N-substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines are opioid receptor pure antagonists

Article abstract of DOI:10.1021/jm058261c

N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [³⁵S] GTP-γ-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl] -3-(piperidin-1-yl)propionamide (6d) with a K_e of 0.27 nM at the κ opioid receptor with 154- and 46-fold selectivity relative to those of the μ and δ receptors, respectively, possessed the best combination of κ potency and selectivity.

Full text of DOI:10.1021/jm058261c

8182
J. Med. Chem. 2005, 48, 8182-8193
N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are
Opioid Receptor Pure Antagonists
F. Ivy Carroll,*,† Sachin Chaudhari,† James B. Thomas,† S. Wayne Mascarella,† Kenneth M. Gigstad,†
Jeffrey Deschamps,‡ and Herna´n A. Navarro†
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and
Laboratory for the Structure of Matter, Naval Research Laboratory, 4555 Overlook Avenue, Washington, D.C. 20375-5341
Received August 16, 2005
N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed
and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahy-
droisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is
either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl
equatorial conformation is responsible for the antagonist activity observed in the (3-
hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the
3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling
studies also suggest that the equatorial conformation has lower potential energy relative to
that of the axial conformation. Evaluation of 6a-g in the [35S]GTP-γ-S in vitro functional assay
showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-
2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a Ke of
0.27 nM at the κ opioid receptor with 154- and 46-fold selectivity relative to those of the µ and
δ receptors, respectively, possessed the best combination of κ potency and selectivity.
Introduction
include alvimopan (4b),13-15 which has reached the NDA
stage for GI motility disorder, (3R,4R)-1-[(S)-3-hydroxy-
3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-
piperidine (LY255,582 (4c)),16,17 which was developed
to treat obesity, and (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-
4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-
2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-car-
boxamide (JDTic, 4d), which we are developing to treat
substance abuse (cocaine, heroin, nicotine, metham-
phetamine, and ethanol).7-10,18 In other previous stud-
ies, we demonstrated that N-phenylpropyl-4â-methyl-
5-(3-hydroxyphenyl)morphan (5a), which can be viewed
as a trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
with the 4-(3-hydroxyphenyl) group locked in an equato-
rial piperidine chair conformation, was an opioid recep-
tor pure antagonist. The addition of a 7R-amino-3-(1-
piperidinyl)propionyl group gave 5b, which was a potent
and selective κ opioid receptor antagonist.19,20 Although
1-5 have proven highly useful in helping to characterize
the pharmacological properties of the opioid system,
much research remains to be done before the pharma-
cology of the opioid receptor system is fully understood.
Structurally different chemotypes showing potent and
selective opioid receptor antagonism will be particularly
helpful.
The opioid receptor system has been extensively
studied, and thousands of compounds have been syn-
thesized and evaluated by in vitro binding and func-
tional assays as well as animal models.1 An integral part
of the effort to characterize the opioid receptor system
has been the discovery of potent, pure antagonists.
Naloxone (1a) and naltrexone (1b), both competitive
antagonists at µ, δ, and κ opioid receptors,1 have been
extensively used as pharmacological tools to identify and
characterize opioid systems. Additionally, 1a is ap-
proved for treating heroin overdose and to reverse
respiratory depression caused by morphine.2 Compound
1b is used to treat heroin and alcohol abuse.
Pioneering structure activity relationship (SAR) stud-
ies by Portoghese et al., based on the lead compound,
1b, led to the discovery of the δ opioid receptor selective
antagonist naltrindole (NTI, 2a) and the κ opioid recep-
tor antagonists, norbinaltorphimine (norBNI, 3) and
guanidinenaltrindole (GNTI, 2b).3-6 The N-substituted
trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (4)
are another interesting class of opioid receptor pure
antagonists. Unlike activities of other antagonists,
including that of the oxymorphone class, antagonist
activity of 4 was not dependent on the structure of the
N-substituent.1 All reported N-substituted analogues,
including the N-methyl analogue 4a, were antago-
nists.1,7-12 A few of the more interesting analogues
As a continuation of our studies to develop new opioid
receptor antagonists, we report in this paper that N-sub-
stituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroiso-
quinolines (6a-g) are potent opioid antagonists in the
[35S]GTP-γ-S functional assay with several analogues
showing preference for the κ opioid receptor.
* Research Triangle Institute, Post Office Box 12194, Research
Triangle Park, NC 27709-2194. Telephone: 919 541-6679. Fax: 919
541-8868. E-mail: fic@rti.org.
† Research Triangle Institute.
‡ Naval Research Laboratory.
10.1021/jm058261c CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/16/2005

Opioid Receptor Pure Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8183
Scheme 1a
Figure 1. Structure of 6a showing labeling of the non-
hydrogen atoms. Displacement ellipsoids are at the 20%
probability level.
a Reagents: (a) s-C4H9Li, THF; (b) Br(CH2)4Cl, (C2H5)2O; (c)
NaI, CH3CN; (d) NaBH4, C2H5OH; (e) HBr, HOAc; (f) ACE-Cl,
(ClCH2)2; (g) CH3OH, reflux; (h) NaBH(OAc)3, C6H5CH2CHO for
6b or C6H5(CH2)2CHO for 6c.
nylethoxy)-2H-pyran (13) to provide the aminal 14. The
addition of bromine to a tetrahydrofuran solution of 14
and triphenylphosphine removed the tetrahydropyran
protecting group and replaced the hydroxyl with a
bromine to give 15 in a single step. Treatment of 15 with
a mixture of acetic anhydride and trifluoroacetic acid
afforded enamine intermediate 16, which was cyclized
by heating in acetonitrile containing potassium carbon-
ate. Treatment of the product with sodium borohydride
resulted in concomitant reduction of the enamine and
hydrolysis of the acetate to give 6-hydroxyoctahydroiso-
quinoline (17). Swern (Moffatt-Swern) oxidation of 17
using oxalyl chloride and dimethyl sulfoxide in meth-
ylene chloride gave ketone 18. Condensation of 18 with
hydroxylamine hydrochloride in ethanol afforded oxime
19, which yielded amine 20 on reduction using sodium
and 2-propanol in refluxing toluene. Treatment of 20
with phthalic anhydride in toluene at reflux yielded the
phthalimide 21. N-Demethylation of 21 to give 22 was
achieved with 1-chloroethyl chloroformate in 1,2-dichlo-
roethane, followed by the hydrolysis of the resulting
carbamate in refluxing methanol. Reductive alkylation
of 22 with hydrocinnamaldehyde using sodium triace-
toxyborohydride gave the N-phenylpropyl analogue 23.
Single-crystal X-ray analysis of 23 showed that the 4a-
(3-hydroxyphenyl) group and the 8a methyl were cis to
one another and that the 4a-(3-hydroxyphenyl) group
was in the equatorial conformation relative to the
piperidine ring (Figure 2). This is similar to the obser-
vation made for 6a‚HCl (Figure 1). In addition, the
6-phthalimide group is in an equatorial conformation
and is trans to both the equatorial 4a-(3-hydroxyphenyl)
and the axial 8a-methyl groups. Treating 23 with
hydrazine in refluxing ethanol provided the N-phenyl-
propyl-6-amino compound, 24. Coupling of 24 with the
appropriately substituted carboxylic acid, using benzo-
triazol-1-yloxy-tris-(dimethylamino)phosphate (BOP, Cas-
tro’s reagent) in tetrahydrofuran/triethylamine provided
the desired methoxy-protected 6-amido compounds,
Chemistry
N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyl-
octahydroisoquinolines (6a-c) were synthesized from
tetrahydropyridine (7),20 as outlined in Scheme 1.
Deprotonation of 7 with sec-butyllithium in tetrahydro-
furan at -78 °C provided the metalated enamine, which
was added to an ethereal solution of 1-bromo-4-chloro-
butane to give the endocyclic enamine 8. Without iso-
lation, this material was treated with sodium iodide in
acetonitrile at reflux followed by reduction with sodium
borohydride in ethanol to give the octahydroisoquinoline
methyl ether 9. O-Demethylation of 9 with refluxing
48% aqueous hydrogen bromide provided the desired 6a.
Single-crystal X-ray analysis of the hydrochloride salt
of 6a showed that the 4a-(3-hydroxyphenyl) group and
the 8a-methyl group were cis to one another and that
the 4a-(3-hydroxyphenyl) group was in the equatorial
conformation relative to the piperidine ring (Figure 1).
The N-phenylethyl and N-phenylpropyl-cis-4a-(3-hy-
droxyphenyl)-8a-methyloctahydroisoquinolines (6b,c)
were prepared starting with 9. Treatment of 9 with
1-chloroethyl chloroformate (ACE-Cl) followed by re-
fluxing the resulting product in methanol afforded the
N-demethylated product 10. Reductive amination of 10
with phenylacetaldehyde or hydrocinnamaldehyde using
sodium triacetoxyborohydride as the reducing agent
afforded the N-phenylethyl and N-phenylpropyl methyl
ether intermediates 11 and 12, respectively. Treatment
of 11 and 12 with refluxing 48% aqueous hydrobromic
acid in acetic acid provided the desired products 6b,c.
The 6-amido N-phenylpropyl-cis-4a-(3-hydroxyphen-
yl)-8a-methyloctahydroisoquinoline analogues 6d-g
were synthesized as outlined in Scheme 2. Deprotona-
tion of 7 with sec-butyllithium in tetrahydrofuran at
-10 to 0 °C provided the metalated enamine, which was
added to an ethereal solution of tetrahydro-(2-oxira-

8184 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Carroll et al.
