Synthesis and in vitro opioid receptor functional antagonism of methyl-substituted analogues of (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-isoquinolinecarboxamide (JDTic

Article abstract of DOI:10.1021/jm900756t

In previous structure-activity relationship (SAR) studies, (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- isoquinolinecarboxamide (JDTic, 3) was identified as the first pote

Full text of DOI:10.1021/jm900756t

J. Med. Chem. 2009, 52, 7463–7472 7463
DOI: 10.1021/jm900756t
Synthesis and In Vitro Opioid Receptor Functional Antagonism of Methyl-Substituted Analogues
of (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-isoquinolinecarboxamide (JDTic)†
ꢀ
Juan Pablo Cueva, Tingwei Bill Cai, S. Wayne Mascarella, James B. Thomas, Hernan A. Navarro, and F. Ivy Carroll*
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Post Office Box 12194, Research Triangle Park,
North Carolina 27709-2194
Received May 29, 2009
In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hy-
droxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-
carboxamide (JDTic, 3) was identified as the first potent and selective κ-opioid receptor antagonist
from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present
study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor
functional antagonism using a [35S]GTPγS binding assay. Compounds 8a-p are analogues of
3 containing one, two, or three methyl groups connected to the JDTic structure at five different
positions. All the analogues with one and two added methyl groups with the exception of 8k had
subnanomolar Ke values at the κ receptor. The three most potent analogues were the monomethyl-
ated (3R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-
2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-
{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3,
4-tetrahydroisoquinoline-3-carboxamide (8e) with Ke values of 0.03 nM at the κ receptor and (3R)-7-
hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with Ke = 0.037 nM at the κ receptor. All three
compounds were selective for the κ receptor relative to the μ and δ receptors. Overall, the results from
this study highlight those areas that are tolerant to substitution on 3.
Introduction
processes that relate to stress, fear, and anxiety as well as
reward-seeking behavior.16 Studies have shown that 3 and 1
dose-dependently reduce fear and stress-induced responses in
multiple behavioral paradigms with rodents (immobility in
the forced-swim assay,8,10 reduction of exploratory behavior
in the elevated plus maze, fear-potentiated startle).17 Further-
more, selective κ antagonists have been shown to reduce
stress-induced reinstatement of cocaine self-administration
in rats,8 block the stress-induced potentiation of cocaine place
preference conditioning,7,9,18 decrease dependence-induced
ethanol self-administration,19 diminish deprivation-induced
eating in rats,20 and prevent prepulse inhibition mediated by
the κ agonist U50,488.21 These observations regarding the
behavioral consequences of receptor blockade in several
animal tests suggest that κ antagonists might be useful for
the treatment of anxiety, depression, schizophrenia, addic-
tion, and eating disorders.
In vivo, 3 has been shown to be more potent at blocking
κ-opioid agonist-induced activity than other κ-opioid antago-
nist.22 Compound 3 was also shown to have oral activity in
antagonizing the antinociceptive activity of the κ agonist
enadoline in mice22 and preventing stress-induced cocaine
reinstatement of self-administration in rats.8 To our knowl-
edge 3 remains the only orally active κ-opioid receptor
antagonist.
Stress can induce despair and increase the risk of clinical
depression and drug abuse.1,2 Dynorphin, the endogenous
ligand for the κ-opioid receptor, is a stress-related neuropep-
tide in the brain thatmay mediatetheseresponses.3 Activation
of the κ-opioid receptor causes place aversion in rodents and
dysphoria in humans.4,5 The dynorphin/κ-opioid receptor
system has been reported to be critical for stress-induced
depression-like behaviors and reinstatement to drug-seeking
behavior.4,6-10 The results from these studies have led to an
increased interest in selective κ-opioid receptor antagonists.
The first nonpeptide, highly selective antagonists of the κ-
opioid receptor were nor-BNI11 (1, Figure 1) and GNTI12 (2,
Figure 1), which were derived from the nonselective opioid
receptor antagonist naltrexone. More recently, JDTic (3,
Figure1) wasdiscoveredasthe first highlypotent andselective
κ-opioid receptor antagonist from the N-substituted trans-
3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4, Figure 1)
class of antagonist,13,14 and arodyn (5, Figure 1) was devel-
oped from dynorphin.15 Studies with these compounds
have shown that this system is intimately involved in brain
†We are pleased to have our study published in this special issue of the
Journal of Medicinal Chemistry that acknowledges the 100th anniversary
of the Division of Medicinal Chemistry.
*To whom correspondence should be addressed. Phone: 919-541-
6679. Fax: 919-541-8868. E-mail: fic@rti.org.
In a recent structure-activity relationship study, it was
reported that 8a, which has an extra methyl group on the
r
2009 American Chemical Society
Published on Web 08/26/2009
pubs.acs.org/jmc

7464 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Cueva et al.
fragments (R3), at the position R to the carboxamide moiety
(R4), and at the isoquinoline nitrogen (R5). Analogues 8a-c
were synthesized as previously reported.14,23 The synthesis of
the new analogues 8d-p is shown in Scheme 1. Coupling of
the appropriate 1,2,3,4-tetrahydroisoquinoline carboxylic
acids 6a-e with 7a-d using benzotriazole-1-yloxy-tris-
(dimethylamino)phosphonium hexafluorophosphate (BOP)
in tetrahydrofuran (THF) or O-(benzotriazol-1-yl)-N,N,N0,N0-
tetramethyluronium hexafluorophosphate (HBTU) in aceto-
nitrile (followed by removal of the Boc-protecting group with
trifluoroacetic acid in methylene chloride when 6a and 6c
were used) yielded 8d-p.
The tetrahydroisoquinoline carboxylic acids 6a-d needed
for the synthesis of 8e, 8g, 8h, 8i, 8l, 8m, 8n, and 8o were
prepared following the transformations outlined in Scheme 2.
D-Alanine (9) was converted to the sodium salt using sodium
hydroxide in ethanol, followed by conversion to the chiral
oxazolidinone 10 by condensation with benzaldehyde under
azeotropic distillation conditions and benzoylation using
benzoyl chloride.25 Alkylation of 10 with 4-methoxyben-
zyl bromide using lithium hexamethyldisilazide as the base
at -78 °C proceeded with high diastereomeric selectivity to
give the p-methoxybenzylated intermediate 11.26 Acid hydro-
lysis of the chiral intermediate 11 gave the amino acid 12.
Formation of the tetrahydroisoquinoline ring system was
achieved via the Pictet-Spengler reaction. This was carried
out by bromination of 12 to give 13 to protect the ortho
positions of the methoxy group, followed by treatment with
hydrobromic acid and formaldehyde at 80 °C to give 14.
Compound 14 was converted to 6a by treatment with con-
centrated hydrobromic acid to demethylate the 7-methoxy to
a phenol, followed by catalytic debromination using palla-
dium on carbon under hydrogen, and finally treatment with
di-tert-butyl dicarbonate in dimethylformamide containing
triethylamine to give 6a. The N-methyl analogue 6b was
obtained by treating 6a with trifluoroacetic acid to give the
free amine followed by reductive methylation using Raney
nickel catalyst, hydrogen, and formaldehyde in methanol.
Compounds 6c and 6d were obtained from 14 by protection
as the tert-butoxycarbonyl ester using di-tert-butyl dicarbo-
nate and then debromination using palladium on carbon as
catalyst under hydrogen to give 6c. Removal of the Boc-
protecting group from 6c using hydrochloric acid followed by
reductivemethylation using the same conditions asfor6b gave
the N-methyl analogue 6d.
Figure 1
(1S)-isopropyl group of 3, had a Ke value of 0.03 nM at the
κ-opioid receptor, relative to 0.02 nM for 3, and retained 100-
and 800-fold κ selectivity relative to the μ and δ opioid
receptors, respectively.23 It was also reported that the methyl
ether 8b was a highly potent antagonist with a Ke value of
0.06 nM at the κ-opioid receptor, making it only 3-fold less
potent than 3. Compound 8b was 857- and 1970-fold selective
for the κ receptor relative to the μ and δ receptors, respectively.
The synthesis of the N-methyl analogue 8c has also been
reported; however, this analogue had not been evaluated for
inhibition of agonist-stimulated [35S]GTPγSa binding at cloned
μ-, δ-, and κ-opioid receptors in our laboratory.14 In this study,
we report the synthesis of a series of methylated analogues of 3
(8d-p, see Table 1 for structures) and report results on their
ability to inhibit agonist-stimulated [35S]GTPγS binding in cells
expressing cloned μ-, δ-, and κ-opioid receptors. Even though
3 has drug-like properties and has performed well in several
animal behavioral tests,8,17,22 we reasoned that analogues 8a-d
could have better pharmacokinetic properties and ability to
penetrate the brain. All 16 analogues (8a-p) had calculated
logBB values24 that suggested they would possess better brain
penetration than 3. All the mono- and dimethylated 3 analo-
gues with the exception of 8k had subnanomolar Ke values at
the κ-opioid receptor. The most potent new analogue was
8e with a Ke value of 0.03 nM for the κ-opioid receptor and
120- and 28000-fold selective relative to the μ- and δ-opioid
receptors. However, analogues 8d and previously reported 8a
and 8b were also potent and selective κ antagonists.
