N-substituted 4β-methyl-5-(3-hydroxyphenyl)-7α-amidomorphans are potent, selective κ opioid receptor antagonists

Article abstract of DOI:10.1021/jm058264p

In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl) -4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl) propanamide (5a, KAA-1) as the first potent and selective κ opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7α-amido group were varied. Most of the analogues showed sub-nanomolar potency for the κ opioid receptor and were highly selective relative to the μ and δ opioid receptors. (-)-3-(3,4- Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl) -4-methyl-2-[2-(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a κ opioid receptor antagonist in the [³⁵S]GTP-γ-S in vitro functional test.

Full text of DOI:10.1021/jm058264p

J. Med. Chem. 2006, 49, 1781-1791
1781
N-Substituted 4â-Methyl-5-(3-hydroxyphenyl)-7r-amidomorphans Are Potent, Selective K
Opioid Receptor Antagonists
F. Ivy Carroll,* Matt S. Melvin, Michel C. Nuckols, S. Wayne Mascarella, Herna´n A. Navarro, and James B. Thomas
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709
ReceiVed August 26, 2005
In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl)propanamide (5a, KAA-1) as the first potent and selective κ
opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report
an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues
5b-r where the morphan N-substituent and 7R-amido group were varied. Most of the analogues showed
sub-nanomolar potency for the κ opioid receptor and were highly selective relative to the µ and δ opioid
receptors. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-
(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and
selective as nor-BNI as a κ opioid receptor antagonist in the [35S]GTP-γ-S in vitro functional test.
Chart 1
N-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)pipe-
ridines (1) are a structurally unique class of opioid receptor
antagonist.1 Unlike naloxone (2a) and naltrexone (2b) as well
as the κ opioid receptor selective nor-BNI (3) and GNTI (4),
where the antagonist activity is dependent on the N-allyl or
N-cyclopropylmethyl substituent, all N-substituted trans-3,4-
dimethyl-4-(3-hydroxyphenyl)piperidines (1) including the N-
methyl analogue 1a are opioid receptor pure antagonists (Chart
1).1-5 A few of the more interesting analogues include alvi-
mopan (1b),4-7 which has reached the NDA stage for GI
motility disorder, LY255 582 (1c),4,8 which was developed to
treat obesity, and the selective κ opioid receptor antagonist JDTic
(1d),9-12 which is active in rat models of stress-induced cocaine
relapse and antidepression.13
In recent studies, we reported that N-substituted 4â-methyl-
5-(3-hydroxyphenyl)morphans (5, Chart 2) were opioid receptor
pure antagonists with in vitro pharmacological properties similar
to those of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)pip-
eridines (1).14,15 The morphans can be viewed as conforma-
tionally rigid analogues of the trans-3,4-dimethyl-4-(3-hydroxy-
phenyl)piperidines (1). These studies identified (-)-N-
[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpro-
pyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl)propana-
mide (5a) as a potent and selective κ opioid receptor antagonist.15
In this study, we report an improved synthesis for this class
of compounds, which provided analogues 5b-r. Several
compounds are more potent and selective κ opioid receptor
antagonists than 5a. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-
N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-(2-meth-
ylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide, 5n
(MTHQ), is at least as potent and selective as nor-BNI for the
κ opioid receptor relative to the µ and δ opioid receptors in the
[35S]GTP-γ-S functional assay.
provided oxime 7 in 88% yield. Reduction of 7 using sodium
and 2-propanol in refluxing toluene gave amine 8 as one isomer
in 95% yield. Condensation of 8 with phthalic anhydride in
refluxing toluene under a Dean-Stark trap provided a 62% yield
of protected amine 9. Treatment of 9 with 1-chloroethyl
chloroformate (ACE-Cl) followed by refluxing the resulting
carbamate in methanol afforded the N-demethylated product,
10. Reductive alkylation of 10 with hydrocinnamaldehyde and
sodium triacetoxyborohydride in dichloroethane gave 11 in 84%
yield. Removal of the phthalimide protecting group with
hydrazine in refluxing ethanol gave amino compound 12 in 97%
yield. Two slightly different procedures were used to convert
12 to the desired final products 5b-k. For analogues 5b-e,
5g, and 5i-k, compound 12 was first treated with 48%
hydrobromic acid in acetic acid to give amino phenol 13.
Coupling 13 with the appropriate 3-substituted propionic acid
using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
Chemistry
Compounds 5b-k were synthesized as outlined in Scheme
1. This procedure is much improved over that previously used
to prepare 5a.15 Condensation of optically pure ketone 615 with
hydroxylamine hydrochloride in ethanol at reflux for 3 h
* Corresponding author. Telephone: 919-541-6679. Fax: 919-541-8868.
E-mail: fic@rti.org.
10.1021/jm058264p CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/07/2006

1782 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Carroll et al.
Chart 2
hexafluorophosphate (BOP) in tetrahydrofuran containing tri-
ethylamine or diisopropylethylamine yielded compounds 5b-
e, 5g, and 5i-k. Compounds 5f and 5h were synthesized by
first coupling 12 with the appropriate acid using 1-ethyl-3-
(dimethylaminopropyl)carbodiimide (EDCI) to give the isopro-
pyl-protected intermediates 14a,b. Treatment of 14a,b with
boron tribromide in methylene chloride yielded the desired 5f
and 5h. The 3-substituted propionic acids were either com-
mercially available or prepared by addition of acrylic acid to
the appropriate substituted tetrahydroisoquinoline (THIQ). The
6-methoxy-, 7-methoxy-, and 7-hydroxy-THIQ were synthesized
by reported methods (see Experimental Section).16-18 THIQ,
5-methoxy-, and 6,7-dimethoxy-THIQ were commercially avail-
able.
Scheme 2 shows the methods used to synthesize compounds
5l-r. Compound 10 was converted to the tert-butylcarbonyl-
protected intermediate 15 using di-tert-butyl dicarbonate in
methylene chloride containing triethylamine. Removal of the
phthalimide-protecting group in 15 with hydrazine in refluxing
ethanol yielded amine 16. Coupling 16 with 3-(3,4-dihydro-
1H-isoquinolin-2-yl)propionic acid using BOP in tetrahydrofuran
afforded amide 17. Treatment of 17 with boron tribromide in
methylene chloride at -78 °C effected removal of both the
phenolic isopropyl and the tert-butylcarbonyl groups to give
18. Reductive amination of 18 with the appropriate aldehyde
using sodium triacetoxyborohydride in dichloroethane gave the
desired compounds 5l-r. The aldehydes were all known
compounds.19-21 However, 2-(2-methylphenyl)acetaldehyde,
3-(2-thienyl)propanal, and 3-(3-thienyl)propanal were synthe-
sized by new procedures (details are given in the Experimental
Section).
selective agonists DAMGO (µ), DPDPE (δ), or U69,593 (κ)
using cloned human opioid receptors expressed in CHO cells.22
Agonist dose response curves were run in the presence or
absence of a single concentration of test compound. The Ke
values were calculated using the formula Ke ) [L]/(DR - 1),
where [L] is the concentration of test compound and DR is the
ratio of agonist EC50 value in the presence or absence of test
compound. The Ke values for 5a-r along with those for the
reference compounds, JDTic and nor-BNI, are shown in Table
1.
Results and Discussion
In the design of novel and selective antagonists for opioid
receptors, we have found the conceptual framework illustrated
in Figure 1 useful for comparing the prototypical oxymorphone
(2-4) antagonists to the trans-3,4-dimethyl-4-(3-hydroxyphe-
nyl)piperidines (1a-d). This is supported by a comparison of
the structure-activity relationship (SAR) displayed by the two
scaffolds. The assumptions made based on SAR are (1) both
prototypes associate with a hydrogen bond acceptor (H) for high
potency antagonist activity; (2) the protonated basic nitrogen
of both prototypes associates with the receptor via a salt bridge
(S); (3) fitting the two antagonist scaffolds between the S and
H domains orients the N-substituents of the two prototypical
scaffolds into different binding domains NS1 and NS2, respec-
tively. The latter follows as a consequence of the 3-hydroxy-
phenyl axial or 3-hydroxyphenyl equatorial piperidine chair
structure or substructure present in both systems. In the case of
the oxymorphones, a phenyl axial arrangement is present due
to physical constraint, whereas in the phenylpiperidines, the
equatorial phenyl orientation results from a conformational
preference. Importantly, the SAR of the N-substituents of the
two types of antagonists is divergent and can best be explained
by interactions at different receptor domains (NS1, NS2). The
oxymorphones display pure antagonist activity within a very
limited number of N-substituents (cyclopropylmethyl, allyl),
Biology
Measures of functional antagonism and selectivity of 5a-r
were obtained by monitoring the ability of test compounds to
inhibit stimulated [35S]GTP-γ-S binding produced by the

Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1783
Scheme 1a
a Reagents: (a) NH2OH‚HCl, EtOH; (b) iPrOH, toluene, Na; (c) phthalic anhydride, toluene, D-S trap: (d) ACE-Cl, dichloroethane and then CH3OH
reflux; (e) NaBH(OAc)3, C6H5(CH2)2CHO; (f) H2NNH2, EtOH, reflux; (g) 48% HBr, HOAc, reflux; (h) BOP, Et3N, THF, RCO2H; (i) EDCI, RCO2H,
HOBT, CH2Cl2; (j) BBr3, CH2Cl2.
Scheme 2a
a Reagents: (a) Boc2O, Et3N, CH2Cl2; (b) H2NNH2, EtOH, reflux: (c) BOP, 3-(3,4-dihydro-1H-isoquinolin-2-yl)propionic acid, Et3N, THF; (d) BBr3,
CH2Cl2; (e) RCHO, NaBH(OAc)3, CH2Cl2.
whereas all N-substituent derivatives of trans-3,4-dimethyl-4-
(3-hydroxyphenyl)piperidines are pure antagonists.
In our initial study of the 4â-methyl-5-(3-hydroxyphenyl)-
morphan class of antagonist, we reported that the lead compound
5a (KAA-1) possessed a Ke ) 0.24 nM at the κ opioid receptor
and was 174- and 137-fold selective for the κ receptor relative
to the µ and the δ receptors, respectively. Parts C and D of
Figure 1 illustrate how the κ-selective oxymorphone derivative
GNTI compares to the κ-selective 5-(3-hydroxyphenyl)morphan
(5a). Note that for both cases the proposed κ receptor address
elements, that is, the guanidine group of GNTI and the 7-amido
group of KAA-1, are oriented in a common direction (space).

1784 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Carroll et al.
Table 1. Inhibition of Agonist Stimulated [35S]GTPγS Binding by
Compounds in Cloned Human µ, δ, and κ Opioid Receptorsa
As a group, compounds substituted with methoxy in the
aromatic THIQ ring provided enhanced κ/µ selectivity. How-
ever, this was not true for 5j the direct analogue of the better
hydroxy derivative 5g. In this case, the potency at κ was shifted
lower by 3-fold while µ and δ activity doubled. The compound
was still potent and selective, but these attributes were clearly
diminished by the change. In this group, the best overall
compound was 5i, the methoxy analogue of the 6-hydroxy
analogue, 5f, which displayed improved potency for κ (Ke )
0.12 versus 0.30 nM) and much lower potency for µ (Ke ) 261
versus 26 nM). The potency for δ was similar in both cases.
