Effect of 1-Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin-1 Receptor

Article abstract of DOI:10.1021/cn500330v

Selective blockade of the orexin-1 receptor (OX₁) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX₁ selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX₁ potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX₁ receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (K_e) of 16.1 nM at the OX₁ receptor and >620-fold selectivity over the OX₂ receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats. (Chemical Equation Presented).

Full text of DOI:10.1021/cn500330v

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Article
The Effect of 1-Substitution on Tetrahydroisoquinolines
as Selective Antagonists for the Orexin-1 Receptor
David A Perrey, Nadezhda A German, Ann M. Decker, David Thorn, Jun-Xu Li, Brian
P Gilmour, Brian F Thomas, Danni L. Harris, Scott P Runyon, and Yanan Zhang
ACS Chem. Neurosci., Just Accepted Manuscript • Publication Date (Web): 02 Feb 2015
Downloaded from http://pubs.acs.org on February 5, 2015
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The Effect of 1ꢀSubstitution on
Tetrahydroisoquinolines as Selective Antagonists for
the Orexinꢀ1 Receptor
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†
†
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‡
‡
David A. Perrey, Nadezhda A. German, Ann M. Decker, David Thorn, Jun-Xu Li, Brian P.
†
†
†
†
†,*
Gilmour, Brian F. Thomas, Danni L. Harris, Scott P. Runyon, and Yanan Zhang,
†
Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States
‡
Department of Pharmacology and Toxicology, University at Buffalo, the State University of
New York, Buffalo, New York 14214, United States
KEYWORDS: Orexin, antagonist, selective, tetrahydroisoquinoline
ABSTRACT: Selective blockade of the Orexinꢀ1 receptor has been suggested as a potential
approach to drug addiction therapy because of its role in modulating the brain’s reward system.
We have recently reported a series of tetrahydroisoquinolineꢀbased OX selective antagonists.
1
Aimed at elucidating SAR requirements in other regions of the molecule and further enhancing
OX potency and selectivity, we have designed and synthesized a series of analogs bearing a
1
variety of substituents at the 1ꢀposition of the tetrahydroisoquinoline. The results show that an
optimally substituted benzyl group is required for activity at the OX receptor. Several
1
compounds with improved potency and/or selectivity have been identified. When combined with
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structural modifications that were previously found to improve selectivity, we have identified
compound 73 (RTIOXꢀ251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1
receptor and >620ꢀfold selectivity over the OX receptor. In vivo, compound 73 was shown to
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block the development of locomotor sensitization to cocaine in rats.
Introduction
Orexins (hypocretins), including orexin A and orexin B, are neuropeptides exclusively
produced in hypothalamic neurons arising in the dorsomedial hypothalamus (DMH), perifornical
1
,
2
area (PFA), and lateral hypothalamus (LH).
The orexinꢀproducing neurons in the
hypothalamus project widely to key areas of the central nervous system (CNS) that are
commonly thought to control sleep–wake states, modulation of food intake, panic, anxiety,
3
ꢀ5
reward and addictive behaviors, suggesting diverse roles for these peptides. Orexin A and B
bind and activate two G proteinꢀcoupled receptors (GPCRs), orexinꢀ1 (OX ) and orexinꢀ2 (OX ),
1
2
6
, 7
with OX signaling via G proteins and OX signaling via G or G proteins.
The OX1
1
q
2
q
i/o
receptor has 10ꢀfold higher affinity for orexin A than for orexin B; whereas OX has equal
2
affinity for both peptides. Interestingly, these receptors are differentially distributed throughout
1
, 8, 9
the brain, suggesting different physiological roles for each receptor.
Originally known for
regulation of metabolic, circadian and stress systems, the orexin system has recently been
10ꢀ13
associated with drug addiction.
The fact that orexin neurons project to the ventral tegmental
area (VTA) and other brain regions involved in reward processing supports this notion. Selective
blockade of the OX receptor has been shown to attenuate stressꢀ and cueꢀinduced reinstatement
1
1
4ꢀ18
of previously extinguished cocaineꢀ, morphineꢀ, and alcoholꢀseeking behavior.
Together,
these findings suggest that OX antagonists may have therapeutic utility for the treatment of drug
1
addiction.
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Figure 1. Orexin Antagonists
In order to elucidate the physiological role of the orexin receptors and explore the potential of
orexin receptor antagonists as therapeutics, a number of groups, mostly from the pharmaceutical
19ꢀ23
industry, have developed orexin receptor antagonists.
In these endeavors, the majority of
research has focused on dual orexin receptor antagonists for new sleep medications
24, 25
development.
Several dual antagonists, including almorexant (1) and SBꢀ649828 (2), have
been advanced into clinical trials, but their development was later halted because of tolerability
and toxicity concerns, respectively. The most success was seen with suvorexant (3), a dual
orexin antagonist developed by Merck. Recently, suvorexant was approved at a lower dose (20
mg) than initially proposed for the treatment of insomnia, and is currently marketed under the
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trade name Belsomra. Several OX receptor selective antagonists have also been developed to
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probe the importance of this receptor. Among these, the OX antagonist SBꢀ334867 (4) was the
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first OX selective antagonist reported and has been extensively studied because it has favorable
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preclinical pharmacokinetics. Its affinity for OX is ∼50ꢀfold higher than for OX , but some in
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vivo studies using high doses should be viewed cautiously because those doses may block both
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receptors. Additionally, Rottapharm Madaus has reported a series of azaspiro compounds as
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selective OX antagonists, and identified the spiro moiety as a key structural feature for OX1
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receptor selectivity.
Several other OX selective antagonists have also been reported,
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including GSKꢀ1059865 and its analogs, as well as ACTꢀ335827, although these compounds
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mostly retained a significant amount of OX activity.
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Our group has been developing OX selective antagonists for the potential treatment of drug
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4ꢀ36
addiction and related disorders.
We recently described our progress toward selective OX
antagonists based on the tetrahydroisoquinoline scaffold, which is found both in 1 and the OX2
37
receptor selective antagonist TCSꢀOX2ꢀ29 (5). The structural modifications focused on the 7ꢀ
position of the tetrahydroisoquinoline ring and the acetamide positions, resulting in several
potent and selective OX antagonists. In particular, RTIOXꢀ276 (6) showed excellent OX1
1
potency and selectivity, and attenuated cocaineꢀinduced conditioned place preference (CPP) in
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rats. However, the structureꢀactivity relationship (SAR) requirements in other regions of the
structure have yet to be explored. Interestingly, at the 1ꢀposition of the tetrahydroisoquinoline,
the dual orexin antagonist 1 has a 4ꢀtrifluoromethylphenylethyl group, whereas the OX selective
2
antagonist 5 does not bear any substitution, suggesting that this position may play an important
role in receptor subtype selectivity. Therefore, we have examined a series of analogs bearing a
variety of modifications at the 1ꢀposition of the tetrahydroisoquinoline. Herein, we report our
effort in the design, synthesis, and in vitro and in vivo characterization of these 1ꢀsubstituted
analogs.
Results and Discussion
Chemistry. The overall approach to the synthesis followed methods detailed in our earlier
34, 36
work (Scheme 1).
