Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands

Article abstract of DOI:10.1039/c3ob42254b

5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2, 3-dimethoxybenzamide 1 is a potent and selective σ₂ receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ₁/σ₂ binding affinity and selectivity. Compounds with a rigid piperidine spacer gave K_i values for the σ₂ receptor between 8.7-845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ₂K_i values of 4.4-133 nM whereas varying the length and flexibility of the carbon spaces gave σ₂K_i values 0.88-15.0 nM, some of the most active, selective σ₂ ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.

Full text of DOI:10.1039/c3ob42254b

Organic &
Biomolecular Chemistry
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Synthesis and in vitro evaluation of
tetrahydroisoquinolines with pendent aromatics
Cite this: DOI: 10.1039/c3ob42254b
as sigma-2 (σ ) selective ligands†
2
a,b
a
a
a
b
Mark E. Ashford, Vu H. Nguyen, Ivan Greguric, Tien Q. Pham, Paul A. Keller*
c
and Andrew Katsifis*
5
-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide 1 is a
potent and selective σ receptor ligand suitable for further development. A series of new analogues,
incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or
cyclic amine spacer have been synthesised and assessed for their σ /σ binding affinity and selectivity.
Compounds with a rigid piperidine spacer gave K values for the σ receptor between 8.7–845 nM. Chan-
ging the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ
values of 4.4–133 nM whereas varying the length and flexibility of the carbon spaces gave σ values
.88–15.0 nM, some of the most active, selective σ ligands to date. Thus, the flexibility and length of the
2
1
2
i
2
2
K
i
2
K
i
0
2
Received 13th November 2013,
Accepted 27th November 2013
carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity
and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic
acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in
pharmacological and imaging studies.
DOI: 10.1039/c3ob42254b
www.rsc.org/obc
ligand-regulated molecular chaperone in the endoplasmic reti-
culum of cells involved in the regulation and modulation of
Introduction
Sigma (σ) receptors are a distinct non-opioid, class of receptors voltage-regulated and ligand-gated ion channels, including
2
+
+
+
−
that are located in the central nervous system as well as in a Ca , K , Na , Cl , and SK channels, and NMDA and IP3 recep-
1
4
variety of peripheral tissues and organs. These receptors are tors. The findings that neuroactive steroids bind with moder-
unique proteins located in plasma, mitochondrial and endo- ate affinity to σ sites, suggest that σ receptors may modulate
plasmic reticulum membranes of tissue derived from brain, the activity of GABA and NMDA receptors in the CNS. These
1
1
5
2
kidney, liver, immune, endocrine and reproductive organs.
observations have rekindled interest in assessing their
Based on drug-binding profiles and specific pharmacological potential role in inhibiting or potentiating ion channels with
characteristics of σ-receptor ligands, two distinct receptor sub- implications in many neurological diseases, amnesia, pain,
6
types denoted sigma-1 (σ ) and sigma-2 (σ ) have been identi- depression, schizophrenia, and neuroprotection.
1
2
fied with molecular weights of ∼25 kDa (σ
1
), and ∼21.5 kDa
The discovery of the presence of σ
1
2
and σ receptors in
3
(
σ ). The σ -receptor has recently been identified as a unique many human and rodent tumours has opened new possibili-
2
1
ties in the area of cancer research, particularly the involvement
7
of σ
2
receptors. In an initial screening of human brain
a
tumours, σ receptors were detected in 15 of 16 tumors exam-
ined. Strong receptor expression was observed in a brain
metastasis from a lung adenocarcinoma and in a human
ANSTO Life Sciences Division, ANSTO, Locked Bag 2001, Kirrawee DC, NSW 2232,
Australia
b
Centre for Medicinal Chemistry, School of Chemistry, University of Wollongong,
NSW 2522, Australia. E-mail: keller@uow.edu.au; Fax: +61 2 4221 4287;
Tel: +61 2 4221 4692
8
neuroblastoma passaged in nude mice, whereas a 2-to-5-fold
9
c
overexpressed in renal and colon carcinomas was also found.
Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital,
Observations that a higher number of binding sites was
Camperdown, 2050, Sydney, NSW 2050, Australia.