The resulting 5i has one of the best potency/selectivity profiles
ever reported for any κ ligand and certainly for any κ antagonist.
The dimethoxy derivative 5k was the least potent at κ (Ke )
0.54 nM), and given that it retained reasonable δ potency (Ke
) 40 nM), there was a loss of κ/δ selectivity. Viewed
collectively, this set of analogues demonstrates that changes to
the 7-amido address group in the 5-(3-hydroxyphenyl)morphan
series have a relatively small effect on κ opioid receptor
antagonist potency but can dramatically impact the selectivity
of the resulting target compounds due to large changes in
potency at the µ and δ opioid receptors.
µ, DAMGO
Ke (nM)
δ, DPDPE
Ke (nM)
κ, U69 593
Ke (nM)
compound
JDTicb
µ/κ
δ/κ
25 ( 4 (3.41) 76 ( 3 (79.3) 0.02 ( 0.01 1250 3800
(0.01)
0.05 ( 0.02
(0.04)
nor-BNIb
26 ( 7 (19)
29 ( 8 (4.4)
520
580
5a (KAA1) 42 ( 4
33 ( 2.7
313 ( 34
77 ( 14
186 ( 58
13 ( 0.1
32 ( 7
0.24 ( 0.01
0.47 ( 0.14
2.2 ( 0.3
175
374
118
94
533
87
138
666
35
5b
5c
5d
5e
5f
176 ( 53
259 ( 89
82 ( 2
48 ( 13
26 ( 7
0.87 ( 0.33
0.09 ( 0.03
0.30 ( 0.17
0.09 ( 0.04
0.07 ( 0.02
214
144
107
689
357
350
125
74
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
52 ( 22
4.6 ( 1.2
261 ( 112
28 ( 6
62 ( 20
25 ( 9
578
66
42 ( 10
35 ( 12
40 ( 11
145 ( 100
20 ( 5
0.12 ( 0.03 2175
0.28 ( 0.09
0.54 ( 0.04
0.20 ( 0.06
0.20 ( 0.07
0.04 ( 0.01
6.1 ( 1.3
100
404
515
205
700
>82 >82
14
47
218 ( 72
103 ( 36
41 ( 5
725
100
625
28 ( 9
25 ( 9
>500
>500
25 ( 8
19 ( 6
1.8 ( 0.4
11
26
163
52 ( 17
35 ( 8
29 ( 6
1.1 ( 0.3
52 ( 8
0.32 ( 0.05
109
a The data represent the mean ( SE from at least three independent
experiments. b Data in parentheses for JDTic and nor-BNI were taken from
ref 10 and were originally supplied by the NIDA Opioid Treatment
Discovery Program.
The set of compounds 5l-r had a fixed 7-amido group and
focused on changes to the morphan amino group. Within the
set of compounds studied, this strategy did not yield as many
potent and selective compounds compared with changes to the
7-amido group, but it clearly demonstrated that modifications
in this domain have an influence on ligand potency. The N-hexyl
derivative 5l for example was found to be 2-fold less potent
than aryl-alkyl derivative 5e but was still very potent at κ with
a Ke of 0.2 nM. Combined with its low activities at µ (Ke )
103) and δ (Ke ) 145), the linear alkane provided a well-
rounded selectivity profile of 515 and 725 for κ/µ and κ/δ,
respectively. Adding a single ortho methyl to 5e to give 5m
results in a 2-fold loss in κ activity with little change in
selectivity. The truncated version of 5m (i.e., the 2-methylphe-
nylethyl derivative, 5n) is more potent at κ than 5e and has
selectivities of 700 and 625 for κ versus µ and δ. Shortening
the chain further to 2-methylbenzyl (5o) results in a 74-fold
drop in κ potency from 5e as well as a loss of selectivity. Thus,
small changes to aryl-alkyl morphan nitrogen substituents can
lead to shifts in ligand potency and considerable loss in
selectivity.
The purpose of the present study was to further explore the effect
of structural diversity in the 7-amido address element of the
phenylmorphans as well as to explore its relationship to
concomitant changes in the morphan N-substituent (NS2).
Modification of the 7-amido group by addition of a methyl
group to the 4-position of the piperidine ring in 5a to give 5b
resulted in an overall loss of affinity for all receptors with the
greatest impact seen at µ (4-fold) and δ (10-fold). However,
the fact that the κ potency of 5b was reduced only 2-fold resulted
in a more selective compound relative to 5a. Changing the
piperidine in 5a to the morpholine group in 5c was not
productive since the resulting compound was not nearly as
potent and was not selective. This followed from 10- and 6-fold
losses in activity for κ and µ, respectively, but only a 2-fold
change at δ. An N-methyl piperazine modification (5d) did not
lead to improved potency or selectivity. There was less of a
loss in κ potency relative to 5a (3.6-fold) compared to that found
for the morpholine 5c, but this change did not appear to be
promising. The lower potency and selectivity for these two
derivatives indicate that the addition of polar substituents to
the 7-amido piperidine ring of 5a is less favored compared with
the addition to that of the hydrophobic moieties.
Changing the 7-amido group from piperidine to THIQ (5e)
afforded a shift toward greater antagonist potency at κ (2.7-
fold, Ke ) 0.09 nM) and δ (2.5-fold, 13 nM) while leaving µ
activity unchanged. This combination of factors revealed an
enhanced selectivity relative to 5a (533-fold κ/µ). Adding
hydroxyl groups to the isoquinoline ring to assess potential
similarities with the hydroxy-Tic group in JDTic (1d) gave
mixed results. All of the compounds (5f, 5g, and 5h) were potent
antagonists for the κ receptor (Ke’s of 0.3, 0.09, and 0.07 nM,
respectively) and in the range of the unsubstituted 5e with 5h
being the most similar (7-fold less potent) and 5f the most
disparate at 30-fold less potent. Curiously these two compounds
were also more active at the µ receptor such that only 5g retained
both κ versus µ and κ versus δ selectivity. It is interesting to
note that 5g has the same 7-hydroxy-THIQ functionality as
JDTic.
Heteroaromatic replacement of the distal phenyl ring of 5e
as in 5p-r gave mixed results with both the 2- and 3-thiophene
analogues 5p and 5q showing a loss of κ potency (Ke ) 1.8
and 1.1 nM, respectively) and concomitantly lower selectivities.
The furan derivative 5r on the other hand retained potency with
a Ke of 0.32 nM and selectivity ratios of 109 and 163 for κ
relative to µ and δ. Taken together, the changes to the morphan
amino substituent can result in compounds of significantly lower
potency when compared to the potency of others with a fixed
7-amido group. In this respect, it seems clear that the phenyl-
propyl group was a reasonable choice to explore changes to
the 7-amido domain. Furthermore, the dramatic swings in
potency between 5b-r illustrate that both groups influence a
ligand’s antagonist activity. This suggests that further manipula-
tion at these positions could result in even more potent and
selective compounds than were found in this study.
In summary, an improved synthesis of the N-substituted 4â-
methyl-5-(3-hydroxyphenyl)-7R-amidomorphans was developed
and used to prepare a series of analogues of our original lead
compound 5a, where the 7R-amido address and the N-
substituted groups were varied. Several compounds were

Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1785
Figure 1. Comparison of the κ opioid receptor binding domains for naltrexone, trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, GNTI, and
KAA1.
concentrated ammonium hydroxide. IUPAC nomenclature is used
in the Experimental Section to name target compounds and
intermediates. Common nomenclature is used for reagents. Common
opioid nomenclature is used in the Results and Discussion.
developed that showed greater κ opioid receptor potency and
selectivity relative to 5a. The most κ potent and selective
compound was (-)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-N-
{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-(2-meth-
ylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n).
While the data set is limited, it appears that the addition of
lipophilic aryl groups to the 7R-amido address group improves
κ opioid receptor potency and selectivity. Similar to the trans-
3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid
antagonist, all N-substituted 4â-methyl-5-(3-hydroxyphenyl)-
7R-amidomorphans studied were opioid antagonists at all three
receptors.
(1R,4S,5R)-5-(3-Isopropoxyphenyl)-2,4-dimethyl-2-azabicyclo-
[3.3.1]nonan-7-one Oxime (7). Ketone (6) (3.11 g, 0.013 mol) and
hydroxylamine hydrochloride (4.50 g, 0.065 mol) in EtOH (abso-
lute, 195 mL) were heated to reflux for 3 h. The reaction mixture
was allowed to cool to room temperature, and the EtOH was
removed under reduced pressure. The crude oil was dissolved in 2
N NaOH (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 yielding crude product.
The crude product was purified by flash chromatography (neutral
alumina, Brockman activity II-III) and was eluted with 9:1
EtOAc-hexane to afford 3.68 g (88%) of the title compound as
an off-white solid: 1H NMR (CDCl3) δ 0.76 (d, 3H, J ) 6.9 Hz),
1.33 (d, 6H, J ) 6.0 Hz), 2.05-1.87 (m, 5H), 2.44-2.40 (m, 4H),
2.51 (d, 1H, J ) 15.9 Hz), 2.94-2.85 (m, 2H), 3.29 (br, 1H), 3.63
(d, 1H, J ) 17 Hz), 4.54 (m, 1H), 7.00-6.72 (m, 3H), 7.23 (t, 1H,
J ) 7.8 Hz), 8.47 (br, 1H).
(1R,4S,5S,7R)-5-(3-Isopropoxyphenyl)-2,4-dimethyl-2-
azabicyclo[3.3.1]nonan-7-amine (8). Oxime (7) (4.87 g, 0.015 mol)
in dry (CH3)2CHOH was added dropwise over 1 h to a refluxing
suspension of Na (51.3 g, 2.23 mol) in dry toluene (450 mL). After
complete addition of the oxime, two portions of (CH3)2CHOH (250
mL) were added dropwise over 30 min. The reaction mixture was
heated to reflux until all of the Na was consumed followed by
cooling to 50 °C and quenching by the careful addition of H2O
(750 mL). The toluene layer was separated, and the aqueous layer
was extracted with CHCl3 (4 × 500 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated under reduced
pressure to yield crude product. The crude product was purified
by flash chromatography (neutral alumina, Brockman activity II-
III) and was eluted with 9:1 EtOAc-EtOH to afford 4.42 g (95%)
Experimental Section
1H NMR were determined on a Bruker 300 spectrometer using
tetramethylsilane as an internal standard. Mass spectral data were
obtained using a Finnegan LCQ electrospray mass spectrometer in
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 using Whatman silica gel
60 TLC plates and were visualized by UV or by charring with the
use of 5% phosphomolybdic acid in ethanol. Optical rotations were
measured on an Auto Pol III polarimeter. All solvents were reagent
grade. Tetrahydrofuran and diethyl ether were dried over sodium
benzophenone ketyl and distilled prior to use. Methylene 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 Life Sciences (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%

1786 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Carroll et al.
of the title compound as an off-white solid: 1H NMR (CDCl3) δ
0.73 (d, 3H, J ) 6.9 Hz), 0.94 (m, 1H), 1.15 (m, 1H), 1.31 (d, 6H,
J ) 6.0 Hz), 1.67 (m, 2H), 2.11 (m, 1H), 2.23 (s, 1H), 2.45-2.32
(m, 4H), 2.62 (m, 1H), 2.96 (m, 1H), 3.15 (m, 1H), 3.51 (m, 1H),
4.52 (sept, 1H, J ) 6.1 Hz), 7.00-6.72 (m, 3H), 7.23 (t, 1H, J )
7.8).