Briefly, commercially available 3,4ꢀdimethoxyphenethylamine (7) and
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phenylacetic acid 8a were coupled using HBTU or BOP to give the amide 9. Cyclization of 9 via
the BischlerꢀNapieralski reaction using phosphorus oxychloride in toluene afforded the
dihydroisoquinoline, which was readily reduced to the tetrahydroisoquinoline 10 with sodium
borohydride. The nitrogen was alkylated using Nꢀbenzyl bromoacetamide with
diisopropylethylamine as base to give final product 11. Similarly, compound 12 was synthesized
from 8b (R = H). Elaboration of the phenol 12 was achieved by alkylation using the appropriate
alkyl bromide in the presence of K CO , esterification via BOPꢀmediated coupling, or by
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sulfonylation using the sulfonyl chloride with triethylamine as base, to afford target compounds
13-23.
a
Scheme 1. Synthesis of 1ꢀsubstituted tetrahydroisoquinolines 11-23
a
Reagents and Conditions: (a) HBTU or BOP, iPr EtN, DMF; (b) (i) POCl , toluene; (ii)
2
3
NaBH , MeOH; (c) BrCH CONHCH Ph, iPr EtN, Bu NI, DMF; (d) R’ꢀBr, K CO , DMF or
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3
CH (CH ) COOH, BOP, iPr EtN, CH Cl or R’SO Cl, Et N, CH Cl .
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Aniline derivatives were synthesized following a similar route (Scheme 2). Amide coupling of
2
4 with the amine 7 followed by alkylation of the hydroxyl group afforded intermediate 25,
which was converted to 27 via BischlerꢀNapieralski reaction, alkylation of the nitrogen and
reduction of the nitro group. The free aniline in 27 was then modified by reductive amination
using sodium triacetoxyborohydride or sodium cyanoborohydride, alkylation via an alkyl
bromide or by amide coupling using BOP in DMF to provide final compounds 28-35. Similarly,
the benzoxazole 38 was prepared from 24 via the 4ꢀhydroxyꢀ3ꢀamino intermediate 37 by
condensation with ethyl acetimidate. In addition to the 3,4ꢀdisubstituted, several monosubstituted
analogs were prepared in analogous fashion (Scheme 3), starting from acid 39, via the
tetrahydroisoquinoline 40 with further elaboration at phenol or aniline. Urea 50 was prepared by
reaction with nꢀhexyl isocyanate in toluene.
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Scheme 2. Synthesis of 1ꢀaminobenzyl substituted tetrahydroisoquinolines 28-38
a
Reagents and Conditions: (a) 3,4ꢀdimethoxyphenethylamine (7), HBTU, iPr EtN, DMF; (b) Meꢀ
2
I, K CO , DMF; (c) POCl , toluene; (d) NaBH , MeOH; (e) BrCH CONHCH Ph, iPr EtN,
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Bu NI, DMF; (f) Raney Ni, NH NH .H O, EtOH; (g) RꢀCHO, Na(AcO) BH, 1,2ꢀDCE or Rꢀ
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Compounds with substituents other than the benzyl group at the 1ꢀposition were made via
PictetꢀSpengler condensation between 7 and the corresponding aldehydes in toluene and
trifluoroacetic acid at 140 °C for 30 minutes in the microwave, followed by Nꢀalkylation as
described above (Scheme 4). The olefin 61 was reduced by hydrogenation on Pd/C in ethanol to
give the saturated analog 62. Nonꢀcommercial aldehydes in the PictetꢀSpengler reaction were
prepared via pyridinium chlorochromate oxidation of the appropriate alcohols.
a
Scheme 3. Synthesis of 1ꢀsubstituted tetrahydroisoquinolines 41-56
MeO
MeO
MeO
MeO
O
OH
NH
N
a
b
n
N
R
O
H
n
n
R
R
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41, CH -3-O-iPrPh
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4, CH -2-naphthyl
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5, CH -6-quinolinyl
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1, CH -4-iPrPh
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6, CHMe-Ph
2, CH -3,4,5-triMeOPh
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60, CH CH -3,4-diMeOPh
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MeO
MeO
MeO
MeO
O
O
c
N
N
N
N
H
H
HO
O
R
44, 3-O-iPr
45, 4-O-nPr
46, 4-O-iPr
MeO
MeO
MeO
MeO
O
O
d
N
N
N
N
H
H
O N
H2N
2
42, 3-NH2
47, 4-NH2
MeO
MeO
O
e
N
43
, R ,R = 3-NMe
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2
N
H
49, R1,R2 = 4-NHAc
0, R ,R = 4-NHCONH-n-hexyl
R1
N
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Reagents and Conditions: (a) (i) 7, HBTU, iPr EtN, DMF; (ii) POCl , toluene; (iii) NaBH ,
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MeOH; (b) BrCH CONHCH Ph, iPr EtN, Bu NI, DMF; (c) RꢀBr, K CO , DMF; (d) Raney Ni,
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Scheme 4. Synthesis of 1ꢀsubstituted tetrahydroisoquinolines 59-69
a
Reagents and Conditions: (a) CF CO H, toluene; (b) BrCH CONHCH Ph, iPr EtN, Bu NI,
3
2
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DMF; (c) H , 10% Pd/C, EtOH.
2
The 7ꢀpropoxy derivative 73 was prepared in a similar fashion as described above (Scheme 5),
starting from 4ꢀhydroxyꢀ3ꢀmethoxyꢀphenethylamine (70). Amide coupling between 70 and 8b,
followed by alkylation of the two hydroxyl groups afforded intermediate 71. Cyclization
followed by reduction provided amine 72 and then a final Nꢀalkylation with the bromoacetamide
gave 73.
a
Scheme 5. Synthesis of 7ꢀpropoxy tetrahydroisoquinoline 73.
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Reagents and Conditions: (a) (i) 8b, HBTU, iPr EtN, DMF; (ii) 1ꢀiodopropane, K CO , DMF;
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(
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3 4 2 2 2 3
Biological Evaluation. Activity of the target compounds at the human OX and OX receptors
1
2
TM
was evaluated using Fluorescent Imaging Plate Reader technology (FLIPR , Molecular
Devices), which measures intracellular calcium mobilization in live cells. The apparent
dissociation constant Ke was calculated from compoundꢀmediated inhibition of orexin A activity
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4ꢀ36
as previously described.
In these assays, the EC for orexin A at OX and OX is 0.13 ± 0.02
50 1 2
nM and 4.2 ± 0.2 nM, respectively. All the compounds that had OX Ke values < 1 ꢀM were also
1
tested for agonist activity at 10 µM; none of them were active.
Our studies aimed at mapping out the SAR requirements at the 1ꢀpositon based on both the
steric and electronic considerations. An examination of several reported orexin antagonists based
on the tetrahydroisoquinoline scaffold revealed the importance of the 1ꢀpostion. The dual orexin
antagonist 1 has a 4ꢀtrifluoromethylphenylethyl group at the 1ꢀposition. Conversely, the OX2
selective antagonist 5 does not bear any substitution at the 1ꢀposition. Compound 11, the hit
identified in a highꢀthroughput screening campaign by Actelion, has a 3,4ꢀdimethoxybenzyl
group at the 1ꢀposition of the tetrahydroisoquinoline, and showed some selectivity for the OX1
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receptor (Table 1).
The OX receptor selective antagonist 6 developed in our lab also has the
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,4ꢀdimethoxy substitution. Taken together, these results suggest that the 1ꢀposition substituents
may have differential effects on the activity of ligands at the two orexin receptors.
