Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (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-is

Article abstract of DOI:10.1021/jm701344b

In previous structure-activity relationship (SAR) studies, we identified (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, 1) as the first poten

Full text of DOI:10.1021/jm701344b

J. Med. Chem. 2008, 51, 1849–1860
1849
Synthesis and In Vitro Opioid Receptor Functional Antagonism of Analogues of the
Selective Kappa Opioid Receptor Antagonist (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)
Tingwei Bill Cai, Zhou Zou, James B. Thomas, Larry Brieaddy, Hernán A. Navarro, and F. Ivy Carroll*
Organic and Medicinal Chemistry, Research Triangle Institute, Post Office Box 12194, Research Triangle Park, North Carolina 27709
ReceiVed October 26, 2007
In previous structure–activity relationship (SAR) studies, we identified (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-iso-
quinolinecarboxamide (JDTic, 1) as the first potent and selective κ opioid receptor antagonist from the
trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report
the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a
[35S]GTPγS binding assay. The results from the studies better define the pharmacophore for this class of κ
opioid receptor antagonist and has identified new potent and selective κ antagonist. (3R)-7-Hydroxy-N-
[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide (3) with a Ke value of 0.03 nM at the κ receptor and 100- and 793-
fold selectivity relative to the µ and δ receptors was the most potent and selective κ opioid receptor antagonist
identified.
Chart 1
Introduction
The opioid receptors, µ, δ, and κ, and the opioid-like receptor
(ORL-1a) belong to the super family of G-protein coupled
receptors (GPCRs) that possess seven helical transmembrane
spanning domains in their architecture.1 The majority of research
efforts focused upon this group of proteins has been directed
toward the µ receptor because it mediates the actions of both
the opiate and opioid analgesics, such as morphine and fentanyl,
respectively.2 Over the years, however, it has become increas-
ingly clear that the entire family of proteins are actively involved
in a host of biological processes.2 Furthermore, the advent of
selective antagonists has demonstrated that pharmacotherapeutic
opportunities exist via both negative and positive modulation
of this receptor family.3–8
The κ opioid receptor system and its endogenous ligands,
the dynorphins, have been linked to numerous physiological
conditions, including stress, depression, anxiety, and psychotic
behaviors, such as schizophrenia.9–12 Stress and depression are
two key triggers for relapse to addictive behaviors including
cocaine abuse, a chronically relapsing disease for which there
is no existing pharmacotherapy.13,14 Kappa receptor antagonists
have been shown to modulate the responses to stress in a number
of animal models.9–11 We recently reported that the κ receptor
antagonist JDTic (1)6–8 demonstrated dose-dependent reduction
of stress-induced relapse to cocaine seeking in abstinent rats.15
Furthermore, compound 1 demonstrated dose-dependent efficacy
in the Porsolt forced swim test that is characteristic of antide-
pressants.15 Taken together, these findings suggest that κ receptor
antagonists may provide a pharmacological means of managing
relapse to cocaine seeking by simultaneous blockade of two
key triggers for relapse, stress, and depression. In this article,
we report the synthesis and evaluation of 2–5, 6a–f, and 7a–k
analogues of 1 (Charts 1–3) for their ability to antagonize in
vitro opioid receptor activation in a [35S]GTPγS binding assay.
The results from these SAR studies provide a better understand-
ing of the key pharmacophore features associated with κ receptor
antagonists related to 1. In addition, new potent and selective κ
opioid receptor antagonists were identified.
Chemistry. The synthesis of compound 2 is given in Scheme
1. 3-[1-(2S-Amino-3-methylbutyl)-3R,4R-dimethyl-4-piperidi-
nyl]phenol (8)16 was first N-protected with a tert-butoxycarbonyl
(Boc) group followed by conversion of the phenol to the triflate
by treatment with triflic anhydride to afford intermediate 9.
Compound 9 was then converted to the methyl ester 10 in 96%
yield by treatment with carbon monoxide and catalytic dichloro-
[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) [PdCl2-
(dppf)] in a methanol and dimethylsulfoxide solution at 70 °C.17
* Telephone: 919-541-6679. Fax: 919-541-8868. E-mail: fic@rti.org.
a Abbreviation: GPCRs, G-protein-coupled receptors; cDNAs, comple-
mentary deoxyribonucleic acid; ORL-1, opioid receptor like; SAR, struc-
ture–activity relationship; [35S]GTPγS, sulfur-35 guanosine-5′-O-(3-
thio)triphosphate; DAMGO, (D-Ala2,MePhe4,Gly-ol5)enkephalin; DPDPE,
[D-Pen2,D-Pen5]enkephalin; U69,593, (5R,7R,8ꢀ)-(-)-N-methyl-N-[7-(1-
pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide; CHO, Chinese
hamster ovary; GDP, guanosine diphosphate; BOP, benzotriazole-1-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate; Tic, tetrahydroiso-
quinoline; PdCl2 (dppf), dichloro-[1,1′-bis(diphenylphosphino)ferrocene]
palladium(II).
10.1021/jm701344b CCC: $40.75
2008 American Chemical Society
Published on Web 02/29/2008

1850 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Cai et al.
Chart 2
Scheme 1a
Chart 3
a Reagents and conditions: (a) (Boc)2O then Tf2O, pyridine; (b)
PdCl2(dppf), CO, MeOH, DMSO; (c) LiOH, H2O then pyridine, (Boc)2O,
NH4HCO3, CH3CN; (d) 2 N HCl in ether, MeOH; (e) Boc-D-7-hydroxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (12), BOP, Et3N, THF.
The synthesis of compound 3, Scheme 2, began with the
coupling of piperidine 14 with Boc-protected isoleucine using
BOP in THF to give 15a. This compound was converted to
15c by reduction with borane in THF followed by refluxing
with 48% hydrobromic acid to deprotect the phenol and remove
the tert-butoxycarbonyl group. Compound 3 was obtained by
coupling of 15c with 12 using BOP in THF followed by
deprotection with 6 N HCl. Compounds 4 and 5 were also
synthesized as outlined in Scheme 2. Compound 14 was coupled
to N-Boc-glycine using BOP in THF followed by N-deprotection
to give 15b. This material was coupled with either isobutyric
acid chloride or 3-methylbutyryl acid chloride, and the resulting
product reduced using borane in THF to give 16a,b. O-
Demethylation using boron tribromide in methylene chloride
followed by coupling with 12 and N-deprotection using trif-
luoroacetic acid gave compounds 4 and 5.
Compounds 6a-e were synthesized by the routes shown in
Scheme 3. Intermediate 18, needed for the synthesis of 6a, was
prepared from 12 by first methylating both the phenol and the
carboxylic acid with dimethylsulfate to give 17. Selective
hydrolysis of the methyl ester using lithium hydroxide in
aqueous methanol followed by coupling of the resulting acid
with 8, using BOP, provided 18. N-Deprotection of 18 with
trifluoroacetic acid yielded 6a. The preparation of compounds
6b, 6d, and 6e were obtained by coupling the appropriate Boc-
D-7-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids
(19–21)19–21 with 8 using BOP conditions to give 24–26.
Deprotection with trifluoroacetic acid afforded 6b, 6d, and 6e.
Reduction of the nitro group in 6b using 10% palladium on
carbon catalyst in methanol afforded 6c.
The syntheses of compounds 7a-k, depicted in Schemes
4-9, all followed a similar path wherein a specific carboxylic
acid was prepared, coupled to 8, and then N- and O-deprotected.
The preparation of indole analogues 7a,b started with 6-meth-
oxy-1H-indole-2-carboxylic acid (27, Scheme 4). The synthesis
of 7c involved treatment of 6-methoxy-1H-indole (28) with
trichloroacetyl chloride to give 2,2,2-trichloro-1-(6-methoxy-
1H-indol-3-yl)ethanone that was subsequently hydrolyzed to
6-methoxy-1H-indole-3-carboxylic acid (29, Scheme 5). This
material was carried forward through intermediate 30 to give
Hydrolysis of the ester to the acid was followed by conversion
to amide 11 using ammonium hydrogen carbonate with di-tert-
butyl pyrocarbonate as an activating agent in acetonitrile
containing a small amount of pyridine in 50% yield.18 Finally,
deprotection of 11 with 2N hydrochloric acid in ether followed
by coupling with Boc-D-7-hydroxy-1,2,3,4-tetrahydroisoquino-
line-3-carboxylic acid (12) using benzotriazole-1-yloxy-tris(di-
methylamino)phosphonium hexafluorophosphate (BOP) in tet-
rahydrofuran (THF) and deprotection gave compound 2.

Kappa Opioid Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1851
Scheme 2a
a Reagents and conditions: (a) N-Boc-isoleucine, BOP, Et3N, THF; (b) N-Boc-glycine, BOP, Et3N, THF; (c) 2 N HCl, ether, CH3OH; (d) isobutyric
chloride, DIPEA; (e) 3-methylbutanoyl chloride, DIPEA; (f) BH3, THF, 6 N HCl; (g) BBr3, CH2Cl2, -78 °C; (h) Boc-D-7-hydroxy-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic acid (12), BOP, Et3N, THF; (i) TFA; (j) 48% HBr reflux; (k) 6 N HCl reflux.
7c as described for 7a,b. The synthesis of benzimidazole
analogues 7d,e started with 4-methoxybenzene-1,2-diamine (31,
Scheme 6), which was treated with methyl 2,2-dichloro-2-
methoxyacetate followed by saponification with lithium hy-
droxide to give 6-methoxy-1H-benzimidazole-2-carboxylic acid
(32). This acid was converted to the target compounds 7d,e as
described above. Quinoline analogues 7f,g were obtained from
3,3-dimethyloxypropionitrile (33) (Scheme 7) by conversion to
3-cyano-7-methoxyquinoline (34) followed by hydrolysis to
7-methoxyquinoline-3-carboxylic acid (35), which was carried
forward as described for 7a and 7b. Isoquinoline analogues 7h,i
(Scheme 8) were obtained from 2-benzotriazolymethyl-7-
methoxy-1,2,3,4-tetrahydroisoquinoline (36) via the (7-methoxy-
3,4-dihydro-1H-isoquinolin-2-yl)acetic acid ethyl ester inter-
mediate (37). Analogues 7j,k (Scheme 9) were prepared from
bis(6-methoxy-N-1,2,3,4-tetrahydroisoquinolinyl)methane (39)
obtained via the Pictet-Spengler reaction using 3-methox-
yphenethylamine 38. This material was then converted to the
(6-ethoxy-3,4-dihydro-1H-isoquinolin-2-yl)acetic acid ethyl ester
(40), as described above. Hydrolysis of the ethyl ester followed
by coupling with 8 afforded 7j. O-Demethylation of 7j gave
7k.
Biology. Compounds 2–5, 6a-f, and 7a-k were first
evaluated at 10 µM for intrinsic activity in the [35S]GTPγS
binding assay at all three opioid receptors. As none of
compounds displayed measurable intrinsic activity at this
concentration, they and the reference compound 1 were evalu-
ated 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 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 following 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, respectively. 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 2-fold shift to the right and there was a clear
upper asymptote to the agonist + compound concentration
response curve. The Ke values for 2–5, 6a-f, and 7a-k along
with those for the reference compound 1 are shown in Table 1.