3H), 2.50 (m, 2H), 2.66 (m, 3H), 2.82 (m, 1H), 3.19 (br, 1H), 3.51
(m, 1H), 4.56 (sept, 1H, J ) 6), 6.71 (m, 3H), 7.18 (m, 6H).
3-[(1R,4S,5S,7R)-7-Amino-4-methyl-2-(3-phenylpropyl)-2-
azabicyclo[3.3.1]non-5-yl]phenol (13). Amine (12) (3.07 g, 0.0078
mol) was dissolved in glacial AcOH (20 mL). A 48% HBr (32.5
mL) solution was added, and the mixture was heated to reflux for
15 h. The reaction mixture was allowed to cool to room temperature
and poured into ice (100 g), and the pH was raised to 10 with 50%
NaOH. The aqueous layer was extracted with 3:1 CH2Cl2-THF
(3 × 100 mL). The combined organic extracts were dried (Na2-
SO4), filtered, and concentrated under vacuum. The crude product
was purified by flash chromatography on silica gel and then eluted
with 65:35 CH2Cl2-CMA-80 to yield 2.8 g (88%) of the desired
product as an off-white solid. Analytical samples were prepared
by dissolving the free base in CHCl3, acidifying with HCl in Et2O,
and precipitating with Et2O. The Et2O-CHCl3 mixture was
decanted, and the precipitate was dissolved in MeOH. The product
was then precipitated out of the MeOH with Et2O. The solvent
was decanted, and the resulting material was dried under vacuum
2-[(1R,4S,5R,7R)-5-(3-Isopropoxyphenyl)-2,4-dimethyl-2-
azabicyclo[3.3.1]non-7-yl]-1H-isoindole-1,3(2H)-dione (9). Amine
(8) (1.69 g, 0.0056 mol) was dissolved in toluene followed by the
addition of phthalic anhydride (2.5 g, 0.017 mol), and the reaction
mixture was heated at reflux under a Dean-Stark trap overnight.
The solution was cooled, diluted with EtOAc, and filtered into a
separatory funnel. The organic layer was washed with 1 N NaOH
(3 × 30 mL) and H2O. The organic layer was collected and dried
(Na2SO4), and the solvent was removed under reduced pressure.
The crude product obtained was purified by filtering through a short
column of neutral alumina (Brockman activity II-III) and was
eluted with EtOAc to afford 1.5 g, (62%) of the title compound as
an off-white solid: 1H NMR (CDCl3) δ 0.73 (d, 3H, J ) 6.9 Hz),
0.94 (m, 1H), 1.15 (m, 1H), 1.31 (d, 6H, J ) 6.0 Hz), 1.67 (m,
2H), 2.11 (m, 1H), 2.23 (s, 1H), 2.45-2.32 (m, 4H), 2.62 (m, 1H),
2.96 (m, 1H), 3.15 (m, 1H), 4.52 (sept, 1H, J ) 6.1 Hz), 5.08 (m,
1H), 7.00-6.72 (m, 3H), 7.23 (t, 1H, J ) 7.8), 7.65 (m, 2H), 7.76
(m, 2H).
2-[(1R,4S,5R,7R)-5-(3-Isopropoxyphenyl)-4-methyl-2-azabicyclo-
[3.3.1]non-7-yl]-1H-isoindole-1,3(2H)-dione (10). Phthalimide (9)
(1.50 g, 0.0035 mol) was dissolved in CH2Cl2 and heated to reflux
followed by the addition of 1-chloroethyl chloroformate (0.410 mL,
3.8 mmol). This solution was allowed to reflux for 3.5 h. The
mixture was cooled, and the solvent was removed under reduced
pressure. The crude material was dissolved in EtOAc and washed
with a saturated NaHCO3 solution (3 × 30 mL). The organic layer
was collected and dried (Na2SO4), and the solvent was removed
under reduced pressure. The residue obtained was dissolved in CH3-
OH and heated at reflux overnight. The CH3OH was removed, and
the crude product was dissolved in 1 N NaOH. The aqueous was
extracted with 3:1 CH2Cl2-THF. The combined organic layers were
collected and dried (Na2SO4), and the solvent was removed under
reduced pressure. This product was used without further purification
in the next step.
2-[(1R,4S,5R,7R)-5-(3-Isopropoxyphenyl)-4-methyl-2-(3-phe-
nylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1H-isoindole-1,3(2H)-di-
one (11). Amine (10) (2.92 g, 0.007 mol) and hydrocinamaldehyde
(1.12 g, 0.0083 mol) were dissolved in CH2Cl2 (115 mL) followed
by the addition of sodium triacetoxyborohydride (2.1 g, 0.0097 mol)
and allowed to react at room temperature overnight. The reaction
was quenched by the addition of a saturated sodium NaHCO3
solution (200 mL), and the organic layer was separated. The aqueous
layer was extracted with CHCl3. The combined organic fractions
were dried (Na2SO4), filtered, and concentrated under vacuum. The
crude product was purified by flash chromatography on an
aluminum oxide (neutral, Brockman activity II-III) column and
was eluted with 8:2 hexanes-EtOAc giving 3.16 g (84%) of the
desired product: 1H NMR (CDCl3) δ 0.78 (d, 3H, J ) 6.9), 1.31
(d, 6H, J ) 6), 1.96-1.78 (m, 4H), 2.25-2.16 (m, 5H), 2.78-
2.52 (m, 6H), 3.08 (dd, 1H, J1 ) 6 Hz, J2 ) 3 Hz), 3.27 (br, 1H),
4.52 (sept, 1H, J ) 6.0 Hz), 5.15 (m, 1H), 6.68 (d, 1H, J ) 7.8),
6.79 (m, 2H), 7.25 (m, 5H), 7.64 (m, 2H), 7.75 (m, 2H).
(1R,4S,5S,7R)-5-(3-Isopropoxyphenyl)-4-methyl-2-(3-phenyl-
propyl)-2-azabicyclo[3.3.1]nonan-7-amine (12). Phthalimide (11)
(3.16 g, 0.0078 mol) and hydrazine (1.4 g, 0.044 mol) were
dissolved in EtOH (150 mL) and refluxed overnight. The solution
was cooled, and the white precipitate was separated by filtration
and washed with cold EtOH. The solution was concentrated under
vacuum, and the crude material was dissolved in 3:1 CH2Cl2-THF.
The resulting white precipitate was separated by filtration and
washed with cold CH2Cl2. The organic layer was concentrated to
yield 3.07 g (97%) of the desired product as a yellow solid: 1H
NMR (CDCl3) δ 0.71 (d, 3H, J ) 7.2), 0.90 (m, 2H), 1.29 (d, 6H,
J ) 6 Hz), 1.80 (m, 1H), 1.82 (m, 2H), 2.11 (m, 1H), 2.34 (m,
at 50 °C overnight: [R]20 -21° (c 1.03, MeOH); 1H NMR
D
(CDC13) δ 0.70 (d, 3H, J ) 6.9 Hz), 0.98 (m, 1H), 1.14 (m, 1H),
1.53 (m, 1H), 1.77 (t, 2H, J ) 7.2), 2.04 (br, 1H), 2.31 (m, 3H),
2.46 (t, 2H, J ) 7.0 Hz), 2.66-2.53 (m, 3H), 2.79 (m, 1H), 3.54
(br, 1H), 4.33 (br, 2H), 6.65-6.58 (m, 3H), 7.27-7.07 (m, 6H);
13C NMR (CD3OD) δ 18.5, 27.4, 28.4, 30.6, 34.0, 37.4, 38.4, 40.1,
44.1, 45.0, 46.8, 51.4, 55.1, 55.8, 56.2, 57.1, 89.9, 113.4, 113.6,
114.9, 115.1, 117.5, 127.9, 129.9, 130.1, 131.4, 141.9, 149.3. Anal.
(C24H34Cl2N2O‚H2O) C, H, N.
(-)-N-[(1R,4S,5S,7R)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(4-methylpiperidin-
1-yl)propanamide (5b) Dihydrochloride. Amine (13) (52.5 mg,
0.14 mmol), 3-(4-methylpiperidin-1-yl)propionic acid (55.7 mg,
0.29 mmol), and triethylamine (72.9 mg, 0.72 mmol) were dissolved
in THF. BOP reagent (70.1 mg, 0.16 mmol) was added, and the
mixture was allowed to stir at room temperature for 4 h. The
solution was diluted with EtOAc and washed with saturated
NaHCO3 (3 × 15 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated under vacuum. The crude material was
purified using preparative TLC (SiO2) eluting with 65:35 CHCl3-
CMA-80 to yield 25.4 mg (34.0%) of the desired product. The
analytical sample was prepared by dissolving the free base in
CHCl3, acidifying with HCl in Et2O, and precipitating with Et2O.
The Et2O-CHCl3 mixture was decanted, and the precipitate was
dissolved in MeOH. The product was then precipitated out of the
MeOH with Et2O. The solvent was decanted, and the resulting
material was dried under vacuum at 50 °C overnight: mp 205-
1
228 °C dec; [R]23 -58° (c 0.92, MeOH); H NMR (CD3OD) δ
D
0.73 (d, 3H, J ) 6.9), 0.90 (d, 3H, J ) 2.4), 1.29-1.14 (m, 6H),
1.69-1.55 (m, 3H), 1.92-1.88 (m, 2H), 2.07-1.95 (m, 2H), 2.34-
2.15 (m, 5H), 2.65-2.56 (m, 7H), 2.85-2.80 (m, 2H), 3.08-2.95
(m, 1H), 3.21 (s, 1H), 4.62-4.49 (m, 1H), 6.68-6.58 (m, 3H),
7.25-7.08 (m, 6H); 13C NMR (CD3OD) δ 19.0, 28.0, 30.9, 31.6,
31.7, 34.6, 38.1, 40.9, 43.8, 45.8, 47.0, 56.6, 58.2, 58.3, 62.9, 113.9,
128.4, 130.4, 130.6, 131.8, 142.4, 150.7, 159.9, 171.4. Anal.
(C33H49Cl2N3O2‚2H2O) C, H, N.