The small set of analogs of 11 reported by Actelion suggests that the substitution pattern on the
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ꢀbenzyl group may have a significant effect on the activity at the orexin receptors. For
instance, the corresponding phenyl analog which lacked the dimethoxy groups at the 3 and 4ꢀ
positons, showed little activity at either receptor. Removing one of the methoxy groups also
resulted in significant loss of activity at both receptors. Therefore, we first evaluated a series of
3,4ꢀdisubstituted benzyl analogs that retained the 3ꢀmethyoxy group but had different alkylꢀ
substituted groups at the 4ꢀposition of the benzyl group (Table 1). All of the target compounds
were prepared racemically, although the 1ꢀposition stereochemistry is undoubtedly important, as
3
4, 39
evidenced by both 1 and our own findings.
While removing the methyl group at the 4ꢀ
methoxy position gave a slight drop in potency in phenol 12, the potency was regained and even
increased by substituting with a larger alkyl group such as butyl 13 or hexyl 14, with 13 having
slightly higher potency. Further increasing the size to a piperidinylethyl group, which may
provide improved drugꢀlike properties due to the basic nitrogen, resulted in a total loss of
activity, suggesting limited size tolerance at this site. Interestingly, the butyric ester 16 was
equally potent to the butyl analog 13, suggesting polar groups can be tolerated at this site.
Analog 17 with a mesyl group, which has the size between a methyl (11) and butyl groups (13)
but a high electron deficiency, had a Ke = 485 nM, only slightly less potent than 11. These
findings indicate that steric bulk may play a more prominent role at this position than electronic
effects. A series of aromatic substituents at the 4ꢀalkoxy position were then examined (18-22).
The Oꢀbenzyl analog 18 was 2ꢀfold less potent than 11. Extending the phenyl group away from
the ring system had no effect on potency (19). The corresponding sulfonyl analog (20) showed
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no potency at the OX receptor. The two pyridylmethyl derivatives 21 and 22 showed similar
1
potency to compound 11. Finally, the phenylsulfonyl analog (23) had a ~9ꢀfold decrease in
potency.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We next synthesized a series of compounds that had modifications at the 3ꢀposition of the 1ꢀ
benzyl group, while retaining the 4ꢀmethoxy group (Table 1). Replacement of the oxygen moiety
with a series of nitrogenꢀcontaining groups, with the aim of reducing logP and improving the
drugꢀlikeness, gave some interesting results. The 3ꢀnitro analog (26) showed ~7ꢀfold reduced
potency, whereas dimethylamino analog 28 gave a significant improvement of potency at the
OX receptor (Ke = 13 nM) but also increased the OX receptor potency. However, larger Nꢀ
1
2
alkyl groups were not as well tolerated and the potency decreased with the increase of the size of
the alkyl groups (29-33), with the benzyl analog (33) having no activity at concentrations up to
10 ꢀM. Interestingly, while the acetyl derivatives 34 had a significant drop in potency, 35, which
had a larger acyl group, regained most of the potency. Finally, the corresponding 4ꢀhydroxyl
substituent had a significant potency reduction compared to its 4ꢀmethoxy analog (36 vs. 26).
The benzoxazole 38 had a Ke in the micromolar range.
Table 1. Effect of benzyl substitution on OX antagonism
b
Ke (OX
2
,
Number
R1
R2
Ke (OX , nM)
c
OX /OX
1
2
1
nM)
11
OMe
OMe
199 ± 47
>10,000
>50.3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
1
2
3
4
OMe
OMe
OMe
OH
419 ± 64
>10,000
2000 ± 860
>10,000
>24
42
OꢀnꢀButyl
OꢀnꢀHexyl
48 ± 27
120 ± 20
>83
Oꢀ(CH2)2ꢀ
d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
OMe
>10,000
a
piperidinyl
16
17
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OCO(CH
OSO Me
OBenzyl
Oꢀ(CH ꢀOPh
OSO (4ꢀMe)Ph
2
)
2
CH
3
43.5 ± 3.7
480 ± 180
399 ± 22
2080 ± 600
48
a
2
1
1
2
2
2
2
2
2
2
8
9
0
1
2
3
6
8
9
a
)
4
385 ± 96
a
2
> 10,000
153 ± 43
a
2
OCH
OCH
ꢀ2ꢀPyridyl
ꢀ3ꢀPyridyl
a
2
250 ± 120
1820 ± 680
1500 ± 230
12.7 ± 2.8
309 ± 39
a
2
OSO
Ph
a
2
NO
NMe
NHEt
NEt
NHꢀnꢀPropyl
N(nꢀPropyl)
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OH
a
2
970 ± 350
76.7
>32
>48
>11
2
>10,000
30
31
32
2
208 ± 38
>10,000
920 ± 140
>10,000
d
857 ± 380
a
a
a
a
a
a
a
2
d
3
3
3
3
3
3
3
4
5
6
7
8
NHꢀBenzyl
NHAc
>10,000
d
>10,000
NHCO(CH
)
2
CH
320± 30
2
3
d
NO
NH
>10,000
2
d
OH
>10,000
2
d
2ꢀMethylꢀ5ꢀbenzoxazole
2620± 870
a. < 35% inhibition at 10 ꢀM;
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b. Values are the mean ± SEM of at least three independent experiments performed in
duplicate;
c. Values are the mean ± SEM of at least two independent experiments performed in
duplicate; for compounds with Ke < 100 nM at OX at least three independent
1
experiments in duplicate were performed.
10
11
12
13
14
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16
17
18
19
20
21
22
23
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29
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46
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49
50
51
52
53
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56
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59
60
d. Values are the mean ± SEM of two independent experiments performed in duplicate.
All of the 1ꢀbenzyl analogs discussed thus far have a 3,4ꢀsubstitution pattern. The relative
importance of each of those positions was then examined by preparing a series of 3ꢀsubstituted
and 4ꢀsubstituted analogs (Table 2). As previously reported, analogs singly substituted with a
methoxyl group at either the 3ꢀ or 4ꢀposition had diminished activity at both OX and OX2
1
3
8
receptors. Therefore, we have examined a series of analogs that bear substituents other than a
methoxyl group at these positions. The 3ꢀisopropoxyl analog (41) had a ~7ꢀfold drop in OX1
potency. In the 3ꢀnitrogen containing analogs, the 3ꢀnitro 42 showed activity only at OX (1200
2
nM), whereas the aniline 43 showed modest potency at the OX receptor and no activity at OX .
1
2
Potency at the OX receptor was further increased by dimethylation (44), which was the most
1
potent monoꢀsubstituted compound in the series. However, 44 also showed significant potency at
the OX receptor (Ke = 660 nM). It appears that the 4ꢀposition may contribute more to the OX1
2
potency as the 4ꢀsubstituted mono isopropoxy derivative (46) showed increased potency
compared to the corresponding 3ꢀsubstituted derivative (41). The differences in OX potency
1
between the nꢀpropyl 45 and the isopropyl 46 were modest and both were slightly less potent
than 11. In the 4ꢀnitrogen series, the 4ꢀaniline 47 showed no OX activity and again this was
1
restored with the 4ꢀdimethylamino analog 48, which had similar potency to compound 11 (253 v
1
99 nM). As with the disubstituted analogs, acylation as the acetamide 49 or the urea 50 caused a
significant drop in potency. Finally, the isopropyl analog 51 had good potency, with a Ke of 85
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
nM, further reinforcing the idea that steric factors are the overriding factor in potency. The OX2
selectivity of the nitro 42 indicates some preference for electronꢀwithdrawing substituents for
OX potency and indeed a trifluoromethyl substituent may contribute to the OX potency of 1.