Results and Discussion
The evaluation of analogues 2–5 listed in Chart 1 provided
insight into changes in in vitro functional antagonism resulting
from structural modification of the trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidine-based portion of 1 (Table 1). The data
for carboxamido derivative 2 provides information as to the
effect of changing to the hydrogen bond donating 3-hydroxy-
phenyl group in the antagonist “message” fragment of 1 to a
3-carboxamidophenyl group. Such modifications have been
successfully employed in other opioid compounds and in some
cases have provided compounds with improved biological
properties.23–25 Compound 2 has a Ke ) 0.1 nM, which is only
5-fold less potent than that of 1. Compound 2 with Ke values
of 21 and 478 at the µ and δ receptors is also selective for the
κ opioid receptor. Changing the (1S)-isopropyl group of 1 to a
(1S)-sec-butyl group gives 3, which has a Ke value of 0.03 nM
at the κ opioid receptor, which is almost as potent as 1. With
Ke values of 3 and 24 nM at the µ and δ opioid receptors,
respectively, 3 also retained good κ selectivity.
Analogues 4 and 5 examined the effect of moving the
isopropyl group in 1 from the carbon next to the amide group
to the amide nitrogen. The one and two methylene linkers were
added to ensure that this group could still reach the same
receptor space as that found in 1. Both of these compounds are
antagonists at all three of the opioid receptors, but the potency
at the κ receptor was much lower than that found for 1. Because
high potency at the κ receptor has always driven the selectivity
in this series of compounds, this change was not favorable and
gave compounds that were not selective for the κ versus the µ
receptor.

1852 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Cai et al.
Scheme 3a
We also examined replacement of the isoquinoline portion
of 7-hydroxy-D-Tic part of 1 with achiral heterocycles (R5, as
depicted in Chart 3). These included a number of 6,5 fused-
ring heterocycles such as 7a–7e and 6,6 fused-ring heterocycles
like 7f–7k. In each of these cases, we retained representative
functional groups found in 1 or 6a, including an oxygen-
substituted (OH or OCH3) aryl ring fused to a nitrogen-bearing
heterocyclic ring. In this modification, we included indole,
benzimidazole, quinoline, and tetrahydroisoquinoline examples.
The two most potent of these compounds at the κ opioid receptor
were 7k with a Ke value of 3.9 nM and 7c with a Ke value of
4.5 nM, which represent 195- and 225-fold decreases in
antagonist potency relative to 1. Overall, this suggests that the
stereocenter in the D-Tic portion of 1 is important for highly
potent antagonist activity at the κ receptor.
Conclusion
This study has identified several potent and selective ana-
logues of 1 and also provided new SAR information, which
has shed new light on the κ opioid receptor antagonist
pharmacophore. First, compound 2 demonstrated that the
hydroxyl group in the phenol ring of the message component
of 1 can be substituted by a carboxamido group and still retain
high κ potency and selectivity. Changing the isopropyl sub-
stituent next to the amide nitrogen in 1 to a sec-butyl group to
give 3, and methylating the phenol in the 7-hydroxy-D-Tic
portion of 1 to a methyl ether to give 6a produced potent and
selective κ opioid receptor antagonists. In contrast, the addition
of large aliphatic groups to the amide nitrogen to give
compounds 4 and 5 and elimination of the chiral center with
concomitant modification of the isoquinoline group in the D-Tic
portion of 1 to give 7a–k all resulted in significant loss of
potency at the κ receptor. In addition, changes to the electron
density in the aromatic portion of 7-hydroxy-D-Tic fragment
(see compounds 6a–6f) strongly influenced antagonist potency
suggesting that this ring is an active part of the pharmacophore
and not simply a molecular scaffold.
a Reagents and conditions: (a) (CH3)2SO4, K2CO3, CH3COCH3; (b)
LiOH, CH3OH, H2O; (c) 8, BOP, Et3N, THF; (d) TFA; (e) 10% Pd/C, H2,
MeOH.
Experimental Section
1H NMR spectra were determined on a Bruker 300 spectrometer
using tetramethylsilane as an internal standard. Mass spectral data
were obtained using a Finnegan LCQ electrospray mass spectrom-
eter 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. Optical rotations
were measured on an Auto Pol III polarimeter. 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% concen-
trated ammonium hydroxide. MMA-80 is a mixture of 80%
methylene chloride, 18% methanol, and 2% concentrated am-
monium hydroxide. IUPAC nomenclature is used in the Experi-
mental Section to name target compounds and intermediates except
12 and 19–21. The names were generated using ACD software.
General Procedure for Coupling of Amines and Acids. The
subject amine (1 equiv) was coupled with the subject carboxylic
acid (1 equiv) by combining with BOP reagent (1 equiv) and
triethylamine (2 equiv) in THF (20 mL/g of subject compound) at
0 °C. The mixture was stirred at room temperature for 2 h and
diluted with ether. The organic layer was washed with saturated
NaHCO3 solution, water, and brine, and the organic layer was dried
(Na2SO4) and concentrated.
Compounds 6a-e are analogues where the hydroxy group
in the 7-hydroxy-D-Tic part of 1 has been replaced with other
groups, Chart 2. The most potent of these groups was the methyl
ether 6a. This compound 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 at the κ receptor relative to 1. The amino
analogue 6c also had a subnanomolar antagonist potency (Ke
) 0.2 nM) and only a 10-fold loss of potency relative to 1.
Changing the amino group to its N-acetyl and N-sulfonamido
derivatives gave 6d and 6e with Ke values of 1.4 and 4 nM,
respectively. The nitro derivative 6b gave a 320-fold loss of
potency at the κ receptor relative to 1. The previously reported
unsubstituted analogue 6f26 was found to have a Ke value of 56
nM for the κ receptor. The high potency of 1, 6a, and 6c relative
to 6f suggests the potential involvement of their hydroxy,
methoxy, and amino groups in a hydrogen bond acceptor
interaction. Alternatively, the κ potency may be due to electronic
effects. Compounds 1, 6a, and 6c, which possess R4 groups
that donate electron density to the aryl ring have higher potency
κ antagonism than compounds wherein electron density was
removed from the ring, 6b, or where resonance donation was
reduced (6d,e relative to 6c). Overall, it is clear that more
analogues will be needed to completely resolve this issue.
General Procedures for N-Deprotection. Method A: The
subject compound (50 mg) was dissolved in 1 mL of MeOH and
to this was added 10 mL of 2 N HCl in ether. The mixture was
stirred at room temperature for 3 h and then concentrated. The

Kappa Opioid Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1853
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 9
resulting residue was dissolved by CH2Cl2 and washed with
NaHCO3 solution. The organic layer was separated, dried (Na2SO4),
and concentrated. Method B: The subject compound (50 mg) was
dissolved in 5 mL of dry CH2Cl2 and cooled to -20 °C. To this
was added 5 mL of trifluoroacetic acid in one portion. The mixture
was stirred at -20 °C for 30 min, whereupon the bath was removed.
When the reaction temperature reached room temperature, the
mixture was concentrated. The residue obtained was dissolved in
CH2Cl2 and washed with saturated NaHCO3. The organic layer was
separated, dried (Na2SO4), and concentrated.
General Procedure for O-Demethylation. The subject com-
pound (1 equiv) was dissolved in dry CH2Cl2 (0.25 mL/mg) under
a nitrogen atmosphere and cooled to -78 °C. A solution of BBr3
in CH2Cl2 (13.5 equiv, 1 M BBr3) was added to this mixture
dropwise and stirred for 3 h. After this time, the reaction mixture
was washed with saturated NaHCO3 solution, and the organic layer
was dried (Na2SO4) and concentrated.
3-[(3R,4R)-1-{(2S)-2-[(tert-Butoxycarbonyl)amino]-3-methyl-
butyl}-3,4-dimethylpiperidin-4-yl]phenyl Trifluoromethane-
sulfonate (9). A solution of 3-[1-(2S-amino-3-methylbutyl)-3R,4R-
dimethyl-4-piperidinyl]phenol (8, 360 mg, 0.92 mmol) and di-tert-
butyl dicarbonate (200 mg, 0.92 mmol) in 10 mL of CH2Cl2 was
stirred at room temperature for 3 h. The reaction mixture was
concentrated to dryness and dissolved in a mixture of pyridine (3
mL) and CH2Cl2 (10 mL) and cooled to 0 °C. Triflic anhydride
(0.5 mL, 3 mmol) dissolved in CH2Cl2 (1 mL) was added slowly
over 10 min. The mixture was warmed to room temperature and
stirred for 3 h. MeOH (2 mL) was added and the mixture stirred
for 10 min. The reaction mixture was quenched with 10% NaOH
and extracted with CH2Cl2. The combined organic layers were

1854 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Cai et al.
Table 1. Inhibition of Agonist Stimulated [35S]GTPγS Binding by
Compounds in Cloned Human µ, δ, and κ Opioid Receptorsa
saturated NaHCO3 solution and CH2Cl2. After thoroughly mixing,
the organic layer was separated and dried (Na2SO4). The organic
layer was filtered and concentrated, and the residue was purified
by flash column chromatography on silica gel using 15% CMA-80
in CH2Cl2 to give 120 mg (50%) of 11 as a syrup. 1H NMR
(CD3OD) δ 7.80 (s, 1H), 7.64 (d, 1H, J ) 7.5 Hz), 7.46 (d, 1H, J
) 7.8 Hz), 7.36 (t, 1H, J ) 7.8 Hz), 3.60–3.54 (m, 1H), 2.78 (d,
1H, J ) 11 Hz), 2.63 (d, 1H, J ) 11 Hz), 2.53–2.49 (m, 1H),
2.44–2.40 (m, 1H), 2.37–2.26 (m, 3H), 2.07–2.05 (m, 1H),
1.78–1.65 (m, 1H), 1.59 (d, 1H, J ) 10.5 Hz), 1.36 (s, 9H), 1.30
(s, 3H), 0.88 (d, 3H, J ) 7 Hz), 0.83 (d, 3H, J ) 7 Hz), 0.68 (d,
3H, J ) 7 Hz); 13C NMR (CD3OD) δ 158.8, 152.7, 135.1, 130.9,
129.7, 126.5, 120.1, 80.0, 61.6, 56.7, 54.0, 52.3, 40.3, 40.2, 32.9,
32.1, 29.3, 28.4, 20.3, 18.2, 17.2; MS (ESI) m/z 419 (M + 1).
tert-Butyl (3R)-3-{[(1S)-1-{[(3R,4R)-4-(3-Carbamoylphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]carbamoyl}-
7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (13). Com-
pound 11 (50 mg, 0.12 mmol) was deprotected according to the
general procedure (method A), and the impure product was coupled
to 12 using the general procedure. The residue was purified by flash
column chromatography on silica gel using 13% CMA-80 in CH2Cl2
as the eluent to give 60 mg (85%) of 13 as a yellow oil. 1H NMR
(CD3OD) δ 7.71 (s, 1H), 7.57 (d, 1H, J ) 7.5 Hz), 7.39 (d, 1H, J
) 7.5 Hz), 7.30 (t, 1H, J ) 7.8 Hz), 6.83 (d, 1H, J ) 7.5 Hz),
6.56–6.49 (m, 2H), 4.64 (br, 1H), 4.47–4.42 (m, 2H), 3.74 (dd, 1H
J ) 12, 6 Hz), 3.04–2.95 (m, 2H), 2.60–2.55 (m, 1H), 2.37 (m,
2H), 2.25–2.10 (m, 4H), 1.90 (d, 1H, J ) 6 Hz), 1.65 (br, 1H),
1.38 (br, 10H), 1.19 (s, 3H), 0.71 (br, 6H), 0.52 (d, 3H, J ) 7 Hz);
13C NMR (CD3OD) δ 174.0, 157.8, 157.4, 152.7, 136.4, 134.9,
131.0, 130.4, 129.7, 126.5, 126.1, 125.2, 115.6, 114.1, 82.5, 61.9,
57.8, 57.3, 53.3, 51.7, 40.4, 40.1, 32.9, 32.5, 32.1, 29.1, 28.3, 20.4,
18.2, 17.2; MS (ESI) m/z 593 (M + 1).
