pain in primary care. J . Am. Board Fam. Pract. 1999,
12, 293-306. (b) J adad, A. R.; Browman, G. P. The WHO
analgesic ladder for cancer pain management. Stepping up the
quality of its evaluation. J . Am. Med. Assoc. 1995, 274, 1870-
1873.
(2) Duthie, D. J . R.; Nimmo, W. S. Adverse effects of opioid analgesic
drugs. Br. J . Anaesth. 1987, 59 (1), 61-77.
(3) Simon, E. J .; Gioannini, T. L. Opiate receptor multiplicity:
isolation, purification, and chemical characterization of binding
sites. In Opioids I; Herz, A., Ed.; Springer-Verlag: Berlin, 1993;
pp 3-21.
2H), 2.69 (br d, J ) 11.5 Hz, 1H), 2.89 (dd, J 1 ) 7.1 Hz, J 2
)
13.9 Hz, 1H), 3.18 (dd, J 1 ) 5.0 Hz, J 2 ) 14.3 Hz, 1H), 3.77 (t,
J ) 7.2 Hz, 2H), 4.78 (s, 1H), 5.12 (d, J ) 10.1 Hz, 1H), 5.19
(d, J ) 16.2 Hz, 1H), 5.71-5.84 (m, 1H), 6.47 (d, J ) 7.3 Hz,
1H), 6.59 (s, 1H), 6.65 (d, J ) 8.0 Hz, 1H), 7.03-7.28 (m, 9H),
(4) (a) Clark, J . A.; Liu, L.; Price, M.; Hersh, B.; Edelson, M.;
Pasternak, G. W. Kappa opiate receptor multiplicity: evidence
for two U50,488 sensitive κ1 subtypes and a novel κ3 subtype.
J . Pharmacol. Exp. Ther. 1989, 251, 461-468. (b) Mattia, A.;
Vanderah, T.; Mosberg, H. I.; Porreca, F. Lack of antinociceptive
cross-tolerance between enkephalin and deltorphin II in mice:
evidence for delta receptor subtypes. J . Pharmacol. Exp. Ther.
1991, 258, 583-587. (c) Portoghese, P. S.; Moe, S. T.; Takemori,
9.35 (s, 1H). [R]20D +5.6° (c 1.1, absolute ethanol). Anal. (C32H38
FN3O2‚HCl‚0.75H2O) C, H, N, Cl.
-
(+)-3-((rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyben zyl)-N-(3-flu or op h en yl)-N-m eth ylben -
zyla m in e (32). Allane was generated in situ by slow addition
of an H2SO4 solution (concentrated H2SO4 diluted to 1 M in
THF, 386 µL) to 1 M LiAlH4 in THF (771 µL) at 0 °C, under
nitrogen. After 1 h, 125 mg (0.257 mmol) of (+)-3-((RR)-R-
((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-
N-(3-fluorophenyl)-N-methylbenzamide (24) in THF was added.
A. E.
A selective δ1 opioid receptor agonist derived from
oxymorphone. Evidence for separate recognition sites for δ1
opioid receptor agonists and antagonists. J . Med Chem. 1993,
36, 2572-2574. (d) Rothman, R. B.; Bykov, V.; Xue, B. G.; Xu,
H.; de Costa, B. R.; J acobson, A. E.; Rice, K C.; Kleinman, J . E.;
Brady, L. S. Interactions of opiate peptides and other drugs with
multiple kappa receptors in rat and human brain. Evidence for
species differences. Peptides 1992, 13, 977-987.

Arylbenzamides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 4 633
(5) For an extensive two-part review on the development of δ opioid
receptor ligands, see the following. (a) Dondio, G.; Ronzoni, S.;
Petrillo, P. Non-peptide δ-opioid agonists and antagonists (Part
II). Expert Opin. Ther. Pat. 1999, 9, 353-374. (b) Dondio, G.;
Ronzoni, S.; Petrillo, P. Non-peptide δ-opioid agonists and
antagonists. Expert Opin. Ther. Pat. 1997, 7, 1075-1098.
(6) Zimmerman, D. M.; Leander, J . D. Selective opioid receptor
agonists and antagonists: research tools and potential thera-
peutic agents. J . Med. Chem. 1990, 33, 895-902.
(19) Bubacz, D. G.; Davis, A. O.; Dickerson, S. H.; Harris, P. A.;
McNutt, R. W.; Collins, M. A.; Chang, K.-J . Synthesis of novel
mixed delta-mu opioid agonists. Abstracts of Papers, 213th
National Meeting of the American Chemical Society, San
Francisco, CA, 1997; MEDI-050.
(20) (a) Bishop, M. J .; McNutt, R. W. An efficient synthesis of the
benzhydrylpiperazine delta opioid agonist (+)-BW373U86. Bioorg.