(-)-N-[(1R,4S,5S,7R)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(morpholin-4-yl)-
propanamide (5c) Dihydrochloride. Amine (13) (55.6 mg, 0.15
mmol), 3-(morpholin-4-yl)propionic acid (55.3 mg, 0.31 mmol),
and diisopropylethylamine (0.132 mL, 0.70 mmol) were dissolved
in THF. BOP reagent (74.2 mg, 0.17 mmol) was added, and the
mixture was allowed to stir at room temperature for 4 h. The
solution was diluted with EtOAc and washed with saturated
NaHCO3 (3 × 15 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated under vacuum. The crude material was
purified using preparative TLC (SiO2) eluting with 65:35 CHCl3-
CMA-80 to yield 35.4 mg (46%) of the desired product. Analytical
samples were prepared by dissolving the free base in CHCl3,
acidifying with HCl in Et2O, and precipitating with Et2O. The
Et2O-CHCl3 mixture was decanted, and the precipitate was
dissolved in MeOH. The product was then precipitated out of the

Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1787
MeOH with Et2O. The solvent was decanted, and the resulting
quinolin-2(1H)-yl)propanoic acid (93.3 mg, 0.36 mmol), and Et3N
(92.1 mg, 091 mmol) were dissolved in THF. BOP reagent (88.1
mg, 0.20 mmol) was added, and the mixture was allowed to stir at
room temperature for 4 h. The solution was diluted with EtOAc
and washed with saturated NaHCO3 (3 × 15 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified using preparative TLC (SiO2) and
was eluted with 65:35 CHCl3-CMA-80 to yield 32.0 mg (31%)
of the desired product. The analytical sample was prepared by
dissolving the free base in CHCl3, acidifying with HCl in Et2O,
and precipitating with Et2O. The Et2O-CHCl3 mixture was
decanted, and the precipitate was dissolved in MeOH. The product
was then precipitated out of the MeOH with Et2O. The solvent
was decanted, and the resulting material was dried under vacuum
material was dried under vacuum at 50 °C overnight: mp 215-
1
225 °C dec; [R]23 -42° (c 0.745, MeOH); H NMR (CD3OD) δ
D
0.73 (d, J ) 7.2, 3H), 1.24-1.14 (m, 3H), 1.92-1.55 (m, 3H),
2.68-2.30 (m, 23H), 3.08 (dd, J1 ) 6.5, J2 ) 2.5), 3.18 (bs, 1H),
3.63 (t, J ) 4.5, 4H), 4.62-4.49 (m, 1H), 6.60 (d, J ) 8.1 hz, 1H),
6.69 (bs, 2H), 7.36-7.08 (m, 6H); 13C NMR (CD3OD) δ 21.6, 30.9,
33.6, 34.3, 34.4, 34.5, 37.3, 40.9, 43.7, 48.4, 57.4, 58.5, 59.2, 61.0,
61.1, 69.5, 131.3, 133.2, 133.5, 133.6, 139.0, 145.2. Anal. (C31H45-
Cl2N3O3‚3.5H2O) C, H, N.
(-)-N-[(1R,4S,5S,7R)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(4-methylpiperazin-
1-yl)propanamide (5d) Dihydrochloride. Amine (13) (112.6 mg,
0.31 mmol), 3-(4-methylpiperidin-1-yl)propionic acid (120.0 mg,
0.62 mmol), and triethylamine (117.6 mg, 1.54 mmol) were
dissolved in THF. BOP reagent (150.3 mg, 0.34 mmol) was added,
and the mixture was allowed to stir at room temperature for 4 h.
The solution was diluted with EtOAc and washed with saturated
NaHCO3 (3 × 15 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated under vacuum. The crude material was
purified using preparative TLC (SiO2) and eluted with 65:35
CHCl3-CMA-80 to yield 41.3 mg (26%) of the desired product.
The analytical sample was prepared by dissolving the free base in
CHCl3, acidifying with HCl in Et2O, and precipitating with Et2O.
The Et2O-CHCl3 mixture was decanted, and the precipitate was
dissolved in MeOH. The product was then precipitated out of the
MeOH with Et2O. The solvent was decanted, and the resulting
material was dried under vacuum at 50 °C overnight: mp 230-
at 50 °C overnight: mp 210-218 °C dec; [R]23 -57° (c 0.07,
D
1
MeOH); H NMR (CD3OD) δ 0.78 (d, 3H, J ) 7.2), 1.52-1.38
(m, 1H), 1.72-1.58 (m, 1H), 2.21-1.95 (m, 3H), 2.53-2.51 (m,
3H), 2.80-2.72 (m, 4H), 3.10 (br, 1H), 3.34-3.30 (m, 5H), 3.57-
3.46 (m, 5H), 3.95 (s, 1H), 4.40 (br, 2H), 4.65-4.47(m, 1H), 6.77-
6.61 (m, 5H), 7.10-7.07 (m, 1H), 7.30-7.16 (m, 6H); 13C NMR
(CD3OD) δ 17.1, 24.6, 26.1, 28.2, 29.8, 32.7, 36.3, 39.1, 43.9, 45.0,
47.2, 50.7, 52.3, 53.6, 54.6, 56.3, 112.0, 112.9, 116.2, 121.4, 126.6,
128.5, 128.7, 128.8, 129.9, 130.1, 140.5, 148.8, 156.9, 158.1, 170.2.
Anal. (C36H47Cl2N3O2‚3H2O) C, H, N.
(-)-N-[(1R,4S,5S,7R)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(6-methoxy-3,4-di-
hydroisoquinolin-2(1H)-yl)propanamide (5i) Dihydrochloride.
Amine (13) (64.3 mg, 0.18 mmol), 3-(6-methoxy-3,4-dihydroiso-
quinolin-2(1H)-yl)propanoic acid (85.8 mg, 0.35 mmol), and Et3N
(89.3 mg, 0.88 mmol) were dissolved in THF. BOP reagent (85.8
mg, 0.19 mmol) was added, and the mixture was allowed to stir at
room temperature for 4 h. The solution was diluted with EtOAc
and washed with saturated NaHCO3 (3 × 15 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified using preparative TLC (SiO2)
eluting with 65:35 CHCl3-CMA-80 to yield 54.8 mg (52%) of
the desired product. The analytical sample was prepared by
dissolving the free base in CHCl3, acidifying with HCl in Et2O,
and precipitating with Et2O. The Et2O-CHCl3 mixture was
decanted, and the precipitate was dissolved in MeOH. The product
was then precipitated out of the MeOH with Et2O. The solvent
was decanted, and the resulting material was dried under vacuum
at 50 °C overnight: mp 235-245 °C; [R]20D -52° (c 0.20, MeOH);
1H NMR (CD3OD) δ 0.72 (d, 3H, J ) 6.9), 1.28-1.02 (m, 3H),
1.69-1.51 (m, 1H), 1.87-1.71 (m, 2H), 2.19-2.11 (m, 1H), 2.43-
2.33 (m, 5H), 2.55-2.52 (m, 2H), 2.84-2.62 (m, 8H), 3.07-2.96
(m, 1H), 3.20 (s, 1H), 3.55 (s, 2H), 3.72 (s, 3H), 4.68-4.51 (m,
1H), 6.67-6.60 (m, 5H), 6.89-6.86 (m, 1H), 7.43-7.08 (m, 6H);
13C NMR (CD3OD) δ 19.5, 30.3, 30.4, 32.8, 33.6, 34.9, 39.1, 41.6,
46.3, 52.1, 55.2, 55.5, 55.9, 56.0, 56.5, 113.6, 113.8, 114.5, 127.2,
127.7, 127.9, 128.9, 129.0, 129.7, 129.9, 130.3, 130.7, 136.5, 143.9,
153.0, 158.9, 160.1, 174.0. Anal. (C37H49Cl2N3O2‚2H2O) C, H, N.
(-)-N-[(1R,4S,5S,7R)-5-(3-Hydroxyphenyl)-4-methyl-2-(3-
phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(7-methoxy-3,4-di-
hydroisoquinolin-2(1H)-yl)propanamide (5j) Dihydrochloride.
Amine (13) (239.7 mg, 0.59 mmol), 3-(7-methoxy-3,4-dihydroiso-
quinolin-2(1H)-yl)propanoic acid (160.2 mg, 0.59 mmol), and Et3N
(131.2 mg, 1.29 mmol) were dissolved in THF. BOP reagent (259.4
mg, 0.59 mmol) was added, and the mixture was allowed to stir at
room temperature for 4 h. The solution was diluted with EtOAc
and washed with saturated NaHCO3 (3 × 15 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified using preparative TLC (SiO2) and
was eluted with 65:35 CHCl3-CMA-80 to yield 141.3 mg (41%)
of the desired product. The analytical sample was prepared by
dissolving the free base in CHCl3, acidifying with HCl in Et2O,
and precipitating with Et2O. The Et2O-CHCl3 mixture was
decanted, and the precipitate was dissolved in MeOH. The product
was then precipitated out of the MeOH with Et2O. The solvent
was decanted, and the resulting material was dried under vacuum
1
255 °C dec; [R]23 -44° (c 0.64, MeOH); H NMR (CD3OD) δ
0.78 (d, 3H, J )D7.5), 1.52-1.31 (m, 1H), 1.72-1.56 (m, 1H),
2.21-1.95 (m, 3H), 2.15-2.09 (m, 7H), 2.80-2.73 (m, 7H), 3.34-
2.90 (m, 10H), 3.68-3.52 (m, 1H), 3.96 (s, 1H), 4.62-4.49 (m,
1H), 6.67-6.65 (m, 3H), 7.31-7.14 (m, 6H); 13C NMR (CD3OD)
δ 17.0, 20.3, 26.1, 28.8, 28.9, 29.6, 29.7, 31.6, 32.7, 36.2, 38.9,
43.8, 45.1, 53.6, 54.8, 56.3, 68.0, 111.8, 126.4, 128.5, 128.6, 128.7,
129.8, 131.3, 140.4, 148.6, 157.9, 169.9. Anal. (C32H49Cl3N4O2‚
1.5H2O) C, H, N.
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-[(1R,4S,5S,7R)-5-
(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo-
[3.3.1]non-7-yl]propanamide (5e) Dihydrochloride. Amine (13)
(55.5 mg, 0.15 mmol), 3-(3,4-dihydro-1H-isoquinolin-2-yl)propionic
acid (69.2 mg, 0.30 mmol), and Et3N (77.0 mg, 0.76 mmol) were
dissolved in THF. BOP reagent (74.1 mg, 0.17 mmol) was added,
and the mixture was allowed to stir at room temperature for 4 h.
The solution was diluted with EtOAc and washed with saturated
NaHCO3 (3 × 15 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated under vacuum. The crude material was
purified using preparative TLC (SiO2) and was eluted with 65:35
CHCl3-CMA-80 to yield 25.6 mg (31%) of the desired product.
The analytical sample was prepared by dissolving the free base in
CHCl3, acidifying with HCl in Et2O, and precipitating with Et2O.
The Et2O-CHCl3 mixture was decanted, and the precipitate was
dissolved in MeOH. The product was then precipitated out of the
MeOH with Et2O. The solvent was decanted, and the resulting
material was dried under vacuum at 50 °C overnight: mp 197-
1
240 °C; [R]20 -50° (c 0.97, MeOH); H NMR (CD3OD) δ 0.78
D
(d, 3H, J ) 7.5), 2.09-2.04 (m, 3H), 2.48-2.32 (m, 1H), 2.54-
2.50 (m, 4H), 2.75-2.55 (m, 1H), 2.84-2.73 (m, 4H), 3.60-3.19
(m, 9H), 3.89-3.78 (m, 1H), 3.96 (s, 1H), 4.42-4.25 (m, 1H),
4.68-4.51 (m, 2H), 6.67-6.65 (m, 3H), 7.46-7.14 (m, 10H); 13
C
NMR (CD3OD) δ 18.3, 26.7, 27.5, 30.0, 31.1, 34.0, 37.6, 40.4,
45.2, 46.2, 51.7, 53.2, 54.8, 55.9, 57.6, 57.7, 113.3, 127.9, 128.3,
128.8, 129.0, 129.8, 130.0, 130.1, 130.3, 131.3, 132.4, 141.8, 150.1,
171.4. 18.3, 26.7, 27.5, 30.0, 31.1, 34.0, 37.6, 40.4, 45.2, 46.2, 51.7,
53.2, 54.8, 55.9, 57.6, 57.7, 113.3, 127.9, 128.3, 128.8, 129.0, 129.8,
130.0, 130.1, 130.3, 131.3, 132.4, 141.8, 150.1, 171.4. Anal.