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Monoꢀsubstituted benzylic substituents at the 1ꢀposition and their effect on OX
antagonism
b
Ke (OX , nM)
Ke (OX
2
,
1
Number
R1
R2
c
OX /OX
2
1
nM)
1
1
OMe
OMe
199± 47
1470± 70
>10,000
1310± 90
75.3± 1.3
370± 50
489± 68
>10,000
>10,000
>50.3
>6.8
41
42
43
OꢀIsopropyl
H
NO
H
1200± 160
a
<0.12
2
2
NH
H
4
4
4
4
4
4
4
5
6
7
8
9
NMe
2
H
660±160
>10,000
>10,000
a
8.8
>27
>20
H
OꢀnꢀPropyl
OꢀIsopropyl
H
d
H
NH
>10,000
2
H
NMe
253± 85
>10,000
a
>40
2
d
H
NHAc
>10,000
NHCONHꢀnꢀ
hexyl
d
5
0
H
H
>10,000
a
51
Isopropyl
85± 21
>10,000
>118
a. < 35% inhibition at 10 ꢀM;
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b. Values are the mean ± SEM of at least three independent experiments performed in
duplicate;
c. Values are the mean ± SEM of at least two independent experiments in performed
duplicate; for compounds with Ke < 100 nM at OX at least three independent
1
experiments in duplicate were performed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
d. Values are the mean ± SEM of two independent experiments performed in duplicate.
We then investigated a series of alternate substituents, including differentially substituted
benzylic and nonꢀaromatic systems to further examine the SAR requirements at this position
(Table 3). Surprisingly, the 3,4,5ꢀtrimethoxy analog 52 was mostly inactive at both receptors.
This clearly shows that the 1ꢀbenzyl substituent is highly sensitive to substitutions, confirming
the earlier observations. The 3,4ꢀdimethylbenzyl analog 53 showed higher potency than 11,
further illustrating the importance of steric effects on potency. The naphthyl (54) and quinoline
(
55) analogs showed a modest reduction in potency compared to 11. Interestingly, removing the
methylene group resulted in a total loss of activity (59 vs. 11). Elongation of the methylene
group (60, 62, 63) also led to significant loss of activity at the OX receptor. This is somewhat
1
surprising as the dual orexin antagonist 1 has a phenethyl group and has high potency at both
receptors. Introduction of rigidity (61) led to diminished activity. The requirement for an
aromatic system was then examined with the replacement of the 1ꢀbenzyl with nonaromatic
systems (Table 3). A series of alkyl analogs were prepared and their OX potency evaluated;
however, none of them (64-69) showed detectable antagonism in our assay at concentrations of
1
0 ꢀM. Taken together, these findings clearly confirm that an optimally substituted benzyl group
is required for OX potency.
1
Table 3. Other substituents at the 1ꢀposition and their effect on OX antagonism
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2
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2
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3
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5
5
5
5
6
b
c
Number
R1
Ke (OX , nM)
Ke (OX , nM)
OX /OX
1
2
2
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
11
199 ± 47
>10,000
>10,000
>50.3
d
52
>10,000
53
94 ± 28
245 ± 40
432 ± 22
>10,000
1620 ± 230
>10,000
>32
6.6
54
5
5
5
6
>23
d
>10,000
>10,000
d
5
6
9
0
>10,000
a
d
>10,000
>10,000
d
61
>10,000
a
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d
6
2
3
>10,000
a
a
10
11
12
13
14
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16
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18
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21
22
23
24
25
26
27
28
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32
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34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
d
6
>10,000
d
6
6
4
5
>10,000
a
a
a
d
>10,000
d
66
67
>10,000
d
>10,000
a
a
d
6
6
8
9
>10,000
d
>10,000
a
a. < 35% inhibition at 10 ꢀM;
b. Values are the mean ± SEM of at least three independent experiments performed in
duplicate;
c. Values are the mean ± SEM of at least two independent experiments in performed
duplicate; for compounds with Ke < 100 nM at OX at least three independent
1
experiments in duplicate were performed.
d. Values are the mean ± SEM of two independent experiments performed in duplicate.
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1
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4
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5
5
6
The structural modifications at the 1ꢀposition have led to the identification of several
compounds that have improved OX potency compared to the 3,4ꢀdimethoxy analog 11. Several
1
compounds also showed improved OX selectivity, greater than 50ꢀfold (e.g. 16, 28, 51), even
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
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1
2
3
4
5
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9
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1
2
3
4
5
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7
8
9
0
though this improvement is only modest. As previously reported by our group, introducing larger
alkyl groups such as a 7ꢀpropoxy at the 7ꢀmethoxy position led to improved potency and
selectivity. Therefore, we synthesized a dipropoxy analog which has a propoxy group at the 7ꢀ
position of the tetrahydroisoquinoline and the 4ꢀposition of the 1ꢀbenzyl group, respectively (73,
RTIOXꢀ251, Figure 2). Indeed, these modifications resulted in an analog that showed
improvement in both OX potency and selectivity (73). Compound 73 had a Ke of 16.1 nM (vs.
1
4
8 nM for the close analog 13), but it was selectivity where the greatest improvement was seen
in 73, which increased to approximately >620ꢀfold.
Figure 2. 7ꢀPropoxyꢀ1ꢀ(4ꢀpropoxy)benzyl tetrahydroisoquinoline derivative 73.
Cocaine-induced Behavioral Sensitization. OX receptor selective antagonist SB334867 has
1
been reported to block the development of locomotor sensitization to cocaine when administrated
40
i.p. We next moved on to test one of the compounds that showed the highest potency and
selectivity in this series of compounds, compound 73, on the development of behavioral
sensitization to cocaine in rats. As expected, acute cocaine treatment induced a doseꢀdependent
hyperactivity (open circles, left panel, Fig. 3). Daily treatment with 15 mg/kg cocaine for 7 days
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induced a significant locomotor sensitization, as demonstrated by a leftward shift of the cocaine
doseꢀeffect curve on day 15 as compared to day 1 (compare gray circles with open circles, right
panel, Fig. 3). Two way ANOVA revealed significant main effects of repeated treatment (F [2,
10
11
12
13
14
15
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17
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23
24
25
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27
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29
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
4] = 24.7, P < 0.0001) and repeated treatment × cocaine dose interactions (F [2, 14] = 35.2, P <
0.0001). Post hoc analysis indicated that on day 15, the effects of 3.2 and 10 mg/kg cocaine were
significantly increased while the effect of 32 mg/kg cocaine was significantly decreased.
Although 10 mg/kg compound 73, a dose that alone did not significantly alter the spontaneous
activity in rats (data not shown), did not alter acute cocaineꢀinduced hyperactivity when given
acutely (left panel, Fig. 3), repeated treatment with compound 73 significantly blocked the
development of cocaine sensitization (compare open circles with open squares, right panel, Fig.
3). Two way ANOVA revealed significant main effects of repeated treatment (F [2, 14] = 7.2, P
<
0.01) and repeated treatment × cocaine dose interactions (F [2, 14] = 10.5, P < 0.01). Post hoc
analysis indicated that on day 15, the effects of 10 mg/kg cocaine were significantly lower while
the effect of 32 mg/kg cocaine was significantly higher in the compound 73 treated group as
compared to control group, suggesting a significant blockade of cocaine sensitization.