25a-d. O-Demethylation of 25a-d with borontribro-
mide in methylene chloride at -78 °C provided final
products 6d-g.
reference compounds JDTic, norBNI, 4c, and naltrex-
one, 6a-g showed no agonist activity. In contrast, all
compounds showed antagonist activity at all three
receptors. Even the N-methyl analogue 6a was an opioid
receptor pure antagonist with Ke’s of 99.4, 477, and 3.37
nM at the µ, δ, and κ receptors, respectively. The
remaining analogues, which possess an N-phenylethyl
(6b) or N-phenylpropyl group (6c-g) show Ke’s of 0.8-
41.7, 1.01-18.9, and 0.22-2.84 nM at the µ, δ, and κ
receptors, respectively. Compound 6c (Ke ) 0.80), 6g
(Ke ) 1.01), and 6e (Ke ) 0.22) are the most potent
compounds at the µ, δ, and κ receptors, respectively. The
most potent and selective κ opioid receptor compound
of the group is 6d, with a Ke of 0.27 nM at the κ receptor
and 154- and 46-fold selectivities for the κ receptor
versus the µ and δ receptors, respectively.
Discussion
Numerous SAR studies have shown that the antago-
nist activity of the N-substituted trans-3,4-dimethyl-4-
(3-hydroxyphenyl)piperidines is dependent on two fac-
tors: (1) the 3-methyl substituent and its trans relative
relationship to the 4-methyl substituent and (2) an
equatorial-oriented 3-hydroxyphenyl group. Although
the 3-hydroxyphenyl ring in the 3,4-dimethyl-4-(3-
hydroxyphenyl)piperidine analogues (4) can be in either
an axial or equatorial position (Figure 3), X-ray and 1H
and 13C NMR studies,16,21,22 as well as molecular model-
ing studies,12 suggest a preference for the 3-hydrox-
yphenyl equatorial conformation. It is believed that the
antagonist activity results from the interaction with the
opioid receptors in this conformation. One approach to
gain additional information on this subject is to measure
agonist/antagonist behavior using conformationally con-
strained analogues of 4. The N-substituted cis-4a-(3-
hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-
g), where the C-4 and C-5 positions on the piperidine
ring are connected through a four-carbon methylene
linker, meet this requirement. The cis ring junction in
6a-g allows the 4a-(3-hydroxyphenyl) group to exist in
either the equatorial or axial conformation relative to
the piperidine ring (Figure 3). However, single-crystal
X-ray studies of 6a and 23 (Figures 1 and 2) show that
the equatorial position is the preferred conformation of
the 3-hydroxyphenyl group in the solid state. In agree-
ment with these X-ray crystallographic observations,
molecular modeling calculations find that the equatorial
position is the favored conformation for the 3-hydrox-
yphenyl group for both compounds. 6a shows a small
preference for the equatorial vs axial conformation (the
global energy minimum for the equatorial conformation
is 0.14 kcal/mol lower in calculated energy than the
lowest-energy axial conformation). The corresponding
global energy minimum conformation of 23 is also
equatorial and is 6.74 kcal/mol lower in energy than the
lowest-energy axial conformation (Figure 3). As a whole,
these observations are consistent with the antagonist
behavior found for 6a-g.
Molecular Modeling
The phenyl axial vs phenyl equatorial preference
relative to the piperidine ring of representative octahy-
droisoquinoline structures was modeled using Spartan
‘04 (version 1.0.1, Wavefunction, Inc.). Monte Carlo
conformational searches were performed using the
Spartan “Conformer Distribution” calculation option.
Molecular mechanics energies based on the MMFF force
field were used to guide the conformational search. The
conformer distribution results were viewed in spread-
sheet format with columns added for relative energy
(energy of each conformer relative to the global energy
minimum conformation expressed in kcal/mol) and
dihedral angle around the 4-4a bond. The lowest-
energy phenyl axial (4-4a dihedral ≈ (60°) and phenyl
equatorial (4-4a dihedral ≈ (180°) conformer of each
structure modeled were identified by examination of the
resulting molecular spreadsheet.
Biological Results
Measures of functional antagonism and selectivity of
6a-g were obtained by monitoring the ability of test
compounds to inhibit stimulated [35S]GTP-γ-S binding
produced by the selective agonists DAMGO [(D-Ala2,-
MePhe4,Gly-ol5)enkephalin] (selective for µ opioid recep-
tor), DPDPE [cyclo[D-Pen2,D-Pen5]enkephalin] (selec-
tive for δ opioid receptor), and U69,593 {(5R,7R,8â)-
(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-
yl]benzeneacetamide} (agonist selective for κ opioid
receptor) using cloned human opioid receptors expressed
in CHO cells. Agonist dose-response curves were run
in the presence or absence of a single concentration of
the test compound. The Kes were calculated using the
formula: Ke ) [L]/[(A′/A) - 1)], where [L] is the
concentration of antagonist and A′ and A are the agonist
EC50 values in the presence or absence of antagonist,
respectively. The results, along with reference com-
pounds JDTic, norBNI, naltrexone, and 4c, are listed
in Table 1.
The N-substituted trans-4a-(3-hydroxyphenyl)decahy-
droisoquinolines (26) are a class of compounds, similar
to 6a-c, that have a trans ring junction that locks the
4a-(3-hydroxyphenyl) group in an axial conformation.23
The N-methyl compound, 26 (R ) CH3), was reported
to be an opioid agonist with twice the potency of
morphine in the mouse-tail flick and writhing analgesic
Compounds 6a-g were tested at 10 µM for agonist
activity at the µ, δ, and κ opioid receptors. Similar to

Opioid Receptor Pure Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8185
Scheme 2a
a Reagents and conditions: (a) s-BuLi, THF, -10 to 0 °C (1.5 h), 70%; (b) (C6H5)3P, Br2, THF, 0 °C to room temperature (12 h), 70%;
(c) TFA, Ac2O, room temperature (1 h); (d) K2CO3, CH3CN, reflux (3 h); (e) NaBH4, CH3OH, 0 °C to room temperature (36 h), 70%; (f)
oxalyl chloride, DMSO, -70 °C to room temperature (1 h), 92%; (g) NH2OH‚HCl, absolute EtOH, reflux (5 h), 96%; (h) Na, (CH3)2CHOH,
toluene, reflux (12 h), 94%; (i) phthalic anhydride, toluene, reflux (12 h), 90%; (j) ACE-Cl, 1,2-dichloroethane, reflux (5 h); (k) CH3OH,
reflux (12 h), 99%; (l) hydrocinnamaldehyde, NaBH(OAc)3, 1,2-dichloroethane, room temperature, 87%; (m) N2H4 hydrate, EtOH, reflux
(12 h), 97%; (n) appropriate acid, BOP reagent, TEA, THF, room temperature (2 h), ∼90%; (o) BBr3, CH2Cl2, -78 °C to room temperature
(1.5 h). [N.B.: All indicated configurations are relative stereochemistry.]
assays. Combining this information with the in vitro
pharmacological results obtained for 6a-g in this study
clearly illustrates the importance of conformation to
antagonist activity and provides additional support that
these compounds are interacting with opioid receptors
with the 4a-(3-hydroxyphenyl) group in the equatorial
conformation. Table 1 lists data obtained from evaluat-
ing 6a-g in the in vitro [35S]GTP-γ-S functional assay.
Details are presented in the Biological Results section.
Note that none of the compounds showed opioid agonist
activity when evaluated at 10 µM. In contrast, all
compounds showed opioid antagonist activity at each
opioid receptor. It is particularly interesting to note that
the N-methyl analogue 6a was a pure antagonist,
distinctly different from 26 (R ) CH3). It was also found
that the potency at the µ opioid receptor was increased
when the N-methyl group was replaced with an N-
phenylethyl and N-phenylpropyl group (see 6b,c). This
is in line with SAR of the related N-substituted trans-
3,4,-dimethyl-(3-hydroxyphenyl) piperidines, such as 4c.
This trait appears to be general for antagonists operat-
ing via a 3-hydroxyphenyl equatorial conformation of
the 4-(3-hydroxyphenyl)piperidine structure or sub-
structure.
The compounds of this study clearly have opioid
receptor properties that suggest they are related to the
trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class
of antagonists. However, the relative selectivity of 6a
for the opioid κ receptor is divergent from those of other
members of this family because it showed some prefer-
ence for the κ receptor relative to the µ and δ receptors.
The potency shift typical with larger N-substituents in

8186 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Carroll et al.
Figure 2. Structure of 23 showing labeling of the non-hydro-
gen atoms. Displacement ellipsoids are at the 30% probability
level.
Figure 4. Comparison of structures of 4a, 6a, 27, 28, and
29. Bolded areas are key substructures for pure antagonist
activity.
Table 1. Inhibition of Agonist Stimulated [35S]GTP-γ-S
Binding by Compounds in Cloned Human µ, δ, and κ Opioid
Receptorsa
relative placement of the bridging ring and 4â-methyl
group significantly impacted potency and selectivity for
the κ receptor.19,20
µ, DAMGO δ, DPDPE κ, U69,593
cmpd
Ke (nM)
Ke (nM)
Ke (nM)
µ/κ
δ/κ
Another important aspect of the present study is that
it adds additional support to the role of the trans-3,4-
dimethyl structure or substructure that is essential for
the antagonist activity of the trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidine (4) series (Figure 4). The 8a
methyl and the 5-position methylene of the bridging ring
fulfill this role in the isoquinoline compounds 6a-g.
Information as to the function of this and similar groups
can be gleaned from the available literature. For 4a,
the trans-3,4-dimethyl is a requisite for potent, pure
antagonist activity. This N-methyl derivative is a weak
but pure antagonist lacking any agonist activity up to
10 µM.11 Without the trans-3,4-dimethyl group, the
compound is an agonist. The related N-methyl 5-(3-
hydroxyphenyl)morphan antagonists 27 and 28 possess
the trans-3,4-dimethyl-like substructure (Figure 4) as
well as a 3-hydroxyphenyl conformation locked in place
by a bridging ring.19,20 Experimentally, both of these
compounds lack agonist activity up to 10 µM and,
importantly, are weak but pure antagonists. N-methyl
5-(3-hydroxyphenyl)morphan, lacking the 4â- or 9â-
methyl groups present in 27 and 28, respectively, is a
potent morphine-like agonist.24 In line with these
observations, the N-methyl analogue 6a in the present
study was found to be a pure antagonist with potency
for the µ receptor in the range observed for 27 and 28.