(C36H47Cl2N3O2‚4H2O) C, H, N.
(-)-3-(7-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-
[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]non-7-yl]propanamide (5g) Dihydrochloride.
Amine (13) (66.0 mg, 0.18 mmol), 3-(7-hydroxy-3,4-dihydroiso-
at 50 °C overnight: mp 232-241 °C dec; [R]23 -56° (c 0.20,
D

1788 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Carroll et al.
1
MeOH); H NMR (CD3OD) δ 0.72 (d, 3H, J ) 6.9), 1.28-1.02
80 to yield 67.8 mg (85%) of the desired product. The analytical
sample was prepared by dissolving the free base in MeOH,
acidifying with HCl in Et2O, and precipitating with Et2O. The
solvent was decanted, and the resulting material was dried under
vacuum at 50 °C overnight: mp 240-247 °C dec; [R]23D -57° (c
(m, 3H), 1.69-1.51 (m, 1H), 1.87-1.71 (m, 2H), 2.19-2.11 (m,
1H), 2.43-2.33 (m, 5H), 2.55-2.52 (m, 2H), 2.84-2.62 (m, 8H),
3.07-2.96 (m, 1H), 3.20 (s, 1H), 3.55 (s, 2H), 3.72 (s, 3H), 4.68-
4.51 (m, 1H), 6.67-6.60 (m, 5H), 6.89-6.86 (m, 1H), 7.43-7.08
(m, 6H); 13C NMR (CD3OD) δ 19.5, 30.3, 30.4, 32.8, 33.6, 34.9,
39.1, 41.6, 46.3, 52.1, 55.2, 55.5, 55.9, 56.0, 56.5, 113.6, 113.8,
114.5, 127.2, 127.7, 127.9, 128.9, 129.0, 129.7, 129.9, 130.3, 130.7,
136.5, 143.9, 153.0, 158.9, 160.1, 174.0. Anal. (C37H49Cl2N3O3‚
4H2O) C, H, N.
1
0.20, MeOH); H NMR (CD3OD) δ 0.72 (d, 3H, J ) 6.9), 1.28-
1.02 (m, 3H), 1.69-1.51 (m, 1H), 1.87-1.71 (m, 2H), 2.19-2.11
(m, 1H), 2.43-2.33 (m, 5H), 2.55-2.52 (m, 2H), 2.84-2.62 (m,
8H), 3.07-2.96 (m, 1H), 3.20 (s, 1H), 3.54 (s, 2H), 4.68-4.51
(m, 1H), 6.62-6.50 (m, 5H), 6.81-6.78 (m, 1H), 7.38-7.11 (m,
6H); 13C NMR (CD3OD) δ 19.40, 30.15, 30.28, 34.87, 39.04, 41.51,
46.23, 50.24, 52.18, 55.34, 55.51, 55.93, 56.60, 57.54, 113.5, 114.9,
116.0, 126.5, 127.2, 128.9, 129.7, 129.9, 130.8, 136.4, 143.8, 152.8,
157.3, 159.0, 174.0. Anal. (C36H47Cl2N3O3‚2H2O) C, H, N.
N-[(1R,4S,5S,7R)-5-(3-Isopropoxyphenyl)-4-methyl-2-(3-phe-
nylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(5-methoxy-3,4-dihy-
droisoquinolin-2(1H)-yl)propanamide (14b). Amine (12) (122.3
mg, 0.30 mmol) was dissolved in CH2Cl2 (5 mL) followed by 3-(5-
methoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid (122.6
mg, 0.45 mmol). Triethylamine was added in excess to the required
number of equivalents (0.71 mL, 0.51 mmol), and the mixture was
allowed to stir for 20 min. EDCI (98.0 mg, 0.51 mmol) and HOBt
(69.1 mg, 0.51 mmol) were added, and the reaction was stirred for
4 h. The reaction was quenched with the addition of H2O, and the
organic layer was washed with H2O. The organic layer was dried
(Na2SO4), filtered, and concentrated under vacuum. The crude
material was purified using preparative TLC (SiO2) and was eluted
with 80:20 CHCl3-CMA-80 to yield 141.0 mg (71%) of the desired
product: 1H NMR (CD3OD) δ 0.72 (d, 3H, J ) 6.9), 1.28-1.02
(m, 3H), 1.69-1.51 (m, 1H), 1.87-1.71 (m, 2H), 2.19-2.11 (m,
1H), 2.43-2.33 (m, 5H), 2.55-2.52 (m, 2H), 2.84-2.62 (m, 8H),
3.07-2.96 (m, 1H), 3.20 (s, 1H), 3.59 (s, 2H), 3.80 (s, 3H), 4.52
(sept, J ) 6 Hz, 1H), 4.68-4.59 (m, 1H), 6.67-6.60 (m, 5H),
6.89-6.86 (m, 1H), 7.43-7.08 (m, 6H).
(-)-3-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-
[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]non-7-yl]propanamide (5k) Dihydrochloride.
Amine (13) (63.5 mg, 0.17 mmol), 3-(6,7-dimethoxy-3,4-dihy-
droisoquinolin-2(1H)-yl)propanoic acid (92.4 mg, 0.35 mmol), and
Et3N (88.1 mg, 091 mmol) were dissolved in THF. BOP reagent
(154.1 mg, 0.35 mmol) was added, and the mixture was allowed
to stir at room temperature for 4 h. The solution was diluted with
EtOAc and washed with saturated NaHCO3 (3 × 15 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated under
vacuum. The crude material was purified using preparative TLC
(SiO2) and was eluted with 65:35 CHCl3-CMA-80 to yield 94.5
mg (89%) of the desired product. The analytical sample was
prepared by dissolving the free base in CHCl3, acidifying with HCl
in Et2O, and precipitating with Et2O. The Et2O-CHCl3 mixture
was decanted, and the precipitate was dissolved in MeOH. The
product was then precipitated out of the MeOH with Et2O. The
solvent was decanted, and the resulting material was dried under
vacuum at 50 °C overnight: mp 240-252 °C dec; [R]23D -54° (c
1
0.2, MeOH); H NMR (CDCl3) δ 0.70 (d, 3H, J ) 7.2), 0.80-
0.66 (m, 1H), 1.09-0.09 (m, 1H), 1.56 (d, J ) 12.0 Hz), 1.77-
1.73 (m, 2H), 2.26 (bs, 1H), 2.30 (m, 2H), 2.44-2.47 (m, 5H),
2.66-2.50 (m, 3H), 2.75-2.73 (m, 7H), 2.75 (m, 1H), 3.02 (bs,
1H), 3.55 (br, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 4.65-4.47(m, 1H),
6.48 (s, 1H), 6.57 (s, 1H), 6.73-6.65 (m, 3H), 7.26-7.10 (m, 6H);
13C NMR (CD3OD) δ 17.3, 25.2, 26.4, 29.2, 30.0, 30.1, 33.0, 36.5,
39.3, 44.2, 45.4, 52.5, 53.5, 54.9, 55.8, 55.9, 56.5, 56.6, 110.3,
112.1, 112.2, 119.8, 123.6, 126.9, 128.8, 129.0, 130.2, 140.8, 149.0,
149.3, 150.2, 158.4, 170.4. Anal. (C39H51Cl2N3O4‚3.5H2O) C, H,
N.
(-)-3-(5-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-
[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]non-7-yl]propanamide (5h) Dihydrochloride.
Amide (14b) (116.9 mg, 0.19 mmol) was dissolved in CH2Cl2 (30
mL), cooled to -78 °C, and BBr3 (4.0 mL, 21.0 mmol, 10 equiv
per protecting group) added. The mixture was allowed to stir at
-78 °C for 30 min and at room temperature for 2 h. The mixture
was cooled to 0 °C, quenched with NaHCO3, and extracted with
CH2Cl2. The organic layer was dried (Na2SO4), filtered, and
concentrated under vacuum. The crude material was purified using
preparative TLC (SiO2) and was eluted with 65:35 CHCl3-CMA-
80 to yield 44.1 mg (41%) of the desired product. The analytical
sample was prepared by dissolving the free base in MeOH,
acidifying with HCl in Et2O, and precipitating with Et2O. The
solvent was decanted, and the resulting material was dried under
vacuum at 50 °C overnight: mp 242-248 °C dec; [R]23D -55° (c
N-[(1R,4S,5S,7R)-5-(3-Isopropoxyphenyl)-4-methyl-2-(3-phe-
nylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(6-methoxy-3,4-dihy-
droisoquinolin-2(1H)-yl)propanamide (14a). Amine (12) (202.3
mg, 0.50 mmol) was dissolved in CH2Cl2 (30 mL) followed by
3-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid (202.8
mg, 0.75 mmol). Triethylamine was added in excess to the required
number of equivalents (0.118.9 mL, 0.85 mmol), and the mixture
was allowed to stir for 20 min. EDCI (162.1 mg, 0.85 mmol) and
HOBt (114.3 mg, 0.85 mmol) were added, and the reaction was
stirred for 4 h. The reaction was quenched with the addition of
H2O, and the organic layer was washed with H2O. The organic
layer was dried (Na2SO4), filtered, and concentrated under vacuum.
The crude material was purified using preparative TLC (SiO2) and
was eluted with 80:20 CHCl3-CMA-80 to yield 88.0 mg (28%)
of the desired product: 1H NMR (CD3OD) δ 0.72 (d, 3H, J )
6.9), 1.28-1.02 (m, 3H), 1.69-1.51 (m, 1H), 1.87-1.71 (m, 2H),
2.19-2.11 (m, 1H), 2.43-2.33 (m, 5H), 2.55-2.52 (m, 2H), 2.84-
2.62 (m, 8H), 3.07-2.96 (m, 1H), 3.20 (s, 1H), 3.59 (s, 2H), 3.80
(s, 3H), 4.51 (sept, J ) 6 Hz, 1H), 4.68-4.59 (m, 1H), 6.67-6.60
(m, 5H), 6.89-6.86 (m, 1H), 7.86-7.17 (m, 6H).
1
0.20, MeOH); H NMR (CD3OD) δ 0.72 (d, 3H, J ) 6.9), 1.28-
1.02 (m, 3H), 1.69-1.51 (m, 1H), 1.87-1.71 (m, 2H), 2.19-2.11
(m, 1H), 2.43-2.33 (m, 5H), 2.55-2.52 (m, 2H), 2.84-2.62 (m,
8H), 3.07-2.96 (m, 1H), 3.20 (s, 1H), 3.55 (s, 2H), 4.68-4.51
(m, 1H), 6.67-6.60 (m, 5H), 6.89-6.86 (m, 1H), 7.43-7.08 (m,
6H); 13C NMR (CD3OD) δ 19.24, 24.71, 29.71, 34.716, 38.72,
41.27, 46.00, 52.07, 55.36, 55.76, 55.96, 57.00, 57.59, 113.5, 113.7,
114.2, 119.0, 122.4, 127.4, 128.0, 129.8, 129.9, 130.9, 136.7, 143.4,
152.2, 156.4, 159.0, 164.1, 174.0. Anal. (C36H4479Cl2N3O2‚3.5H2O)
C, H, N.