Compound 7b was synthesized by coupling N-Boc-L-valine
with (3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine
(16a)27 using BOP in tetrahydrofuran followed by reduction
with diborane in tetrahydrofuran (Scheme 3). Coupling of 16b
and 16a with N-Boc-L-isoleucine using HBTU in acetonitrile
followed by reduction with diborane gave 7c and 7d, res-
pectively. Compound 7a was synthesized as previously
reported.28
Chemistry
The structure of 3 was modified to introduce methyl
groups at five different sites of the molecule (see Table 1 for
structure): at the phenol moieties (R1, R2), on the linker of the
phenylpiperidine to the tetrahydroisoquinoline carboxamide
Pharmacology
a Abbreviations: GPCRs, G-protein-coupled receptors; cDNAs,
cDNA; SAR, structure-activity relationship; [35S]GTPγS, sulfur-35
guanosine-50-O-(3-thio)triphosphate; DAMGO, [D-Ala2,MePhe4,Gly-
ol5]enkephalin; DPDPE, [D-Pen2,D-Pen5]enkephalin; U69,593, (5R,
7R,8β)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]ben-
zeneacetamide; CHO, Chinese hamster ovary; GDP, guanosine dipho-
sphate; BOP, benzotriazole-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate; HBTU, O-(benzotriazol-1-yl)-N,N,N0,N0-tetra-
methyluronium hexafluorophosphate; Tic, tetrahydroisoquinolinecar-
boxylic acid; tPSA, topological polar surface area.
Compounds 1, 3, and 8a-p were first evaluated at 10 μM
for intrinsic activity in the [35S]GTPγS binding assay at all
three opioid receptors. As none of the compounds displayed
measurable intrinsic activity at this concentration, they and
the reference compound 1 were evaluated for functional
antagonism and selectivity at the opioid receptors. These data
were obtained by monitoring the ability of test compounds
to inhibit stimulated [35S]GTPγS binding produced by the

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7465
Table 1. Comparison of Inhibition of Agonist Stimulated [35S]GTPγS Binding in Cloned Human μ, δ, and κ-opioid Receptors for Compounds 8a-d to
3 and 1a
compd
R1
R2
R3
R4
R5
μ, DAMGO Ke (nM)
δ, DPDPE Ke (nM)
κ, U69,593 Ke (nM)
μ/κ
δ/κ
580
1
26 ( 7
25.1 ( 3.5b
3 ( 1c
29 ( 8
76.4 ( 2.7b
24 ( 4c
0.05 ( 0.02
0.02 ( 0.01b
0.03 ( 0.02c
0.06 ( 0.01c
0.16 ( 0.06
0.037 ( 0.003
0.03 ( 0.008
0.96 ( 0.4
0.93 ( 0.05
0.26 ( 0.1
0.11 ( 0.01
0.11 ( 0.03
4.3 ( 2.7
520
1255
100
857
1313
649
120
5
3
H
H
H
H
H
3830
800
8a
8b
8c
8d
8e
8f
8g
8h
8i
H
H
CH3
H
H
H
CH3
H
H
H
H
51.4 ( 15c
210 ( 60
24 ( 8
118 ( 45c
491 ( 120
21.2 ( 5
854 ( 210
1170 ( 400
36.8 ( 6.9
2200 ( 900
149 ( 13
132 ( 24
2300 ( 900
IAd
1970
3070
573
H
H
H
CH3
H
H
CH3
H
H
H
H
H
CH3
H
H
3.6 ( 1
5.1 ( 2
28500
1220
40
H
CH3
H
CH3
H
H
CH3
H
CH3
CH3
CH3
H
H
3.8 ( 1.1
123 ( 30
8.7 ( 2.7
7.2 ( 1.8
880 ( 220
1450 ( 490
17.5 ( 3.6
59.1 ( 16
7.0 ( 1.4
360 ( 120
4
CH3
H
H
H
473
79
8500
1350
1200
535
H
CH3
CH3
H
H
8j
H
H
CH3
CH3
H
66
8k
8l
H
CH3
CH3
H
H
204
95
CH3
CH3
H
H
CH3
CH3
CH3
CH3
H
15.2 ( 3.7
3.5 ( 0.8
0.52 ( 0.2
2.2 ( 0.6
8m
8n
8o
8p
CH3
CH3
H
H
18.7 ( 1.5
2100 ( 600
117 ( 30
IAd
5
5
4040
53
CH3
H
H
114
3
CH3
H
CH3
CH3
CH3
CH3
2.03 ( 0.03
180
a The data represent the means ( SE from at least three independent experiments. b The Ke values for 3 supplied by the NIDA Opioid
Treatment Discovery Program (OTDP) were 3.41, 79.3, and 0.01 nM for the μ, δ, and κ receptors, respectively (ref 14). c Data taken from
ref 23. d Inactive or >10000 nM.
Scheme 1a
a Reagents: (a) BOP, THF, Et3N (for 8d, 8f-g, 8i-l, 8n-p), or HBTU, CH3CN, Et3N, (for 8e, 8h, 8m) for coupling with 6a and 6c; (b) CF3CO2H,
CH2Cl2; (c) Raney Ni, H2, HCHO, CH3OH.
selective agonists DAMGO (μ), DPDPE (δ), or U69,593 (κ)
using cloned human opioid receptors expressed in CHO
cells.29 Agonist dose response curves were run in the presence
or absence of a single concentration of test compound. Test
compound assay concentrations ranged from 1-5000 nM,
depending on their activity. The Ke values were calculated
using the formula: Ke = [L]/DR - 1, where [L] is the concen-
tration of test compound and DR is the ratio of agonist EC50
value in the presence or absence of test compound, respec-
tively. At least two different concentrations of test compound
were used to calculate the Ke, and the concentrations were
chosen such that the agonist EC50 exhibited at least a 4-fold
shift to the right and there was a clear upper asymptote to the
agonist þ compound concentration response curve. The Ke
values along with those for the reference compound 1 are
shown in Table 1.
The calculated logP, tPSA, and logBB values for com-
pounds 1, 3, and 8a-p are given in Table 2. The logBB values
were calculated using eq 6 (the Clark equation) given in ref 24.
Topological polar surface areas (tPSA) and logP values were

7466 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Cueva et al.
Scheme 2a
Scheme 3a
a Reagents: (a) N-Boc-L-valine, BOP, THF; (b) N-Boc-L-isoleucine,
HBTU, CH3CN, Et3N, THF; (c) B2H6, THF.
Table 2. Calculated logP, tPSA, and logBB for 1, 3, and 8a-pa
compd
logP
tPSA
logBB
1
1.57
3.75
4.09
4.11
4.12
3.83
3.98
4.18
4.33
4.06
4.32
4.46
4.20
4.74
4.71
4.41
4.69
4.55
121.65
84.83
84.83
73.83
76.04
73.83
84.83
73.83
73.83
73.83
84.83
76.04
65.04
62.83
73.83
73.83
65.04
65.04
-1.42
-0.55
-0.49
-0.33
-0.36
-0.37
-0.51
-0.32
-0.30
-0.34
-0.46
-0.31
-0.19
-0.07
-0.24
-0.28
-0.11
-0.13
3
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
a logBB was calculated using eq 6 in ref 24.
compounds had 100-fold or greater selectivity for the
κ receptor relative to the μ receptor. The κ selectivity for 8a
and 8e relative to the δ receptor was 800 and 28500, res-
pectively. The N-methyl compound 8c (R5 = CH3) with a
Ke value of 0.16 nM at the κ-opioid receptor and 1313- and
3070-fold selectivity for the κ receptor relative to the μ and
δ receptors was the most κ selective analogue of this new
series. Compound 8b (R2 = CH3), with a Ke value of 0.06 nM,
was 3 times less potent than 3, and with μ/κ and μ/δ ratios of
857 and 1970, it was also highly κ selective.
Compound 8d, with a methyl substituted at the 3-hydroxyl
inthe phenylpiperidinefragment, hadonlya 2-folddecreasein
potency for the κ receptor (Ke = 0.037 nM) relative to 3.
Methylation of the alkyl side chain on the linker between
the phenylpiperidine and tetrahydroisoquinoline carboxa-
mide fragments (R3) produced compounds 8a, 8f, 8i, 8j, and
8m that had increased potency at μ receptors compared to 3.
This effect was most notable in the monomethyl substituted
compound 8a, which had an 8-fold increase in potency at
μ receptors compared to 3. These observations mirror those
seen in previous studies where large substituents at this
position increased μ receptor potency.28
a Reagents: (a) NaOH, C6H5CHO; (b) C6H5COCl; (c) LiHMDS,
THF, -78 °C; CH3OC6H4CH2Br; (d) conc HCl; (e) Br2, HCl; (f)
HCHO, HBr, H2O, CF3CO2H; (g) conc HBr, reflux; (h) H2, Pd/C,
CH3OH; (i) (Boc)2O, DMF, Et3N; (j) CF3CO2H, CH2Cl2; (k) Raney Ni,
H2, CH3OH, HCHO; (l) 12 M HCl, THF.
calculated using ChemAxon’s Instant JChem version 5.03
software.