Rice and Hashimoto have shown that 5-(3-hydroxy-
phenyl)morphans, such as 27 and 28 but lacking a 4â-
or 9â-methyl group, are antagonists if the N-substituent
is larger than a methyl (phenylethyl or phenylpropyl).25
Even earlier work by Awaya and May24 showed weak
antagonism in 9R-methyl 5-(3-hydroxyphenyl)morphans
and also in a similar series, the hexahydro-1H-1-
pyridine (29) (Figure 4).26 These findings, together with
the data from the N-methyl derivatives 27 and 28,
indicate that the 3,4-dimethyl groups in the 4 series or
the 4â-methyl group in the 27 series and the 9â-methyl
group in 28 series all serve to block agonist activity
irrespective of the N-substituent structure. This phe-
nomenon may arise as a consequence of the methyl
group’s interaction with an excluded volume in the
agonist domain or perhaps may be acting at an “acces-
6a
6b
6c
6d
6e
6f
99.4 ( 28.3 477 ( 137 3.37 ( 0.47 29
141
7
0.84 ( 0.22 18.9 ( 5.2 2.84 ( 0.97
0.80 ( 0.10 12.4 ( 2.9 1.03 ( 0.14
0.3
0.8
12
41.7 ( 7.8 12.3 ( 3.1 0.27 ( 0.08 154
9.82 ( 3.7 4.56 ( 1.2 0.22 ( 0.02 45
46
21
3
2
7930
110
1.46 ( 0.15 6.46 ( 2.3 1.93 ( 0.48
0.8
6g
11.3 ( 2.0 1.01 ( 0.22 0.46 ( 0.13 25
JDTicb, 4d
3.41
19
79.3
4.4
0.01
0.04
341
475
norBNIb, 3
Naltrexone, 1b 3.35 ( 0.95 60.7 ( 10.6 4.63 ( 1.49
LY255, 582, 4c 0.10 ( 0.04 0.60 ( 0.11 0.29 ( 0.06
a The data represent the mean ( SE from at least three
independent experiments. The final GDP assay concentration was
10 µM. b Taken from ref 18.
Figure 3. Conformational structures of 4, 6a, and 23.
this case serves to level the potency among the opioid
receptors. It may be that the bridging ring in 6a
interacts with a lipophillic site that is more pronounced
in the κ opioid receptor. Such an interaction is consistent
with our studies with κ-selective 5-(3-hydroxyphenyl)-
morphans (4a, 27, and 28), where we found that the

Opioid Receptor Pure Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8187
creased selectivity for the κ opioid receptor relative to
those for the µ and δ opioid receptors that retain high
κ potency. The most potent and κ-selective analogue
identified in this study was N-[4a-(3-hydroxyphenyl)-
8a-methyl-2-(3-phenylpropyl)octahydroisoquinolin-6-yl]-
3-piperidin-1-yl]propionamide (6d). The similarities and
differences in structural features between the 4â-
methyl-5-(3-hydroxyphenyl)morphan and the octahy-
droisoquinoline classes have revealed new information
regarding subtype selectivity in novel opioid receptor
pharmacophores, which will be useful in the design of
future κ- and δ-selective compounds.
Experimental Section
1H NMR spectra were determined on a Bruker 300 spec-
trometer using tetramethylsilane as an internal standard.
Mass spectral data were obtained using a Finnegan LCQ
electrospray mass spectrometer in the positive ion mode at
atmospheric pressure. Silica gel 60 (230-400 mesh) was used
for column chromatography. All reactions were followed by
thin-layer chromatography (TLC) using Whatman silica gel
60 TLC plates and were visualized by UV or by charring using
5% phosphomolybdic acid in ethanol. All solvents were reagent
grade. Tetrahydrofuran and diethyl ether were dried over
sodium benzophenone ketyl and distilled prior to use. Meth-
ylene chloride and chloroform were distilled from calcium
hydride if used as reaction solvents. HCl in dry diethyl ether
was purchased from Aldrich Chemical Co. and used while fresh
before discoloration.
DAMGO, DPDPE, and U69,593 were obtained via the
Research Technology Branch, NIDA, and were prepared by
Multiple Peptide Systems (San Diego, CA). [35S]GTP-γ-S was
obtained from Perkin-Elmer Inc., (Boston, MA). GTP-γ-S and
GDP were obtained from Sigma Chemical Company (St. Louis,
MO). CMA-80 is a mixture of 80% chloroform, 18% methanol,
and 2% concentrated ammonium hydroxide.
The nomenclature for 6a-g follows IUPAC guidelines. All
other compounds are named using typical opioid nomenclature.
N-Methyl-4a-(3-methoxyphenyl)-8a-methyloctahy-
droisoquinoline (9). To a dry three-neck round-bottomed
flask was charged 2.27 g (0.01 mol) of 720 and 50 mL of dry
THF. This was cooled to -78 °C, and to this was added 11.2
mL (14.6 mmol) of s-BuLi (1.3 M in cyclohexane) via syringe
over 20 min. The flask was warmed to -20 °C and aged for 30
min. The flask was cooled to -78 °C and transferred by
cannula into a mixture of 50 mL of dry Et2O and 5.90 g (0.034
mol) of 1-bromo-4-chlorobutane at -50 °C over 20 min. This
mixture was aged for 1 h and then quenched with ice-cold 1 N
HCl. The contents of the flask were transferred to a separatory
funnel with ice-cold Et2O and ice-cold 1 N HCl. The aqueous
layer was removed and stored in an ice bath, and the organic
layer was twice extracted with ice-cold 1 N HCl. The combined
aqueous layers were placed into a new separatory funnel and
extracted twice with ice-cold Et2O. The aqueous layer was
made basic with 50% NaOH to pH 10. The aqueous layer was
extracted 3× with ice-cold Et2O. The Et2O extracts were dried
(K2CO3) and filtered, and the solvent was removed at 0 °C.
The resulting residue was dissolved in 40 mL of dry CH3CN,
and to this was added 3.91 g (0.027 mol) of NaI and 2.89 g
(0.021 mol) of K2CO3. The flask was attached to a reflux
condenser and heated to reflux with stirring for 20 h. The
reaction mixture was cooled to room temperature and filtered.
The solvent was removed on a rota-evaporator, and the residue
was dissolved in 100 mL of EtOH. To this mixture was added
3.35 g (0.089 mol) of NaBH4 in one portion, and the mixture
was allowed to stir overnight. On the following day, 1 N HCl
was added to the mixture until no further evolution of
hydrogen was observed. The mixture was stirred for 10 min,
and then 50% NaOH and H2O were added until the mixture
was clear and basic. The volatiles were removed on a rota-
evaporator, and the residue was extracted with CH2Cl2. The
sory site” to prevent a conformational change by the
receptor or by some other mechanism.27,28 Regardless
of the mode of action, the data for 6a-g illustrate in a
novel series that the presence of this substructure
coupled with the proper conformation confers pure
antagonist activity in a reliable and predictable manner.
In recent reports, we have shown that opioid receptor
subtype selectivity can be realized in the trans-3,4-
dimethyl-4-(3-hydroxyphenyl)piperidine and the 4â-
methyl-5-(3-hydroxyphenyl)morphan series by attaching
suitable address elements onto nonselective scaffolds.9,19
For example, we found that the addition of a 7R-(2-
piperidinylethylamido) group to N-phenylpropyl-4â-
methyl-5-(3-hydroxyphenyl)morphan (4a) to give 4b
resulted in an enhanced potency and selectivity for the
κ opioid receptor.19 In this study, the addition of a 6R-
(2-piperidinylethylamido) group to 6c provided 6d,
which showed a Ke of 0.27 nM at the κ receptor with
154- and 46-fold selectivity relative to those at the µ and
δ receptors, respectively. Compound 6e results from the
addition of a 2-benzoisoquinolinylethylamido group to
6c. This compound retains high potency for the κ
receptor (Ke ) 0.22 nM); however, the potency at the µ
and δ receptors is also enhanced, resulting in only 45-
and 21-fold selectivity, respectively. The 5-(3-hydrox-
yphenyl)morphan (30), which has a 7-(1-phenyl-1-cy-
clopentyl)amido side chain, is a potent and selective
antagonist at the δ opioid receptor relative to the µ and
κ receptors.29 The addition of a 6R-[7-(1-phenyl-1-cyclo-
pentyl)]amido group to 6d to give 6f did not result in
an appreciable enhancement of δ opioid receptor po-
tency. This difference in selectivity suggests that the
side chains of these two series may be interacting
differently with the δ receptor. Compound 6g, which has
a 6-(2-benzothiophenylethyl)amido group, possessed the
highest potency for the δ receptor (Ke ) 1.01 nM) but
was not selective for the δ receptor.
In summary, the N-substituted cis-4a-(3-hydroxyphen-
yl)-8a-methyloctahydroisoquinolines, 6a-g, represent a
new chemotype whose SARs suggest that they are
related to the trans-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidine class of opioid antagonist. The addition of a
6-amido address group possessing an amino function to
the core structure provides compounds with an in-

8188 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Carroll et al.
organic layer was dried over anhydrous Na2SO4. The removal
of the solvent on a rota-evaporator yielded crude product,
which was purified by chromatography on alumina using 15%
EtOAc-hexanes as the eluent and gave 2.1 g (76%) of the
desired product 9 as a colorless viscous oil: 1H NMR (CDCl3)
δ 7.20 (m, 2H), 7.08 (s, 1H), 6.74 (br, 1H), 3.81 (s, 3H), 2.50
(m, 3H), 2.11 (s, 3H), 1.88 (m, 3H), 1.54 (br, 8H), 1.09 (s, 3H);
13C NMR (CDCl3) δ 158.1, 127.8, 121.6, 115.9, 109.7, 64.6, 54.7,
46.2, 41.6, 36.5, 35.3, 21.5, 21.2.