(-)-3-(6-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-
[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-
2-azabicyclo[3.3.1]non-7-yl]propanamide (5f) Dihydrochloride.
Amide (14a) (88.0 mg, 0.14 mmol) was dissolved in CH2Cl2 (30
mL), cooled to -78 °C, and BBr3 (3.0 mL, 21.0 mmol, 10 equiv
per protecting group added). The mixture was allowed to stir at
-78 °C for 30 min and at room temperature for 2 h. The mixture
was cooled to 0 °C, quenched with NaHCO3, and extracted with
CH2Cl2. The organic layer was dried (Na2SO4), filtered, and
concentrated under vacuum. The crude material was purified using
preparative TLC (SiO2) and was eluted with 65:35 CHCl3-CMA-
3-(6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic Acid
Hydrochloride. 6-Methoxy-1,2,3,4-tetrahydroisoquinoline (10.2 g,
54.0 mmol) was dissolved in MeOH followed by the addition of
acrylic acid (4.7 g, 64.8 mmol) and diisopropylethylamine (cat.)
and heated to reflux for 4 h. The solution was diluted with H2O
and extracted with CHCl3 (3 × 50 mL). The pH of the aqueous
layer was adjusted to 6.5 with concentrated HCl by measurement
with a pH meter. The water was removed under reduced pressure
to yield the zwitterion and NaCl. The zwitterion was dissolved in
(CH3)2CO, filtered to remove the NaCl, and converted to the HCl
salt by addition of 1 N HCl (5 mL). The solvent was removed

Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1789
under reduced pressure to yield 11.2 g (76.5%) of the HCl salt as
an off-white solid: 1H NMR (CDCl3) δ 2.51 (t, 2H, J ) 6.3 Hz),
2.74 (t, 2H, J ) 6.3 Hz), 2.81 (m, 2H), 2.86 (m, 2H), 3.34 (s, 2H),
3.85 (s, 3H), 7.01 (m, 1H), 7.11 (m, 2H).
oil. Purification by flash chromatography on silica eluting with 1:1
EtOAc-petroleum ether gave 6.49 g (99%) of 15 as a colorless
oil that gave a white foam under vacuum: recrystallized from
1
hexanes, mp 141-143 °C; H NMR (CDCl3) δ 0.64 (d, 3H, J )
7.2 Hz), 1.32 (d, 6H, J ) 6.0 Hz), 1.48 (d, 9H, J ) 3.0 Hz), 1.81-
1.98 (m, 1H), 1.99-2.15 (m, 1H), 2.16-2.46 (m, 4H), 2.53 (td,
1H, J ) 12.9, 3.6 Hz), 3.65 (td, 1H, J ) 15.6, 3.4 Hz), 3.75-3.87
(m, 1H), 4.52 (dt, 2H, J ) 12.1, 6.0 Hz), 4.70-4.79 (m, 1H), 5.07
(ddd, 1H, J ) 19.4, 12.8, 6.2 Hz), 6.71 (dd, 1H, J ) 7.9, 2.3 Hz),
6.74-6.83 (m, 2H), 7.19 (t, 1H, J ) 7.9 Hz), 7.68 (dd, 2H, J )
5.7, 3.0 Hz), 7.78 (dd, 2H, J ) 5.8, 2.4 Hz); 13C NMR (CDCl3) δ
17.7, 22.0, 28.4, 30.7, 32.9, 37.1, 40.1, 41.9, 45.5, 47.3, 48.3, 69.6,
79.5, 79.6, 112.6, 113.8, 117.5, 123.0, 129.1, 131.8, 133.8, 149.9,
155.5, 157.8, 168.1; MS (ESI) 518 (M)+.
tert-Butyl (1R,4S,5S,7R)-7-Amino-5-(3-isopropoxyphenyl)-4-
methyl-2-azabicyclo[3.3.1]nonane-2-carboxylate (16). Phthalim-
ide (15) (6.91 g, 0.019 mmol) was dissolved in 330 mL of 95%
EtOH in a 1000-mL three-neck round-bottom flask with magnetic
stirrer and reflux condenser. Hydrazine hydrate (3.63 mL, 0.075
mmol) was added, and the mixture was heated to reflux and
monitored by TLC (silica 1:4 EtOAc-hexane), which showed the
reaction progressing quickly and was complete in approximately 1
h. The mixture was allowed to cool to room temperature. Upon
slow cooling, the phthalic hydrazide byproduct precipitated out,
the mixture was filtered, and the solvent was removed. The solid
residue was dissolved in 3:1 CH2Cl2-THF, and the remaining
phthalic hydrazide was, again, filtered off. The solvent was removed
to give very clean product 16 as a thick yellow oil, 5.03 g (97%)
which was used directly in the next step: 1H NMR (CDCl3) δ 0.60
(d, 3H, J ) 7.2 Hz), 1.16-1.30 (m, 2H), 1.33 (d, 6H, J ) 6.0 Hz),
1.47 (d, 9H, J ) 7.2 Hz), 1.58 (t, 1H, J ) 12.2 Hz), 2.06-2.36
(m, 4H), 2.41 (dd, 1H, J ) 13.6, 5.3 Hz), 3.45-3.62 (m, 3H), 4.51
(br s, 2H, J ) 54.6 Hz), 4.54 (dt, 1H, J ) 12.3, 6.1 Hz), 6.66-
6.88 (m, 3H), 7.15-7.26 (m, 1H); 13C NMR (CDCl3) δ 17.8, 22.0,
28.5, 31.2, 36.9, 40.3, 41.0, 46.0, 47.6, 48.4, 50.4, 69.8, 79.5, 112.5,
113.8, 117.4, 129.1, 150.5, 155.7, 157.9; MS (ESI) 389.9 (M +
H)+.
tert-Butyl (1R,4S,5S,7R)-7-{[3-(3,4-Dihydroisoquinolin-2(1H)-
yl)propanoyl]amino}-5-(3-isopropoxyphenyl)-4-methyl-2-
azabicyclo[3.3.1]nonane-2-carboxylate (17). The amine (16) (1.38
g, 0.0036 mol) was dissolved in 90 mL of anhydrous THF in a
250-mL round-bottom flask. 3-(3,4-Dihydro-1H-isoquinoline-2-yl)-
propionic acid HCl salt (1.29 g, 0.0054 mol) and Et3N (2.47 mL,
17.8 mmol) were added and stirred at room temperature for 1.5 h.
The BOP reagent (1.73 g, 0.0039 mol) was added, and the mixture
was monitored by TLC (silica 1:1 CHCl3-CMA-80). The reaction
was complete in 1 h. EtOAc (20 mL) and saturated NaHCO3 (30
mL) were added to the mixture. The layers were separated, and
the organic layer was washed with saturated NaHCO3 (2 × 20 mL).
The aqueous layers were back extracted with Et2O (20 mL), and
the combined organic layers were washed with 1 N NaOH (20 mL),
dried over Na2SO4, and concentrated to give 2.35 g of a colorless
oil/foam. This material was purified by CombiFlash chromatography
(silica CHCl3 to 85:15 CHCl3-CMA-80) to give 1.84 g (85%):
1H NMR (CDCl3) δ 0.56 (d, 3H, J ) 6.8 Hz), 0.99-1.18 (m, 2H),
1.32 (d, 6H, J ) 6.0 Hz), 1.40-1.54 (m, 9H), 2.04-3.08 (m, 11H),
3.48-3.81 (m, 4H), 4.30-4.77 (m, 3H), 6.54-7.25 (m, 7H), 7.88-
8.14 (m, 1H); 13C NMR (CDCl3) δ 17.6, 22.0, 28.4, 30.8, 31.2,
32.5, 36.5, 37.2, 39.9, 43.3, 46.7, 47.2, 47.7, 48.2, 49.8, 53.7, 55.3,
69.7, 79.5, 112.6, 113.6, 117.4, 125.8, 126.3, 126.4, 128.6, 129.1,
133.6, 150.3, 155.6, 157.8, 171.6; MS (ESI) 576.8 (M + H)+.
3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-[(1R,4S,5R,7R)-5-(3-
hydroxyphenyl)-4-methyl-2-azabicyclo[3.3.1]non-7-yl]propana-
mide (18). The starting material (17) (1.47 g, 0.0026 mol) was
dissolved in 100 mL of CH2Cl2 and cooled to -78 °C in a 250-
mL round-bottom flask. (As the solution cooled, it became cloudy.)
BBr3 (12.77 mL, 1 M in CH2Cl2, 12.77 mmol) was added dropwise
resulting in a turbid solution with a light brown hue. TLC analysis
(silica 1:1 CHCl3-CMA-80) showed the starting material was
consumed within 4 min. The cooling bath was removed, and the
mixture was allowed to warm. Around 0 °C (judging by frost
3-(7-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic Acid.
7-Hydroxy-1,2,3,4-tetrahydroisoquinoline (6.3 g, 30.2 mmol) was
dissolved in MeOH (50 mL) followed by the addition of acrylic
acid (3.1 mL, 45.3 mmol) and diisopropylethylamine (200 µL, 1.1
mmol) and heated to reflux for 4 h. The mixture was cooled to
room temperature, and the CH3OH was removed under reduced
pressure. The crude material was then dissolved in NaHCO2 and
extracted with CHCl3. The organic layer was dried (Na2SO4),
filtered, and evaporated to dryness. The crude material was purified
by use of flash chromatography (neutral alumina, Brockman activity
II-III) with 8:2 hexanes-EtOAc as the eluent. The combined
organic fractions yielded 5.0 g (75%) of the title compound as an
off-white solid: 1H NMR (CD3OD) δ 2.96 (t, 2H, J ) 6.3 Hz),
3.40-3.30 (m, 4H), 3.54 (t, 2H, J ) 6.3 Hz), 3.49 (m, 2H), 6.62-
6.61 (m, 1H), 6.77-6.73 (m, 1H), 7.09-7.02 (m, 1H).
3-(7-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic Acid.
7-Methoxy-1,2,3,4-tetrahydroisoquinoline (7.0 g, 46.7 mmol) was
dissolved in MeOH (50 mL) followed by the addition of acrylic
acid (3.2 mL, 46.7 mmol) and diisopropylethylamine (200 µL, 1.1
mmol) and heated to reflux for 4 h. The mixture was cooled to
room temperature, and the CH3OH was removed under reduced
pressure. The crude material was then dissolved in NaHCO3 and
extracted with CHCl3. The organic layer was dried (Na2SO4),
filtered, and evaporated to dryness. The crude material was purified
using flash chromatography (neutral alumina, Brockman activity
II-III) with 8:2 hexanes-EtOAc as the eluent. The combined
organic fractions yielded 9.1 g (83%) of the title compound as an
off-white solid: 1H NMR (CD3OD) δ 2.96 (t, 2H, J ) 6.3 Hz),
3.40-3.30 (m, 4H), 3.54 (t, 2H, J ) 6.3 Hz), 3.49 (m, 2H), 3.81
(s, 3H), 6.62-6.61 (m, 1H), 6.77-6.73 (m, 1H), 7.09-7.02 (m,
1H).