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2
2
2
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2
2
2
2
2
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3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 3. Compound 73 attenuated the development of cocaineꢀinduced behavioral sensitization.
Left: compound 73 did not significantly alter acute cocaineꢀinduced hyperactivity (n=8/group).
Right: compound 73 significantly reduced the development of cocaine sensitization during the
challenge test (* P < 0.05 as compared with control group). Dashed line represents the replotted
data of control group in Day 1 for comparison in Day 15. Data represent the mean ± SEM. The
absence of error bars indicates that the variability is contained within the data point. V, vehicle.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusions
Recently, the orexin system has been indicated to play an important role in the reward pathway
and OX receptor selective antagonists have been suggested to hold value for the treatment of
1
addiction to a number of illicit drugs. While several OX antagonists have been reported so far,
1
they tend to retain some activity at the OX receptor. In our continued effort to investigate the
2
SAR on the tetrahydroisoquinoline scaffold and develop highly potent and selective OX1
antagonists, we have designed and synthesized a series of compounds with a range of
substituents at the 1ꢀposition. These compounds were then evaluated for the potency at the OX1
and OX receptors in FLPRꢀbased calcium mobilization assays. The SAR results indicate that an
2
optimally substituted benzyl group is required for activity at the OX receptor. Shortening or
1
elongation of the methylene unit in the benzyl group both led to dramatic decreases in OX1
potency. Other nonaromatic systems including straight chain or cyclic alkyl groups were also not
well tolerated. A number of analogs (e.g. 13, 16 and 51) showed improvement on potency at the
OX receptor compared with the dimethoxy substitution (11). In particular, the 3ꢀdimethylaminoꢀ
1
4
ꢀmethyoxy substitution pattern (28) provided the best OX potency (Ke = 12.7 nM) and
1
reasonable selectivity (76.7ꢀfold), although some activity at the OX potency remains (Ke = 970
2
nM). When structural modifications at the 7ꢀposition of the tetrahydroisoquinoline that have
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been shown to improve potency were introduced, OX potency and selectivity were further
1
enhanced. Compound 73 (RTIOXꢀ251) is both a potent and highly selective OX receptor
1
antagonist. At 10 mg/kg 73 did not alter acute cocaineꢀinduced hyperactivity when given acutely,
but blocked the development of locomotor sensitization to cocaine in rats when repeatedly
administrated.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Procedures
General. All solvents and chemicals were reagent grade. Unless otherwise mentioned, all were
purchased from commercial vendors and used as received. Flash column chromatography was
done on a Teledyne ISCO CombiFlash Rf system using prepacked columns. Solvents used were
hexane,
ethyl
acetate
(EtOAc),
dichloromethane
(DCM),
methanol
and
chloroform:methanol:ammonium hydroxide (80:18:2) (CMAꢀ80). Purity and characterization of
compounds was established by a combination of high pressure liquid chromatography (HPLC),
thin layer chromatography (TLC), mass spectrometry (MS) and nuclear magnetic resonance
1
13
(
NMR) analysis. H and C NMR spectra were recorded on a Bruker Avance DPXꢀ300 (300
MHz) spectrometer and were determined in chloroformꢀd or methanolꢀd4 with tetramethylsilane
TMS) (0.00 ppm) or solvent peaks as the internal reference. Chemical shifts are reported in ppm
(
relative to the reference signal, and coupling constant (J) values are reported in Hz. TLC was
done on EMD precoated silica gel 60 F254 plates, and spots were visualized with UV light or
iodine staining. Low resolution mass spectra were obtained using a Waters Alliance
HT/Micromass ZQ system (ESI). High resolution mass spectra were obtained using an Agilent
6230 timeꢀofꢀflight mass spectrometer. Melting points were determined using a Mel Temp II
melting point apparatus and are uncorrected. All test compounds were greater than 95% pure as
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determined by HPLC on an Agilent 1100 system using an Agilent Zorbax SBꢀPhenyl, 2.1 mm x
150 mm, 5 ꢀm column with gradient elution using the mobile phases (A) H O containing 0.1%
2
CF COOH and (B) MeCN, with a flow rate of 1.0 mL/min.
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General procedures:
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(3-hydroxy-4-methoxyphenyl)acetamide
Hydroxyꢀ4ꢀmethoxyphenylacetic acid (1.0 g, 5.49 mmol), 3,4ꢀdimethoxyphenethylamine (1.0 g,
.93 mL, 5.49 mmol) and HBTU (2.08 g, 5.49 mmol) were combined in dry DMF (55 mL) at RT
(9).
3ꢀ
0
under N . Diisopropylethylamine (1.77 g, 2.4 mL, 13.72 mmol) was added and the reaction
2
stirred at RT overnight. The reaction was diluted with EtOAc, washed with 2N HCl, NaHCO3
solution and brine, dried over MgSO and the solvent removed under reduced pressure to give
4
1
the desired amide as a yellow oil which solidified upon standing (1.50 g, 79%). H NMR (300
MHz, CHLOROFORMꢀd) δ 7.39 ꢀ 7.50 (m, 1H), 6.81 ꢀ 6.88 (m, 1H), 6.71 (d, J = 8.19 Hz, 1H),
6
.57 ꢀ 6.67 (m, 3H), 6.50 (dd, J = 1.98, 8.10 Hz, 1H), 5.52 (br. s., 1H), 3.86 (s, 3H), 3.83 (s, 3H),
3.82 (s, 3H), 3.47 (s, 2H), 3.43 (t, J = 6.12 Hz, 2H), 2.67 (t, J = 6.83 Hz, 2H).
-[(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]-2-methoxyphenol
4
(10).
Amide 9 (1.51 g, 4.37 mmol) was suspended in anhydrous toluene (22 mL) and phosphorous
oxychloride (4.02 g, 2.45 mL, 26.23 mmol) added slowly. The reaction was heated to 90 °C for 2
hr, during which the solid went into solution, then a red oil separated. The reaction was cooled,
then quenched by slow addition of the reaction mixture to water and heated until a solution
formed. The toluene layer was removed, 2N sodium hydroxide solution was added until pH was
8ꢀ9, then the solution was extracted 3 times with DCM. The combined extracts were dried over
MgSO and the solvent removed under reduced pressure.
4
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The crude dihydroisoquinoline was dissolved in methanol (25 mL) and cooled in an ice bath
under N . Sodium borohydride (0.83 g, 21.99 mmol) was added portionwise and the reaction
2
allowed to warm slowly to RT overnight. The reaction was quenched with water then the
methanol removed under reduced pressure. The aqueous solution was extracted 3 times with
10
11
12
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14
15
16
17
18
19
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60
DCM and the combined extracts were dried over MgSO and the solvent removed under reduced
4
1
pressure to give the desired tetrahydroisoquinoline as an offꢀwhite foam (0.73 g, 91%). H NMR
(300 MHz, CHLOROFORMꢀd) δ 6.86 (d, J = 7.82 Hz, 1H), 6.70 ꢀ 6.79 (m, 2H), 6.66 (s, 1H),
6.60 (s, 1H), 4.13 (dd, J = 4.29, 9.18 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.11 ꢀ 3.27
(m, 2H), 2.83 ꢀ 2.98 (m, 4H), 2.63 ꢀ 2.79 (m, 2H).