E-mail: andrewk@nucmed.rpa.cs.nsw.gov.au; Fax: +61 2 9515 5142;
Tel: +61 2 9515 5150
3
observed for the non-subtype-selective σ agonist [ H]1,3-di-
3
o-tolylguanidine ([ H]DTG) than for the σ -subtype selective
1
†
Electronic supplementary information (ESI) available: Synthesis details for
-methoxytetrahydroisoquinoline starting material. Spectral data for piperidine
3
3
agonist [ H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([ H]3-
PPP) in renal and colon carcinomas cell lines, suggested that
7
1
8
starting materials; NMR spectra for all final compounds. See DOI:
0.1039/c3ob42254b
1
the σ2 receptor is more abundant than the σ1 subtype.
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However, immunocytochemical staining did detect σ
1
recep- shown that Pgrmc1 is required for tumour cell proliferation,
tors in the majority of human primary breast carcinomas, par- motility and tumour formation in vivo. Furthermore, small
ticularly in tumours with a positive progesterone receptor molecule inhibitors of Pgrmc1, such as AG-205 (5, Fig. 1), sup-
1
0
status.
pressed the growth of lung, breast and cervical cancer cell
2
0
Over-expression of σ2 receptors has been observed in lines.
primary colon cancers, renal carcinomas and sarcomas and
pancreatic cancers. Recently it was shown that the σ
9
A number of structurally-diverse compounds have been
1
1
21
2
recep- shown to possess high affinity to σ receptors. However, most
tor density in proliferative breast cancer cells is about tenfold of these compounds were shown to bind selectively to the σ1
1
2
higher than in quiescent breast cancer cells and that σ
receptor expression is up-regulated during the transition from Some early σ
quiescence to proliferation and down-regulated during the include the benzomorphan-7-one analogue CB-64D (3), the
2
receptor or have similar affinities to both σ
1
and σ
2
receptors.
2
selective ligands reported in the literature
2
2
1
3
transition from proliferation to quiescence. Consequently, σ
receptor density has been proposed as a tool to determine the 4), ibogaine, and the tropane analogue WC-59 (6). These,
proliferative status of tumours. Most significantly, selective and later σ ligands, have been recently comprehensively
2
σ receptor ligands e.g. SV119 2 (Fig. 1) were shown to not only reviewed.
2
3-(ω-aminoalkyl)-1H-indole analogue Lu 28-179 (siramesine,
2
3
24
25
2
3
2
2
6
bind to these tumour cells, but also induce apoptosis in a
SAR studies based on a series of conformationally-flexible
1
3,14
dose-dependent fashion in vitro and in vivo.
Furthermore, benzamide analogues, initially developed as D -selective
3
1
5
27d,e,f
σ
2
expression has been linked to tumour cell proliferation.
ligands,
produced a class of compounds having a high
2
7
Although the exact mechanism for the modulation of the affinity for σ
2
receptors and excellent σ
2
1
: σ selectivity ratios.
signalling pathways downstream of σ2 receptors leading to A key development in this series of compounds was the pres-
cancer cell death is not known, they are thought to involve ence of a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ring.
1
6
changes in cytosolic calcium and sphingolipid signalling.
This not only resulted in compounds having a high affinity
Furthermore, σ receptor ligands may have a potential role in and excellent selectivity for σ versus σ receptors, but dramati-
2
2
1
1
7
the treatment of tumours while specific radiolabelled σ
2
cally reduced their affinity for dopamine receptors. Further
receptor ligands can be used to image tumour cell prolifer- modifications, including the incorporation of fluorescent and
ation in vivo using positron emission tomography (PET) or radiolabelled probes produced molecules, e.g. WC-59 (6) with
1
8
28
single-photon emission computed tomography (SPECT).
The σ receptor has not been cloned and its structure has ligands have subsequently been used to directly identify,
not been determined. However, recently, the σ receptor, was locate and quantify this protein using a variety of receptor-
significant σ
2
affinity and selectivity. These σ
2
selective
2
2
2
9
identified as the progesterone receptor membrane component binding and molecular imaging techniques.
(Pgrmc1) using photo-affinity studies and a σ ligand con- Molecules based on the conformationally-flexible benz-
taining both a photoactive azide moiety and a fluorescein iso- amide 1 have proven to be an important source of σ -selective
1
2
2
1
9
thiocyanate group for protein visualisation. This protein was compounds. Preliminary work has shown that having a confor-
also found to be up-regulated in multiple types of cancer and mationally flexible spacer unit of four carbon atoms was
Fig. 1 Selected examples of σ
2
ligands with their corresponding σ
1
activities and the sigma selectivity index between the two targets. The tetra-
hydroisoquinolylamide 1 was the starting point for this project.
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2
7a
beneficial for σ
2
binding affinity and selectivity.