Results and Discussion
Even though 3 (Ke = 0.02 nm) was more potent as a
κ-opioid receptor antagonist than any of the methylated
analogues studied, many of the analogues were potent and
selective κ antagonists. All of the monomethylated analogues
8a-8e, the dimethylated analogues 8f-8j, and the trimethy-
lated analogue 8m retained subnanomolar potency at the κ-
opioid receptor. All of the monomethylated compounds
8a-8e, the dimethylated compounds 8h and 8k, and the
trimethylated compound 8n retained greater than 100-fold κ
selectivity relative to the μ and δ receptors. The two most
potent analogues were 8a (R3=CH3) and 8e (R4=CH3), both
with Ke values of 0.03 nM at the κ-opioid receptor. Both
N-Methylation at the tetrahydroisoquinoline nitrogen to
give the N-methyl 3 analogue 8c resulted in a reduction in
potency at all receptor subtypes. At κ receptors, this modifica-
tion consistently gave decreases in potency for all analogues

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7467
8j, 8k, 8o, and 8p. Nevertheless, analogues 8c and 8j, with Ke
values of 0.16 and 0.11 nM, respectively, were still highly
potent κ antagonists.
stirred at -78 °C for 3 h and then at room temperature over-
night. Saturated NH4Cl solution was added, the THF was
removed in vacuo, Et2O (100 mL) was added, and the phases
were separated. The organic layer was washed with 50 mL of
NaHCO3 solution and brine. After drying (Na2SO4), filtration,
and removal of the solvent, the residue was purified by chro-
matography using a silica gel Isco column with 9% EtOAc in
hexanes as eluent. Concentration of the product fractions
gave 7.4 g (82%) of 11 as a white solid: mp 128-129 °C;
In general, it was observed that introduction of multiple
methyl groups into the structure of 3 was detrimental for
potency and selectivity at κ receptors. Compounds 8i and 8j
with Ke values of 0.11 nM each at the κ receptor were the two
most potent analogues with multiple methyl groups. The
effect was more noticeable for compounds with three methyl
substitutions. The most potent analogue containing three
methyl groups was 8n, which had a Ke value of 0.52 nM at
the κ receptor.
The calculated logP, tPSA, and logBB values for 1, 3, and
8a-p are given in Table 2.24 In contrast to standard com-
pound 1 (calculated logBB = -1.42), the calculated logBB for
3 and 8a-p (-0.07 to -0.55) are above the threshold pro-
posed by Clark to indicate low blood-brain barrier penetra-
tion. The calculated logBB values24 show that all 16 methyl-
ated analogues would be expected to show enhanced brain
penetration relative to 3. In the case of 8b for instance,
monomethylation shifts the calculated logBB value positively
by0.22 logunits (calculated logBBsfor 3 and 8bare -0.55and
-0.33, respectively). This change in the relative concentration
of drugs implies an approximately 66% increase in the con-
centration of the drug in the brain.
1
[R]25D =-260 (c 0.8, MeOH). H NMR (CDCl3) δ 7.27 (2H,
d, J = 8 Hz), 7.19-7.14 (2H, m), 7.09-7.05 (4H, m), 6.94 (d, 2H,
J = 8 Hz), 6.76-6.72 (m, 4H), 5.68 (s, 1H), 3.88 (d, 1H, J = 12
Hz), 3.86 (s, 3H), 3.27 (d, 1H, J = 12 Hz), 2.14 (s, 3H). 13C NMR
175.1, 169.4, 159.6, 136.7, 131.5, 130.1, 130.0, 128.8, 128.7,
128.2, 127.2, 126.3, 114.6, 90.7, 65.9, 55.8, 40.5, 24.6. ESIMS:
m/z 402 (M þ 1, 100).
O,r-Dimethyl-D-tyrosine (12). Compound 11 (2.2 g, 0.0055
mol) was suspended in 20 mL of concentrated HCl solution.
After nitrogen flush, the mixture was heated under reflux for 3 h.
After filtration and removal of the HCl solution, the white pre-
cipitate was dried. 1H NMR (CD3OD) δ 7.24 (d, 2H, J = 6 Hz),
6.91 (d, 2H, J = 6 Hz), 3.77 (3H, s), 3.26 (d, 1H, J = 14 Hz), 3.13
(d, 1H, J = 14 Hz), 1.66 (s, 3H). 13C NMR 173.8, 161.3, 132.9,
115.9, 62.4, 56.4, 43.5, 23.2. MS (ESI) 210 (M þ 1). The product
was used in the next step without purification.
3,5-Dibromo-O,r-dimethyl-D-tyrosine (13). To a solution of
compound 12 from above in distilled water (20 mL), 12 M HCl
(4 mL) was added. The reaction mixture was cooled to 5 °C, and
bromine (2.1 mL, 41 mmol) was injected into the stirred solu-
tion. After 15 min, N2 gas was passed through the reaction
mixture until the product precipitated. APCIMS: m/z 366 (M þ
1, 100). The product was used in the next step without purifica-
tion.
Conclusions
In summary, 16 analogues of 3 with methyl substituents at
five different positions on the 3 structure were synthesized.
Eleven of the analogues had subnanomolar Ke values at the κ
opioid receptor. The monomethylated analogues 8a, 8b, 8d,
and 8e with Ke values of 0.03-0.06 nM were the most potent
compounds. Even though the efficacy at the κ opioid receptor
isnot asgoodasthatfor 3, thecalculated logBB values suggest
that these analogues may have activity comparable to that of
3 in vivo. While beyond the scope of this investigation, a
pharmacokinetic (PK) study could suggest further develop-
ment of one or more of these analogues.
(3R)-6,8-Dibromo-7-methoxy-3-methyl-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic Acid (14). Compound 13 from above
(assumed to be 4.8 mmol) was added to trifluoroacetic acid
(5 mL). HBr (33% in acetic acid, 0.9 mL, 4.8 mmol) was added
dropwise to the reaction mixture under a nitrogen atmosphere.
After the addition of the acid, formaldehyde (8.64 mmol,
260 mg, 0.7 mL) was added dropwise and the mixture stirred
at 70-80 °C for 17 h. The reaction mixture was cooled, dried,
and concentrated. APCIMS: m/z 378 (M þ 1). The product was
used in the next step without purification.
(3R)-6,8-Dibromo-2-(tert-butoxycarbonyl)-7-methoxy-3-methyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (15). The crude
compound 14 reported above (assumed to be 4.8 mmol)
was dissolved in DMF (7 mL) and water (2 mL). Triethylamine
(1.01 g, 0.01 mol) was added, followed by di-tert-butyl dicarbo-
nate (1.57 g, 0.007 mol). The reaction mixture was stirred at
room temperature for 4 h and then concentrated to dryness. The
resulting residue was treated with water (30 mL) and EtOAc
(30 mL). KHSO4 (2 g) was added to the mixture (pH = 2), and
the organic layer was separated, dried, and concentrated. The
product was purified by chromatography on silica gel (Isco
column) using 35% EtOAc in hexanes as eluent to afford 500 mg
of 15 (22% from 13) as a syrup. 1H NMR (CD3OD) δ 7.55 (s,
1H), 4.84 (d, 1H, J = 16 Hz), 4.54 (d, 1H, J = 16 Hz), 3.85 (s,
3H), 3.19 (d, 1H, J = 16 Hz), 2.92 (d, 1H, J = 16 Hz), 1.47 (s,
9H), 1.42 (s, 3H). 13C NMR 177.7, 154.7, 138.1, 135.4, 132.9,
118.6, 117.9, 62.5, 62.0, 46.1, 41.7, 29.1, 28.3, 23.9. ESIMS: m/z
478 (M þ 1).
Experimental Section
1H NMR spectra were determined on a Bruker 300 spectro-
meter 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.
Medium-pressure flash column chromatography was done on a
CombiFlash Companion system using Teledyne Isco prepacked
˚
silica gel columns or using EM Science silica gel 60 A (230-400
mesh). All reactions were followed by thin-layer chromatography
using Whatman silica gel 60 TLC plates and were visualized by
UV. Optical rotations were measured on an Auto Pol III polari-
meter. All solvents were reagent grade. HCl in dry diethyl ether
was purchased from Aldrich Chemical Co. and used while fresh
before discoloration. CMA-80 is a mixture of 80% chloroform,
18% methanol, and 2% concentrated ammonium hydroxide.
Purity of compounds (>95%) was established by elemental
analysis. Elemental analyses were performed by Atlantic Micro-
lab, Inc., Atlanta, GA. Care should be used when using BOP in
coupling reactions as it yields the carcinogenic byproduct
HMPA.