N-Methyl-4a-(3-hydroxyphenyl)-8a-methyloctahy-
droisoquinoline (6a) Hydrochloride. To a 25-mL single-
necked flask was added 180 mg (0.65 mmol) of 9, 5 mL of
glacial AcOH, and 5 mL of 48% HBr. This mixture was heated
under reflux for 18 h and then cooled to room temperature.
The pH was adjusted to 10 with cooling using 50% NaOH. This
mixture was extracted 3× with CH2Cl2. The organic extracts
were dried (Na2SO4) and concentrated under reduced pressure
to give 0.17 g (99%) of crude product as a white solid.
Purification by chromatography on alumina using 15% EtOAc-
hexanes gave 0.140 g (83%) of desired product as a crystalline,
white solid.
This free base was dissolved in MeOH, and to this solution
was added 3 equiv of 1 N HCl in dry Et2O to give the
hydrochloride salt: mp 291-293 °C; 1H NMR (DMSO-d6) δ
9.71 (br s, 1H), 9.18 (s, 1H), 7.09-6.73 (m, 3H), 6.51 (m, 1H),
3.90 (t, 1H), 3.38 (s, 3H), 2.57-2.49 (m, 4H), 2.28 (s, 1H), 1.61-
1.29 (m, 6H), 1.02 (d, 2H), 0.91 (s, 3H); 13C NMR (DMSO-d6)
δ 156.9, 147.5, 128.7, 119.4, 116.3, 113.0, 59.8, 49.9, 43.3, 36.8,
36.6, 34.4, 32.5, 31.3, 24.7, 21.3, 20.5. Anal. (C17H26ClNO‚
0.75H2O) C, H, N.
4a-(3-Methoxyphenyl)-8a-methyloctahydroisoquino-
line (10). To a solution of 430 mg (1.59 mmol) of 9 in
anhydrous CH2Cl2 (15 mL) at reflux was added 250 mg (1.75
mmol) of 1-chloroethyl chloroformate dropwise. The resulting
solution was heated under reflux for 20 h and then cooled to
room temperature. The mixture was washed with saturated
NaHCO3 solution and H2O, the organic layer was evaporated,
and the resulting oil was dissolved immediately in MeOH and
heated under reflux overnight. After cooling to room temper-
ature, the MeOH was removed under reduced pressure, and
the residue was treated with saturated NaHCO3 solution. The
mixture was extracted with 3:1, CH2Cl2-THF, and the com-
bined organic extracts were washed once with H2O. The
removal of the solvent provided 0.36 g (89%) of crude 10 as a
yellow oil: 1H NMR (CDCl3) δ 6.98 (m, 3H), 6.76 (m, 1H), 3.80
(s, 3H), 3.06 (m, 2H), 2.45-1.43 (m, 13H), 1.04 (s, 3H); 13C
NMR (CDCl3) δ 159.0, 128.3, 122.2, 116.9, 110.0, 55.6, 55.5,
43.8, 43.5, 36.4, 35.3, 30.7, 24.4, 22.4, 21.9.
N-(2-Phenylethyl)-4a-(3-methoxyphenyl)-8a-methyl-
octahydroisoquinoline (11). Phenylacetaldehyde (87 mg,
0.72 mmol) and 10 (190 mg, 0.72 mmol) were mixed in
CH2Cl2 (15 mL) and then treated with sodium triacetoxyborohy-
dride (230 mg, 1.08 mmol). The reaction mixture remained
cloudy throughout the reaction. The mixture was stirred at
room temperature under a N2 atmosphere for 2 h. The reac-
tion mixture was quenched by adding saturated NaHCO3,
and the product was extracted with EtOAc. The EtOAc extract
was dried (MgSO4), and the solvent was evaporated to give
0.25 g (95%) of a light-yellow oil. Purification by chromatog-
raphy on alumina using 10% EtOAc-hexanes gave 0.23 g
(89%) of desired product 11 as a colorless, clear viscous oil:
13C NMR (CDCl3) δ 158.9, 129.1, 128.6, 128.1, 126.2, 122.5,
117.1, 109.9, 63.2, 61.1, 55.5, 43.1, 37.4, 36.3, 34.0, 30.7, 22.4,
22.1.
N-(3-Phenylpropyl)-4a-(3-methoxyphenyl)-8a-meth-
yloctahydroisoquinoline (12). Hydrocinnamaldehyde (110
mg, 0.75 mmol) and 10 (190 mg, 0.75 mmol) were mixed in
CH2Cl2 (15 mL) and then treated with sodium triacetoxyboro-
hydride (240 mg, 1.12 mmol). The reaction mixture remained
cloudy throughout the reaction. The mixture was stirred at
room temperature under a N2 atmosphere for 2.5 h. The
reaction mixture was quenched by adding saturated NaHCO3,
and the product was extracted with EtOAc. The EtOAc ex-
tract was dried (MgSO4), and the solvent was evaporated to
give 0.28 g (99%) of 12 as a light-yellow viscous oil. Purification
by chromatography on alumina using 5% EtOAc-hexanes
gave 0.22 g (79%) of desired product 12 as a colorless, clear
viscous oil, which was used without further purification to
synthesize 6c.
N-(2-Phenylethyl)-4a-(3-hydroxyphenyl)-8a-methyl-
octahydroisoquinoline (6b) Hydrochloride. To a 25-mL
single-necked flask was added 230 mg (0.64 mmol) of 11, 5
mL of glacial AcOH, and 5 mL of 48% HBr. This mixture was
heated under reflux for 18 h and then cooled to room temper-
ature. The pH was adjusted to 10 with cooling using 50%
NaOH. This mixture was extracted 3× with CH2Cl2. The
resulting organic extracts were dried (Na2SO4) and concen-
trated under reduced pressure to give 0.22 g (98%) of crude
product as a white solid. Purification by chromatography on
alumina using 20% EtOAc-hexanes gave 0.18 g (81%) of
desired product 6b as a crystalline, white solid.
The free base was dissolved in MeOH, and to this was added
3 equiv of 1 N HCl in dry Et2O to give the hydrochloride salt
as a crystalline, white solid: mp 226-228 °C; 13C NMR
(DMSO-d6) δ 156.9, 147.5, 147.6, 129.0, 128.9, 128.7, 127.1,
119.4, 116.3, 113.0, 57.3, 48.7, 41.2, 36.6, 34.5, 32.4, 29.7, 24.8,
21.3, 20.6. Anal. (C24H32ClNO‚0.5H2O) C, H, N.
N-(3-Phenylpropyl)-4a-(3-hydroxyphenyl)-8a-meth-
yloctahydroisoquinoline (6c) Hydrochloride. To a 25-mL
single-necked flask was added 220 mg (0.59 mmol) of 12, 5
mL of glacial AcOH, and 5 mL of 48% HBr. This mixture was
heated under reflux for 18 h and then cooled to room temper-
ature. The pH was adjusted to 10 with cooling using 50%
NaOH. This mixture was extracted 3× with CH2Cl2. The
resulting organic extracts were dried (Na2SO4) and concen-
trated under reduced pressure to give 0.21 g (98%) of crude
product as a white solid. Purification by chromatography on
alumina using 15% EtOAc-hexanes gave 0.16 g (76%) of
desired product 6c as a crystalline, white solid.
This free base was dissolved in MeOH, and to this was
added 3 equiv of 1 N HCl in dry Et2O to give the hydrochloride
1
salt as a crystalline, white solid: mp 262-264 °C; H NMR
(CDCl3) δ 9.66 (br s, 1H), 9.32 (s, 1H), 7.34-7.22 (m, 5H), 7.21-
6.95 (m, 3H), 6.62 (d, 1H), 3.35 (m, 3H), 2.92 (m, 4H), 2.5 (m,
4H), 2.39-1.82 (m, 4H), 1.56 (m, 4H), 1.28 (d, J ) 6 Hz, 1H),
1.13 (s, 3H). Anal. (C25H34ClNO‚0.5H2O) C, H, N.
Tetrahydro-2-(oxiranylethoxy)-2H-pyran (13).30 To a
chilled solution (0 °C) of 3,4-dihydro-2H-pyran (117 g, 1.4 mol)
in anhydrous Et2O (600 mL) were added p-toluensulfonic acid
(0.5 g) and 3-buten-1-ol (25.0 g, 0.35 mol). The resulting
mixture was stirred at room temperature for 5 h before
quenching by the addition of concentrated NH4OH (5 mL) and
MeOH (50 mL). The solvent was evaporated in vacuo, and
ether was added to the residue. The precipitated ammonium
p-toluenesulfate was separated by filtration, the filtrate was
concentrated, and the crude product was purified by flash
column chromatography on silica gel (0-5% EtOAc-hexanes)
to give 2-(3-butenyloxy) tetrahydropyran (49 g, 90%) as a
colorless, viscous liquid: 1H NMR (CDCl3) δ 5.80-5.89 (m, 1H,
dCH-C), 5.02-5.06 (m overlapping, 2H, dCH2), 4.59-4.60
(m, 1H, 2-H of THP), 3.77-3.83 (m, 2H, -CH2O), 3.44-3.50
(m, 2H, CH2O of THP), 2.33-2.38 (m, 2H, CH2-CHdCH2),
1.51-1.71 (m, 6H, H’s of THP).
Into a 500-mL flask containing 2-(3-butenyloxy) tetrahy-
dropyran (49.0 g, 0.314 mol) in CH2Cl2 (500 mL) under a N2
atmosphere and cooled to 0 °C was added freshly crystallized
m-chloroperoxybenzoic acid (95 g, 0.55 mol). The mixture was
maintained at 0 °C for a period of 24 h. The precipitated
benzoic acid was removed via vacuum filtration. The filtrate
was washed successively with 10% aqueous NaOH (500 mL)
and saturated aqueous sodium sulfite (500 mL); the organic
layer was dried over anhydrous MgSO4 and concentrated in
vacuo to afford tetrahydro-2-(oxiranylethoxy)-2H-pyran (13)
as a pure, clear, colorless liquid (52 g, 95%), which was used
without further purification: 1H NMR (CDCl3) δ 4.62 (s, 1H),
3.86-3.92 (m, 2H), 3.52-3.55 (m, 2H), 3.08 (br, 1H), 2.78-
2.81 (t, J ) 3 Hz, 1H), 2.53-2.55 (t, J ) 3 Hz, 1H), 1.53-1.88
(m, 8H).