(3R)-N-[(1S)-1-{[(3R,4R)-4-(3-Carbamoylphenyl)-3,4-dimeth-
ylpiperidin-1-yl]methyl}-2-methylpropyl]-7-hydroxy-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (2) Dihydrochloride. Com-
pound 13 (60 mg, 0.1 mmol) was deprotected according to the
general procedure (method A). The residue was purified by flash
column chromatography on silica gel using 20% CMA-80 in CH2Cl2
as the eluent to give 40 mg (82%) of 2 as a white solid: 1H NMR
(CD3OD) δ 7.84 (s, 1H), 7.69 (d, 1H, J ) 7.5 Hz), 7.51 (d, 1H, J
) 8 Hz), 7.41 (t, 1H, J ) 7.8 Hz), 6.92 (d, 1H, J ) 8 Hz), 6.59
(dd, 1H, J ) 8, 2.4 Hz), 6.50 (d, 1H, J ) 1.8 Hz), 4.05–4.00 (m,
1H), 3.95–3.93 (m, 2H), 3.55 (dd, 1H, J ) 12, 6 Hz), 2.93 (dd,
1H, J ) 11, 5 Hz), 2.84–2.80 (m, 2H), 2.70–2.55 (m, 2H), 2.52–2.35
(m, 4H), 2.10 (d, 1H, J ) 7 Hz), 1.94–1.88 (m, 1H), 1.68 (d, 1H,
J ) 12.6 Hz), 1.35 (s, 3H), 0.96 (d, 3H, J ) 7 Hz), 0.93 (d, 3H, J
) 7 Hz), 0.70 (d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 174.3,
155.7, 151.2, 136.4, 133.6, 129.8, 129.6, 128.3, 125.1, 124.7, 124.6,
113.9, 112.1, 73.5, 60.3, 57.1, 55.8, 51.4, 50.8, 46.9, 39.0, 38.8,
31.3, 31.0, 27.0, 19.0, 16.8, 15.7; MS (ESI) 493 (M + 1). The
HCl salt prepared using 1.1 equiv of HCl (1.25 N in MeOH)
had mp 223–225 °C; [R]D +86° (c 0.5, CH3OH). Anal.
(C29H42Cl2N4O3 ·2H2O) C, H, N.
tert-Butyl [(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimeth-
ylpiperidin-1-yl]carbonyl}-2-methylpentyl]carbamate (15a). To
a heterogeneous solution of 14 (5.86 g, 0.023 mol), BOP (0.13 g,
0.023 mol), and N-Boc-L-isoleucine (5.30 g, 0.023 mol) in THF
(120 mL) was added Et3N (7.40 g, 0.073 mol) in THF (40 mL).
The reaction mixture was stirred at room temperature for 90 min
to give a cloudy light yellow mixture. To this mixture was added
ether (500 mL)/H2O (200 mL). The organic phase was separated,
washed with 10% NaHCO3 (800 mL), and brine (300 mL), dried
(Na2SO4), and concentrated to yield 9.9 g of a foam. This residue
was purified by column chromatography on silica gel, eluting with
70% hexane/EtOAc, to afford 8.25 g (83%) of 15a as a white
amorphous solid. 1H NMR (CDCl3) δ 7.28 (m, 1H), 6.84 (m, 3H),
5.26 (dd, 1H, J ) 9.6, 4.2 Hz), 4.73 (d, 1H, J ) 12.0 Hz), 4.59 (m,
1H), 4.32 (d, 1H, J ) 13.5 Hz), 3.95 (d, 1H, J ) 3.3 Hz), 3.80 (s,
3H), 3.65 (q, 1H, J ) 2.7 Hz), 3.42 (t, 1H, J ) 0.8, 2.7 Hz), 3.15
(dd, 1H, J ) 2.7, 10.8 Hz), 2.94 (t, 1H, J ) 3.0 Hz), 2.20 (m, 2H),
µ, DAMGO Ke δ, DPDPE Ke κ, U69,593 Ke
cmpd
(nM)
(nM)
(nM)
µκ
δκ
1
2
3
4
25 ( 4b
76 ( 3b
0.02 ( 0.01b 1250
3800
4780
800
21
21 ( 3
478 ( 75
24 ( 4
0.10 ( 0.04
0.03 ( 0.02
1.9 ( 0.4
1.2 ( 0.5
0.06 ( 0.01
6.4 ( 1.7
0.20 ( 0.03
1.4 ( 0.4
4.0 ( 0.3
56 ( 3
10.9 ( 1.8
34.1 ( 9.9
4.5 ( 0.6
28.4 ( 10.2
22.4 ( 10.4
11.4 ( 0.4
9.3 ( 2.8
16.8 ( 3
210
100
3 ( 1
1.0 ( 0.2
0.5 ( 0.1
51.4 ( 15
7.9 ( 1.4
12.6 ( 2
11 ( 4
39 ( 9
0.5
0.4
857
1.2
63
5
9.3 ( 2.1
118 ( 45
65 ( 25
373 ( 70
555 ( 61
106 ( 16
ND
8
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
7g
7 h
7i
1976
10
1865
7.9 396
4.4
17.7 ( 6
ND
27
13.7 ( 2.1
23.8 ( 5.7
4.8 ( 1.2
8.5 ( 1.2
15.6 ( 1.9
19.5 ( 6.1
48 ( 15
17.7 ( 6
9.2 ( 4.3
11.4 ( 1.3
21.4 ( 5
282 ( 78
97 ( 19
224 ( 90
102 ( 44
290 ( 50
158 ( 48
229 ( 85
51.7 ( 10
177 ( 27
76 ( 31
408 ( 160
1.3
0.7
1.1
0.3
0.7
1.7
5.2
1.0
0.4
0.4
26
3
50
3.6
13
14
25
3
7.5
3
23.5 ( 11
26 ( 9
7j
7k
3.9 ( 1.6
5.5 105
a The data represent the means ( SE from at least three independent
experiments. b The Ke values for JDTic 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 4).
washed with brine, dried (Na2SO4), filtered, and concentrated to
yield a brown oil that was purified by flash column chromatography
on silica gel using 5% CMA-80 in CH2Cl2 as the eluent to afford
450 mg (94%) of 9 as a yellow oil. 1H NMR (CD3OD) δ 7.4–7.30
(m, 2H), 7.14 (t, 1H, J ) 1.8 Hz), 7.08–7.05 (m, 1H), 3.51–3.48
(m, 1H), 2.72 (d, 1H, J ) 11 Hz), 2.57 (d, 1H, J ) 11 Hz),
2.48–2.42 (m, 1H), 2.39–2.34 (m, 1H), 2.35–2.17 (m, 3H),
1.95–1.93 (m, 1H), 1.70–1.64 (m, 1H), 1.55–1.51 (m, 1H), 1.31
(s, 9H), 1.24 (s, 3H), 0.82 (d, 3H, J ) 7 Hz), 0.77 (d, 3H, J ) 7
Hz), 0.63 (d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 158.9, 155.7,
151.8, 131.6, 127.5, 122.7, 120.3, 119.7, 80.1, 61.5, 56.6, 54.1,
52.1, 40.5, 40.4, 32.8, 32.1, 29.2 28.2, 20.3, 18.2, 17.0; MS (ESI)
m/z 523 (M + 1).
Methyl 3-[(3R,4R)-1-{(2S)-2-[(tert-Butoxycarbonyl)amino]-3-
methylbutyl}-3,4-dimethylpiperidin-4-yl]benzoate (10). A mix-
ture of 9 (150 mg, 0.29 mmol), PdCl2(dppf) (2.5 mg, 0.003 mmol),
and MeOH (5 mL) in DMSO (15 mL) was heated at 70 °C for 2
days under an atmosphere of CO gas. The solution was concentrated
and purified by flash column chromatography on silica gel using
5% CMA-80 in CH2Cl2 as the eluent to afford 120 mg (96%) of
10 as a yellow oil. 1H NMR (CD3OD) δ 7.86 (t, 1H, J ) 1.8 Hz),
7.73 (dt, 1H, J ) 7.8, 1.2 Hz), 7.46 (dt, 1H, J ) 6.6, 1.5 Hz), 7.32
(t, 1H, J ) 7.8 Hz), 3.80 (s, 3H), 3.50 (m, 1H), 2.72 (d, 1H, J )
10.5 Hz), 2.56 (d, 1H, J ) 10 Hz), 2.4–2.18 (m, 5H), 1.97 (d, 1H,
J ) 6 Hz), 1.68 (m, 1H), 1.55 (d, 1H, J ) 12 Hz), 1.30 (s, 9H),
1.23 (d, 3H), 0.82 (d, 3H, J ) 7 Hz), 0.77 (d, 3H, J ) 7 Hz), 0.62
(d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 169.3, 158.8, 152.7, 132.2,
131.5, 129.9, 128.1, 80.0, 61.6, 56.7, 54.1, 53.0, 52.2, 50.3, 40.4,
40.2, 32.9, 32.2, 29.3, 28.4, 20.3, 18.2, 17.1; MS (ESI) m/z 433
(M + 1).
tert-Butyl [(1S)-1-{[(3R,4R)-4-(3-Carbamoylphenyl)-3,4-di-
methylpiperidin-1-yl]methyl}-2-methylpropyl]carbamate (11).
Compound 10 (250 mg, 0.58 mmol) was dissolved in 10 mL of
THF and MeOH (3:1). A solution of LiOH monohydrate (73 mg,
1.74 mmol) in water (2 mL) was added, and the mixture was stirred
at room temperature overnight. The solution was neutralized with
6 N HCl and concentrated. The product obtained was dissolved in
15 mL of acetonitrile, and pyridine (0.03 mL, 29 mg, 0.37 mmol),
(Boc)2O (164 mg, 0.75 mmol), and ammonium hydrogen carbonate
(59 mg, 0.75 mmol) were added. After 10 h at room temperature,
the reaction mixture was added to a separatory funnel containing

Kappa Opioid Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1855
1.66 (m, 2H), 1.43 (s, 9H), 1.40 (d, 3H, J ) 5.1 Hz), 1.08 (m, 1H),
0.87 (m, 6H), 0.62 (t, 3H, J ) 6.9 Hz).
(t, 2H, J ) 6 Hz), 2.48 (m, 2H), 2.45–2.20 (m, 5H), 1.93 (br, 1H),
1.70 (m, 1H), 1.55 (d, 1H, J ) 12 Hz), 1.21 (s, 3H), 0.93 (m, 1H),
0.80 (d, 6H, J ) 7 Hz), 0.66 (d, 3H, J ) 7 Hz); 13C NMR (CD3OD)
δ 161.6, 130.5, 130.4, 119.5, 113.6, 111.6, 59.1, 58.4, 57.4, 56.0,
51.9, 47.6, 40.5, 40.1, 32.3, 29.4, 28.5, 21.9, 21.4, 21.3, 17.2; MS
(ESI) m/z 319 (M + 1).
3-[1-(2S-Amino-3-methylpentyl)-3R,4R-dimethyl-4-piperidi-
nyl]phenol (15c). Borane (42 mL, 0.042 moL, 1 M) was added
dropwise to 15a in THF (75 mL). The reaction mixture was heated
under reflux for 90 min and cooled, 6 N HCl (10 mL) was added,
the mixture was refluxed for 90 min, and then concentrated in vacuo.