N-Benzyl-2-{1-[(4-hydroxy-3-methoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-2-yl}acetamide (12). Amine 10 (0.20 g, 0.61 mmol), Nꢀbenzylꢀ2ꢀ
bromoacetamide (0.152 g, 0.67 mmol) and tetrabutylammonium iodide (0.045 g, 0.12 mmol)
were combined in dry DMF (6 mL) and diisopropylethylamine (0.196 g, 0.26 mL, 1.52 mmol)
was added. The reaction was stirred at RT overnight under N . The reaction was diluted with
2
EtOAc, washed with NaHCO solution, water and brine (x2), then dried over MgSO and the
3
4
solvent removed under reduced pressure. The crude was purified by chromatography on silica (0ꢀ
1
6
0% EtOAc in hexane) to obtain the desired product as a pale yellow oil (0.097 g, 33%). H
NMR (300 MHz, CHLOROFORMꢀd) δ 7.21 ꢀ 7.36 (m, 3H), 7.14 (d, J = 6.69 Hz, 2H), 6.93 ꢀ
7
.04 (m, 1H), 6.76 ꢀ 6.84 (m, 1H), 6.66 ꢀ 6.73 (m, 1H), 6.64 (d, J = 1.51 Hz, 1H), 6.59 (s, 1H),
.45 (s, 1H), 5.50 (s, 1H), 4.48 (dd, J = 8.01, 14.69 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.76 (s,
6
3H), 3.56 ꢀ 3.72 (m, 2H), 3.35 ꢀ 3.49 (m, 1H), 3.09 ꢀ 3.34 (m, 2H), 2.79 ꢀ 3.01 (m, 4H), 2.42 ꢀ
+
2
.56 (m, 1H). m/z 477 (M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H]
3
28 33
2
5
477.2384, m/z found 477.2411.
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N-Benzyl-2-{1-[(4-butoxy-3-methoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-2-yl}acetamide (13). Phenol 12 (50 mg, 0.105 mmol), potassium
carbonate (29 mg, 0.210 mmol) and tetrabutylammonium iodide (8 mg, 0.021 mmol) were
combined in DMF (1 mL) and 1ꢀbromobutane (16 mg, 12 ꢀL, 0.115 mmol) was added. The
reaction was heated at 50 °C overnight. It was diluted with EtOAc, washed with water and brine,
0
1
2
3
4
5
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7
8
9
0
1
2
3
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0
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9
0
dried over MgSO and the solvent removed under reduced pressure. The crude was purified by
4
chromatography on silica (0ꢀ75% EtOAc in hexane) to give the desired product as a yellow
1
glassy solid (47 mg, 84%). H NMR (300 MHz, CHLOROFORMꢀd) δ 7.18 ꢀ 7.34 (m, 3H), 7.11
(
d, J = 6.50 Hz, 2H), 6.96 ꢀ 7.06 (m, 1H), 6.63 ꢀ 6.72 (m, 3H), 6.58 (s, 1H), 6.44 (s, 1H), 4.49
(dd, J = 8.05, 14.93 Hz, 1H), 3.83 ꢀ 3.91 (m, 5H), 3.81 (s, 3H), 3.79 (s, 3H), 3.58 ꢀ 3.71 (m, 2H),
3
.34 ꢀ 3.51 (m, 1H), 3.10 ꢀ 3.34 (m, 2H), 2.78 ꢀ 3.00 (m, 4H), 2.41 ꢀ 2.56 (m, 1H), 1.72 ꢀ 1.87 (m,
2
H), 1.39 ꢀ 1.53 (m, 2H), 0.97 (t, J = 7.35 Hz, 3H). m/z 533 (M+H). HRMS (ESI, CH OH) m/z
3
+
calcd for C H N O [M+H] 533.3010, m/z found 533.3057.
3
2
41
2
5
N-Benzyl-2-(1-{[4-(hexyloxy)-3-methoxyphenyl]methyl}-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-2-yl)acetamide (14). This was made by the general procedure from
1
phenol 12 in 73% yield. H NMR (300 MHz, CHLOROFORMꢀd) δ 7.19 ꢀ 7.34 (m, 3H), 7.08 ꢀ
7
4
2
1
.16 (m, 2H), 7.01 (dd, J = 5.23, 7.49 Hz, 1H), 6.63 ꢀ 6.73 (m, 3H), 6.59 (s, 1H), 6.44 (s, 1H),
.49 (dd, J = 8.01, 14.88 Hz, 1H), 3.84 ꢀ 3.90 (m, 5H), 3.81 (s, 3H), 3.79 (s, 3H), 3.58 ꢀ 3.71 (m,
H), 3.34 ꢀ 3.49 (m, 1H), 3.10 ꢀ 3.34 (m, 2H), 2.79 ꢀ 2.99 (m, 4H), 2.41 ꢀ 2.56 (m, 1H), 1.74 ꢀ
.88 (m, 2H), 1.29 ꢀ 1.51 (m, 6H), 0.91 (t, J = 6.78 Hz, 3H). m/z 561 (M+H). HRMS (ESI,
+
CH OH) m/z calcd for C H N O [M+H] 561.3323, m/z found 561.3362.
3
34 45
2
5
N-Benzyl-2-[6,7-dimethoxy-1-({3-methoxy-4-[2-(piperidin-1-yl)ethoxy]phenyl}methyl)-
1,2,3,4-tetrahydroisoquinolin-2-yl]acetamide (15). This was prepared from 12 using the
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general procedure in 27% yield. H NMR (300 MHz, CHLOROFORMꢀd) δ 7.19 ꢀ 7.35 (m, 3H),
7.12 (d, J = 6.69 Hz, 2H), 7.03 (dd, J = 5.09, 7.44 Hz, 1H), 6.66 ꢀ 6.73 (m, 3H), 6.59 (s, 1H),
6
.43 (s, 1H), 4.48 (dd, J = 7.96, 14.93 Hz, 1H), 4.02 (t, J = 6.31 Hz, 2H), 3.87 (s, 3H), 3.81 (s,
10
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14
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49
50
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54
55
56
57
58
59
60
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H), 3.78 (s, 3H), 3.59 ꢀ 3.72 (m, 2H), 3.34 ꢀ 3.48 (m, 1H), 3.11 ꢀ 3.34 (m, 2H), 2.83 ꢀ 2.99 (m,
4H), 2.76 ꢀ 2.82 (m, 2H), 2.42 ꢀ 2.56 (m, 5H), 1.61 (quin, J = 5.49 Hz, 4H), 1.40 ꢀ 1.51 (m, 2H).
+
m/z 588 (M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H] 588.3432, m/z found
3
35 46
3
5
5
88.3489.