Opioid Receptor Pure Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8189
5-(3-Methoxyphenyl)-8,9-dimethyl-3-[(tetrahydro-2H-
pyran-2-yl)oxy]methyl-2-oxa-8-azabicyclo[3.3.1]nonane
(14). Into a dry 1-L flask containing a solution of 1,3-dimethyl-
4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (7) (24 g, 0.11
mol) in dry THF (600 mL) cooled in a salted ice bath was added
1.4 M s-BuLi in cyclohexane (85 mL, 119 mmol) dropwise
under a N2 atmosphere over a period of 0.5 h. The dark-red
solution was further stirred at reduced temperature for an
additional 15 min, whereupon the mixture was transferred by
cannula into a second dry 2-L flask containing tetrahydro-2-
(oxiranylethoxy)-2H-pyran (13) (20 g, 0.11 mol) in anhydrous
Et2O (150 mL) cooled to -10 °C. Upon complete addition of
the metalated enamine to the epoxide, the resulting mixture
was stirred for an additional 30 min at -5 °C. The reaction
was quenched with a solution of 13 g of NaOH and 42 g of
NaCl in 350 mL of H2O at such a rate so as to maintain the
solution temperature below 0 °C. The mixture was subse-
quently poured into 500 mL of H2O, the layers were separated,
and the aqueous layer was extracted with Et2O-EtOAc (1:1,
3 × 200 mL). The combined organic layers were dried over
anhydrous K2CO3, concentrated, and purified by flash column
chromatography on silica gel (50% EtOAc-hexanes to 100%
EtOAc gradient) to afford 5-(3-methoxyphenyl)-8,9-dimethyl-
3-[(tetrahydro-2H-pyran-2-yl)oxy]methyl-2-oxa-8-azabicyclo-
[3.3.1]nonane (14) as a mixture of diastereomers (30 g, 70%):
1H NMR (CDCl3) δ 7.22-7.28 (m, 1H), 6.71-6.97 (m, 3H), 4.59
(br m, 1H), 4.48 (br m, 1H), 4.19 (br m, 1H), 3.81-3.87 (m,
2H), 3.80 (s, 3H), 3.52 (br m, 2H), 2.62-2.64 (m, 3H), 2.37 (s,
3H), 2.45 (m, 1H), 1.51-1.82 (m, 2H), 0.69 (d, J ) 6 Hz, 3H);
LCMS (ESI): m/z 390.5 [M + H]+.
3-(2-Bromoethyl)-5-(methoxyphenyl)-8,9-dimethyl-2-
oxa-8-azabicyclo[3.3.1]nonane (15). In a dry 1-L flask
containing 5-(3-methoxyphenyl)-8,9-dimethyl-3-[(tetrahydro-
2H-pyran-2-yl)oxy]methyl-2-oxa-8-azabicyclo[3.3.1]nonane (14)
(30 g, 0.076 mol) and triphenylphospine (31 g, 0.12 mol)
dissolved in anhydrous THF (600 mL) under a N2 atmosphere
and cooled to 0 °C was added Br2 (6.0 mL, 117 mmol) over a
period of 30 min. During the course of addition, the solution,
which was initially clear and yellowish, became a precipitous
slurry. Upon complete addition, the mixture was stirred 30
min at reduced temperature and overnight at room temper-
ature (reaction mixture becomes homogeneous brownish-
black). After this time, MeOH (50 mL) was added dropwise,
and the mixture was concentrated. The residue was partitioned
between cold Et2O (500 mL) and cold 1 N NaOH (500 mL).
The organic layer was further washed with H2O (400 mL),
dried over anhydrous K2CO3, and concentrated to afford
semisolid material. The residue obtained was dissolved in a
minimum amount of CHCl3 and further diluted with hexane
until precipitation of triphenylphosphine oxide was observed.
The removal of the precipitate followed by concentration of the
filtrate and purification by flash chromatography (30% EtOAc-
hexanes) afforded 20 g (70%) of 3-(2-bromoethyl)-5-(meth-
oxyphenyl)-8,9-dimethyl-2-oxa-8-azabicyclo[3.3.1]nonane (15)
as a mixture of diastereomers: 1H NMR (CDCl3) δ 7.24-7.29
(m, 1H), 6.73-6.90 (m, 3H), 4.51-4.52 (m, 2H), 3.80 (s, 3H),
3.52-3.56 (m, 2H), 2.61-2.66 (m, 3H), 2.36 (s, 3H), 1.71-2.04
(m, 5H), 0.69 (d, J ) 6 Hz, 3H); LCMS (APCI): m/z 370.3 [M
+ H]+.
dry MeOH (200 mL). The solution was cooled to 0 °C,
whereupon NaBH4 (11.9 g, 0.031 mol) was added over 30 min.
The mixture was gradually warmed to room temperature and
stirred for 36 h. The reaction was quenched with the addition
of 4 N aqueous HCl (pH 1) and stirred for an additional 15
min. The solution was made basic (pH 14) through the addition
of cold 50% aqueous NaOH. The resulting solution was
concentrated and partitioned between a 1:1 mixture of Et2O-
EtOAc (200 mL) and H2O (200 mL). The aqueous phase was
further extracted with a 1:1 mixture of Et2O-EtOAc (2 × 100
mL), and the combined organic layers were dried over anhy-
drous K2CO3-Na2SO4 and concentrated to afford the crude
product (6.72 g). Purification via flash chromatography (35%
EtOAc-hexanes gradient) using neutral alumina (activity
II-III) afforded a diastereomeric mixture of N-methyl-4a-
(3-methoxyphenyl)-8a-dimethyloctahydroisoquinoline-ols (17)
(4.39 g, 58%): 1H NMR (CDCl3) δ 7.12-7.26 (m, 3H), 6.72-
6.91 (m, 1H), 4.01 (m, 1H), 3.80 (s, 3H), 2.63-2.79 (m, 2H),
2.31 (s, 3H), 2.26-2.28 (m, 3H), 2.17-2.21 (m, 2H), 2.03-2.10
(m, 2H), 1.86 (m, 1H), 1.63-1.73 (m, 2H), 1.40 (m, 2H), 1.19
(s, 3H); 13C NMR (CDCl3) δ 158.8, 149.3, 128.2, 121.3, 116.0,
109.8, 67.5, 64.9, 55.1, 52.6, 46.7, 43.9, 41.4, 36.2, 35.7, 35.1,
30.9, 25.3; LCMS (APCI): m/z 290.4 [M + H]+.
N-Methyl-4a-(3-methoxyphenyl)-8a-methyl-6-oxo-
octahydroisoquinoline (18). Into a dry flask containing
oxalyl chloride (3.45 mL, 6.9 mmol, 2.0 M solution in CH2Cl2)
in CH2Cl2 (15 mL) cooled to -70 °C was added DMSO (0.83
mL, 11.7 mmol) in CH2Cl2 (10 mL) over 10 min. The solution
was stirred for an additional 10 min at -70 °C, and 1.54 g,
5.32 mmol of 17 in CH2Cl2 was added over 30 min. After an
additional 30 min at -70 °C, Et3N (1.11 mL, 7.98 mmol) was
added, and the solution was warmed to room temperature,
washed with saturated aqueous NaHCO3 (100 mL), dried over
Na2SO4, concentrated, and purified via flash chromatography
(4% MeOH-CHCl3) to afford 1.40 g (92%) of 18: 1H NMR
(CDCl3) δ 7.18 (t, J ) 3 Hz, 1H), 6.75-6.83 (m, 3H), 3.76 (s,
3H), 3.05 (d, J ) 15 Hz, 1H), 2.73-2.94 (m, 2H), 2.35-2.63
(m, 6H), 2.33 (s, 3H), 1.77 (m, 1H), 1.27-1.32 (m, 2H), 0.97 (s,
3H); 13C NMR (CDCl3) δ 213.3, 159.3, 147.1, 128.8, 121.1,
115.1, 111.7, 63.1, 55.4, 52.6, 47.3, 47.1, 45.7, 37.8, 36.4, 33.8,
32.9, 25.8; LCMS (ESI): m/z 288.6 [M + H]+.
N-Methyl-4a-(3-methoxyphenyl)-8a-methyl-6-oxo-
octahydroisoquinoline Oxime (19). N-Methyl-4a-(3-meth-
oxyphenyl)-8a-methyl-6-oxoisoquinoline (18) (1.41 g, 4.9 mmol)
and hydroxylamine hydrochloride (1.70 g, 24.5 mmol) in EtOH
(absolute, 100 mL) were heated to reflux for 5 h. The reaction
mixture was allowed to cool to room temperature. Ethanol was
removed under reduced pressure. The crude product was
dissolved in aqueous 2 N NaOH solution (100 mL) and
extracted with 3:1 CH2Cl2-THF (4 × 50 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude product was purified by
flash chromatography (neutral alumina, Brockmann activity
II-III) eluting with 9:1 EtOAc-hexanes to afford 1.43 g (96%)
of 19 as a white solid (mixture of E/Z isomers): LCMS (ESI):
m/z 303.5 [M + H]+.
N-Methyl-6-amino-4a-(3-methoxyphenyl)-8a-methyl-
octahydroisoquinoline (20). A slurry of oxime 19 (2.35 g,
0.077 mol) in anhydrous (CH3)2CHOH (100 mL) and anhydrous
toluene (200 mL) was heated to reflux until the solution
became clear. The heat was turned off, and Na (20 g, 0.87 mol)
was added with care at such a rate as to maintain a steady
reflux (make 30-40 pieces and store under hexane and add
over 1.5 h). The first addition was kept small. (Note hydrogen
evolution!) At the end, the reaction was slower; as a result,
the heating mantle was turned back on to bring back to reflux.