The resulting residue was dissolved in water (150 mL) and
neutralized using solid Na2CO3 and extracted with CHCl3. The
CHCl3 extracts were dried (Na2SO4) and concentrated to give 6.1 g
(>100%) of a thick clear oil; Rf ) 0.50, silica, 50% CMA-80/
CH2Cl2. This material was dissolved in 48% HBr (30 mL) and
stirred at reflux for 4 h. The residue obtained after concentration
was dissolved in water, made basic with Na2CO3, and extracted
with CHCl3. The CHCl3 layer was dried (Na2CO3) and concentrated
to afford 4.43 g (77%) of 15c as a white solid: mp 150–152 °C; Rf
) 0.33, silica, CMA-80/EtOAc/hexane (2:1:1). 1H NMR (CDCl3)
δ 7.15 (t, 1H, J ) 8.1 Hz), 6.77 (d, 1H, J ) 7.5 Hz), 6.70 (s, 1H),
6.65 (dd, 1H, J ) 6.0, 2.1 Hz), 3.85 (s, 3H), 2.82 (m, 2H), 2.56
(m, 2H), 2.26–2.43 (m, 4H), 1.95 (m, 1H), 1.39–1.57 (m, 3H), 1.24
(s, 3H), 1.23 (m, 1H), 0.93 (t, 6H, J ) 4.5 Hz), 0.73 (d, 3H, J )
6.9 Hz).
(3R)-7-Hydroxy-N-{2-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]ethyl}-N-(2-methylpropyl)-1,2,3,4-tetrahy-
droisoquinoline-3-carboxamide (4) Dihydrochloride. Compound
16a (70 mg, 0.22 mmol) was O-demethylated according to the
general procedure. The residue was coupled with 12 and deprotected
(method B) according to the general procedures. Purification by
flash column chromatography on silica gel using 15% CMA-80 in
CH2Cl2 as the eluent gave 27 mg (26%) of 4 as a syrup. 1H NMR
(CD3OD) δ 7.00 (td, 1H, J ) 8, 5 Hz), 6.80 (dd, 1H, J ) 12, 8
Hz), 6.69–6.61 (m, 2H), 6.5–6.47 (m, 2H), 6.38 (d, 1H, J ) 2 Hz),
3.84 (m, 3H), 3.4 (m, 1H), 3.31 (m, 1H), 3.15 (d, 1H, J ) 8 Hz),
3.00 (m, 1H), 2.7–2.6 (m, 3H), 2.55–2.42 (m, 4H), 2.34 (t, 1H, J
) 12 Hz), 2.2–2.1 (m, 1H), 1.94–1.88 (m, 2H), 1.47 (t, 1H, J ) 12
Hz), 1.20 (s, 3H), 0.86–0.82 (m, 6H), 0.67 (d, 3H, J ) 7 Hz); 13
C
NMR (CD3OD) δ 175.6, 158.7, 157.2, 153.2, 137.2, 131.4, 130.4,
125.5, 118.5, 115.4, 114.3, 113.7, 113.4, 59.4, 58.1, 57.4, 56.7,
55.1, 52.1, 47.2, 45.1, 40.6, 39.8, 32.4, 29.6, 28.5, 20.9, 20.4, 17.2;
MS (ESI) m/z 480 (M + 1). The HCl salt prepared using 1 N HCl
in ether had mp 209–211 °C; [R]D +107.7° (c 0.9, MeOH). Anal.
(C29H43Cl2N3O3 ·H2O) C, H, N.
(3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphe-
nyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide Dihydrochloride (3).
Compound 3 was prepared from 15c (4.0 g, 14.5 mmol) and Boc-
D-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (12,
4.4 g, 14.5 mmol) according to the general procedure and purified
by column chromatography on silica gel using CMA-80 as the
eluent to afford 6.6 g (95%) of 3 as a foam. 1H NMR (CD3OD) δ
7.02 (t, 1H, J ) 8.1 Hz), 6.85 (d, 1H, J ) 2.4 Hz), 6.62–6.68 (m,
2H), 6.47–6.52 (m, 2H), 6.43 (d, 1H J ) 2.4 Hz), 4.02 (m, 1H),
3.88 (d, 2H, J ) 3.6 Hz), 3.51 (dd, 1H, J ) 8.7 Hz), 2.56–2.89 (m,
8H), 2.40 (t, 1H, J ) 14.0 Hz), 2.15 (m, 1H), 1.68 (d, 1H, J )
14.4 Hz), 1.55 (d, 2H), 1.50 (m, 1H), 1.23 (s, 3H), 1.07 (t, 3H, J
N-{2-[(3R,4R)-4-(3-Methoxyphenyl)-3,4-dimethylpiperidin-1-
yl]-2-oxoethyl}-3-methylbutanamide (16b). Compound 16b was
prepared from 15b (200 mg, 0.64 mmol) using 3-methylbutanoyl
chloride by a procedure similar to that used for compound 16a to
give 210 mg (99%) of 16b. 1H NMR (CD3OD) δ 7.38 (t, 1H, J )
8 Hz), 7.07 (d, 1H, J ) 8 Hz), 6.99 (s, 1H), 6.90 (dd, 1H, J ) 8,
2 Hz), 3.95 (s, 3H), 3.59 (m, 1H), 3.05–2.56 (m, 10H), 2.22 (br,
1H), 182–1.76 (m, 3H), 1.45 (s, 3H), 1.09 (d, 6H, J ) 6 Hz), 0.94
(d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 161.7, 153.5, 130.7, 119.8,
113.8, 111.8, 72.2, 63.4, 57.7, 56.1, 51.8, 47.1, 40.7, 38.9, 32.4,
28.6, 27.8, 23.4, 17.2.
) 6.9 Hz), 0.84 (d, 6H, J ) 6.9 Hz), 0.74 (d, 3H, J ) 7.2 Hz); 13
C
NMR (CD3OD) δ 171.5, 164.1, 159.2, 158.5, 150.9, 131.6, 131.0,
130.0, 122.2, 117.8, 117.3, 114.5, 114.1, 62.3, 57.8, 55.3, 53.5,
52.5, 50.4, 45.8, 38.9, 30.2, 29.1, 27.4, 26.4, 16.2, 16.0, 11.7. The
HCl salt prepared using ethereal HCl had mp 225–229 °C; [R]D
+108° (c 0.61, MeOH). Anal. (C29H43Cl2N3O3 ·1.5H2O), C, H, N.
2-[(3R,4R)-4-(3-Methoxyphenyl)-3,4-dimethylpiperidin-1-yl]-
2-oxoethanamine (15b). (3R,4R)-3,4-Dimethyl-4-(3-methoxyphe-
nyl)piperidine (14, 1 g, 3.9 mmol) and N-Boc-glycine (683 mg,
3.9 mmol) were coupled and deprotected (method A) according to
the general procedures to yield 1.07 g (99%) of the title compound.
The material was used in the next step without purification. 1H
NMR (CD3OD) δ 7.25 (t, 1H, J ) 8 Hz), 6.92–6.77 (m, 3H), 4.28
(m, 1H), 4.12 (d, 1H, J ) 16 Hz), 3.98 (d, 1H, J ) 16 Hz), 3.80
(s, 3H), 3.72 (m, 1H), 3.46 (m, 1H), 3.10 (m, 1H), 2.23–2.19 (m,
2H), 1.72 (d, 1H, J ) 14 Hz), 1.44 (s, 3H), 0.63 (d, 3H, J ) 7 Hz).
N-{2-[(3R,4R)-4-(3-Methoxyphenyl)-3,4-dimethylpiperidin-1-
yl]ethyl}-2-methylpropan-1-amine (16a). Compound 15b (200
mg, 0.64 mmol), N,N-diisopropylethylamine (412 mg, 0.56 mL,
3.2 mmol), and isobutyric acid chloride (82 mg, 0.08 mL, 0.77
mmol) were stirred in 20 mL of CH2Cl2 at room temperature for
3 h. The reaction mixture was washed with saturated NaHCO3 and
brine. The organic layer was dried (Na2SO4) and concentrated to
give the intermediate as a viscous oil. Borane (1 M solution in
THF, 3.2 mL, 3.2 mmol) was added in THF (20 mL) under nitrogen,
with the reaction flask immersed in a water bath. After the addition,
the reaction mixture was stirred at reflux for 1.5 h and cooled to
room temperature, followed by the careful addition of 6 N HCl (1
mL). The reaction mixture was concentrated to remove THF, made
basic with saturated NaHCO3 and solid Na2CO3, and extracted with
CH2Cl2 (50 mL). The organic layer was dried (Na2SO4) and
concentrated to give the impure product, which was purified by
flash column chromatography on silica gel using 10% CMA-80 in
CH2Cl2 as the eluent to give 200 mg (98%) of 16a as a sticky
liquid. 1H NMR (CD3OD) δ 7.10 (t, 1H, J ) 8 Hz), 6.78–6.64 (m,
2H), 6.60 (dd, 1H, J ) 8, 2 Hz), 3.67 (s, 3H), 2.71 (m, 1H), 2.58
(3R)-7-Hydroxy-N-{2-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]ethyl}-N-(1-methylethyl)-1,2,3,4-tetrahy-
droisoquinoline-3-carboxamide (5) Trihydrochloride. Compound
5 was prepared from 16b (50 mg, 0.15 mmol) using a procedure
similar to that described for 4 to give 31 mg (42%) of 5. 1H NMR
(CD3OD) δ 7.11 (td, 1H, J ) 8, 5 Hz), 6.95 (t, 1H, J ) 8 Hz),
6.8–6.73 (m, 2H), 6.67–6.6 (m, 2H), 6.51 (d, 1H, J ) 1.5 Hz),
4.00 (m, 2H), 3.90 (t, 1H, J ) 8 Hz), 3.74 (t, 1H, J ) 7 Hz), 3.53
(t, 1H, J ) 7 Hz), 3.50–3.36 (m, 2H), 2.95 (m, 1H), 2.83 (d, 2H,
J ) 8 Hz), 2.73 (d, 1H, J ) 3 Hz), 2.65–2.62 (m, 3H), 2.5–2.48
(m, 1H), 2.47–2.4 (m, 1H), 1.91 (m, 1H), 1.62–1.5 (m, 4H), 1.33
(s, 3H), 0.96 (d, 6H, J ) 7 Hz), 0.78 (d, 3H, J ) 7 Hz); 13C NMR
(CD3OD) δ 153.1, 136.8, 131.4, 130.5, 118.4, 115.5, 115.4, 114.3,
113.8, 113.7, 113.4, 64.5, 60.5, 59.5, 58.0, 56.6, 53.7, 46.0, 45.1,
40.6, 39.7, 37.9, 32.3, 28.5, 27.7, 23.3, 23.2, 17.1; MS (ESI) m/z
494 (M + 1). The HCl salt had mp 213–215 °C; [R]D +128.3° (c
0.24, MeOH). Anal. (C30H46Cl3N3O3 ·0.5H2O) C, H, N.
2-tert-Butyl 3-Methyl (3R)-7-Methoxy-3,4-dihydroisoquino-
line-2,3(1H)-dicarboxylate (17). 7-Hydroxy-Boc-D-Tic (12, 500
mg, 1.7 mmol), dimethylsulfate (5 mL), and K2CO3 (5 g) were
stirred in acetone (20 mL) under reflux for 5 h. The filtrate obtained
after filtration was concentrated, and the residue was washed with
water. This material was purified by flash column chromatography
on silica gel, eluting with 50 mL of CH2Cl2/EtOAc (3:1) to afford
1
414 mg (76%) of 17 as a syrup. H NMR (CDCl3) δ 7.03 (d, 1H,
J ) 7.5 Hz), 6.72–6.63 (m, 2H), 5.12 (m, 0.5H), 4.77–4.70 (m,
2H), 4.65 (d, 0.5H, J ) 5 Hz), 4.47 (t, 1H, J ) 17 Hz), 4.09 (s,
0.5H), 3.75 (s, 3H), 3.63 (s, 1.5H), 3.59 (s, 1.5H), 3.21–3.03 (m,
2H), 2.14 (s, 0.5H), 1.53 (s, 4.5H), 1.45 (s, 4.5H); MS (ESI) m/z
322 (M + 1).
tert-Butyl (3R)-3-{[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-
dimethylpiperidin-1-yl]methyl}-2-methylpropyl]carbamoyl}-7-
methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (18). Com-
pound 17 (100 mg, 0.3 mmol) was dissolved in 20 mL of MeOH.