(3R)-2-(tert-Butoxycarbonyl)-7-hydroxy-3-methyl-1,2,3,4-tetra-
hydroisoquinoline-3-carboxylic Acid (6a). A suspension of 14
(5.00 g, 0.012 mol) in 75 mL of 48% aqueous HBr was heated to
reflux for 5 h. The solution was then evaporated to dryness
under reduced pressure and dissolved in 30 mL of MeOH and
7.00 mL of Et3N (0.05 mol). This solution was added to 300 mg
of 10% Pd on carbon and shaken for 12 h in a Parr hydrogenator
under 60 psig H2. The suspension was filtered and the solvents
removed under reduced pressure to leave a solid product
(2S,4R)-4-(4-Methoxybenzyl)-4-methyl-2-phenyl-3-(phenyl-
carbonyl)-1,3-oxazolidin-5-one (11). Compound 1025 (6.35 g,
0.023 mol) in 50 mL of THF at -78 °C was added over
20 min to a solution of LiHMDS in THF (25 mL of 1 M solution
in THF). After 10 min, 1.1 equiv of 4-methoxybenzyl bromide
(25 mmol, 5 mL) was added in one portion. The mixture was

7468 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Cueva et al.
(containing the product and triethylammonium salts) with a
mass of 9.77 g. This solid was dissolved in 15 mL of H2O, 40 mL
of DMF, and 4.78 mL (34.29 mmol) of Et3N. Into this solution,
di-tert-butyl dicarbonate (2.1 mL, 22.26 mmol) was introduced
and the mixture stirred for 10 h. The solution was reduced to 1/
10 of its volume under reduced pressure and partitioned between
30 mL of H2O and 30 mL of EtOAc. The water layer was
extracted with EtOAc (3 ꢀ 15 mL). The pooled organic extracts
were washed once each with 10 mL of H2O, 10 mL of brine, dried
over MgSO4, filtered, and concentrated to dryness to yield 3.42 g
of 6a as a foam that was pure by NMR. 1H NMR (CDCl3) δ 7.17
(d, 1H, J = 8.1 Hz), 6.73 (m, 2H), 4.60-4.41 (2d, 2H), 3.12 (d,
1H, J = 14.7 Hz), 2.78 (d, 1H, J = 14.7 Hz), 1.56-1.24 (2s,
12H). ESIMS: m/z 207 (M þ 1-Boc).
a spatula. The mixture was stirred under an atmosphere of H2
for 5 h and was filtered through celite. To the filtered solution
was added 10 mL of a 2 M solution of HCl in ethanol. The
solvents were removed under reduced pressure, and the residue
was recrystallized from MeOH to give 879 mg (64%) of 6e HCl
3
as a white powder: mp >220 °C. 1H NMR (DMSO-d6) δ 9.59 (s,
1H), 7.09 (d, 1H, J = 8.4 Hz), 6.73 (m, 1H), 6.59 (s, 1H), 4.53 (b,
1H), 4.38 (b, 2H), 3.31 (dd, 1H, J = 5.7 Hz), 3.16-3.07 (m, 1H),
2.91 (s, 3H). ESIMS: m/z 208 (M þ 1, 100).
(2S)-1-[(3R,4R)-4-(3-Methoxyphenyl)-3,4-dimethylpiperidin-
1-yl]-3-methylbutan-2-amine (7b). To a heterogeneous solu-
tion of (3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine27
(41.1 g, 0.161 mol), N-Boc-L-valine (34.9 g, 0.161 mol), BOP
reagent (71.0 g, 0.161 mol) in THF (450 mL) was added
triethylamine (51.9 g, 0.513 mol) in THF (50 mL). The reaction
mixture became homogeneous within 5 min after addition of
Et3N. The reaction was stirred for 4 h at room temperature and
then added to ether (500 mL)/H2O (300 mL). The organic layer
was separated, washed with saturated NaHCO3 and then brine,
and separated. The extracts were dried (Na2SO4) and concen-
trated in vacuo to afford an off-white solid. This material
was purified by silica gel column chromatography, eluting with
70% hexanes in EtOAc to yield 63.6 g (94%) of a white
amorphous solid.
(R)-7-Hydroxy-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxylic Acid (6b) Triethylammonium Salt. The Boc-pro-
tected isoquinoline 6a (534 mg, 1.74 mmol) was dissolved in
5 mL of a 1:1 mixture of CF3CO2H/CH2Cl2 and stirred over-
night. The solvents were removed under reduced pressure and
the residue suspended in 2 mL of water. The pH of the solution
was adjusted to 7 by addition of saturated NaHCO3. To this
solution was added 300 mg of Raney Ni slurry in MeOH using a
spatula along with 1 mL of a 37% solution of formaldehyde in
water (13.4 mmol), and the resulting suspension was stirred
under 1 atm of H2 overnight. The suspension was filtered, and
the solvents were removed under reduced pressure to yield a
residue that was subjected to silica gel flash-column chroma-
tography. Elution with CHCl3/MeOH/NH4OH (60:30:10) af-
forded 384 mg of the ammonium salt of 6b after removal of
solvents. The triethylammonium salt of 6b was prepared by
addition of 5 mL of Et3N to a solution of the compound in 2 mL
of MeOH, followed by removal of the volatiles: mp >220 °C. 1H
NMR (CD3OD) δ 7.07 (d, 1H, J = 8 Hz), 7.77 (d, 1H), 6.58 (s,
1H), 4.43 (bd, 1H), 4.31 (bd, 1H), 3.37 (d, 1H), 3.20 (m, 9H), 2.95
(d, 1H, J = 14.7 Hz), 1.52 (s, 3H), 1.25 (t, 9H), 2.88 (m, 1H), 2.75
(m, 1H). ESIMS: m/z 222 (M þ 1, 100).
Diborane (260 mL, 1.0 M in THF, 0.260 mol) was added to
the material described above (54.6 g, 0.130 mol) in THF (350
mL). The reaction mixture was stirred under N2 at reflux for 2 h.
The slightly heterogeneous reaction mixture was cooled to room
temperature, and 6 N HCl was added (initially cautiously). After
stirring at reflux for 2 h, the mixture was concentrated in vacuo
and diluted with water. The reaction mixture was made basic
with solid Na2CO3 and extracted with CH2Cl2. The organic
layer was separated, dried (Na2SO4), and concentrated in
1
vacuo to afford 44 g (100%) of a thick oil. H NMR (CDCl3)
δ 7.21 (t, 1H), 6.88 (d, 1H, J = 8.1 Hz), 6.83 (s, 1H), 6.71 (d, 1H),
3.81 (s, 3H), 2.77 (m, 1H), 2.63-2.13 (m, 8H), 2.10 (bm, 1H),
2.00 (m, 1H), 1.60 (m, 1H), 1.41 (s, 3H), 0.91 (m, 7H), 0.76
(d, 3H, J = 7.2 Hz). ESIMS: m/z 305 (M þ Hþ, 100). Anal.
(C19H32N2O) C, H, N.
(3R)-2-(tert-Butoxycarbonyl)-7-methoxy-3-methyl-1,2,3,4-tetra-
hydroisoquinoline-3-carboxylic Acid (6c). Triethylamine (3 mmol,
0.42 mL) and 10% Pd/C (20 mg) were added to 15 (337 mg,
1.05 mmol) in MeOH (5 mL). This mixture was shaken for 90 min
under 40 psig of H2 in a Parr apparatus. The mixture was then
filtered and concentrated under reduced pressure to give 6c in
quantitative yield. An analytical sample was prepared by recrys-
tallization from EtOAc-hexanes: mp 191 °C dec. 1H NMR
(CD3OD) δ 7.10 (d, 1H, J = 8 Hz), 6.82 (m, 3H), 4.69 (d, 1H),
4.40 (d, 1H), 3.18 (d, 1H, J = 14.7 Hz), 2.79 (d, 1H, J = 14.7 Hz),
1.46 (s, 9H), 1.39 (s, 3H). ESIMS: m/z 322 (M þ 1, 100).
3-{(3R,4R)-1-[(2S,3S)-2-Amino-3-methylpentyl]-3,4-dimethyl-
piperidin-4-yl}phenol (7c).23 3-[(3R,4R)-3,4-Dimethylpiperidin-
4-yl]phenol (2.42 g, 11.79 mmol) and L-Boc-Ile (2.73 g, 11.79
mmol) were stirred in 30 mL of CH3CN and the solution cooled
to 0 °C. Into this solution, HBTU (4.47 g, 11.79 mmol) was
added followed by Et3N (3.3 mL, 23.57 mmol). The solution was
stirred for 2 h and was then partitioned between 60 mL of EtOAc
and 20 mL of H2O. The organic layer was washed with saturated
NaHCO3 (10 mL ꢀ 3) and brine (10 mL). The solvent was dried
over Na2SO4, filtered, and removed under reduced pressure.