4-({2-[(Benzylcarbamoyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
yl}methyl)-2-methoxyphenyl butanoate (16). To a mixture of phenol 12 (50 mg, 0.105 mmol),
butyric acid (9 mg, 10 ꢀL, 0.105 mmol) and BOP (46 mg, 0.105 mmol) in DCM (1 mL) was
added diisopropylethylamine (34 mg, 46 ꢀL, 0.262 mmol) and the reaction stirred at RT under
N overnight. The reaction was diluted with EtOAc, washed with 2N HCl, NaHCO solution and
2
3
brine, then dried over MgSO and the solvent was removed under reduced pressure. The crude
4
was purified by chromatography on silica (0ꢀ75% EtOAc in hexane) to give the desired ester as a
1
yellow oil (54 mg, 95%). H NMR (300 MHz, CHLOROFORMꢀd) δ 7.23 ꢀ 7.35 (m, 3H), 7.14 ꢀ
7
.21 (m, 2H), 7.07 (t, J = 6.22 Hz, 1H), 6.78 ꢀ 6.85 (m, 1H), 6.66 ꢀ 6.74 (m, 2H), 6.58 (s, 1H),
6.36 (s, 1H), 4.40 ꢀ 4.50 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.70 (s, 3H), 3.63 ꢀ 3.95 (m, 2H),
3
.11 ꢀ 3.47 (m, 3H), 2.78 ꢀ 3.04 (m, 4H), 2.42 ꢀ 2.63 (m, 3H), 1.73 ꢀ 1.89 (m, 2H), 1.07 (t, J =
+
7
.39 Hz, 3H). m/z 547 (M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H]
3
32 39
2
6
547.2803, m/z found 547.2845.
4-({2-[(Benzylcarbamoyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
yl}methyl)-2-methoxyphenyl methanesulfonate (17). To a solution of phenol 12 (30 mg, 0.063
mmol) in DCM (0.5 mL) cooled in ice was added methanesulfonyl chloride (14 mg, 10 ꢀL,
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.126 mmol) and triethylamine (16 mg, 22 ꢀL, 0.157 mmol). The reaction was allowed to warm
to RT overnight. The reaction mixture was applied directly to silica for chromatography (0ꢀ100%
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EtOAc in hexane) to give the desired sulfonate as a yellow oil (21 mg, 60%). H NMR (300
0
1
2
3
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MHz, CHLOROFORMꢀd) δ 7.22 ꢀ 7.37 (m, 3H), 7.17 (d, J = 6.88 Hz, 2H), 7.09 (d, J = 8.29 Hz,
2H), 6.68 ꢀ 6.77 (m, 2H), 6.60 (s, 1H), 6.32 (s, 1H), 4.44 (dd, J = 7.25, 14.88 Hz, 1H), 3.95 (dd, J
=
5.09, 14.98 Hz, 1H), 3.87 (s, 3H), 3.77 (s, 6H), 3.66 ꢀ 3.74 (m, 1H), 3.28 ꢀ 3.42 (m, 2H), 3.22
(br. s., 1H), 3.14 (s, 3H), 2.81 ꢀ 3.06 (m, 4H), 2.53 (d, J = 16.20 Hz, 1H). m/z 555 (M+H).
+
HRMS (ESI, CH OH) m/z calcd for C H N O S [M+H] 555.2160, m/z found 555.2212.
3
29 35
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7
N-Benzyl-2-(1-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-2-yl)acetamide (18). This was prepared from phenol 12 by the general
1
procedure in 15% yield. H NMR (300 MHz, CHLOROFORMꢀd) δ 7.19 ꢀ 7.45 (m, 8H), 7.12 (d,
J = 6.78 Hz, 2H), 6.98 ꢀ 7.07 (m, 1H), 6.61 ꢀ 6.74 (m, 3H), 6.58 (s, 1H), 6.41 (s, 1H), 5.00 (s,
2
H), 4.45 (dd, J = 8.01, 14.98 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.55 ꢀ 3.76 (m,
2
H), 3.34 ꢀ 3.48 (m, 1H), 3.10 ꢀ 3.33 (m, 2H), 2.77 ꢀ 2.99 (m, 4H), 2.41 ꢀ 2.55 (m, 1H). m/z 567
+
(M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H] 567.2854, m/z found 567.2917.
3
35 39
2
5
N-Benzyl-2-(6,7-dimethoxy-1-{[3-methoxy-4-(4-phenoxybutoxy)phenyl]methyl}-1,2,3,4-
tetrahydroisoquinolin-2-yl)acetamide (19). This was prepared from 12 using the general
1
procedure in 71% yield. H NMR (300 MHz, CHLOROFORMꢀd) δ 7.18 ꢀ 7.35 (m, 5H), 7.11
(d, J = 6.88 Hz, 2H), 7.02 (dd, J = 5.04, 7.39 Hz, 1H), 6.87 ꢀ 6.98 (m, 3H), 6.65 ꢀ 6.73 (m, 3H),
6.60 (s, 1H), 6.45 (s, 1H), 4.50 (dd, J = 8.01, 14.98 Hz, 1H), 4.04 (t, J = 5.89 Hz, 2H), 3.90 ꢀ
3.97 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.60 ꢀ 3.73 (m, 2H), 3.36 ꢀ 3.51 (m, 1H),
3.11 ꢀ 3.35 (m, 2H), 2.80 ꢀ 3.01 (m, 4H), 2.44 ꢀ 2.57 (m, 1H), 1.91 ꢀ 2.04 (m, 4H). m/z 625
+
(M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H] 625.3272, m/z found 625.3335.
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-({2-[(Benzylcarbamoyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
yl}methyl)-2-methoxyphenyl 4-methylbenzene-1-sulfonate (20). This was prepared from 12 as
1
sulfonate 17 above. Yield 80%. H NMR (300 MHz, CHLOROFORMꢀd) δ 7.76 (d, J = 8.29 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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2
H), 7.21 ꢀ 7.36 (m, 5H), 7.17 (d, J = 6.97 Hz, 2H), 7.05 (br. s., 1H), 6.91 (d, J = 8.10 Hz, 1H),
6.54 ꢀ 6.67 (m, 3H), 6.31 (s, 1H), 4.44 (dd, J = 7.30, 14.74 Hz, 1H), 3.92 (d, J = 4.90 Hz, 1H),
3
.86 (s, 3H), 3.76 (s, 3H), 3.62 ꢀ 3.71 (m, 1H), 3.49 (s, 3H), 3.10 ꢀ 3.39 (m, 3H), 2.75 ꢀ 3.03 (m,
4
H), 2.49 ꢀ 2.57 (m, 1H), 2.46 (s, 3H). m/z 631 (M+H). HRMS (ESI, CH OH) m/z calcd for
3
+
C H N O S [M+H] 631.2473, m/z found 631.2536.
35
39
2
7
N-Benzyl-2-(6,7-dimethoxy-1-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]methyl}-
1,2,3,4-tetrahydroisoquinolin-2-yl)acetamide (21). This was prepared from 12 using the
1
general procedure in 92% yield. H NMR (300 MHz, CHLOROFORMꢀd) δ 8.59 (dd, J = 0.85,
4.05 Hz, 1H), 7.61 ꢀ 7.71 (m, 1H), 7.53 (d, J = 7.82 Hz, 1H), 7.17 ꢀ 7.32 (m, 4H), 7.10 (d, J =
6.59 Hz, 2H), 6.96 ꢀ 7.05 (m, 1H), 6.69 ꢀ 6.75 (m, 2H), 6.62 ꢀ 6.68 (m, 1H), 6.59 (s, 1H), 6.42 (s,
1H), 5.15 (s, 2H), 4.46 (dd, J = 7.86, 14.84 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.58
ꢀ 3.74 (m, 2H), 3.34 ꢀ 3.48 (m, 1H), 3.11 ꢀ 3.33 (m, 2H), 2.78 ꢀ 3.00 (m, 4H), 2.50 (d, J = 15.82
+
Hz, 1H). m/z 568 (M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H] 568.2806,
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3
5
m/z found 568.2869.