1856 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Cai et al.
LiOH (20 mg, 0.45 mmol) was added, and the reaction mixture
was stirred overnight. The reaction mixture was neutralized with 6
N HCl and concentrated to dryness. The impure carboxylic acid
was coupled to 12 according to the general procedure to give 65
mg (80%) of 18 as a syrup. 1H NMR (CD3OD) of selected
resonances δ 7.11 (t, 1H, J ) 8 Hz), 7.06 (d, 1H, J ) 8 Hz),
6.7–6.73 (m, 4H), 6.61 (d, 1H, J ) 8 Hz), 3.91 (s, 3H), 1.50 (br,
9H), 1.24 (m, 3H), 0.61 (d, 6H, J ) 7 Hz), 0.67 (d, 3H, J ) 7 Hz);
MS (ESI) m/z 580 (M + 1). This product was used directly in the
next step without further purification.
(3R)-N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimeth-
ylpiperidin-1-yl]methyl}-2-methylpropyl]-7-methoxy-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (6a) Dihydrochloride. Com-
pound 18 (60 mg, 0.1 mmol) was deprotected according to the
general procedure to give 49 mg (100%) of 6a (method B). 1H
NMR (CD3OD) δ 7.10 (t, 1H, J ) 8 Hz), 6.99 (d, 1H, J ) 8 Hz),
6.76–6.74 (m, 2H), 6.70 (dd, 1H, J ) 8, 3 Hz), 6.61–6.59 (m, 2H),
4.04–3.89 (m, 3H), 3.72 (s, 3H), 3.55 (q, 1H, J ) 5 Hz), 2.96 (dd,
1H, J ) 16, 5 Hz), 2.85–2.77 (m, 2H), 2.64 (d, 2H, J ) 9 Hz),
2.54–2.35 (m, 4H), 2.25 (td, 1H, J ) 13, 4 Hz), 2.00–1.82 (m,
2H), 1.28 (s, 3H), 0.96 (d, 3H, J ) 7 Hz), 0.89 (d, 3H, J ) 7 Hz),
0.71 (d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 174.1, 158.5, 157.3,
152.2, 136.5, 129.9, 129.1, 125.9, 117.0, 112.8, 112.8, 112.3, 110.7,
60.3, 57.0, 55.9, 54.7, 51.4, 50.9, 39.2, 38.5, 31.2, 31.1, 27.2, 19.0,
16.9, 15.8; MS (ESI) m/z 480 (M + 1). The HCl salt prepared
using 1 N HCl in ether had mp 201–203 °C; [R]D +111.9° (c 0.27,
MeOH). Anal. (C29H43Cl2N3O3 ·H2O) C, H, N.
tert-Butyl (3R)-3-{[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-
dimethylpiperidin-1-yl] methyl}-2-methylpropyl]carbamoyl}-7-
nitro-3,4-dihydroisoquinoline-2(1H)carboxylate (24). Boc-D-7-
nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (19, 150 mg,
0.465 mmol) was coupled to 8 (115 mg, 0.396 mmol) according to
the general procedure. The product obtained was purified by flash
column chromatography on silica gel using 10–15% CMA-80 in
CH2Cl2 as the eluent to give 181 mg (77%) of 24 as a white foam.
1H NMR (CD3OD) δ 8.10–8.02 (m, 2H), 7.39 (d, 1H, J ) 8.3
Hz), 7.08 (t, 1H, J ) 8.2 Hz), 6.71–6.68 (m, 2H), 6.57 (dd, 1H, J
) 7.1, 1.3 Hz), 4.74–4.66 (m, 2H), 3.85–3.79 (m, 1H), 2.45–2.39
(m, 2H), 2.38–2.30 (m, 3H), 2.16–2.12 (m, 1H), 1.88–1.85 (m, 1H),
1.75–1.71 (m, 1H), 1.49 (s, 9H), 1.22 (s, 3H), 0.80 (d, 3H, J ) 6.1
Hz), 0.79 (d, 3H, J ) 6.4 Hz), 0.58 (d, 3H, J ) 6.9 Hz); 13C NMR
(CD3OD) δ 172.9, 158.3, 153.2, 152.0, 148.3, 142.2, 137.5, 130.5,
130.0, 123.0, 122.4, 117.9, 113.8, 113.3, 82.5, 61.6, 56.9, 53.0,
51.6, 51.0, 40.2, 39.4, 37.1, 37.0, 32.2, 32.0, 28.7, 28.0, 20.1, 18.0,
16.7; MS (ESI) m/z 595.8 (M + H)+.
under H2 (balloon overnight). The catalyst was removed by
filtration, and the filtrate was concentrated to afford 33 mg (82%)
of 6c as a white foam. H NMR (CD3OD) δ 7.09 (t, 1H, J ) 7.9
1
Hz), 6.84 (d, 1H, J ) 8.1 Hz), 6.7–6.71 (m, 2H), 6.59–6.52 (m,
2H), 6.44 (d, 1H, J ) 2.1 Hz), 4.73 (s, 3H), 4.05–3.96 (m, 1H),
3.90 (d, 2H, J ) 6.9 Hz), 3.53 (dd, 1H, J ) 10.1, 4.9 Hz), 2.90
(dd, 1H, J ) 15.7, 4.8 Hz), 2.83–2.75 (m, 2H), 2.66–2.62 (m, 1H),
2.57–2.48 (m, 1H), 2.45–2.37 (m, 3H), 2.21 (td, 1H, J ) 12.6, 4.1
Hz), 1.98–1.93 (m, 1H), 1.92–1.84 (m, 1H), 1.56 (d, 1H, J ) 12.2
Hz), 1.28 (s, 3H), 0.94 (d, 3H, J ) 6.9 Hz), 0.91 (d, 3H, J ) 6.9
Hz), 0.71 (s, 3H); 13C NMR (CD3OD) δ 175.3, 158.3, 153.2, 146.8,
136.8, 130.5, 130.1, 124.5, 118.1, 115.7, 113.84, 113.77, 113.3,
74.5, 61.4, 58.3, 56.9, 52.4, 51.9, 48.0, 40.3, 39.5, 32.4, 32.1, 28.1,
20.0, 17.8, 16.7; MS (ESI) m/z 465.9 (M + H)+. The HCl salt
25
prepared using 1.0 N HCl in ether had mp 192–194 °C; [R]D
+121.4° (c 1, CH3OH). Anal. (C28H43Cl3N4O2 ·4.25H2O) C, H, N.
tert-Butyl (3R)-7-(Acetylamino)-3-{[(1S)-1-{[(3R,4R)-4-(3-hy-
droxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpro-
pyl]carbamoyl}-3,4-dihydroisoquinoline-2(1H)carboxylate (25).
Boc-D-7-acetylamino-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid19 (20, 80 mg, 0.24 mmol) was coupled to 8 (65 mg, 0.22 mmol)
according to the general procedure. The product was purified by
flash column chromatography using 10–15% MMA-80 in CH2Cl2
as the eluent to give 88 mg (65%) of 25 as a white foam. 1H NMR
(CD3OD) δ 7.47 (s, 1H), 7.38–7.34 (m, 1H), 7.12–7.06 (m, 2H),
6.74–6.69 (m, 2H), 6.57 (dd, 1H, J ) 7.9, 1.9 Hz), 4.57 (s, 3H),
4.16–4.14 (m, 1H), 3.81 (d, 1H, J ) 5.7 Hz), 3.13 (dd, 2H, J )
13.9, 5.9 Hz), 2.64–2.59 (m, 1H), 2.46 (s, 2H), 2.30–2.28 (m, 3H),
2.13–2.07 (m, 1H), 2.09 (s, 3H), 1.93–1.74 (m, 3H), 1.59–1.48 (m,
2H), 1.48 (s, 9H), 1.21 (s, 3H), 0.80 (d, 6H, J ) 5.8 Hz), 0.62 (d,
3H, J ) 6.9 Hz); 13C NMR (CD3OD) δ 173.5, 171.6, 158.2, 153.2,
138.8, 135.6, 130.0, 129.9, 129.5, 119.8, 119.4, 118.7, 118.1, 113.8,
113.3, 82.3, 61.5, 57.0, 56.1, 52.9, 51.2, 40.2, 39.4, 32.4, 32.3, 31.9,
28.8, 28.1, 23.9, 20.0, 17.9, 16.7; MS (ESI) m/z 608.0 (M + H)+.
(3R)-7-(Acetylamino)-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-
3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (6d) Dihydrochloride. Com-
pound 25 (50 mg, 0.082 mmol) was deprotected according to the
general procedure (method B). The product was purified by flash
column chromatography on silica gel using 10–25% MMA-80 in
CH2Cl2 as the eluent to give 34 mg (81%) of 6d as a white foam.
1H NMR (CD3OD) δ 7.32 (s, 1H), 7.27–7.21 (m, 1H), 7.11–7.00
(m, 2H), 6.76–6.67 (m, 2H), 6.57 (d, 1H, J ) 7.8, 2.0 Hz), 4.32 (s,
1H), 4.04–3.95 (m, 2H), 3.57 (dd, 1H, J ) 9.8, 5.0 Hz), 2.98 (dd,
1H, J ) 15.9, 4.6 Hz), 2.89–2.77 (m, 1H), 2.64–2.35 (m, 5H),
2.28–2.18 (m, 2H), 2.09 (s, 3H), 1.96–1.77 (m, 3H), 1.54 (d, 1H,
J ) 12.8 Hz), 1.27 (s, 3H), 0.94 (d, 3H, J ) 6.9 Hz), 0.91 (d, 3H,
J ) 6.8 Hz), 0.70 (d, 3H, J ) 6.9 Hz); 13C NMR (CD3OD) δ
175.5, 171.9, 158.6. 153.6, 138.4, 137.3, 131.2, 130.6, 130.4, 119.9,
118.9, 118.4, 114.2, 113.6, 89.9, 61.8, 58.2, 57.2, 52.8, 52.3, 48.2,
40.6, 39.8, 32.8, 32.4, 28.4, 24.2, 20.3, 18.2, 17.0; MS (ESI) m/z
507.4 (M + H)+. The HCl salt of 6d prepared using 1.0 N HCl in
ether had mp 190 °C (dec); [R]D25 +110.2° (c 0.5, CH3OH). Anal.
(C30H44Cl2N4O3 ·1.25H2O·2CH3OH) C, H, N.
(3R)-N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimeth-
ylpiperidin-1-yl]methyl}-2-methylpropyl]-7-nitro-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (6b) Dihydrochloride. Com-
pound 24 (120 mg, 0.2 mmol) was deprotected according to the
general procedure (method B). The product was purified by flash
column chromatography on silica gel using 10–25% MMA-80 in
CH2Cl2 as the eluent to give 86 mg (86%) of 6b as a white foam.