Flash column chromatography on silica gel eluting with a
solvent gradient (80% hexanes in EtOAc to 66% hexanes in
EtOAc) gave fractions that contained 3.39 g of pure amide. The
amide (3.37 g, 8.33 mmol) was dissolved in 20 mL of dry THF,
and 16.67 mL of a 1 M solution of BH3 in THF was added. The
solution was heated at reflux for 3 h, cooled to ambient
temperature, and carefully added to 3 mL of H2O. Then 7 mL
of conc HCl was added. The mixture was heated at reflux for 2 h,
and the volume of the reaction was reduced to one-third under
reduced pressure. The remaining mixture was made basic by
addition of solid NaHCO3 and extracted thoroughly with a 4:1
mixture of CH2Cl2/THF. The pooled extracts were washed once
with 20 mL of H2O, dried over MgSO4, filtered, and concen-
trated to give 2.50 g (70%) of a clear oil that slowly crystallized.
An analytical sample was prepared by recrystallization from
EtOAc: mp 150-153 °C. 1H NMR (CDCl3) δ 7.13 (t, 1H), 6.80
(m, 1H), 6.71 (s, 1H), 6.64 (d, 1H), 2.82-2.78 (m, 3H), 2.74-2.52
(m, 4H), 2.42-2.26 (m, 6H), 1.97 (m, 1H), 1.54 (m, 2H),
1.49-1.38 (m, 1H), 1.31 (s, 3H), 1.27-1.19 (m, 1H), 0.89 (t,
6H), 0.77 (d, 3H, J = 6.9 Hz). ESIMS: m/z 305 (M þ Hþ, 100).
Anal. (C19H32N2O) C, H, N.
(3R)-7-Methoxy-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxylic Acid (6d) Triethylammonium Salt. At 0 °C, 6c (266
mg, 1.13 mmol) was dissolved in 5 mL of THF and 2 mL of 12 M
HCl. After this solution was strirred for 4 h, the solvents were
removed under reduced pressure. The residue was dissolved in
5 mL of MeOH. Into this solution were added 0.12 mL of Et3N,
0.5 mL of 37% formaldehyde in H2O, and 0.3 mL of Raney Ni
slurry in MeOH. The mixture was stirred overnight under an
atmosphere of H2, filtered, and the solvents removed under
reduced pressure to yield a residue that contained the title
compound and Et3N HCl. This residue was used without
3
1
further purification. H NMR (CD3OD) δ 7.13 (d, 1H), 6.88
(d, 1H), 6.75 (s, 1H), 4.57 (d, 1H), 4.32 (d, 1H) 3.77 (s, 3H), 3.41
(d, 1H, J = 14.7 Hz), 3.21 (q, 6H), 2.99 (d, 1H), 2.90 (s, 3H), 1.53
(s, 3H), 1.31 (t, 9H). ESIMS: m/z 322 (M þ 1, 100).
(3R)-7-Hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic Acid (6e) Hydrochloride. Compound 6f30 (1.087 g,
0.0034 mol) was suspended in 15 mL of CH2Cl2, and the mixture
was cooled to 0 °C. Into this solution was added 7 mL of
CF3COOH, and the mixture was stirred for 6 h. The solvents
were removed under reduced pressure, and the residue was
suspended in 100 mL of MeOH and 5 mL of formalin. Into this
suspension was added 1 g of a slurry of Raney Ni in MeOH using

Article
(2S,3S)-1-[(3R,4R)-4-(3-Methoxyphenyl)-3,4-dimethylpiperi-
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7469
saturated NaHCO3 and 10 mL of EtOAc. The layers were
separated, and the aqueous layer was extracted 2ꢀ with 5 mL
EtOAc. The pooled EtOAc extracts were washed once with
3 mL of brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure to yield a crude residue. When needed,
the impure compound was purified by preparative thick layer
chromatography. The dihydrochloride salts were formed by
dissolving the freebase in 5 mL of EtOH, followed by addition
of 5 mL of 2 M HCl in EtOH and evaporation of the solvents
under reduced pressure.
din-1-yl]-3-methylpentan-2-amine (7d). (3R,4R)-4-(3-Methoxy-
phenyl)-3,4-dimethylpiperidine27 (533 mg, 2.43 mmol) and
Boc-L-Ile (562 mg, 2.43 mmol) were stirred in 20 mL of CH3CN,
and the solution was cooled to 0 °C. Into this solution was added
HBTU (922 mg, 2.43 mmol), followed by Et3N (0.7 mL, 4.87
mmol). The solution was stirred for 2 h and was then partitioned
between 30 mL of EtOAc and 10 mL of H2O. The organic
layer was washed with saturated NaHCO3 (7 mL ꢀ 3) and brine
(5 mL) solutions. The solvent was dried over Na2SO4, filtered,
and removed under reduced pressure. Flash column chroma-
tography on silica gel eluting with 83% hexanes in EtOAc gave
fractions that after removal of solvent yielded 680 mg of pure
amide. The amide (675 mg, 1.56 mmol) was dissolved in 20 mL
of dry THF, and 3.12 mL of a 1 M solution of BH3 in THF was
added. The solution was heated at reflux for 3 h, cooled to room
temperature, and then 1 mL of H2O was added carefully,
followed by 3 mL of conc HCl. The mixture was heated at reflux
for 2 h, and the volume of the reaction was reduced to one-third
under reduced pressure. The remaining mixture was made basic
by addition of NaHCO3 and extracted thoroughly with CH2Cl2.
The pooled extracts were washed once with 10 mL of H2O, dried
over MgSO4, filtered, and the solvents removed to give 540 mg
(3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (8d) Dihydrochloride. Gen-
eral procedure (a) was employed using 100 mg (0.328 mmol) of
7b and 112 mg (0.382 mmol) of 6f to afford 65 mg (35%) of the
freebase. 1H NMR (CD3OD) δ 7.26 (t, 1H, J = 8.1 Hz), 7.00 (d,
1H, J = 8.1 Hz), 6.91 (d, 1H, J = 8.1 Hz), 6.86-6.75 (m, 2H),
6.63 (s, 1H), 4.30-4.37 (m, 3H), 3.50 (m, 2H), 3.15-3.11 (m,
1H), 2.80-2.71 (m, 1H), 2.45 (m, 1H), 1.93-1.87 (m, 1H), 1.49
(s, 3H), 1.29-1.13 (m, 1H), 1.07 (2d, 6H), 0.85 (d, 3H). The
hydrochloride salt synthesized by the general procedure had mp
>220 °C dec [R]D þ69° (c 0.35, MeOH). 1H NMR (CD3OD) δ
25
7.31 (t, 1H, J = 9 Hz), 7.12 (d, 1H, J = 9 Hz), 6.95 (d, 1H),
6.86-6.73 (m, 3H), 6.63 (s, 1H), 4.40 (d, 1H), 4.34 (d, 1H), 4.27
(m, 2H), 3.81 (s, 3H), 3.63 (d, 1H), 3.60-3.24 (m, 6H), 3.20 (d,
1H), 2.63 (dt, 1H), 2.43 (m, 1H), 1.95 (m, 1H), 1.48 (s, 3H),
1.03-0.87 (m, 3H), 0.83 (d, 3H, J = 9 Hz), 0.80-0.68 (m, 6H).
1
(70%) of a clear oil. H NMR (CD3OD) δ 7.20 (t, 1H, ArH),
6.89 (m, 1H, ArH), 6.82 (s, 1H, ArH), 6.72 (m, 1H, ArH), 3.77 (s,
3H, CH3OAr), 2.88-2.25 (m, 9H), 2.03 (m, 1H), 2.57-2.40 (m,
3H), 1.30 (d, 3H, CH3, J = 6.6 Hz).), 1.28-1.10 (m, 1H),
0.96-0.89 (m, 7H), 1.60-1.70 (dd, 3H, CH3). EIMS: m/z 319
(M þ Hþ, 100). Anal. (C20H34N2O) C, H, N.
ESIMS: m/z 480 (M þ 1, 50). Anal. (C29H43Cl2N3O3 2H2O) C,
3
H, N.
General Procedures for the Preparation of Compounds 8d-p.
a. BOP Coupling Procedure. A phenylpiperidine 7 (1 equiv) was
dissolved along with a tetrahydroisoquinoline 6 (1.05 equiv) in
10 mL of dry THF and cooled to 0 °C. Into this flask was
introduced BOP (1.05 equiv) dissolved in 5 mL of dry THF.
Immediately afterward, Et3N (1.05 equiv) was added and the
solution was warmed to room temperature and allowed to stir
for 3 h. The solution was added to 30 mL of saturated NaHCO3.
The resulting mixture was extracted 3ꢀ with 10 mL of EtOAc.
The pooled organic solvents were washed once with 5 mL of
water and dried over MgSO4. The mixture was then separated
by flash chromatography on silica gel. For the reactions employ-
ing Boc-protected tetrahydroisoquinolines, and the crude cou-
pling mixture was dissolved in 10 mL of a 20% CF3CO2H
solution in CH2Cl2 and stirred overnight. The solvents were
removed and the crude product stirred in 10 mL of saturated
NaHCO3 and 10 mL of EtOAc. The layers were separated, and
the aqueous layer was extracted 2ꢀ with 5 mL of EtOAc. The
pooled EtOAc extracts were washed once with 3 mL of brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure to yield a crude residue. When needed, the impure
compound was purified by preparative thick layer chromatog-
raphy. The dihydrochloride salts were formed by dissolving the
freebase in 5 mL of EtOH, followed by addition of 5 mL of 2 M
HCl in EtOH and evaporation of the solution under reduced
pressure.