The reaction mixture was heated until all of the Na was
consumed followed by cooling to 50 °C and quenching with the
careful addition of H2O (250 mL). The toluene layer was
separated, and the aqueous layer was extracted with EtOAc
(3 × 100 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography (50%
CMA-80 in CHCl3) to afford 2.11 g (94%) of 20 as a colorless
N-Methyl-4a-(3-methoxyphenyl)-8a-methyloctahy-
droisoquinoline-6-ol (17). A solution of 3-(2-bromoethyl)-5-
(methoxyphenyl)-8,9-dimethyl-2-oxa-8-azabicyclo[3.3.1]-
nonane (15) (9.6 g, 0.026 mol), acetic anhydride (35 mL), and
trifluoroacetic acid (35 mL) was stirred under a N2 atmosphere
at ambient temperature for 1 h and poured into a mixture of
ice (300 g) and 50% aqueous NaOH (50 mL) sufficient to make
the solution strongly basic, and the product was extracted into
cold Et2O (400 mL). The ether layer was washed once with
cold H2O, dried over anhydrous K2CO3, and concentrated at 0
°C to afford enamine 16 as a yellow viscous oil (10.8 g). The
oil was immediately dissolved in molecular sieve-dried
CH3CN (200 mL) and heated at reflux over K2CO3 (12 g) for 3
h under a N2 atmosphere. Upon cooling, the solution was
filtered and concentrated, and the residue was taken up in

8190 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Carroll et al.
oil: 1H NMR (CDCl3) δ 7.14-7.44 (m, 3H), 6.71-6.74 (m, 1H),
3.80 (s, 3H), 3.05 (m, 1H), 2.77 (m, 1H), 2.64 (d, J ) 12 Hz,
1H), 2.27-2.30 (m, 2H), 2.26 (s, 3H), 2.02-2.12 (m, 3H), 1.68-
1.71 (m, 2H), 1.46-1.49 (m, 2H), 1.24 (m, 3H), 1.20 (s, 3H);
13C NMR (CDCl3) δ 159.2, 150.2, 128.5, 121.8, 116.5, 110.0,
65.4, 55.5, 53.0, 47.1, 46.7, 43.8, 43.3, 36.6, 36.2, 32.2, 25.8;
LCMS (APCI): m/z 289.4 [M + H]+.
1H), 4.81 (m, 1H), 3.85 (s, 3H), 3.31 (t, J ) 12 Hz, 1H), 2.94
(d, J ) 12 Hz, 1H), 2.80 (d, J ) 9 Hz, 1H), 2.67-2.73 (m, 3H),
2.34-2.53 (m, 4H), 2.25 (d, J ) 12 Hz, 1H), 1.78-1.94 (m, 3H),
1.51-1.62 (m, 2H), 1.49 (d, J ) 12 Hz, 1H), 1.31-1.37 (m, 1H),
1.26 (s, 3H); 13C NMR (CDCl3) δ 170.4, 160.9, 150.3, 144.5,
135.7, 134.0, 130.4, 130.3, 130.2, 127.6, 124.9, 123.5, 117.6,
112.6, 90.0, 63.6, 59.9, 57.2, 52.9, 49.5, 46.2, 38.6, 38.5, 37.3,
35.7, 35.6, 31.0, 28.3, 25.9. LCMS (ESI): m/z 523.7 [M + H]+.
Anal. (C34H38N2O3) C, H, N.
N-(3-Phenylpropyl)-6-amino-4a-(3-methoxyphenyl)-8a-
methyloctahydroisoquinoline (24). Compound 23 (2.00 g,
0.0038 mol) and hydrazine hydrate (1.02 mL, 21.0 mmol) were
dissolved in EtOH (100 mL) and heated at reflux overnight.
The filtrate was cooled, and the white precipitate was filtered
and washed with cold EtOH. The solution was concentrated
under reduced pressure, and the crude material was taken up
in 3:1 CH2Cl2-THF (100 mL). The resulting white precipitate
was separated by filtration and washed with cold CH2Cl2 (50
mL). The combined organic layer was dried (Na2SO4) and
concentrated under reduced pressure to yield crude product.
The crude product was purified by flash chromatography (40%
CMA-80 in CHCl3) to afford 1.45 g (97%) of 24 as a colorless
oil: 1H NMR (CDCl3) δ 7.14-7.30 (m, 8H), 6.70-6.74 (m, 1H),
3.86 (s, 3H), 3.05 (m, 1H), 2.77-2.79 (br m, 1H), 2.65 (ddd, J1
) J2 ) 9 Hz, J3 ) 3 Hz, 2H), 2.58 (d, J ) 12 Hz, 1H), 2.26-
2.36 (m, 4H), 2.04-2.12 (m, 3H), 1.68-1.81 (m, 4H), 1.44-
1.50 (m, 4H), 1.32 (m, 1H), 1.21 (s, 3H); 13C NMR (CDCl3) δ
159.2, 150.3, 142.9, 128.9, 128.6, 128.5, 126.0, 121.8, 116.5,
110.0, 62.6, 58.2, 55.5, 51.3, 46.9, 44.5, 43.2, 36.7, 36.3, 34.0,
32.1, 29.2, 25.8; LCMS (APCI): m/z 393.8 [M + H]+.
N-[4a-(3-Methoxyphenyl)-8a-methyl-2-(3-phenylpro-
pyl)octahydroisoquinolin-6-yl]-3-(piperidin-1-yl)propi-
onamide (25a). To 24 (105 mg, 0.267 mmol) dissolved in
anhydrous THF (15 mL) was added 1-piperidinepropionic acid
(63 mg, 0.40 mmol), Et3N (0.17 mL, 1.33 mmol), and BOP
reagent (140 mg, 0.32 mmol), and the reaction mixture was
allowed to stir at room temperature for 1.5 h. The reaction
progress was monitored by TLC (50% CMA-80 in CH2Cl2). The
reaction mixture was diluted with EtOAc (25 mL) and washed
with saturated aqueous NaHCO3 (25 mL) followed by H2O (25
mL). The aqueous layers were back extracted with EtOAc (2
× 20 mL). The combined organic layers were washed with 1
N NaOH (25 mL), dried (MgSO4), and concentrated under
reduced pressure to afford crude amide. The crude product was
purified by flash chromatography (30% CMA-80 in CH2Cl2) to
afford 121 mg (85%) of 25a as a shiny, white solid: 1H NMR
(CDCl3) δ 8.77 (d, J ) 6 Hz, 1H), 7.15-7.30 (m, 8H), 6.72-
6.75 (m, 1H), 4.24 (m, 1H), 3.82 (s, 3H), 2.76 (br, 1H), 2.65-
2.68 (m, 2H), 2.42-2.56 (m, 3H), 2.32-2.37 (m, 6H), 2.07-
2.30 (m, 7H), 1.62-1.83 (m, 5H), 1.59-1.61 (m, 4H), 1.48-
1.59 (m, 4H), 1.25-1.27 (br, 1H), 1.21 (s, 3H); 13C NMR (CDCl3)
δ 172.2, 159.2, 148.8, 142.8, 128.8, 128.7, 128.6, 126.0, 122.2,
116.2, 110.9, 62.4, 58.4, 55.6, 54.9, 54.0, 51.4, 45.5, 44.1, 38.1,
37.0, 36.8, 35.5, 34.0, 32.5, 29.2, 28.4, 26.9, 26.7, 24.6; LCMS
(ESI): m/z 532.8 [M + H]+.
N-Methyl-6-amino-4a-(3-methoxyphenyl)-8a-methyl-
octahydroisoquinoline Phthalimide (21). Amine 20 (1.70
g, 0.0058 mol) was dissolved in anhydrous toluene (100 mL)
followed by the addition of phthalic anhydride (2.61 g, 0.018
mol), and the mixture was heated at reflux overnight using a
Dean-Stark trap to collect H2O. The solution was cooled and
washed with 1 N NaOH (3 × 50 mL) and H2O. The organic
layer was collected and dried (Na2SO4), and the solvent was
removed under reduced pressure yielding crude product. The
crude product was purified by flash chromatography (30%
EtOAc-hexanes on neutral Al2O3 Brockman activity II-III)
to afford 2.22 g (90%) of 21 as a white solid: 1H NMR (CDCl3)
δ 7.80-7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.23-7.27 (m, 3H),
6.77-6.79 (m, 1H), 4.81 (m, 1H), 3.85 (s, 3H), 3.28 (t, J ) 12
Hz, 1H), 3.01 (d, J ) 12 Hz, 1H), 2.83-2.85 (m, 1H), 2.65-
2.81 (m, 1H), 2.40-2.47 (m, 2H), 2.37 (s, 3H), 2.16-2.20 (m,
1H), 1.89 (ddd, J1 ) J2 ) 15 Hz, J3 ) 6 Hz, 1H), 1.48-1.58
(m, 3H), 1.33-1.39 (m, 1H), 1.26 (s, 3H); 13C NMR (CDCl3) δ
168.8, 159.2, 148.4, 134.1, 132.4, 128.7, 123.3, 121.8, 116.0,
111.0, 64.8, 55.5, 52.9, 47.8, 47.2, 43.8, 36.7, 35.6, 34.1, 26.7,
24.3; LCMS (ESI): m/z 419.9 [M + H]+.
6-Amino-4a-(3-methoxyphenyl)-8a-methyloctahydroiso-
quinoline Phthalimide (22). To a solution of 21 (2.09 g,
0.005 mol) in anhydrous CH2Cl2 (100 mL) at reflux was added
1-chloroethyl chloroformate (0.82 mL, 7.47 mmol) dropwise.