3-(5-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoic Acid
Hydrochloride. 5-Methoxy-1,2,3,4-tetrahydroisoquinoline (2.3 g,
10.8 mmol) was dissolved in MeOH (100 mL) followed by the
addition of acrylic acid (1.2 mL, 16.2 mmol) and diisopropylethyl-
amine (200 µL, 1.1 mmol) and heated to reflux for 4 h. The solution
was diluted with H2O and extracted with CHCl3 (3 × 50 mL). The
pH of the aqueous layer was adjusted to 6.5 with concentrated HCl
by measurement with a pH meter. The H2O was removed under
reduced pressure to yield the zwitterion and NaCl. The zwitterion
was dissolved in (CH3)2CO, filtered to remove the NaCl, and
converted to the HCl salt by addition of 1 N HCl (5 mL). The
solvent was removed under reduced pressure to yield 2.0 g (84%)
of the HCl salt of the title compound as an off-white solid: 1H
NMR (CDCl3) δ 2.55-2.49 (m, 2H), 2.84-2.82 (m, 2H), 2.96-
2.93 (m, 4H), 3.78 (s, 3H), 3.81 (s, 2H), 6.67-6.51 (m, 2H), 7.02-
6.93 (m, 1H).
3-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propano-
ic Acid Hydrochloride. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquino-
line hydrochloride (1.34 g, 5.8 mmol), diisopropylethylamine (cat.),
and acrylic acid (501.5 mg, 6.5 mmol) were dissolved in CH3OH
(20 mL) and heated at reflux overnight. The solution was cooled
to room temperature, and a white precipitate formed. This precipitate
was filtered and washed with cold CH3OH to yield 1.43 g (93%)
of the title compound as the HCl salt: 1H NMR (CD3OD + 2 drops
NaOD) δ 2.49 (m, 2H), 2.87-2.70 (m, 6H), 3.46 (s, 2H), 3.70 (s,
6H), 6.28 (s, 1H), 6.34 (s, 1H).
tert-Butyl (1R,4S,5S,7R)-7-(1,3-Dioxo-1,3-dihydro-2H-isoin-
dol-2-yl)-5-(3-isopropoxyphenyl)-4-methyl-2-azabicyclo[3.3.1]-
nonane-2-carboxylate (15). In a 1000-mL round-bottomed flask,
the amine (10) (5.30 g, 0.013 mmol) was dissolved in 50 mL of
CH2Cl2 followed by the addition of Et3N (1.94 mL, 13.93 mmol)
and solid (still cold) di-tert-butyl dicarbonate (2.90 g, 0.013 mol).
Upon addition of the Boc2O the reaction immediately began to
evolve gas. After 1 h, only a faint starting material spot could be
seen by TLC analysis (basic alumina, 5% EtOAc-hexane). The
solvent was removed by rotary evaporation to give a dark brown

1790 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Carroll et al.
melting) water (40 mL) was added to the reaction mixture. The
aqueous layer was acidified by adding a small amount of 6 N HCl.
The layers were separated, and the organic layer was extracted with
1 N HCl (50 mL). The acid layer was washed with a small amount
of CH2Cl2. The combined acid layers were made basic (pH 9-10)
while they were stirred in an Erlenmeyer flask with 50% NaOH.
This mixture was transferred to a separatory funnel using 1 N HCl
(50 mL). EtOAc (100 mL) was added, and while the mixture was
rapidly stirred, the pH was adjusted to 9-10 with 50% NaOH. This
mixture was transferred to the separatory funnel. The layers were
separated, and the basic layer was extracted with EtOAc (2 × 50
mL). The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated to give 100% of the product: 1H
NMR (CDCl3) δ 0.60 (d, 3H, J ) 6.8 Hz), 1.09 (t, 1H, J ) 12.6
Hz), 1.26 (d, 1H, J ) 2.6 Hz), 1.46 (d, 1H, J ) 11.7 Hz), 2.03 (s,
1H), 2.15 (d, 2H, J ) 8.3 Hz), 2.41 (d, 2H, J ) 3.0 Hz), 2.51 (d,
1H, J ) 7.9 Hz), 2.62-2.77 (m, 4H), 2.81 (d, 2H, J ) 5.7 Hz),
3.34-3.45 (m, 2H), 3.53-3.66 (m, 2H), 4.81 (d, 1H, J ) 6.0 Hz),
5.28 (br s, 1H), 6.53-6.74 (m, 3H), 6.92-7.01 (m, 1H), 7.00-
7.20 (m, 4H), 7.81-8.05 (m, 1H); 13C NMR (CDCl3) δ 17.2, 28.7,
31.4, 32.5, 36.7, 38.3, 39.8, 44.6, 46.9, 48.1, 48.7, 49.9, 53.6, 55.2,
112.2, 113.0, 115.7, 125.7, 126.3, 126.4, 128.5, 129.2, 133.5, 133.6,
151.1, 157.3, 171.9; MS (ESI) 434.6 (M + H)+.
1H), 1.58 (m, 1H), 2.11-2.59 (m, 9H), 2.60-2.96 (m, 10H), 3.12
(dd, 1H, J ) 12 Hz, J ) 3 Hz), 3.29 (s, 1H), 3.63 (m, 2H), 4.60
(m, 1H), 5.75 (bs, 1H), 6.48-6.85 (m, 3H), 6.98 (m, 1H), 7.02-
7.23 (m, 8H), 8.0 (bs, 1H); MS (ESI) 552.9 (M + H)+. Anal.
(C36H47Cl2N3O2‚2H2O) C, H, N.
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-[(1R,4S,5S,7R)-5-
(3-hydroxyphenyl)-4-methyl-2-(2-methylbenzyl)-2-azabicyclo-
[3.3.1]non-7-yl]propanamide (5o) Dihydrochloride. The title
compound was prepared in 72% yield using a procedure similar to
that described in 5l starting from amine 18 and o-tolylacetalde-
1
hyde: [R]20 -54.8° (c 1.15, CH3OH); H NMR (CDCl3) δ 0.62
(d, 3H, J )D6 Hz), 0.89 (m, 2H), 1.04 (dd, 1H, J ) 12 Hz, J ) 12
Hz), 1.26 (m, 2H), 1.45 (d, 1H, J ) 6 Hz), 2.04 (m, 1H), 2.22 (d,
1H, J ) 12 Hz), 2.32 (s, 3H), 2.36-2.60 (m, 4H), 2.65-2.92 (m,
5H), 3.01 (s, 1H), 3.11 (dd, 1H, J ) 12 Hz, J ) 3 Hz), 3.42-3.78
(m, 4H), 4.75 (m, 1H), 6.52-6.92 (m, 3H), 6.97 (d, 1H, J ) 6
Hz), 7.02-7.23 (m, 8H), 7.80 (bs, 1H); 13C NMR (CDCl3) δ 18.7,
19.5, 29.1, 31.9, 33.0, 33.1, 37.9, 40.7, 45.2, 47.7, 50.5, 52.7, 54.1,
55.6, 56.0, 57.9, 112.9, 113.7, 116.7 (113.7 and 116.7 show up as
broad signals with a poor S/N ratio.), 125.7, 126.4, 126.9, 127.0,
127.3, 129.1, 129.6, 129.8, 130.6, 133.8, 134.0, 137.6, 138.1, 152.0,
157.3, 172.4. MS (ESI) 538.6 (M + H)+. Anal. (C35H45Cl2N3O2‚
1.5H2O) C, H, N.
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-[(1R,4S,5S,7R)-2-
hexyl-5-(3-hydroxyphenyl)-4-methyl-2-azabicyclo[3.3.1]non-7-
yl]propanamide (5l) Dihydrochloride. Amine 18 (0.038 mg, 0.088
mmol) was dissolved in 11 mL of anhydrous CH2Cl2 in a 100-mL
round-bottom flask. The solution remained cloudy and was slow
to dissolve. Hexanal (0.013 mL, 0.105 mmol) was added followed
by sodium triacetoxyborohydride (26 mg, 0.123 mmol). This
mixture was stirred at room temperature and monitored by TLC
(silica 1:1 CHCl3-CMA-80), which showed the starting material
was consumed in 1 h. Aqueous saturated NaHCO3 (30 mL) and
CHCl3 (15 mL) were added and stirred for about 5 min. The layers
were separated, and the aqueous layer was washed with CHCl3 (20
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated. The product was isolated by column chroma-
tography (silica 1:4 CHCl3-CMA-80). The purified product was
dissolved in anhydrous Et2O (1 mL) and anhydrous MeOH (4
drops), and 1 M HCl in Et2O (1 mL) was added dropwise with
rapid stirring resulting in a white precipitate. The solvent was
evaporated with nitrogen, and the residual solid was pumped on
high vacuum for 1.5 h. The salt was triturated with Et2O (4 × 2.5
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-
(3-hydroxyphenyl)-4-methyl-2-[3-(2-thienyl)propyl]-2-azabicyclo-
[3.3.1]non-7-yl}propanamide (5p) Dihydrochloride. The title
compound was prepared in 43% yield using a procedure similar to
that described in 5l starting from amine 18 and 3-(2-thienyl)-
propanal: [R]20D -45° (c 1.05, CH3OH). 1H NMR (CDCl3) δ 0.68
(d, 3H, J ) 9 Hz), 0.86 (dd, 1H, J ) 12 Hz, J ) 12 Hz), 1.05 (dd,
1H, J ) 12 Hz, J ) 12 Hz), 1.53 (d, 1H, J ) 12 Hz), 1.74 (m,
2H), 2.10 (bs, 1H), 2.28 (dd, 2H, J ) 12 Hz, J ) 12 Hz), 2.36-
2.54 (m, 5H), 2.61 (m, 3H), 2.66-2.88 (m, 7H), 3.01 (dd, 1H, J )
12 Hz, J ) 3 Hz), 3.13 (s, 1H), 3.61 (s, 2H), 4.60 (m, 1H), 6.49-
6.77 (m, 3H), 6.88 (d, 1H, J ) 3 Hz), 6.97 (m, 1H), 7.02-7.15
(m, 4H), 7.19 (dd, 1H, J ) 6 Hz), 7.96 (bs, 1H); 13C NMR (CDCl3)
δ 19.09, 28.22, 28.33, 28.46, 29.36, 31.90, 32.87, 37.84, 40.53,
45.10, 47.72, 50.51, 53.59, 54.16, 54.66, 55.73, 56.26, 112.89,
113.49, 116.59, 120.50, 125.59, 126.39, 126.90, 127.01, 128.75,
129.13, 129.79, 134.13, 142.97, 151.68, 157.59, 172.61; MS (ESI)
558.7 (M + H)+. Anal. (C34H45Cl2N3O2S‚H2O) C, H, N.