(3R)-7-Hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl]-3-methyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8e) Dihydrochlo-
ride. General procedure (b) was employed using 100 mg
(0.344 mmol) of 7a and 111 mg (0.361 mmol) of 6a to afford
65 mg (35%) of the freebase after separation by preparative
TLC eluting with 1:1 CMA-80/CH2Cl2. 1H NMR (CD3OD) δ
7.09 (t, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.70 (m, 2H),
6.55 (m, 2H), 6.47 (s, 1H), 4.02 (d, 1H), 3.77 (m, 2H), 3.16 (d,
1H), 2.74-2.33 (m, 7H), 2.14 (dt, 1H), 1.89-1.75 (m, 2H), 1.47
(d, 1H), 1.38 (d, 3H), 1.26-1.17 (m, 7H), 0.82 (t, 6H), 0.58 (d,
3H). The hydrochloride salt synthesized by the general proce-
25
dure had mp >220 °C dec [R]D þ47.2° (c 1, MeOH). 1H NMR
(CD3OD) δ 7.18 (m, 2H), 6.75 (m, 3H), 6.62 (m, 1H), 4.42 (d,
1H), 4.27 (d, 1H), 4.25 (m, 1H), 3.67-3.30 (m, 6H), 3.18 (d, 1H),
2.63 (dt, 1H), 2.39 (m, 1H), 1.90 (d, 1H), 1.85-1.60 (m, 1H), 1.79
(s, 3H), 0.85 (d, 3H, J = 9 Hz), 0.68 (2d, 6H). ESIMS: m/z 480
(M þ 1, 50). Anal. (C29H41Cl2N3O3 2H2O) C, H, N.
3
(3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutanyl]-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (8f) Dihydrochloride. Gen-
eral procedure (a) was employed using 120 mg (0.377 mmol) of
7d and 116 mg (0.396 mmol) of 6f to afford 50 mg (27%) of the
freebase after separation by preparative TLC eluting with 1:1
1
CMA-80/Et2O. H NMR (CD3OD) δ 7.19 (t, 1H), 6.87-6.81
(m, 2H), 6.80 (s, 1H), 6.69 (ds, 1H), 6.58 (ds, 1H), 6.47 (s, 1H),
4.06 (m, 1H), 3.77 (dd, 2H), 3.75 (s, 3H), 3.50 (dd, 1H), 2.82 (dd,
1H), 2.78-2.70 (m, 2H), 2.65-2.39 (m, 5H), 2.27 (dt, 1H), 1.99
(m, 1H), 1.70-1.50 (m, 4H), 1.40 (m, 5H), 1.22-1.03 (m, 2H),
0.8 (m, 9H), 0.69 (d, 3H). The hydrochloride salt synthesized by
b. HBTU Coupling Procedure. A phenylpiperidine 7 (1 equiv)
was dissolved along with a tetrahydroisoquinoline 6 (1.05 equiv)
in 15 mL of a 50% solution of THF in CH3CN and cooled to
0 °C. Into this flask was introduced HBTU (1.05 equiv) dissolved
in 10 mL of CH3CN. Immediately afterward, Et3N (1.05 equiv)
was added and the solution was warmed to room temperature
and allowed to stir for 3 h. To the reaction solution was added
30 mL of saturated NaHCO3. The resulting mixture was extracted
three times with 10 mL of EtOAc. The pooled organic solvents
were washed once with 5 mL of water and dried over MgSO4.
The mixture was then separated by chromatography. For the
reactions employing Boc-protected tetrahydroisoquinolines,
the crude coupling mixture was dissolved in 10 mL of a 20%
CF3CO2H solution in CH2Cl2 and stirred overnight. The sol-
vents were removed and the crude product stirred in 10 mL of
25
the general procedure had mp >220 °C dec [R]D þ95.9° (c
0.71, MeOH). 1H NMR (CD3OD) δ 7.30 (t, 1H, J = 9 Hz), 7.12
(d, 1H, J = 9 Hz), 6.91 (d, 1H, J = 9 Hz), 6.89-6.73 (m, 2H),
6.62 (s, 1H), 4.40-4.20 (m, 3H), 3.89 (d, 1H), 3.81 (s, 3H),
3.67-3.23 (m, 7H), 3.12 (m, 1H), 2.82 (dt, 1H), 2.45 (m, 1H),
1.92 (d, 1H), 1.70 (m, 1H), 1.55 (m, 1H), 1.50 (s, 3H), 1.42 (m,
1H), 1.31 (m, 1H), 1.20 (m, 1H), 1.10-0.89 (m, 9H). ESIMS: m/z
494 (M þ 1, 80). Anal. (C30H45Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Methoxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-
dimethylpiperidin-1-yl]methyl}-(2-methylpropyl]-3-methyl-1,2,3,
4-tetrahydroisoquinoline-3-carboxamide (8g) Dihydrochloride.

7470 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Cueva et al.
General procedure (b) was employed using 172 mg (0.593 mmol)
of 7a and 200 mg (0.622 mmol) of 6c to afford 250 mg of the
freebase after isolation (68% yield): mp 210-212 °C. 1H NMR
(CD3OD) δ 7.09 (t, 1H, J = 8.1 Hz), 6.73-6.57 (m, 2H), 4.13 (d,
1H), 3.95-3.87 (m, 2H), 3.64 (s, 3H), 3.25 (d, 2H), 2.68 (m, 1H),
2.65-2.50 (m, 2H), 2.40 (m, 4H), 2.18 (dt, 1H), 1.82 (m, 2H),
1.52 (d, 1H), 1.37 (s, 3H), 1.24 (s, 3H), 0.85 (2d), 0.47 (d, 3H).
The hydrochloride salt synthesized by the general procedure had
(d, 1H, J = 15 Hz), 1.68 (m, 1H), 1.51-1.40 (m, 4H), 1.21 (m,
2H), 1.02 (d, 3H, J = 6 Hz), 0.97-0.80 (m, 6H). ESIMS: m/z 494
(M þ 1, 100). Anal. (C30H45Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-2-methyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8k) Dihydrochlor-
ide. General procedure (a) was employed using 120 mg
(0.394 mmol) of 7b 86 mg (0.414 mmol) of 6e to afford 67 mg
(35%) of the freebase after separation by preparative TLC
25
mp 210-212 °C dec [R]D þ15° (c 1.2, MeOH). 1H NMR
1
(CD3OD) δ 7.17-6.74 (m, 5H), 6.61 (m, 1H), 4.44 (d, 1H), 4.25
(d, 1H), 4.23 (m, 1H), 3.79 (s, 3H), 3.65-3.29 (m, 6H), 3.17 (d,
1H), 2.63 (dt, 1H), 2.40 (m, 1H), 1.91 (d, 1H), 1.84-1.59 (m,
1H), 1.79 (s, 3H), 0.84 (d, 3H, J = 9 Hz), 0.67 (2d, 6H). ESIMS:
eluting with 2:1:1 CMA-80/EtOAc/hexanes. H NMR (CD3-
OD) δ 7.20 (t, 1H, J = 8.1 Hz), 6.91 (d, 1H, J = 8.1 Hz), 6.86 (d,
1H, J = 8.1 Hz), 6.81 (s, 1H), 6.71 (dd, 1H), 6.59 (dd, 1H), 6.51
(d, 1H), 4.09 (q, 1H), 3.92 (m, 1H), 3.84 (dd, 1H), 3.77 (s, 1H),
3.50 (d, 1H), 3.13 (dd, 1H), 3.05 (dd, 1H), 2.96 (dd, 1H), 2.73 (m,
1H), 2.53 (dd, 1H), 2.50-2.40 (m, 4H), 2.40-2.37 (m, 2H), 2.22
(dt, 1H) 1.98 (m, 2H), 1.84 (m, 1H), 1.57 (t, 1H), 1.33 (m, 5H),
0.94-0.84 (m, 8H), 0.84-075 (dd, 1H), 0.73-0.68 (m, 3H). The
hydrochloride salt synthesized by the general procedure had mp
m/z 494 (M þ 1, 100). Anal. (C30H45Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-3-methyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8h) Dihydrochlo-
ride. General procedure (b) was employed using 100 mg
(0.328 mmol) of 7b and 120 mg (0.390 mmol) of 6a to afford