Med. Chem. Lett. 1995, 5, 1311-1314. (b) Delorme, D.; Ber-
thelette, C.; Lavoie, R.; Roberts, E. Asymmetric synthesis of
diarylmethylamines: preparation of selective opioid delta recep-
tor ligands. Tetrahedron: Asymmetry 1998, 9, 3963-3966.
(21) X-ray crystallography and structural determination of compound
24 were performed by Dr. Steven J . Geib at the University of
Pittsburgh Chemistry X-Ray Diffraction Facility using a Siemens
P3 single-crystal diffractometer. See Supporting Information for
details.
(7) Portoghese, P. S.; Sultana, M.; Takemori, A. E. Naltrindole, a
highly selective and potent nonpeptide δ opioid receptor antago-
nist. Eur. J . Pharmacol. 1988, 146, 185-186.
(8) (a) Dappen, M. S.; Pitzele, B. S.; Rafferty, M. F. U.S. Patent 5,-
223,507, 1993; Chem. Abstr. 1993, 119, 152105. (b) Schmidham-
mer, H. PCT Application: WO9531464, 1995; Chem. Abstr. 1995,
124, 176606.
(9) (a) Dondio, G.; Clarke, G. D.; Giardina, G.; Petrillo, P.; Petrone,
G.; Ronzoni, S.; Visentin, L.; Vecchietti, V. The role of the
“spacer” in the octahydroisoquinoline series: Discovery of SB
213698, a non-peptidic, potent and selective delta opioid agonist.
Analgesia 1995, 1, 394-399. (b) Nagase, H.; Wakita, H.; Kawai,
K.; Endo, T.; Matsumoto, O. Patent J P 04275288 A2, 1992;
Chem. Abstr. 1992, 119, 49376.
(10) Tsushima, M.; Tadauchi, K.; Asai, K.; Miike, N.; Imai, M.; Kudo,
T. PCT Int. Appl. WO 0160796 A1, 2001; Chem. Abstr. 2001,
135, 195564.
(11) Chang, K.-J .; Rigdon, G. C.; Howard, J . L.; McNutt, R. W. A
novel, potent and selective nonpeptidic delta opioid receptor
agonist BW373U86. J . Pharmacol. Exp. Ther. 1993, 267, 852-
857.
(22) Calderon, S. N.; Rice, K. C.; Rothman, R. B.; Porreca, F.; Flippen-
Anderson, J . L.; Kayakiri, H.; Xu, H.; Becketts, K.; Smith, L.
E.; Bilsky, E. J .; Davis, P.; Horvath, R. Probes for narcotic
receptor mediated phenomena. 23. Synthesis, opioid receptor
binding, and bioassay of the highly selective δ agonist (+)-4-
[(RR)-R-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-
benzyl]-N,N-diethylbenzamide (SNC 80) and related novel non-
peptide δ opioid receptor ligands. J . Med. Chem. 1997, 40 (5),
695-704.
(23) Calderon, S. N.; Rothman, R. B.; Porreca, F.; Flippen-Anderson,
J . L.; McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J .; Davis,
P.; Rice, K. C. Probes for Narcotic Mediated Phenomena. 19.
Synthesis of (+)-4-[(RR)-R((2S,5R)-4-Allyl-2,5-dimethyl-1-piper-
azinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80):
A
(12) Comer, S. D.; Hoenicke, E. M.; Sable, A. I.; McNutt, R. W.;
Chang, K.-J .; de Costa, B. R.; Mosberg, H. I.; Woods, J . H.
Convulsive effects of systemic administration of the delta opioid
agonist BW373U86 in mice. J . Pharmacol. Exp. Ther. 1993, 267,
888-895.
(13) O’Neill, S. J .; Collins, M. A.; Pettit, H. O.; McNutt, R. W.; Chang,
K.-J . Antagonistic modulation between the delta opioid agonist
BW373U86 and the mu opioid agonist fentanyl in mice. J .
Pharmacol. Exp. Ther. 1997, 282, 271-277.
highly selective, nonpeptide delta opioid receptor agonist. J . Med.
Chem. 1994, 37, 2125-2128.
(24) For an early example of this type of displacement, see the
following. Newman, M. S. The preparation of naphthonitrile. J .
Am. Chem. Soc. 1937, 59, 2472.
(25) Wissner, A.; Grudzinskas, C. V. Reaction of tert-butyldimethyl-
silyl esters with oxalyl chloridesdimethylformamide: prepara-
tion of carboxylic acids under neutral conditions. J . Org. Chem.
1978, 43, 3972-3974.
(14) (a) Vaught, J . L.; Takemori, A. E. Differential effects of leucine
and methionine enkephalin on morphine-induced analgesia,
acute tolerance and dependence. J . Pharmacol. Exp. Ther. 1979,
208, 86-90. (b) Heyman, J . S.; J iang, Q.; Rothman, R. B.;
Mosberg, H. I.; Porreca, F. Modulation of mu-mediated anti-
nociception by delta-agonists: characterization with antagonists.