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-
(3-hydroxyphenyl)-4-methyl-2-[3-(3-thienyl)propyl]-2-azabicyclo-
[3.3.1]non-7-yl}propanamide (5q) Dihydrochloride. The title
compound was prepared in 64% yield using a procedure similar to
mL) to give 24 mg (46%) of the hydrochloride salt: [R]20 -44°
D
1
(c 0.75, CH3OH); H NMR (CDCl3) δ 0.70 (d, 3H, J ) 9 Hz),
0.77-0.96 (m, 4H), 1.06 (t, 1H, J ) 15 Hz), 1.24 (s, 8H), 1.14 (s,
2H), 1.57 (d, 1H, J ) 12 Hz), 2.13 (s, 1H), 2.31 (m, 2H), 2.45 (m,
5H), 2.60-2.91 (m, 7H), 2.91-3.10 (m, 1H), 3.17 (s, 1H), 3.50-
3.75 (m, 2H), 4.60 (m, 1H), 6.38-6.79 (m, 3H), 6.90-7.22 (m,
5H), 8.0 (bs, 1H). Anal. (C33H49Cl2N3O2‚H2O) C, H, N. MS (ESI)
518.8 (M + H)+.
that described in 5l starting from amine 18 and 3-(3-thienyl)-
1
propanal: [R]20 -41° (c 1.2, CH3OH); H NMR (CDCl3) 0.70
D
(d, 3H, J ) 6 Hz), 0.86 (m, 1H), 1.05 (dd, 1H, J ) 12 Hz, J ) 12
Hz), 1.53 (d, 1H, J ) 12 Hz), 1.79 (m, 2H), 2.12 (s, 1H), 2.28 (m,
2H), 2.37-2.59 (m, 5H), 2.59-2.91 (m, 10H), 3.03 (dd, 1H, J )
12 Hz, J ) 3 Hz), 3.12 (s, 1H), 3.62 (s, 2H), 4.61 (m, 1H), 6.50-
6.82 (m, 4H), 6.89 (dd, 1H, J ) 6 Hz, J ) 3 Hz), 6.98 (m, 1H),
7.02-7.21 (m, 5H), 8.05 (bs, 1H); 13C NMR (CDCl3) 19.06, 27.73,
29.35, 29.67, 32.00, 32.92, 37.86, 40.57, 45.11, 47.75, 50.50, 53.73,
54.16, 55.73, 56.08, 112.88, 113.59, 116.69, 123.32, 124.62, 126.38,
126.89, 126.99, 127.11, 129.12, 129.75, 134.12, 145.58, 151.74,
157.51, 172.56; MS (ESI) 558.8 (M + H)+. Anal. (C34H45Cl2N3O2S‚
1.5H2O) C, H, N.
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-
(3-hydroxyphenyl)-4-methyl-2-[3-(2-methylphenyl)propyl]-2-
azabicyclo[3.3.1]non-7-yl}propanamide (5m) Dihydrochloride.
The title compound was prepared in 63% yield using a procedure
similar to that described for 5l starting from amine 18 and 3-(2-
methoxyphenyl)propanal: [R]20D -47° (c 1.1, CH3OH); 1H NMR
(CDCl3) 0.69 (d, 3H, J ) 6 Hz), 0.88 (dd, 1H, J ) 15 Hz, J ) 15
Hz), 1.07 (dd, 1H, J ) 12 Hz, J ) 12 Hz), 1.55 (d, 1H, J ) 12
Hz), 1.71 (m, 2H), 2.12 (s, 1H), 2.25 (s, 3H), 2.28-2.961 (series
of m, 16H), 3.05 (dd, 1H, J ) 12 Hz, J ) 3 Hz), 3.16 (s, 1H), 3.62
(m, 2H), 4.63 (m, 1H), 6.49-6.82 (m, 3H), 6.98 (d, 1H, J ) 9
Hz), 7.01-7.21 (m, 8H), 8.10 (bs, 1H); MS (ESI) 566.5 (M +
H)+. Anal. (C37H49Cl2N3O2‚1.5H2O) C, H, N.
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-[(1R,4S,5S,7R)-2-
[3-(2-furyl)propyl]-5-(3-hydroxyphenyl)-4-methyl-2-azabicyclo-
[3.3.1]non-7-yl]propanamide (5r) Dihydrochloride. The title
compound was prepared in 47% yield using a procedure similar to
that described in 5l starting from amine 18 and 3-(2-furyl)-
propanal: [R]20D -35° (c 1.0, CH3OH); 1H NMR (CDCl3) δ 0.72
(d, 3H, J ) 6 Hz), 0.78-0.96 (m, 2H), 0.98-1.14 (m, 1H), 1.25
(m, 2H), 1.55 (d, 1H, J ) 6 Hz), 1.77 (m, 2H), 2.07-2.20 (m,
1H), 2.20-2.37 (m, 2H), 2.38-2.57 (m, 4H), 2.59-2.71 (m, 3H),
2.71-2.79 (m, 3H), 2.79-2.89 (m, 2H), 3.07 (dd, 1H, J ) 12 Hz,
J ) 3 Hz), 3.21 (s, 1H), 3.64 (m, 2H), 4.59 (m, 1H), 5.98 (d, 1H,
J ) 3 Hz), 6.25 (d, 1H, J ) 3 Hz), 6.50-6.81 (m, 3H), 6.98 (m,
(-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-
(3-hydroxyphenyl)-4-methyl-2-[2-(2-methylphenyl)ethyl]-2-
azabicyclo[3.3.1]non-7-yl}propanamide (5n) Dihydrochloride.
The title compound was prepared in 45% yield using a procedure
similar to that described in 5l starting from amine 18 and 2-(2-
methylphenyl)acetaldehyde: [R]20 -26° (c 0.95, CH3OH); 1H
D
NMR (CDCl3) 0.74 (d, 3H, J ) 6 Hz), 0.93 (m, 1H), 1.08 (m,

Opioid Receptor Antagonists
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1791
(5) Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.; Schoepp, D. D.;
Johnson, B. G.; Leander, J. D. Discovery of a potent, peripherally
selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid
antagonist for the treatment of gastrointestinal motility disorders. J.
Med. Chem. 1994, 37, 2262-2265.
1H), 7.02-7.21 (m, 4H), 7.27 (d, 1H, J ) 3 Hz), 8.10 (bs, 1H);
MS (ESI) 542.8 (M + H)+. Anal. (C34H45Cl2N3O3‚2H2O) C, H, N.
(2-Methylphenyl)acetaldehyde. To o-tolylacetic acid (1.22 g,
8.12 mmol) in 20 mL of absolute EtOH was added 2 drops of
concentrated H2SO4, and the mixture was heated under reflux
overnight. The solvent was then removed by rotary distillation. The
residue was dissolved in Et2O (40 mL), washed with saturated
aqueous NaHCO3 (40 mL) and brine (40 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure to a colorless oil
in near quantitative yield. The crude product was reduced to
2-methylphenylacetaldehyde following Mandell’s procedure.19
3-(2-Thienyl)propanal. Methyl (E)-3-(2-thiophenyl)acrylate was
made as described by Mouloungui20 and was reduced to methyl
3-(2-thiophenyl)propionate as described by Robertson.21 The methyl
3-(2-thiophenyl)propionate (0.467 g, 2.74 mmol) was dissolved in
Et2O (8 mL) and cooled to -78 °C. Diisobutylaluminum hydride
(4.57 mL, 6.85 mmol, 1.5 M in toluene) was added and stirred at
-78 °C for 1 h. The cooling bath was removed, H2O (5 mL) was
added, and the mixture was stirred vigorously for 15 min. The
reaction mixture was filtered through a coarse sintered glass frit,
and the solids were washed generously with Et2O and H2O. The
layers were separated, and the organic layer was washed with brine
(20 mL), dried over MgSO4, and concentrated under reduced
pressure to a colorless oil giving 0.36 g (92%).
Oxalyl chloride (0.173 g, 1.36 mmol, 0.117 mL) was dissolved
in CH2Cl2 (8 mL) and cooled to -78 °C. DMSO (0.212 g, 2.72
mmol, 0.193 mL) was added and stirred at -78 °C for 10 min.
3-(2-Thiophenyl)propanol (0.176 g, 1.23 mmol) was added dropwise
as a 1 mL solution in CH2Cl2. The mixture was stirred at -78 °C
for 1 h at which point Et3N (0.163 g, 1.61 mmol, 0.224 mL) was
added. The mixture was allowed to warm to room temperature.
Water (10 mL) and CH2Cl2 (10 mL) were added, the layers were
separated, and the organic layer was dried over MgSO4 and
concentrated under reduced pressure giving the product as short
white needles, 0.145 g (83%).
3-(3-Thienyl)propanal and 3-(2-furyl)propanal were prepared
from 3-thiophene carboxaldehyde and 2-furanaldehyde, respectively,
in the same manner as 3-(2-thienyl)propanal. 3-(2-Methylphenyl)-
propanal was also prepared in this manner from ethyl 2-methyl-
cinnamate.
(6) Schmidt, W. K. Alvimopan* (ADL 8-2698) is a novel peripheral
opioid antagonist. Am. J. Surg. 2001, 182, 27S-38S.
(7) Leone, N.; Wentz, L. News Release from Adolor CorporationsFDA
Accepts Entereg(TM) (alvimopan) New Drug Application (NDA)
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irol-newsArticle&t)Regular&id)611171& (accessed 2004).
(8) Statnick, M. A.; Suter, T. M.; Gackenheimer, S. L.; Emmerson, P.
J.; Quimby, S. J.; Gehlert, D. R.; Wheeler, W. J.; Mitch, C. H. Na+-
dependent high affinity binding of [3H]LY515300, a 3,4-dimethyl-
4-(3-hydroxyphenyl)piperidine opioid receptor inverse agonist. Eur.
J. Pharmacol. 2003, 482, 139-150.
(9) Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman, R. B.; Mascarella,
S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.; McCullough, K. B.;
Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification of
an opioid κ receptor subtype-selective N-substituent for (+)-(3R,4R)-
dimethyl-4-(3-hydroxyphenyl)piperidine. J. Med. Chem. 1998, 41,
5188-5197.
(10) Thomas, J. B.; Atkinson, R. N.; Vinson, N. A.; Catanzaro, J. L.;
Perretta, C. L.; Fix, S. E.; Mascarella, S. W.; Rothman, R. B.; Xu,
H.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I.
Identification of (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxy-
phenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetra-
hydro-3-isoquinolinecarboxamide as a novel potent and selective
opioid kappa receptor antagonist. J. Med. Chem. 2003, 46, 3127-
3137.
(11) Thomas, J. B.; Atkinson, R. N.; Rothman, R. B.; Fix, S. E.;
Mascarella, S. W.; Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y.;
Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Identification of
the first trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine de-
rivative to possess highly potent and selective opioid kappa receptor
antagonist activity. J. Med. Chem. 2001, 44, 2687-2690.
(12) Carroll, F. I.; Thomas, J. B.; Dykstra, L. A.; Granger, A. L.; Allen,
R. M.; Howard, J. L.; Pollard, G. T.; Aceto, M. D.; Harris, L. S.
Pharmacological properties of JDTic: A novel κ-opioid receptor
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N. A.; Xu, H.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.;
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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 University, Philadelphia, PA; hKOR).
Supporting Information Available: Results from elemental
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
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