27 mg (17%) of the freebase after separation by preparative
TLC eluting with 75:1 EtOAc/Et3N. 1H NMR (CD3OD) δ 7.17
(t, 1H), 6.79-6.90 (m, 2H), 6.70 (m, 1H), 6.56 (m, 1H), 6.48 (s,
1H), 4.00 (d, 1H), 3.87 (m, 2H), 3.78 (s, 3H), 3.17 (d, 1H),
2.72-2.28 (m, 7H), 2.15 (dt, 1H), 1.89 (m, 1H), 1.79 (sextet, 1H),
1.50 (d, 1H), 1.38-1.20 (m, 7H), 1.10-0.77 (m, 7H), 0.56 (d,
3H). The hydrochloride salt synthesized by the general proce-
210-215 °C dec [R]D þ75.7° (c 1, MeOH). 1H NMR (CD3OD)
25
δ 7.29 (t, 1H, J = 9 Hz), 7.12 (d, 1H, J = 9 Hz), 6.91 (d, 1H),
6.87-6.61 (m, 3H), 4.48 (d, 1H), 4.35 (d, 1H), 4.30 (m, 1H), 3.81
(s, 3H), 3.78 (d, 1H), 3.63-3.15 (m, 6H), 3.09 (s, 3H), 3.07 (m,
1H), 2.80 (dt, 1H), 2.45 (m, 1H), 1.91 (m, 2H), 1.49 (s, 3H),
1.08-0.90 (m, 7H), 0.86 (d, 3H, J = 9 Hz). ESIMS: m/z 494
(M þ 1, 100). Anal. (C30H45Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Methoxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-3-methyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8l) Dihydrochlor-
ide. General procedure (a) was employed using 126 mg
(0.414 mmol) of 7b 140 mg (0.435 mmol) of 6c to afford 51 mg
(23%) of the freebase after separation by preparative TLC
eluting with 2:1 CHCl3/CMA-80. 1H NMR (CD3OD) δ
7.39-7.19 (m, 2H), 7.92-6.78 (m, 5H), 4.5-4.32 (q, 2H), 4.25
(m, 1H), 3.70 (d, 6H), 3.6-3.30 (m), 3.20 (d, 1H), 2.67 (dt, 1H),
2.45 (m, 1H), 1.92 (bd, 1H), 1.78 (s, 3H), 1.75-1.60 (m, 1H), 1.47
(s, 3H), 0.86 (d, 3H), 0.70 (t, 6H). The hydrochloride salt
synthesized by the general procedure had mp >220 °C dec
25
1
dure had mp >220 °C dec [R]D þ49.8° (c 0.45, MeOH). H
NMR (CD3OD) δ 7.30 (t, 1H, J = 9 Hz), 7.13 (d, 1H, J = 9 Hz),
6.94 (d, 1H, J = 9 Hz), 6.85-6.74 (m, 3H), 6.63 (s, 1H), 4.41 (d,
1H), 4.35 (d, 1H), 4.27 (m, 1H), 3.81 (s, 3H), 3.63 (d, 1H),
3.60-3.25 (m, 6H), 3.20 (d, 1H), 2.63 (dt, 1H), 2.45 (m, 1H), 1.95
(m, 1H), 1.78 (s, 3H), 1.48 (s, 3H), 1.05-0.89 (m, 3H), 0.83 (d,
3H, J = 9 Hz), 0.80-0.68 (m, 6H). ESIMS: m/z 494 (M þ 1, 80).
Anal. (C30H45Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutanyl]-3-methyl-1,
2,3,4-tetrahydroisoquinoline-3-carboxamide (8i) Dihydrochlor-
ide. General procedure (a) was employed using 104 mg of 7d
(0.341 mmol) and 110 mg (0.358 mmol) of 6a to afford 29 mg of
the freebase after separation by preparative TLC eluting with
1:1 CMA-80/CH2Cl2 (17% yield). 1H NMR (CD3OD) δ 7.19 (t,
1H), 6.79 (d, 1H, J = 8.1 Hz), 6.77-6.66 (m, 2H), 6.58 (m, 2H),
6.48 (s, 1H), 4.09 (q, 1H), 4.02-3.95 (d, 1H), 3.93-3.8 (m, 2H),
3.15 (d, 2H), 2.70-2.50 (m, 3H), 2.49-2.32 (m, 3H), 2.15 (dt,
1H), 1.88 (m, 1H), 1.62-1.3 (m, 11H), 0.91-0.79 (m, 9H), 0.58
(d, 3H, CH3). The hydrochloride salt synthesized by the general
25
[R]D þ49.8° (c 1, MeOH). 1H NMR (CD3OD) δ 7.30 (t, 1H),
7.26 (d, 1H, J = 6 Hz), 6.92-6.80 (m, 2H), 6.84-6.80 (m, 2H),
4.48 (d, 1H), 4.36 (d, 1H), 4.38 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H),
3.58 (d, 1H), 3.44-3.25 (m, 6H), 3.23 (d, 1H), 2.64 (dt, 1H),
2.46 (m, 1H), 1.95 (d, 1H), 1.78 (s, 3H), 1.80 (m, 1H), 0.83 (d, 3H,
J = 7.5 Hz), 0.79 (m, 6H). ESIMS: m/z 508 (M þ 1, 100). Anal.
(C31H47Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Methoxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-
3,4-dimethylpiperidin-1-yl]}-2-methylbutanyl]-3-methyl-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (8m) Dihydrochloride.
General procedure (b) was employed using 65 mg (0.213 mmol)
of 7c and 46 mg (0.224 mmol) of 6c to afford 25 mg (25%) of the
freebase after separation by preparative TLC eluting with 1:1
25
procedure had mp >220 °C dec [R]D þ42.2° (c 0.51, MeOH).
1H NMR (CD3OD) δ 7.20 (t, 1H, J = 9 Hz), 7.13 (d, 1H, J = 9
Hz), 6.80-6.75 (m, 2H), 6.69-6.64 (m, 2H), 4.41 (d, 1H), 4.30
(d, 1H), 4.28 (m, 1H), 3.64-3.32 (m, 7H), 3.17 (d, 1H), 2.63 (dt,
1H), 2.40 (m, 1H), 1.92 (d, 1H), 1.76 (s, 3H), 1.47 (m, 4H), 1.20
(m, 2H), 0.92-0.71 (m, 9H). ESIMS: m/z 494 (M þ 1, 80). Anal.
1
CMA-80/CH2Cl2. H NMR (CDCl3) δ 7.41 (d, 1H), 7.12 (t,
1H), 6.96 (d, 1H), 6.82-6.52 (m, 5H), 4.18-3.77 (m, 4H), 3.73 (s,
3H), 3.11 (d, 1H), 2.82-2.57 (m, 4H), 2.48-2.28 (m, 4H),
2.17-2.02 (m, 2H), 1.91-1.54 (m, 3H), 1.55-1.22 (m, 9H),
0.98-083 (m, 6H), 0.48 (d, 3H). 1.47 (d, 1H), 1.38 (d, 3H),
1.26-1.17 (m, 7H), 0.82 (t, 6H), 0.58 (d, 3H). The hydrochloride
salt synthesized by the general procedure had mp >220 °C dec
(C30H45Cl2N3O3 H2O) C, H, N.
3
(3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutanyl]-2-methyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8j) Dihydrochlor-
ide. General procedure (a) was employed using 130 mg
(0.427 mmol) of 7c and 109 mg (0.448 mmol) of 6e to afford
55 mg (25%) of the freebase after separation by preparative
TLC eluting with 2:1 CMA-80/CH2Cl2. 1H NMR (CD3OD) δ
7.19 (t, 1H, J = 8.1 Hz), 6.90 (d, 1H, J = 8.1 Hz), 6.73 (m, 2H),
6.59 (m, 2H), 6.51 (s, 1H), 4.09 (q, 1H), 3.98 (m, 1H), 3.84 (d,
1H), 3.50 (d, 1H), 3.13 (t, 1H), 2.99 (m, 1H), 2.88 (m, 1H), 2.75
(m, 1H), 2.55 (m, 2H), 2.45 (s, 3H), 2.37 (m, 2H), 2.23 (m, 1H)
1.94 (m, 2H), 1.63 (m, 1H), 1.50 (m, 2H), 1.62-1.3 (m, 11H),
0.80-1.0 (m, 9H), 0.7 (d, 3H, CH3). The hydrochloride salt
25
1
[R]D þ44.7° (c 0.45, MeOH). H NMR (CD3OD) δ 7.24 (d,
1H, J = 9 Hz), 7.18 (t, 1H, J = 9 Hz), 6.92 (m, 1H), 6.80 (s, 1H),
6.76 (m, 1H), 6.68 (m, 1H), 4.48 (d, 1H), 4.38 (d, 1H), 4.30 (m,
1H), 3.79 (s, 3H), 3.70 (d, 1H, J = 15.9 Hz), 3.60-3.31 (m, 5H),
3.20 (d, 1H, J = 15.9 Hz), 2.67 (dt, 1H), 2.40 (m, 1H), 1.91 (d,
1H), 1.79 (s, 3H), 1.46 (bs, 4H), 1.13 (m, 1H), 0.85 (d, 3H),
0.80-0.69 (m, 6H). ESIMS: m/z 508 (M þ 1, 100). Anal.
(C31H47Cl2N3O3 2H2O) C, H, N.