N-Benzyl-2-(6,7-dimethoxy-1-{[3-methoxy-4-(pyridin-3-ylmethoxy)phenyl]methyl}-
1,2,3,4-tetrahydroisoquinolin-2-yl)acetamide (22). This was prepared from 12 using the
1
general procedure in 42% yield. H NMR (300 MHz, CHLOROFORMꢀd) δ 8.65 (d, J = 1.60
Hz, 1H), 8.57 (dd, J = 1.27, 4.76 Hz, 1H), 7.76 (d, J = 7.82 Hz, 1H), 7.18 ꢀ 7.34 (m, 4H), 7.12 (d,
J = 6.59 Hz, 2H), 7.04 (br. s., 1H), 6.64 ꢀ 6.74 (m, 3H), 6.60 (s, 1H), 6.42 (s, 1H), 4.95 (s, 2H),
4.49 (dd, J = 7.91, 15.16 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.62 ꢀ 3.77 (m, 2H),
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.13 ꢀ 3.50 (m, 3H), 2.80 ꢀ 3.02 (m, 4H), 2.52 (d, J = 15.73 Hz, 1H). m/z 568 (M+H). HRMS
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(ESI, CH OH) m/z calcd for C H N O [M+H] 568.2806, m/z found 568.2869.
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4-({2-[(Benzylcarbamoyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-
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yl}methyl)-2-methoxyphenyl benzenesulfonate (23). This was prepared from 12 as sulfonate
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17 above. Yield 69%. H NMR (300 MHz, CHLOROFORMꢀd) δ 7.85 ꢀ 7.92 (m, 2H), 7.62 ꢀ
7.71 (m, 1H), 7.48 ꢀ 7.57 (m, 2H), 7.21 ꢀ 7.36 (m, 3H), 7.17 (d, J = 6.78 Hz, 2H), 7.04 (t, J =
5.93 Hz, 1H), 6.93 (d, J = 8.10 Hz, 1H), 6.64 (d, J = 8.19 Hz, 1H), 6.55 ꢀ 6.60 (m, 2H), 6.31 (s,
1H), 4.44 (dd, J = 7.39, 14.74 Hz, 1H), 3.86 (s, 3H), 3.84 ꢀ 3.96 (m, 1H), 3.76 (s, 3H), 3.63 ꢀ
3.72 (m, 1H), 3.45 (s, 3H), 3.11 ꢀ 3.38 (m, 3H), 2.76 ꢀ 3.03 (m, 4H), 2.41 ꢀ 2.55 (m, 1H). m/z 617
+
(M+H). HRMS (ESI, CH OH) m/z calcd for C H N O S [M+H] 617.2316, m/z found
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617.2377.
N-Benzyl-2-{6,7-dimethoxy-1-[(4-methoxy-3-nitrophenyl)methyl]-1,2,3,4-
tetrahydroisoquinolin-2-yl}acetamide (26). Phenol 36 (40 mg, 0.08 mmol) and potassium
carbonate (17 mg, 0.12 mmol) were combined in DMF (2 mL) and iodomethane (14 mg, 6 ꢀL,
0.097 mmol) was added. The reaction was heated to 50 °C for 2 hr. The reaction was diluted
with EtOAc, washed with NaHCO solution and brine, dried over MgSO and the solvent was
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4
removed under reduced pressure. The crude was purified by chromatography on silica (0ꢀ100%
1
EtOAc in hexane) to give the desired product (30 mg, 75%).
H NMR (300 MHz,
CHLOROFORMꢀd) δ 7.99 (s, 1H), 7.68 (d, J = 2.26 Hz, 1H), 7.28 ꢀ 7.39 (m, 4H), 7.02 ꢀ 7.14
m, 1H), 6.75 (d, J = 8.29 Hz, 1H), 6.60 (s, 1H), 6.44 (s, 1H), 4.37 ꢀ 4.54 (m, 1H), 3.90 ꢀ 3.96 (m,
1H), 3.85 ꢀ 3.88 (m, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.65 (dd, J = 5.46, 9.23 Hz, 1H), 3.38 ꢀ 3.47
(
(m, 2H), 3.11 ꢀ 3.22 (m, 1H), 2.90 ꢀ 3.00 (m, 4H), 2.46 ꢀ 2.58 (m, 1H). m/z 506 (M+H). HRMS
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(ESI, CH OH) m/z calcd for C H N O [M+H] 506.2286, m/z found 506.2327.
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-{1-[(3-Amino-4-methoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-
yl}-N-benzylacetamide (27). To the nitro derivative 26 (200 mg, 0.4 mmol) in ethanol (20 mL)
was added hydrazine monohydrate (198 mg, 0.19 mL, 4.0 mmol) and then heated to 50 °C for 15
min. Raney nickel (2800 type as a slurry in water, 232 mg, 4.0 mmol) was added and heating
continued for 1 hr. The reaction was filtered through Celite, rinsed with ethanol then the solvent
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was removed under reduced pressure to give the desired amine as a clear oil (100 mg, 53%). H
NMR (300 MHz, CHLOROFORMꢀd) δ 7.68 (s, 2H), 7.20 ꢀ 7.35 (m, 5H), 7.09 (d, J = 6.78 Hz,
2
H), 6.85 (br. s., 1H), 6.75 (d, J = 8.48 Hz, 1H), 6.59 (s, 1H), 6.43 (s, 1H), 4.47 (dd, J = 7.44,
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5.16 Hz, 1H), 3.87 (s, 3H), 3.85 ꢀ 3.98 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.60 ꢀ 3.71 (m, 1H),
3.11 ꢀ 3.48 (m, 3H), 2.83 ꢀ 3.05 (m, 4H), 2.51 (d, J = 16.77 Hz, 1H). m/z 476 (M+H).
N-Benzyl-2-(1-{[3-(dimethylamino)-4-methoxyphenyl]methyl}-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolin-2-yl)acetamide (28). To a solution of amine 27 (50 mg, 0.10 mmol) in
methanol (1 mL) was added formaldehyde (37% solution in water, 1 mL) and glacial acetic acid
(
21 mg, 20 ꢀL, 0.35 mmol). To this was then added sodium cyanoborohydride (31 mg, 0.5
mmol) and the reaction stirred at RT for 2 hr. 1N HCl (0.1 mL) was added then the reaction was
diluted with EtOAc, washed with NaHCO solution and brine, dried over MgSO and the solvent
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was removed under reduced pressure. The crude was purified by chromatography on silica (0ꢀ
1
50% EtOAc in hexane) to give the desired dimethylamine (26 mg, 52%). H NMR (300 MHz,
CHLOROFORMꢀd) δ 7.18 ꢀ 7.34 (m, 3H), 7.01 ꢀ 7.14 (m, 3H), 6.70 ꢀ 6.78 (m, 2H), 6.55 ꢀ 6.65
(
m, 2H), 6.41 (s, 1H), 4.48 (dd, J = 7.82, 14.98 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.75 (s, 3H),
3
.59 ꢀ 3.72 (m, 2H), 3.37 ꢀ 3.51 (m, 1H), 3.13 ꢀ 3.35 (m, 2H), 2.79 ꢀ 3.00 (m, 4H), 2.75 (s, 6H),
+
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.44 ꢀ 2.56 (m, 1H). m/z 504 (M+H). HRMS (ESI, CH OH) m/z calcd for C H N O [M+H]
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504.2857, m/z found 504.2906.
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