The resulting solution was heated under reflux for 5 h and
then cooled to room temperature. This was washed once with
saturated NaHCO3 solution and once with H2O. The dried
(Na2SO4) organic layer was evaporated, and the resulting
carbamate (foamy, white solid, almost quantitative yield) was
dissolved immediately in MeOH (100 mL), and the solution
was refluxed overnight. After cooling to room temperature,
MeOH was removed under reduced pressure, and the residue
was treated with saturated NaHCO3 solution. This was
extracted with 3:1 CH2Cl2-THF, and the combined organic
extracts were washed once with H2O and dried (Na2SO4). The
removal of solvent under reduced pressure afforded 2.01 g
(99%) of 22 as a foamy, white solid: 1H NMR (CDCl3) δ 7.80-
7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.23-7.28 (m, 3H), 6.78-
6.81 (m, 1H), 4.84 (m, 1H), 3.86 (s, 1H), 3.75-3.80 (m, 2H),
3.32 (t, J ) 12 Hz, 1H), 3.03-3.15 (m, 2H), 2.90 (br s, 1H),
2.61-2.67 (m, 1H), 2.45 (d, J ) 12 Hz, 1H), 2.27-2.31 (m, 1H),
1.83-1.93 (m, 2H), 1.64 (dd, J1 ) 15 Hz, J2 ) 6 Hz, 2H), 1.31-
1.48 (m, 3H), 1.24 (s, 3H); 13C NMR (CDCl3) δ 167.5, 158.1,
147.0, 132.9, 131.1, 127.5, 122.1, 120.5, 114.7, 109.8, 67.0, 54.3,
53.2, 46.5, 43.5, 41.8, 35.2, 34.8, 33.9, 32.9, 29.4, 24.7, 24.1,
22.9; LCMS (APCI): m/z 405.2 [M + H]+.
N-(3-Phenylpropyl)-6-amino-4a-(3-methoxyphenyl)-8a-
methyloctahydroisoquinoline Phthalimide (23). Hydro-
cinnamaldehyde (0.65 mL, 0.0049 mmol) and 22 (2.00 g, 0.0049
mol) were mixed in anhydrous CH2Cl2 (50 mL) and then
treated with sodium triacetoxyborohydride (1.57 g, 0.0074
mol). The reaction mixture remained cloudy throughout the
reaction. The mixture was stirred at room temperature under
a N2 atmosphere for 3 h. The reaction was monitored by
TLC (20% EtOAc-hexanes; neutral Al2O3 Brockman activity
II-III). After completion, the reaction mixture was quenched
by adding saturated aqueous NaHCO3, and the product was
extracted with EtOAc (3 × 50 mL). The combined EtOAc
extracts were dried (MgSO4), and the solvent was removed
under reduced pressure to give crude product. The crude
product was purified by flash chromatography (10% EtOAc-
hexanes on neutral Al2O3 Brockman activity II-III) to afford
2.25 g (87%) of 23 as a shiny, white solid. The sample used
for X-ray analysis was recrystallized from a mixture of hexane
N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpro-
pyl)octahydroisoquinolin-6-yl]-3-(piperidin-1-yl)propi-
onamide (6d) Dihydrochloride. To 25a (90 mg, 0.169
mmol), dissolved in anhydrous CH2Cl2 (15 mL) and cooled to
-78 °C, was slowly added a 1.0 M solution in CH2Cl2 of BBr3
(0.85 mL, 0.85 mmol). The reaction mixture was allowed to
stir at -78 °C for 30 min and at room temperature for 2 h.
The reaction mixture was cooled to 0 °C, quenched with
saturated aqueous NaHCO3, and extracted with CH2Cl2 (2 ×
25 mL). The combined organic layers were washed with 1 N
NaOH (25 mL), dried (Na2SO4), filtered, and concentrated in
vacuo to afford crude product. The crude product was purified
by flash chromatography (40% CMA-80 in CH2Cl2) to afford
75 mg (86%) of 6d as a white solid: 1H NMR (CDCl3) δ 8.73
(d, J ) 6 Hz, 1H), 7.09-7.31 (m, 8H), 6.68-6.72 (m, 1H), 4.30
(m, 1H), 2.78-2.85 (br, 1H), 2.59-2.69 (m, 4H), 2.50-2.55 (br,
4H), 2.36-2.42 (m, 4H), 2.20-2.27 (m, 3H), 2.05 (m, 2H), 1.78-
1.85 (m, 5H), 1.62-1.65 (m, 4H), 1.43-1.50 (m, 4H), 1.21-
1.25 (m, 2H), 1.19 (s, 3H); 13C NMR (CDCl3) δ 171.8, 155.7,
1
and CH2Cl2: mp 136-138 °C; H NMR (CDCl3) δ 7.79-7.82
(m, 2H), 7.68-7.71 (m, 2H), 7.18-7.32 (m, 8H), 6.76-6.81 (m,

Opioid Receptor Pure Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8191
148.2, 142.4, 128.5, 128.2, 125.7, 121.1, 116.5, 112.8, 61.8, 58.0,
54.3, 53.5, 50.9, 45.4, 43.6, 37.4, 36.6, 36.3, 35.0, 33.6, 31.9,
28.6, 27.9, 26.6, 25.9, 24.0; LCMS (ESI): m/z 518.9 [M + H]+.
An analytical sample of the dihydrochloride salt was
prepared by dissolving the free base in MeOH and adding 6
equiv of 1.0 M HCl in Et2O. The removal of the solvent under
reduced pressure afforded the dihydrochloride salt as a white
solid, which was recrystallized from a mixture of MeOH-
Et2O: mp 240-242 °C (fus.). Anal. (C33H49Cl2N3O2‚2.75H2O)
C, H, N.
mixture was allowed to stir at room temperature for 2 h. The
reaction progress was monitored by TLC (30% CMA-80 in
CH2Cl2). The reaction mixture was diluted with EtOAc (25 mL)
and washed with saturated aqueous NaHCO3 (25 mL) followed
by H2O (25 mL). The aqueous layers were back extracted with
EtOAc (2 × 20 mL). The combined organic layers were washed
with 1 N NaOH (30 mL), dried (MgSO4), and concentrated
under reduced pressure to afford crude product. The crude
product was purified by flash chromatography (25% CMA-80
in CH2Cl2) to afford 94 mg (92%) of 25c: 1H NMR (CDCl3) δ
7.17-7.36 (m, 13H), 6.71-6.73 (m, 1H), 4.92 (d, J ) 6 Hz, 1H),
4.19 (m, 1H), 3.79 (s, 3H), 2.74 (br, 1H), 2.62-2.64 (m, 2H),
2.33-2.45 (m, 5H), 2.10-2.31 (m, 2H), 1.98-2.09 (m, 3H),
1.61-1.84 (m, 10H), 1.46 (d, J ) 12 Hz, 1H), 1.20-1.33 (m,
2H), 1.15 (s, 3H); 13C NMR (CDCl3) δ 176.1, 159.2, 148.9, 144.8,
142.8, 129.0, 128.9, 128.7, 128.6, 127.2, 127.1, 126.0, 121.9,
116.3, 110.7, 62.2, 59.6, 58.2, 55.5, 51.2, 46.2, 44.2, 37.8, 37.4,
37.2, 36.9, 36.6, 35.6, 33.9, 29.2, 28.1, 26.6, 24.4; LCMS (ESI):
m/z 565.6 [M + H]+.
1-Phenylcyclopentanecarboxylic Acid [4a-(3-Hydroxy-
phenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquin-
olin-6-yl]amide (6f) Hydrochloride. Compound 25c (94 mg,
0.166 mmol) was dissolved in anhydrous CH2Cl2 (15 mL),
cooled to -78 °C, and added slowly to a 1.0 M solution of BBr3
(0.832 mL, 0.832 mmol) in CH2Cl2. The reaction mixture was
allowed to stir at -78 °C for 30 min and at room temperature
for 1.5 h. The reaction mixture was cooled to 0 °C, quenched
with saturated aqueous NaHCO3, and extracted with CH2Cl2
(2 × 25 mL). The combined organic layer was dried (Na2SO4),
filtered, and concentrated in vacuo to afford crude product.
The crude product was purified by flash chromatography (30%
CMA-80 in CH2Cl2) to afford 78 mg (86%) of 6f as a white
solid: 1H NMR (CDCl3) δ 7.09-7.34 (m, 14 H), 6.68-6.70 (br,
1H), 5.06 (d, J ) 9 Hz, 1H), 4.26 (m, 1H), 2.71 (br, 1H), 2.61-
2.64 (m, 2H), 2.35-2.45 (m, 5H), 2.00-2.10 (m, 5H), 1.63-
1.98 (m, 10H), 1.41 (d, J ) 12 Hz, 1H), 1.18-1.23 (m, 2H),
1.13 (s, 3H); 13C NMR (CDCl3) δ 176.7, 156.2, 148.5, 144.5,
142.7, 129.1, 128.9, 128.7, 128.6, 127.3, 127.2, 126.0, 121.3,
116.8, 113.3, 62.1, 59.6, 58.2, 51.1, 46.4, 44.0, 37.5, 37.4, 37.3,
36.9, 36.6, 35.4, 33.9, 29.0, 28.0, 26.8, 24.4; LCMS (APCI): m/z
551.2 [M + H]+.
3-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-[4a-(3-meth-
oxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroiso-
quinolin-6-yl]propionamide (25b). To 24 (80 mg, 0.203
mmol), dissolved in anhydrous THF (15 mL) were added 3-(3,4-
dihydro-1H-isoquinolin-2-yl)-propioinic acid hydrochloride (73
mg, 0.305 mmol) and Et3N (0.142 mL, 1.01 mmol), and the
reaction mixture was stirred at room temperature for 15 min.