3
(3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutanyl)-3-methyl-1,
2,3,4-tetrahydroisoquinoline-3-carboxamide (8n) Dihydrochlor-
ide. General procedure (a) was employed using 145 mg
(0.455 mmol) of 7d and 146 mg (0.478 mmol) of 6a to afford
25
synthesized by the general procedure had mp 180 °C dec [R]D
þ84.3° (c 0.6, MeOH). 1H NMR (CD3OD) δ 7.19-7.11 (m, 2H),
6.89-6.65 (m, 4H), 4.50 (m, 2H), 4.32 (m, 1H), 3.73 (d, 1H),
3.55-3.16 (m, 8H), 3.08 (s, 3H), 2.78 (dt, 1H), 2.39 (m, 1H), 1.86

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7471
60 mg (26%) of the freebase after separation by preparative
TLC eluting with 3:1 CHCl3/CMA-80. H NMR (CD3OD) δ
(2) Koob, G.; Kreek, M. J. Stress, dysregulation of drug reward
pathways, and the transition to drug dependence. Am. J. Psychia-
try 2007, 164, 1149–1159.
(3) Nestler, E. J.; Carlezon, W. A., Jr. The mesolimbic dopamine
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2008, 28, 407–414.
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1
7.18 (t, 1H, J = 8.1 Hz), 6.88 (d, 1H, J = 8.1 Hz), 6.82 (d, 1H),
6.78 (t, 1H), 6.89 (dd, 1H, J2 = 5.7 Hz, J1 = 2.1 Hz), 6.53 (dd,
1H J2 = 5.7 Hz, J1 = 2.1 Hz), 6.46 (d, 1H, J = 2.4 Hz), 3.96 (d,
1H), 3.92 (m, 1H), 3.76 (s, 3H), 3.30 (m, 1H), 3.15 (d, 1H, J =
15.9 Hz), 2.69 (m, 1H), 2.64 (d, 1H), 2.54 (b, 1H), 2.47-2.36 (m,
5H), 2.17 (dt, 1H), 1.91 (m, 1H), 1.52-1.35 (m, 5H), 1.32 (s, 3H),
1.26 (m, 4H), 1.15 (d, 1H), 1.06-0.9 (m, 2H), 0.86 (t, 3H, J = 7.2
Hz), 0.81 (d, 3H, J = 6.9 Hz), 0.57 (d, 3H, J = 6.9 Hz). The
hydrochloride salt synthesized by the general procedure had mp
25
210 °C dec [R]D þ39.7° (c 0.41, MeOH). 1H NMR (CD3OD) δ
7.27 (t, 1H, J = 9 Hz), 7.11 (d, 1H, J = 9 Hz), 6.90-6.70 (m,
3H), 6.61 (s, 1H), 4.38 (d, 1H), 4.29 (m, 1H), 3.65 (d, 1H),
3.60-3.25 (m, 5H), 3.15 (d, 1H), 2.64 (dt, 1H), 2.42 (m, 1H), 1.92
(d, 1H), 1.76 (s, 3H), 1.46 (bs, 4H), 1.12 (m, 1H), 0.82 (d, 3H, J =
9 Hz), 0.78-0.71 (m, 6H). ESIMS: m/z 508 (M þ 1, 100). Anal.
(C31H47Cl2N3O3 2H2O) C, H, N.
3
(3R)-7-Methoxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-2,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8o) Dihydrochlo-
ride. General procedure (a) was employed using 104 mg
(0.358 mmol) of 7a and 88 mg (0.376 mmol) of 6d to afford 80
mg (44%) of the freebase after separation by preparative TLC
eluting with 3:1 CHCl3/CMA-80. 1H NMR (CD3OD) δ 7.07 (t,
1H), 6.93 (d, 1H), 6.73-6.52 (m, 5H), 4.86 (s, 3H), 4.07 (d, 1H,
J = 16.5 Hz), 3.89 (m, 1H), 3.80 (d, 1H, J = 16.5 Hz), 3.67 (s,
3H), 3.14 (d, 1H, J = 16.5 Hz), 2.72 (m, 1H), 2.62-2.57 (m, 2H),
2.50-2.37 (m, 5H), 2.31 (dd, 1H), 2.18 (dt, 1H), 1.90 (m, 1H),
1.89-1.75 (m, 1H), 1.51 (bd, 1H), 1.37-1.25 (m, 7H), 1.01-0.84
(m, 8H), 0.54 (d, 3H, J = 6.9 Hz). The hydrochloride salt syn-
25
thesized by the general procedure had mp 199 °C dec [R]D
þ50.2° (c 0.55, MeOH). 1H NMR (CD3OD) δ 7.29 (d, 1H, J =
9 Hz), 7.18 (t, 1H, J = 9 Hz), 6.95 (d, 1H, J = 9 Hz), 6.83-6.68
(m, 2H), 6.67 (d, 1H), 4.70-4.48 (bm, 2H), 4.33 (bm, 1H), 3.80
(s, 3H), 3.67-3.30 (m, 7H), 2.99 (s, 1H), 2.68 (dt, 1H), 2.42 (m,
1H), 1.92 (d, 1H), 1.48 (s, 3H), 0.99-0.50 (s, 9H). ESIMS: m/z
(12) Jones, R. M.; Hjorth, S. A.; Schwartz, T. W.; Portoghese, P. S.
Mutational evidence for a common kappa antagonist binding
pocket in the wild-type kappa and mutant mu[K303E] opioid
receptors. J. Med. Chem. 1998, 41, 4911–4914.
508 (M þ 1, 100). Anal. (C31H47Cl2N3O3 2H2O) C, H, N.
(13) 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
derivative to possess highly potent and selective opioid kappa
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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-
hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-
1,2,3,4-tetrahydro-3-isoquinolinecarboxamide as a novel potent
and selective opioid kappa receptor antagonist. J. Med. Chem.
2003, 46, 3127–3137.
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opioid receptor antagonist. J. Med. Chem. 2002, 45, 5617–5619.
(16) Metcalf, M. D.; Coop, A. Kappa opioid antagonists: past successes
and future prospects. AAPS J. 2005, 7, E704–E722.
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W. A., Jr. Anxiolytic-Like Effects of K-Opioid Receptor Antago-
nists in Models of Unlearned and Learned Fear in Rats.
J. Pharmacol. Exp. Ther. 2007, 323, 838–845.
(18) Redila, V. A.; Chavkin, C. Stress-induced reinstatement of cocaine
seeking is mediated by the kappa opioid system. Psychopharmacol-
ogy (Berlin) 2008, 200, 59–70.
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mu and kappa opioid antagonists in the nucleus accumbens alter
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M.; Puddu, M.; Mereu, G.; Gessa, G. L. Kappa opioid receptor
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Biol. Psychiatry 2005, 57, 1550–1558.
3
(3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl]-2-methylbutanyl]-2-methyl-1,
2,3,4-tetrahydroisoquinoline-3-carboxamide (8p) Dihydrochlor-
ide. General procedure (a) was employed using 100 mg
(0.328 mmol) of 7d and 71 mg (0.345 mmol) of 6e to afford 40
mg (34%) of the freebase after separation by preparative TLC
1
eluting with 1:1 CMA-80/Et2O. H NMR (CD3OD) δ 7.19 (t,
1H, J = 7.8 Hz), 6.92-6.84 (m, 2H), 6.82 (s, 1H), 6.71 (d, 1H),
6.59 (m, 1H), 6.21 (m, 1H), 4.09 (q, 1H), 3.98 (m, 1H), 3.87 (m,
1H), 3.77 (s, 3H), 3.49 (d, 1H, J = 15 Hz), 3.14-2.82 (m, 4H),
2.79-2.60 (m, 2H), 2.60-2.28 (m, 9H), 2.23 (dt, 1H) 1.97 (m,
1H), 1.68-1.35 (m, 4H), 1.29 (d, 3H), 1.23 (t, 3H), 0.93 (t, 5H),
0.90-0.77 (m, 2H), 0.70 (t, 3H). The hydrochloride salt, synthe-
25
sized by the general procedure, had mp 180 °C dec [R]D þ66.2°
(c 0.5, MeOH). 1H NMR (CD3OD) δ 7.29 (t, 1H, J = 9 Hz), 7.13
(d, 1H, J = 9 Hz), 6.93-6.78 (m, 3H), 6.67 (d, 1H), 6.85-6.74
(m, 3H), 6.67 (d, 1H), 4.48-4.28 (m, 3H), 3.81 (s, 3H), 3.63 (d,
1H), 3.60-3.25 (m, 6H), 3.09-3.01 (m, 4H), 2.78 (dt, 1H),
2.46 (m, 1H), 1.92 (m, 1H), 1.78 (s, 3H), 1.48 (bs, 4H), 1.1-0.8
(m, 10H). ESIMS: m/z 508 (M þ 1, 100). Anal. (C31H47Cl2-
N3O3 H2O) C, H, N.
3
Acknowledgment. This research was supported by the Na-
tional Institute on Drug Abuse, grant DA 09045.
Supporting Information Available: Elemental analysis data
for compounds 7c,d, 8d-p. This material is available free of
charge via the Internet at http://pubs.acs.org.
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