1H NMR (CD3OD) δ 7.97 (d, 2H, J ) 5.9 Hz), 7.33 (d, 1H, J )
9.1 Hz), 7.07 (t, 1H, J ) 8.2 Hz), 6.72–6.69 (m, 2H), 6.56 (dd,
1H, J ) 7.3, 1.7 Hz), 4.17 (d, 1H, J ) 16.8 Hz), 4.04 (s, 1H),
4.03–3.96 (m, 1H), 3.68–3.63 (dd, 1H, J ) 8.9, 5.3 Hz), 3.14 (dd,
1H, J ) 17.0, 5.2 Hz), 3.01 (dd, 1H, J ) 17.1, 8.9 Hz), 2.84–2.76
(m, 1H), 2.51–2.34 (m, 5H), 2.25–2.15 (m, 1H), 1.93–1.81 (m, 2H),
1.53 (d, 1H, J ) 13.0 Hz), 1.26 (s, 3H), 0.95 (d, 3H, J ) 6.9 Hz),
0.92 (d, 3H, J ) 6.9 Hz), 0.62 (d, 3H, J ) 6.9 Hz); 13C NMR
(CD3OD) δ 174.9, 158.6, 153.5, 148.1, 143.7, 139.1, 131.6, 130.4,
122.5, 122.3, 118.3, 114.1, 113.6, 61.9, 57.2, 57.1, 52.9, 52.5, 47.6,
40.6, 39.8, 32.8, 32.5, 32.4, 28.4, 20.4, 18.3, 17.0; MS (ESI) m/z
495.6 (M + H)+. The HCl salt prepared using 1.0 N HCl in ether
(3R)-N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimeth-
ylpiperidin-1-yl]methyl}-2-methylpropyl]-7-[(methylsulfonyl)-
amino]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (6e) Di-
hydrochloride. Boc-D-7-[(methylsulfonyl)amino]-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic acid21 (21, 49 mg, 0.13 mmol) was
coupled to 8 (43 mg, 0.148 mmol) according to the general
procedure. The crude product 26 was deprotected according to the
general procedure (method B). The product was purified by flash
column chromatography on silica gel using 10–25% CMA-80 in
CH2Cl2 as the eluent to give 29 mg (40%) of 6e as a white foam.
1H NMR (CD3OD) δ 7.13–6.99 (m, 3H), 6.96 (s, 1H), 6.77–6.69
(m, 2H), 6.57 (dd, 1H, J ) 7.8, 2.1 Hz), 4.06–3.95 (m, 3H), 3.57
(dd, 1H, J ) 9.9, 5.0 Hz), 3.25–3.22 (m, 1H), 3.01 (dd, 1H, J )
16.2, 4.8 Hz), 2.88 (s, 3H), 2.86–2.83 (m, 2H), 2.67–2.63 (m, 1H),
2.55–2.49 (m, 1H), 2.49–2.35 (m, 3H), 2.30–2.20 (m, 1H),
2.01–1.94 (m, 1H), 1.91–1.82 (m, 1H), 1.56 (d, 1H, J ) 13.2 Hz),
1.28 (s, 3H), 0.95 (d, 3H, J ) 6.9 Hz), 0.91 (d, 3H, J ) 6.9 Hz),
25
had mp 190–191 °C; [R]D +126.3° (c 1, CH3OH). Anal.
(C28H40Cl2N4O4 ·1.5H2O) C, H, N.
(3R)-7-Amino-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-
dimethylpiperidin-1-yl] methyl}-2-methylpropyl]-1,2,3,4-tet-
rahydroisoquinoline-3-carboxamide (6c) Trihydrochloride. Com-
pound 6b (43 mg, 0.087 mmol) was dissolved in MeOH (8 mL),
and 10% Pd/C (8 mg) was added under N2. The mixture was stirred

Kappa Opioid Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1857
0.70 (d, 3H, J ) 7.0 Hz); 13C NMR (CD3OD) δ 175.1, 158.3, 153.3,
137.8, 137.6, 131.7, 131.0, 130.1, 120.4, 119.3, 118.1, 113.8, 113.3,
74.5, 61.4, 57.8, 56.9, 52.4, 52.0, 47.8, 40.2, 39.0, 32.3, 32.1, 32.0,
28.1, 20.0, 17.9, 16.7; MS (ESI) m/z 543.9 (M + H)+. The HCl
1H, J ) 8 Hz), 7.79 (s, 1H), 7.10–7.06 (m, 1H), 6.92 (d, 1H, J )
2 Hz), 6.8–6.7 (m, 3H), 6.60–6.55 (m, 1H), 4.23 (m, 1H), 3.79 (s,
3H), 2.8–2.3 (m, 5H), 2.01–1.93 (m, 3H), 1.53 (d, 1H, J ) 12 Hz),
1.26 (s, 3H), 0.99 (d, 3H, J ) 7 Hz), 0.94 (d, 3H, J ) 7 Hz), 0.61
(d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 167.4, 157.2, 157.0, 152.2,
137.8, 129.0, 126.7, 121.2, 120.3, 116.9, 112.7, 112.3, 112.2, 111.1,
94.8, 59.5, 55.2, 55.0, 53.4, 51.2, 39.0, 31.7, 27.1, 19.0, 18.9, 15.7;
MS (ESI) m/z 464 (M + 1).
6-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]methyl}-2-methylpropyl]-1H-indole-3-car-
boxamide (7c) Hydrochloride. Compound 30 (115 mg, 0.25 mmol)
was O-demethylated according to the general procedure to afford
100 mg (89%) of compound 7c. 1H NMR (CD3OD) δ 7.85 (d, 1H,
J ) 8 Hz), 7.73 (s, 1H), 7.06 (t, 1H, J ) 7.8 Hz), 6.80 (d, 1H, J
) 2 Hz), 6.73–6.7 (m, 3H), 6.55 (dd, 1H, J ) 8, 1.5 Hz), 4.22 (m,
1H), 3.72 (m, 1H), 2.91–2.77 (m, 2H), 2.69–2.57 (m, 2H), 2.27
(td, 1H, J ) 12, 2 Hz), 2.0–1.9 (m, 2H), 1.87 (m, 1H), 1.57 (d,
1H, J ) 12 Hz), 1.28 (s, 3H), 1.01 (d, 3H, J ) 7 Hz), 0.99 (d, 3H,
J ) 7 Hz), 0.62 (d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 167.6,
157.2, 153.8, 151.0, 138.2, 129.0, 126.6, 121.2, 119.7, 116.9, 112.7,
112.2, 112.2, 111.1, 97.0, 59.6, 55.1, 51.2, 51.1, 38.9, 38.4, 31.7,
30.7, 27.0, 18.8, 17.6, 15.4; MS (ESI) 450 (M + 1). The HCl salt
prepared using 1 N HCl in ether had mp 213–215 °C; [R]D +42°
(c 0.4, CH3OH). Anal. (C27H36ClN3O3 ·H2O) C, H, N.
5-Methoxy-1H-benzoimidazole-2-carboxylic Acid (32). 4-Meth-
oxy-1,2-phenylendiamine (31; 1 g, 7.25 mmol), methyl 2,2-dichloro-
2-methoxyacetate (5 g, 29.1 mmol), and DIPEA (7.74 g, 10.4 mL,
60 mmol) were stirred in CH2Cl2 (30 mL) at room temperature
overnight. The reaction mixture was dissolved in CH2Cl2 and
washed with saturated NaHCO3 solution. The residue obtained on
concentration was purified by flash column chromatography on
silica gel using hexane/ethyl acetate (1:1) as the eluent to give 1.1 g
(73%) of methoxy-1H-benzimidazole-2-carboxylic acid methyl ester
as a white solid. This compound (300 mg, 1.5 mmol) and LiOH
(61 mg, 1.5 mmol) were dissolved in 8 mL of THF and 2 mL of
water. The mixture was stirred in a microwave reactor for 4 h at
160 °C. The reaction mixture was concentrated to afford 300 mg
(100%) of 32. 1H NMR (DMSO) δ 12.3 (s, 1H), 7.45 (d, 1H, J )
9 Hz), 6.84 (dd, 1H, J ) 9, 3 Hz), 6.75 (d, 1H, J ) 3 Hz), 3.95 (s,
3H), 3.79 (s, 3H); 13C NMR (DMSO) δ 158.4, 153.6, 150.9, 131.8,
127.5, 124.7, 111.4, 98.8, 55.8, 54.2; MS (ESI) 207 (M + 1).
25
salt prepared using 1.0 N HCl in ether had mp 182 °C (dec); [R]D
+93.6° (c 0.5, CH3OH). Anal. (C29H44Cl2N4O4Cl2 · CH3OH)
C, H, N.
N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethylpiperi-
din-1-yl]methyl}-2-methylpropyl]-6-methoxy-1H-indole-2-car-
boxamide (7a) Hydrochloride. Commercially available methyl-
6-methoxy-2-indolecarboxylate (27, 205 mg, 1 mmol) and NaOH
(200 mg, 5 mmol) were stirred in a mixture of MeOH (10 mL)
and water (1 mL) overnight at room temperature. The reaction
solution was neutralized with concentrated HCl and concentrated
to dryness. The 6-methoxy-2-indolecarboxylic acid obtained was
coupled to 8 according to the general procedure. The product was
purified by column chromatography on silica gel using 30% CMA-
80 in CH2Cl2 as the eluent to give 405 mg (87%) of 7a as a white
1
foam. H NMR (CD3COCD3) δ 7.45 (d, 1H, J ) 8 Hz), 7.14 (s,
1H), 7.06 (t, 1H, J ) 8 Hz), 7.02 (d, 1H, J ) 2 Hz), 6.7–6.68 (m,
3H), 6.62 (dd, 1H, J ) 8, 2 Hz), 4.31 (m, 1H), 3.79 (s, 3H), 3.67
(br, 1H), 2.98–2.84 (m, 2H), 2.73–2.60 (m, 4H), 2.31–2.22 (m, 1H),
2.02–1.91 (m, 2H), 1.58 (d, 1H, J ) 13 Hz), 1.26 (s, 3H), 1.00 (d,
3H, J ) 7 Hz), 0.98 (d, 3H, J ) 7 Hz), 0.63 (d, 3H, J ) 7 Hz);
13C NMR (CD3COCD3) δ 162.7, 158.3, 157.6, 138.3, 138.2, 129.4,
122.7, 122.4, 122.4, 116.9, 112.9, 112.7, 111.8, 103.2, 94.5, 60.3,
55.3, 55.1, 51.8, 51.7, 51.2, 38.9, 38.4, 31.4, 27.2, 19.3, 18.1, 15.7;
MS (ESI) m/z 465 (M + 1). The HCl salt prepared using 1 N HCl
in ether had mp 183–185 °C; [R]D +74.3° (c 1, CH3OH). Anal.
(C28H38ClN3O3 ·1.5H2O) C, H, N.
6-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]methyl}-2-methylpropyl]-1H-indole-2-car-
boxamide (7b) Hydrochloride. Compound 7a (300 mg, 0.65
mmol) was O-demethylated according to the general procedure.
The product was purified by flash column chromatography on silica
gel using 30% CMA-80 in CH2Cl2 as the eluent to give 260 mg
(90%) of 7b. 1H NMR (CD3OD) δ 7.41 (d, 1H, J ) 8.7 Hz), 7.07
(t, 1H, J ) 8 Hz), 7.04 (d, 1H, J ) 0.6 Hz), 6.81 (d, 1H, J ) 2
Hz), 6.75–6.71 (m, 2H), 6.66 (dd, 1H, J ) 8.7, 2.4 Hz), 6.55 (dd,
1H, J ) 7.5, 1.8 Hz), 4.06 (m, 1H), 2.84 (m, 1H), 2.73–2.46 (m,
5H), 2.27 (td, 1H, J ) 12, 4 Hz), 1.99–1.88 (m, 2H), 1.58 (d, 1H,
J ) 12 Hz), 1.28 (s, 3H), 1.01 (d, 3H, J ) 7 Hz), 1.00 (d, 3H, J
) 7 Hz), 0.65 (d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 164.6,
158.6, 156.7, 153.6, 140.0, 131.5, 130.4, 123.8, 123.3, 118.4, 114.1,
113.6, 112.7, 105.5, 97.8, 61.1, 56.6, 53.0, 52.4, 47.6, 40.5, 33.2,
28.4, 20.3, 18.9, 16.8, 11.1; MS (ESI) m/z 451 (M + 1). The HCl
salt prepared using 1 N HCl in ether had mp 208–210 °C; [R]D
+89.3° (c 0.38, CH3OH). Anal. (C27H36ClN3O3 ·H2O) C, H, N.