After this time, BOP reagent (99 mg, 0.22 mmol) was added,
and the reaction mixture was allowed to stir at room temper-
ature for 1.5 h. The reaction progress was monitored by TLC
(50% CMA-80 in CH2Cl2). The reaction mixture was diluted
with EtOAc (25 mL) and washed with saturated aqueous
NaHCO3 (25 mL) followed by H2O (25 mL). The aqueous layers
were back extracted with EtOAc (2 × 20 mL). The combined
organic layer was washed with 1 N NaOH (30 mL), dried
(MgSO4), and concentrated under reduced pressure to afford
crude amide, 25b. The crude product was purified by flash
chromatography (30% CMA-80 in CH2Cl2) to afford 94 mg
(80%) of 25b as a shiny, white solid: 1H NMR (CDCl3) δ 8.29
(d, J ) 6 Hz, 1H), 7.03-7.31 (m, 12H), 6.70-6.73 m, 1H), 4.23
(m, 1H), 3.80 (s, 1H), 3.68 (s, 2H), 2.94 (t, J ) 6 Hz, 2H), 2.77-
2.82 (m, 4H), 2.62-2.67 (m, 3H), 2.42 (t, J ) 6 Hz, 2H), 2.25-
2.35 (m, 2H), 1.74-1.87 (m, 7H), 1.19-1.34 (m, 3H), 1.14 (s,
3H); 13C NMR (CDCl3) δ 171.9, 159.2, 148.8, 142.8, 134.4,
134.1, 129.1, 128.9, 128.7, 128.6, 127.4, 126.9, 126.8, 126.3,
126.1, 122.1, 116.2, 110.8, 62.1, 58.2, 55.6, 54.1, 51.1, 50.5, 45.6,
44.0, 37.9, 36.8, 36.7, 35.3, 34.0, 33.0, 29.7, 29.2, 28.3, 26.8;
LCMS (ESI): m/z 580.9 [M + H]+.
3-(3,4-Dihydro-1H-isoquinolin-2-yl)-N-[4a-(3-hy-
droxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroiso-
quinolin-6-yl]propionamide (6e) Dihydrochloride. 25b
(70 mg, 0.120 mmol) was dissolved in anhydrous CH2Cl2 (15
mL), cooled to -78 °C, and added slowly to a 1.0 M solution of
BBr3 (0.60 mL, 0.60 mmol) in CH2Cl2. The reaction mixture
was allowed to stir at -78 °C for 30 min and at room
temperature for 1.5 h. The reaction mixture was cooled to 0
°C, quenched with saturated aqueous NaHCO3, and extracted
with CH2Cl2 (2 × 25 mL). The combined organic layer was
dried (Na2SO4), filtered, and concentrated in vacuo to afford
crude product. The crude product was purified by flash
chromatography (30% CMA-80 in CH2Cl2) to afford 60 mg
(88%) of 6e as a white solid: 1H NMR (CDCl3) δ 8.55 (d, J )
6 Hz, 1H), 7.05-7.31 (m, 12H), 6.66-6.69 (m, 1H), 4.28 (m,
1H), 3.68 (s, 2H), 2.94 (t, J ) 6 Hz, 2H), 2.78-2.83 (m, 4H),
2.61-2.66 (3H), 2.45 (t, J ) 6 Hz, 2H), 2.23-2.34 (m, 3H),
2.02-2.13 (m, 2H), 1.69-1.80 (m, 8H), 1.251.32 (m, 3H), 1.11
(s, 3H); 13C NMR (CDCl3) δ 172.2, 156.0, 148.6, 142.8, 134.3,
134.1, 129.1, 128.9, 126.6, 126.9, 126.3, 126.1, 121.1, 116.8,
113.2, 62.1, 58.2, 55.6, 54.0, 51.0, 50.4, 45.7, 43.9, 37.7, 36.8,
36.6, 35.2, 34.0, 32.8, 29.6, 29.1, 28.2, 27.0; LCMS (ESI): m/z
566.5 [M + H]+.
An analytical sample of the hydrochloride salt was prepared
by dissolving the free base in MeOH and adding 3 equiv of
1.0 M HCl in Et2O. The removal of the solvent under reduced
pressure afforded the hydrochloride salt as a white solid, which
was recrystallized from a MeOH-EtOAc combination: mp
194-195 °C (fus.). Anal. (C37H47ClN3O2‚0.75H2O) C, H, N.
Benzo[b]thiophene-2-carboxylic Acid [4a-(3-Methoxy-
phenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquin-
olin-6-yl]amide (25d). To 24 (52 mg, 0.132 mmol) dissolved
in anhydrous THF (10 mL) was added benzo[b]thiophene-2-
carboxylic acid (35 mg, 0.198 mmol), Et3N (0.092 mL, 0.662
mmol), and BOP reagent (64 mg, 0.145 mmol), and the reac-
tion mixture was allowed to stir at room temperature for 1.5
h. The reaction was monitored by TLC (30% CMA-80 in
CH2Cl2). The reaction mixture was diluted with EtOAc (20 mL)
and washed with saturated aqueous NaHCO3 (20 mL) followed
by H2O (20 mL). The aqueous layers were back extracted with
EtOAc (2 × 20 mL). The combined organic layers were washed
with 1 N NaOH (25 mL), dried (MgSO4), and concentrated
under reduced pressure to afford crude product. The crude
product was purified by flash chromatography (20% CMA-80
in CH2Cl2) to afford 70 mg (96%) of 25d: 1H NMR (CDCl3) δ
7.74-7.81 (m, 3H), 7.36-7.40 (m, 2H), 7.18-7.31 (m, 7H),
6.74-6.75 (m, 1H), 6.12 (d, J ) 9 Hz, 1H), 4.47 (m, 1H), 3.81
(s, 3H), 2.76-2.79 (br, 1H), 2.59-2.67 (m, 3H), 2.36-2.39 (m,
2H), 2.15-2.29 (m, 4H), 1.89-1.94 (m, 3H), 1.60-1.81 (m, 4H),
1.53 (d, J ) 12 Hz, 1H), 1.26-1.32 (m 1H), 1.24 (s, 3H); 13C
NMR (CDCl3) δ 161.9, 159.3, 148.7, 142.8, 141.2, 139.5, 139.2,
128.9, 128.8, 128.7, 126.6, 126.1, 125.3, 125.2, 123.1, 122.0,
116.4, 110.8, 62.3, 58.3, 55.6, 51.2, 47.1, 44.4, 38.1, 37.0, 36.8,
35.6, 34.0, 29.2, 28.3, 26.7; LCMS (ESI): m/z 553.9 [M + H]+.
An analytical sample of the dihydrochloride salt was
prepared by dissolving the free base in MeOH and adding 6
equiv of 1.0 M HCl in Et2O. The removal of the solvent under
reduced pressure afforded the dihydrochloride salt as a white
solid, which was recrystallized from a mixture of MeOH-
EtOAc: mp 178-180 °C (fus.). Anal. (C37H49Cl2N3O2‚2H2O) C,
H, N.
1-Phenylcyclopentanecarboxylic Acid [4a-(3-Methoxy-
phenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquin-
olin-6-yl]amide (25c). To 24 (71 mg, 0.180 mmol) dissolved
in anhydrous THF (15 mL) was added 1-phenyl-1-cyclopen-
tanecarboxylic acid (51 mg, 0.27 mmol), Et3N (0.126 mL, 0.904
mmol), and BOP reagent (88 mg, 0.20 mmol), and the reaction
Benzo[b]thiophene-2-carboxylic Acid [4a-(3-Hydroxy-
phenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquin-

8192 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Carroll et al.
olin-6-yl]amide (6 g) Hydrochloride. Compound 25d (70
mg, 0.260 mmol) was dissolved in anhydrous CH2Cl2 (15 mL),
cooled to -78 °C, and slowly added to a 1.0 M solution of BBr3
(0.633 mL, 0.633 mmol) in CH2Cl2. The reaction mixture was
allowed to stir at -78 °C for 30 min and at room temperature
for 1.5 h. The reaction was cooled to 0 °C, quenched with
saturated aqueous NaHCO3, and extracted with CH2Cl2 (2 ×
25 mL). The combined organic layer was dried (Na2SO4),
filtered, and concentrated in vacuo to afford crude product.
The crude product was purified by flash chromatography (25%
CMA-80 in CH2Cl2) to afford 60 mg (88%) of 6g as a white
solid: 1H NMR (CDCl3) δ 7.77-7.81 (m, 3H), 7.37-7.41 (m,
2H), 7.25-7.27 (m, 3H), 7.12-7.19 (m, 5H), 6.73-6.76 (m, 1H),
6.27 (d, J ) 12 Hz, 1H), 4.48 (m, 1H), 2.74 (m, 1H), 2.58-2.65
(m, 3H), 2.36-2.38 (m, 2H), 2.15-2.26 (m, 4H), 1.78-1.86 (m,
5H), 1.56-1.70 (m, 1H), 1.47 (d, J ) 12 Hz, 1H), 1.21-1.23
(m, 2H), 1.19 (s, 3H); 13C NMR (CDCl3) δ 162.0, 155.8, 148.2,
142.4, 140.9, 139.2, 138.6, 128.6, 128.4, 126.4, 125.8, 125.3,
125.1, 125.0, 122.8, 121.3, 116.5, 113.2, 61.9, 58.0, 50.8, 47.0,
43.9, 37.5, 36.7, 36.4, 35.2, 33.6, 28.7, 27.9, 26.4; LCMS
(APCI): m/z 539.3 [M + H]+.
Ke from the formula: Ke ) [L]/(DR - 1), where [L] equals the
concentration of test compound in the assay and DR equals
the dose ratio or A′/A. A′ was used only when it was at least
2-fold greater than A.
Acknowledgment. This work was supported by the
National Institute on Drug Abuse, Grant DA09045. The
CHO cells expressing the human opioid receptors were
kind gifts of Dr. Lawrence Toll (SRI, Menlo Park, CA;
hMOR and hDOR) and Dr. Liu-Chen (Temple Univer-
sity, Philadelphia, PA; hKOR).
Supporting Information Available: Crystal data, struc-
tural refinement analysis, atomic coordinates, bond lengths,
bond angles, anisotropic displacement parameters, hydrogen
coordinates, and isotropic displacement parameters of 6a‚HCl
and 23. Elemental analysis data for 6a-g and 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
References
An analytical sample of the hydrochloride salt was prepared
by dissolving the free base in MeOH and adding 3 equiv of
1.0 M HCl in Et2O. The removal of solvent under reduced
pressure afforded the hydrochloride salt as a white solid, which
was recrystallized from a mixture of MeOH-EtOAc: mp 206-
208 °C (fus.). Anal. (C34H39Cl2N2O2S‚0.75H2O) C, H, N.
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