Eur. J . Pharmacol. 1989, 169, 43-52. (c) Lee, P. H. K.; McNutt,
R. W.; Chang, K.-J . A nonpeptidic delta opioid receptor agonist,
BW373U86, attenuates the development and expression of
morphine abstinence precipitated by naloxone in rat. J . Phar-
macol. Exp. Ther. 1993, 267, 883-887. (d) Kieffer, B. L.;
Gaveriaux-Ruff, C. Exploring the opioid system by gene knock-
out. Prog. Neurobiol. 2002, 6, 285-306.
(15) Su, Y.-F.; McNutt, R. W.; Chang, K.-J . Delta-opioid ligands
reverse alfentanil-induced respiratory depression but not anti-
nociception. J . Pharmacol. Exp. Ther. 1998, 287, 815-823.
(16) There have been reports of successful in vivo experiments with
compounds that have mixed µ agonist/δ antagonist profiles. For
instance, see the following. (a) Schiller, P. W.; Weltrowska, G.;
Schmidt, R.; Nguyen, T. M.-D.; Berezowska, I.; Lemieux, C.;
Chung, N. N.; Carpenter, K. A.; Wilkes, B. C. Four different
types of opioid peptides with mixed µ agonist/δ antagonist
properties. Analgesia 1995, 1 (4-6), 703-706. (b) Wells, J . L.;
Bartlett, J . L.; Ananthan, S.; Bilsky, E. J . In vivo pharmacologi-
cal characterization of SoRI 9409, a nonpeptidic opioid µ-agonist/
δ-antagonist that produces limited antinociceptive tolerance and
attenuates morphine physical dependence. J . Pharmacol. Exp.
Ther. 2001, 297 (2), 597-605.
(26) Krishnamurthy, S. A highly efficient and general N-monom-
ethylation of functionalized primary amines via formylations
borane:methyl sulfide reduction. Tetrahedron Lett. 1982, 23,
3315-3318.
(27) Chien, P.; Cheng, C. C. 2,8-Bis(substituted amino)phenothiazine
5,5-dioxides. J . Med. Chem. 1966, 9, 960-962.
(28) Review: Abramovitch, R. A.; Barton, D. H.; Finet, J .-P. Newer
methods of arylation. Tetrahedron 1988, 44, 3039-3071.
(29) Ellefson, C. R.; Cusic, J . W. Some 10-substituted 5-ethyl-10-
dialkylaminoalkyl-10,11-dihydro-5H-dibenz[b,f]azepines as po-
tential antiarrythmic agents. J . Med. Chem. 1976, 19, 1345-
1349.
(30) Kramer, T. H.; Davis, P.; Hruby, V. J .; Burks, T. F.; Porreca, F.
In vitro potency, affinity and agonist efficacy of highly selective
delta opioid receptor ligands. J . Pharmacol. Exp. Ther. 1993,
266 (2), 577-584.
(31) (a) See ref 6 for a discussion of potency discrepancies in opioid
assays. (b) Adham, N.; Zgombick, J . M.; Bard, J .; Branchek, T.
A. Functional characterization of the recombinant human
5-hydroxytryptamine7(a) receptor isoform coupled to adenylate
cyclase stimulation. J . Pharmacol. Exp. Ther. 1998, 287, 508-
514.
(32) Lord, J . A. H.; Waterfield, A. A.; Hughes, J .; Kosterlitz, H. W.
Endogenous opioid peptides: multiple agonists and receptors.
Nature 1977, 267 (5611), 495-499.
(33) Bradford, M. M. A rapid and sensitive method for the quanti-
tation of microgram quantities of protein utilizing the principle
of protein-dye binding. Anal. Biochem. 1976, 72, 248-253.
(34) Cheng, Y. C.; Prusoff, W. H. Relationship between the inhibition
constant (Ki) and the concentration of inhibitor which causes
50% inhibition (IC50) of an enzymatic reaction. Biochem. Phar-
macol. 1973, 22, 3089-3108.
(35) Ibbitson, D. A.; Grocock, D. E.; Hallas, G.; Hepworth, J . D.;
Hudson, J . A. The ortho-effect in 2-amino- and 2-(methylamino)-
benzylidyne trifluoride (2-trifluoromethyl- and 2-trifluoromethyl-
N-methylamine). J . Chem. Soc. B 1971, 457-459.
(17) (a) Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E.
J . Med. Chem. 1988, 31 (2), 281-282. (b) Schwyzer, R. Molecular
mechanism of opioid receptor selection. Biochemistry 1986, 25
(20), 6335-6342.
(18) Dondio, G.; Ronzoni, S.; Eggleston, D. S.; Artico, M.; Petrillo,
P.; Petrone, G.; Visentin, L.; Farina, C.; Vecchietti, V.; Clarke,
G. D. Discovery of a novel class of substituted pyrrolooctahy-
droisoquinolines as potent and selective δ opioid agonists, based
on an extension of the message-address concept. J . Med. Chem.
1997, 40 (20), 3192-3198.
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