6-Methoxy-1H-indole-3-carboxylic Acid (29). To a solution of
6-methoxyindole (206 mg, 1.4 mmol) in THF (5 mL) was added
pyridine (148 µL, 1.8 mmol), and the solution was cooled to 2 °C.
Trichloroacetyl chloride (201 µL, 1.8 mmol) was added dropwise
over 1 h. The mixture was warmed to room temperature over 16 h
and concentrated under reduced pressure. The residue was parti-
tioned between EtOAc and HCl (1 N). The organic layer was
separated, dried (Na2SO4), and concentrated to give 6-methoxy-3-
trichloroacetylindole as an off-white solid.27 1H NMR (CDCl3) δ
8.85 (br, 1H), 8.28 (d, 1H, J ) 12 Hz), 8.27 (s, 1H), 7.01 (dd, 1H,
J ) 12, 2 Hz), 6.93 (d, 1H, J ) 2 Hz), 3.87 (s, 3H); 13C NMR
(CDCl3) δ 158.3, 136.8, 133.5, 123.7, 113.4, 107.7, 95.6, 76.7, 56.1;
MS (ESI) 292 (M + 1). The residue was dissolved in CH3OH (10
mL), and to this was added KOH (280 mg, 5 mmol) and water (1
mL). The reaction mixture was heated under reflux for 12 h. The
solution was neutralized with 12 N HCl and concentrated to dryness.
The 6-methoxy-3-carboxylindole was used in the next step without
further purification.
N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethylpiperi-
din-1-yl]methyl}-2-methylpropyl]-6-methoxy-1H-benzimidazole-
2-carboxamide (7d) Dihydrochloride. Compound 32 (288 mg,
1.5 mmol) was coupled to 8 (406 mg, 1.4 mmol) by the general
procedure to give 325 mg (50%) of 7d. 1H NMR (CD3OD) δ 7.54
(d, 1H, J ) 9 Hz), 7.07 (m, 2H), 6.97 (dd, 1H, J ) 9, 2 Hz), 6.71
(m, 2H), 6.56 (d, 1H, J ) 8 Hz), 4.22 (m, 1H), 3.85 (s, 3H),
2.8–2.63 (m, 6H), 2.30 (m, 1H), 2.00 (m, 2H), 1.58 (d, 1H, J )
13.5 Hz), 1.31 (s, 3H), 1.04 (m, 6H), 0.63 (d, 3H, J ) 7 Hz); 13
C
NMR (CD3OD) δ 159.6, 158.2, 157.1, 128.9, 116.8, 114.7, 112.6,
112.2, 59.7, 55.0, 54.9, 51.8, 51.1, 38.2, 35.9, 35.8, 31.2, 26.8, 18.7,
17.1, 15.1; MS (ESI) 465 (M + 1). The HCl salt prepared using 1
N HCl in ether had mp 185–188 °C; [R]D +71° (c 1, CH3OH).
Anal. (C27H38Cl2N4O3 ·1.25H2O) C, H, N.
6-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]methyl}-2-methylpropyl]-1H-benzimida-
zole-2-carboxamide (7e) Dihydrochloride. Compound 7e (14 mg)
was prepared in 64% yield from 7d (15 mg, 0.032 mmol) by the
general O-demethylation procedure. 1H NMR (CD3OD) δ 7.54 (d,
1H, J ) 9 Hz), 6.95 (t, 1H, J ) 7.8 Hz), 6.84 (d, 1H, J ) 2 Hz),
6.76 (dd, 1H, J ) 9, 2.4 Hz), 6.58 (m, 2H), 6.43 (dd, 1H, J ) 8,
1.8 Hz), 4.07 (m, 1H), 2.72 (d, 1H, J ) 11 Hz), 2.61–2.34 (m,
5H), 2.12 (m, 1H), 1.87 (m, 2H), 1.41 (d, 1H, J ) 13 Hz), 1.17 (s,
3H), 0.92 (d, 3H, J ) 7 Hz), 0.90 (d, J ) 7 Hz), 0.49 (d, 3H, J )
7 Hz); 13C NMR (CD3OD) δ 164.3, 161.9, 160.2, 157.0, 149.6,
133.7, 121.6, 119.2, 117.4, 116.9, 64.5, 59.9, 56.7, 55.8, 43.9, 43.1,
36.0, 35.4, 31.6, 23.6, 21.8, 20.0; MS (ESI) m/z 451 (M + 1). The
HCl salt had mp 211–213 °C; [R]D +112° (c 0.85, CH3OH). Anal.
(C26H36Cl2N4O3 ·1.5H2O) C, H, N.
6-Methoxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]methyl}-2-methylpropyl]-1H-indole-3-car-
boxamide (30). Compound 29 (267 mg, 1.4 mmol) was coupled
to 8 (406 mg, 1.4 mmol) according to the general procedure to
give 520 mg (80%) of 30 as a solid. 1H NMR (CD3OD) δ 7.94 (d,

1858 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Cai et al.
3-Cyano-7-methoxy-quinoline (34). To a suspension of NaH
(50% dispension in oil, 3.0 g, 0.063 mol) in dry ether (75 mL) was
added 3,3-dimethyloxypropionitrile (33, 6.25 mL, 0.055 mol) and
methyl formate (6.85 mL, 0.110 mol). The mixture was stirred at
room temperature for 2 days under argon. The resulting precipitate
was separated by filtration, washed with ether, and dried under
vacuum to yield 7.75 g (86%) of 3,3-dimethyloxy-2-formylpropi-
onitrilie sodium salt as a white solid.28 This compound (520 mg,
3.13 mmol) was added to a solution of m-anisidine (308 mg, 2.5
mmol) in methanol (10 mL) followed by 12 N HCl (0.63 mL, 7.5
mmol). The resulting mixture was heated at reflux for 2 h. After
cooling, the mixture was filtered, and the precipitate was washed
with cooled methanol and dried under vacuum for 3 h to afford a
yellow solid. This solid was dissolved in toluene (40 mL),
p-toluenesulfonic acid (1 g, 5 mmol) was added, and the mixture
was heated at reflux for 16 h. After adding 10% Na2CO3 solution
(40 mL), the organic layer was separated and the aqueous solution
was extracted with CH2Cl2. The combined organic layers were dried
(Na2SO4) and purified by flash column chromatography on silica
gel using 65% CH2Cl2 in hexane as the eluent to give 290 mg (65%)
the literature procedure,29 1-chloroethyl chloroformate (243 mg,
1.7 mmol) and NaHCO3 (142 mg, 1.7 mmol) were refluxed in
ClCH2CH2Cl (5 mL) overnight. The reaction mixture was cooled
and filtered. The filtrate was dried (Na2SO4), KOH (100 mg) in
CH3OH (5 mL) was added, and the reaction mixture was refluxed
overnight. After concentration, the residue was extracted with
CH2Cl2. The organic layer was washed (2 N NaOH), dried
(Na2SO4), and concentrated. The impure product was purified by
column chromatography on silica gel using 10% CMA-80 in CH2Cl2
as the eluent to give 39 mg (71%) of 7-methoxy-1,2,3,4-tetrahy-
droisoquinoline. 1H NMR (CD3OD) δ 7.07 (d, 1H, 8 Hz), 6.82 (d,
1H, J ) 8 Hz), 6.60 (s, 1H), 4.26 (s, 2H), 3.78 (s, 3H), 3.41 (t, 2H,
J ) 6 Hz), 3.01 (t, 2H, J ) 6 Hz). 7-Methoxy-1,2,3,4-tetrahy-
droisoquinoline (515 mg, 3.16 mmol) was dissolved in CH2Cl2,
triethylamine (0.73 mL) was added, followed by ethyl bromoacetate
(528 mg, 3.16 mmol). The reaction mixture was stirred for 30 min
at room temperature, poured into CH2Cl2, and washed with saturated
NaHCO3 solution. The organic layer was concentrated and purified
by column chromatography on silica gel using hexane/EtOAc/Et3N
1
(5:4:1) as the eluent to give 787 mg (92%) of 37 as a liquid. H
1
of 34 as a slightly yellow solid. H NMR (CDCl3) δ 8.97 (d, 1H,
NMR (CD3OD) δ 7.02 (d, 1H, J ) 7 Hz), 6.73 (dd, 1H, J ) 7, 2
Hz), 6.60 (d, 1H, J ) 2 Hz), 4.21 (q, 2H, J ) 7 Hz), 3.75 (s, 3H),
3.74 (s, 2H), 3.46 (s, 2H), 2.81 (s, 4H), 1.25 (t, 3H, J ) 7 Hz).
J ) 2.1 Hz), 8.42 (d, 1H, J ) 2.1 Hz), 7.73 (d, 1H, J ) 9.3 Hz),
7.46 (d, 1H, J ) 2.4 Hz), 7.32 (dd, 1H, J ) 9.3, 2.4 Hz), 3.98 (s,
3H); 13C NMR (CDCl3) δ 150.8, 141.0, 129.7, 122.4, 108.1, 101.6,
56.2; MS (ESI) 185 (M + 1).
N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethylpiperi-
din-1-yl]methyl}-2-methylpropyl]-2-(7-methoxy-3,4-dihydroiso-
quinolin-2(1H)-yl)acetamide (7h) Dihydrochloride. A portion of
37 (255 mg, 1.02 mmol) was dissolved in MeOH (20 mL) and
40% NaOH (0.3 mL) and heated for 2 h. The solution was
neutralized with concentrated HCl and concentrated to afford the
acid. This material was coupled with 8 according to the general
procedure to afford 7h in 50% yield. 1H NMR (CD3OD) δ 7.13 (t,
1H, J ) 8 Hz), 7.99 (d, 1H, J ) 8 Hz), 6.75–6.71 (m, 3H), 6.57
(dd, 1H, J ) 8, 3 Hz), 6.50 (d, 1H, J ) 3 Hz), 4.00 (p, 1H, J ) 5
Hz), 3.72 (s, 3H), 3.68 (q, 2H, J ) 15 Hz), 3.16 (q, 1H, J ) 17
Hz), 2.95–2.68 (m, 6H), 2.51–2.42 (m, 3H), 2.31 (m, 2H), 1.96
(m, 1H), 1.84 (m, 1H), 1.56 (d, 1H, J ) 13 Hz), 1.28 (s, 3H), 0.95
(d, 3H, J ) 7 Hz), 0.89 (d, 3H, J ) 7 Hz), 0.69 (d, 3H, J ) 7 Hz);
13C NMR (CD3OD) δ 171.5, 158.3, 157.3, 152.3, 135.5, 129.7,
129.1, 125.9, 116.9, 113.0, 112.8, 112.3, 111.0, 61.1, 60.3, 56.1,
55.2, 54.7, 51.6, 51.3, 39.1, 38.5, 31.0, 28.3, 27.1, 19.0, 17.3, 15.9;
MS (ESI) 494 (M + 1). The HCl salt prepared using 1 N HCl in
ether had mp 183–185 °C; [R]D +48° (c 1.2, CH3OH). Anal.
(C30H45Cl2N3O3 ·H2O) C, H, N.
2-(7-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[(1S)-1-
{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-
methyl}-2-methylpropyl]acetamide (7i) Dihydrochloride. Com-
pound 7i was prepared from 7h (140 mg, 0.284 mmol) using the
general O-demethylation procedure to give 106 mg (78%). 1H NMR
(CD3OD) δ 6.99 (t, 1H, J ) 8 Hz), 6.85 (d, 1H, J ) 8 Hz),
6.65–6.63 (m, 2H), 6.49 (td, 1H, J ) 8, 3 Hz), 6.35 (d, 1H, J ) 3
Hz), 3.88 (p, 1H, J ) 5 Hz), 3.52 (d, 2H, J ) 5 Hz), 3.01 (dd, 2H,
J ) 26, 16 Hz), 2.71–2.55 (m, 6H), 2.37–2.30 (m, 3H), 2.25–2.19
(m, 2H), 1.74 (m, 1H), 1.72 (m, 1H), 1.44 (d, 1H, J ) 13 Hz),
1.17 (s, 3H), 0.83 (d, 3H, J ) 7 Hz), 0.78 (d, 3H, J ) 7 Hz), 0.60
(d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 171.6, 157.2, 155.4, 152.3,
135.4, 129.7, 129.1, 124.6, 117.0, 114.1, 112.8, 112.6, 112.3, 78.5,
61.2, 60.3, 56.1, 55.3, 51.7, 51.6, 51.3, 39.1, 38.5, 31.0, 28.4, 27.1,
19.1, 17.2, 15.9; MS (ESI) 480 (M + 1). The HCl salt had mp
195–197 °C; [R]D +106° (c 0.55, CH3OH). Anal. (C29H43
Cl2N3O3 ·H2O) C, H, N.
7-Methoxyquinoline-3-carboxylic Acid (35). Compound 34
(145 mg, 0.79 mmol) and NaOH (90 mg, 2.24 mmol) in ethanol
(0.68 mL) were heated under reflux for 1 h. The solution was
acidified with 1 N HCl. Concentration afforded 130 mg (100%) of
1
35 as a white precipitate. H NMR (CD3OD) δ 9.20 (d, 1H, J )
2.1 Hz), 8.64 (d, 1H, J ) 2.1 Hz), 7.79 (d, 1H, J ) 9.3 Hz), 7.29
(d, 1H, J ) 2.4 Hz), 7.15 (dd, 1H, J ) 9.3, 2.4 Hz), 3.94 (s, 3H);
13C NMR (CDCl3) δ 173.3, 163.9, 152.9, 151.5, 139.2, 131.7,
130.3, 124.5, 121.6, 107.3, 56.5; MS (ESI) 204 (M + 1).
N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethylpiperi-
din-1-yl]methyl}-2-methylpropyl]-7-methoxyquinoline-3-car-
boxamide (7f) Dihydrochloride. Compound 35 (130 mg, 0.64
mmol) was coupled with 8 (186 mg, 0.64 mmol) according to the
1
general procedure to give 294 mg (97%) of 7f. H NMR (CDCl3)
δ 9.18 (d, 1H, J ) 2.1 Hz), 8.53 (s, 1H), 7.70 (d, 1H, J ) 9 Hz),
7.40 (d, 1H, J ) 2.1 Hz), 7.20 (dd, 1H, J ) 9, 2.1 Hz), 7.07 (t, 1H,
J ) 9 Hz), 6.73–6.78 (m, 3H), 6.63 (dd, 1H, J ) 7.8, 1.5 Hz), 4.21
(m, 1H), 3.91 (s, 3H), 2.82–2.79 (m, 1H), 2.65–2.62 (m, 2H),
2.55–2.43 (m, 4H), 2.24–2.11 (m, 2H), 1.96–1.84 (m, 1H), 1.53
(d, 1H, J ) 13 Hz), 1.24 (s, 3H), 1.00 (d, 6H, J ) 7 Hz), 0.49 (d,
3H, J ) 7 Hz); 13C NMR (CDCl3) δ 166.5, 162.6, 156.6, 152.2,
151.3, 148.7, 135.8, 130.2, 129.5, 125.8, 122.6, 121.3, 117.8, 113.3,
113.0, 107.4, 58.2, 56.0, 54.9, 52.0, 38.9, 38.7, 31.2, 30.9, 27.7,
18.9, 18.8, 16.5; MS (ESI) 476 (M + 1). The HCl salt prepared
using 1 N HCl in ether had mp 181–183 °C; [R]D +136.9° (c 0.8,
CH3OH). Anal. (C29H39Cl2N3O3 ·H2O) C, H, N.
7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-di-
methylpiperidin-1-yl]methyl}-2-methylpropyl]quinoline-3-car-
boxamide (7g) Dihydrochloride. Compound 7g (67 mg) was
prepared from 7f (107 mg, 0.23 mmol) by the general O-
demethylation procedure in 64% yield. 1H NMR (CD3OD) δ 9.08
(d, 1H, J ) 2.1 Hz), 8.64 (d, 1H, J ) 1.5 Hz), 7.88 (d, 1H, J ) 9
Hz), 7.31 (d, 1H, J ) 2.1 Hz), 7.24 (dd, 1H, J ) 9, 2.1 Hz), 7.06
(t, 1H, J ) 9 Hz), 6.70–6.63 (m, 2H), 6.54 (dd, 1H, J ) 7.8, 1.5
Hz), 4.26 (m, 1H), 2.87–2.81 (m, 2H), 2.70–2.65 (m, 1H), 2.55–2.51
(m, 3H), 2.26 (td, 1H, J ) 12, 4 Hz), 1.98–1.89 (m, 2H), 1.56 (d,
1H, J ) 13 Hz), 1.28 (s, 3H), 1.03 (d, 3H, J ) 7 Hz), 1.01 (d, 3H,
J ) 7 Hz), 0.49 (d, 3H, J ) 7 Hz); 13C NMR (CDCl3) δ 168.8,
162.9, 158.6, 153.5, 152.0, 137.7, 132.1, 130.4, 126.8, 123.3, 122.2,
118.3, 114.1, 113.6, 110.5, 61.3, 56.3, 53.7, 52.8, 40.5, 39.9, 33.3,
32.2, 28.4, 20.5, 19.1, 17.0; MS (ESI) 462 (M + 1). The HCl salt
had mp 211–213 °C; [R]D +137.8° (c 2.7, CH3OH). Anal. (C28H37
Cl2N3O3 ·2H2O) C, H, N.
Bis(6-methoxy-N-1,2,3,4-tetrahydroisoquinolinyl)methane (39).
Formaldehyde (37% solution, 2.2 g, 27 mmol) was added dropwise
to the 3-methoxyphenethylamine 38 (4 g, 26.5 mmol). The reaction
mixture was heated at 100 °C for 1 h. The oil was extracted with
CH2Cl2, and the extract was washed with water. Concentration of
the extract afforded a viscous oil that was dissolved in HCl (2.45
mL of 37% solution, 29.2 mmol) and concentrated. The residue
was made alkaline with NaOH solution and extracted with ether.
Concentration of the dried (Na2SO4) ether extracts yielded 4.45 g
(7-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-acetic Acid Eth-
yl Ester (37). 2-Benzotriazolymethyl-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (36, 100 mg, 0.34 mmol), prepared according to
1
(99%) of 39 as a white solid. H NMR (CDCl3) δ 6.94 (d, 1H, J

Kappa Opioid Receptor Antagonist
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1859
Identification of (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphe-
nyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tet-
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) 9 Hz), 6.75–6.63 (m, 2H), 3.75 (s, 3H), 3.66 (s, 2H), 3.23 (s,
1H), 2.88–2.80 (m, 4H).
(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)acetic Acid Eth-
yl Ester (40). The preparation of 40 from 39 was carried out using
1
a procedure similar to that described for 37. H NMR (CDCl3) δ
6.90 (d, 1H, J ) 8 Hz), 6.69–6.62 (m, 2H), 4.23 (q, 2H, J ) 8
Hz), 3.77 (s, 3H), 3.37 (s, 2H), 2.90–2.77 (m, 4H), 1.28 (t, 3H, J
) 8 Hz); 13C NMR (CDCl3) δ 170.9, 158.4, 135.4, 127.8, 126.7,
113.6, 112.5, 61.0, 59.4, 55.6, 55.2, 51.0, 29.6, 14.7; MS (ESI)
250 (M + 1).
N-[(1S)-1-{[(3R,4R)-4-(3-Hydroxyphenyl)-3,4-dimethylpiperi-
din-1-yl]methyl}-2-methylpropyl]-2-(6-methoxyl-3,4-dihydroiso-
quinolin-2(1H)-yl)acetamide (7j) Dihydrochloride. Compound 40
(130 mg, 0.52 mmol) was hydrolyzed as described for the synthesis
of 7h and coupled with 8 according to the general procedure to
give 257 mg (100%) of 7j. 1H NMR (CD3OD) δ 7.11 (t, 1H, J )
8 Hz), 6.69 (d, 1H, J ) 8 Hz), 6.7–6.70 (m, 4H), 6.61–6.58 (m,
1H), 4.00 (m, 1H), 3.76 (s, 3H), 3.68 (d, 1H, J ) 15 Hz), 3.65 (d,
1H, J ) 15 Hz), 3.28 (d, 1H, J ) 16 Hz), 3.10 (d, 1H, J ) 16 Hz),
2.92–2.74 (m, 6H), 2.51–2.20 (m, 5H), 2.45–2.25 (m, 5H),
1.98–1.83 (m, 2H), 1.57 (d, 1H, J ) 13 Hz), 1.29 (s, 3H), 0.95 (d,
3H, J ) 7 Hz), 0.89 (d, 3H, J ) 7 Hz), 0.69 (d, 3H, J ) 7 Hz);
13C NMR (CD3OD) δ 171.6, 158.7, 157.3, 152.2, 135.0, 129.1,
127.4, 126.6, 117.0, 113.3, 112.8, 112.4, 112.3, 78.5, 61.3, 60.3,
55.5, 55.3, 54.7, 51.6, 51.3, 39.1, 38.4, 31.0, 29.4, 27.0, 19.0, 17.2,
15.8; MS (ESI) 494 (M + 1). The HCl salt prepared using 1 N
HCl in ether had mp 184–186 °C; [R]D +50° (c 1, CH3OH). Anal.
(C29H43Cl2N3O2 ·CH3OH) C, H, N.
2-(6-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[(1S)-1-
{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-
2-methylpropyl]acetamide (7k) Dihydrochloride. Compound 7j
(147 mg, 0.29 mmol) was O-demethylated according to the general
procedure to give 120 mg (86%) of 7k. 1H NMR (CD3OD) δ 7.01
(t, 1H, J ) 8 Hz), 6.73 (d, 1H, J ) 8 Hz), 6.6–.63 (m, 2H),
6.52–6.43 (m, 3H), 3.90–3.88 (m, 1H), 3.54 (d, 1H, J ) 15 Hz)
3.51 (d, 1H, J ) 15 Hz), 2.92–2.68 (m, 6H), 2.37–2.25 (m, 5H),
2.45–2.25 (m, 5H), 1.98–1.83 (m, 2H), 1.57 (d, 1H, J ) 13 Hz),
1.18 (s, 3H), 0.84 (d, 3H, J ) 7 Hz), 0.78 (d, 3H, J ) 7 Hz), 0.61
(d, 3H, J ) 7 Hz); 13C NMR (CD3OD) δ 171.6, 157.2, 155.9, 152.2,
135.0, 129.0, 127.4, 125.4, 117.0, 114.8, 113.4, 112.7, 112.2, 78.4,
61.3, 60.2, 55.6, 55.3, 51.6, 51.4, 39.1, 38.4, 31.0, 29.3, 27.0, 18.9,
17.1, 15.8; MS (ESI) 480 (M + 1). The HCl salt had mp 222–224
°C; [R]D +48° (c 0.85, CH3OH). Anal. (C29H43Cl2N3O2 ·0.25H2O)
C, H, N.
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Acknowledgment. This research was supported by the
National Institute on Drug Abuse, Grant DA 09045.
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Supporting Information Available: Elemental analysis. This
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