However, 24 were synthesised to observe the effects of changing the
limited work was undertaken on the effects of substitutions on heteroatom from an oxygen, to a nitrogen 23 or sulphur 24.
the carboxylic acid and no work had been performed to The compounds were still selective for the σ receptor (σ /σ
2
1
2
=
observe what effect restricting conformational freedom has on 4.2 and 0.98 respectively); however, the benzofuran 33
σ2 receptor activity in this class. Further, little work has been remained the better derivative. Changing to the larger
conducted on varying the substitution pattern of the methoxy 1-naphthyl (28), the 3-quinolyl (26) or the styryl (25) derivatives
groups on the tetrahydroisoquinoline ring, although, it has substantially weakened the activity. Changing the point of
been shown that either opening the tetrahydroisoquinyl ring attachment for various heterocycles (e.g. indole C6 or C3)
or replacing the methoxy groups with methylene-, ethylene- resulted in some of the weakest activity observed. However,
2
7b,30
and propylenedioxy rings decrease the σ
2
activity.
Despite adding a substituent to indole C5 resulted in increasing
these results, there remains considerable scope for further activity across the range. Translating this result to the ‘best’
modifications to this structure for the preparation of radio- terminal moiety, the 2-benzofuran with the addition of C5
labeled probes to image this receptor in vitro and in vivo. In bromo (34) improved the activity by an order of magnitude (σ
this study, the effect of modulating the conformational = 8.7 nM, σ /σ = 292). The use of an iodo substituent (35) was
2
1
2
freedom of the spacer, varying the carboxylic acid substitution not as effective (σ
2
= 11.0 nM, σ
1
2
/σ = 62.0). Starting from the
on the amide and modifying the methoxy substitution on the bromobenzofuran derivative 34, and extending the linker by
tetrahydroisoquinolyl ring was investigated with the purpose one methylene (36) and two methylene units (37) resulted in
of expanding the scope of analogues synthesised and evalu- slight improvements in activity but at a significant expense to
ated to produce a candidate that was suitable for radiolabelling selectivity.
with SPECT and PET isotopes.
The lead compound 1 had a flexible four carbon linker and
a bromodimethoxyphenyl ring at the terminus. The incorpor-
ation of the restricted linker and the methylpiperidine core
Results and discussion
Chemistry
(
3
22) decreased activity and selectivity for the σ receptor (σ =
2
2
67 nM, σ
1
2
/σ = 5.9) compared to the lead 1. Given the best
terminal aromatic group was a bromobenzofuran, the corres-
ponding flexible linker versions were synthesised (54–59). Sur-
prisingly the C5-iodosubstituted benzofuran 59 produced the
Using the tetrahydroisoquinoline benzamide 1 as our lead
compound, we synthesised a series of analogues and tested
them as selective σ
idines 7–9 were Boc N-protected (10–12), followed by the incor-
poration of leaving group using standard chemistry
Scheme 1). The addition of the 6,7-dimethoxy-1,2,3,4-tetra-
2
ligands. Therefore, the substituted piper-
best outcome (σ
2
= 0.88 nM, σ
1
/σ
2
= 886) with an order of mag-
nitude better σ activity and the best selectivity over σ that we
2
1
a
have seen.
(
Our final series of analogues investigated examined the
removal of one of the tetrahydroisoquinoline methoxy substi-
tuents and the size of the flexible linker (60–63). While signifi-
cant activity was noted for the monomethoxy derivative 61, the
selectivity was notably reduced.
hydroisoquinoline unit under S 2 reaction conditions (16–18)
N
followed by N-deprotection yielded the secondary amines
1
9–21 which underwent coupling with a variety of aromatic
carboxylic acids to produce target tetrahydroisoquinolylamides
2–32. Additionally, the use of variously substituted benzo-
2
2
Therefore, the optimal ligand for σ activity and selectivity
furan-2-carboxylic acids yielded ligands 33–39. The synthesis
of target ligands with more flexible central linkers (Scheme 2)
started with the alkylation of tetrahydroisoquinolines with
was the iodobenzofuran 59 containing a benzofuran carbox-
amide moiety with a halogen substitution at C5 and a 6,7-
dimethoxytetrahydroisoquinoline separated by a six carbon
bromonitriles of varying lengths (40–46) followed by LiAlH
4
flexible spacer. This possessed a σ
2
activity of 0.88 nM with a
reduction to the corresponding primary amines 47–53. Coup-
ling of the amines to 5-bromo- or 5-iodobenzofuran-2-carb-
oxylic acids yielded the targets 54–63.
selectivity index of 886. On the other hand, the best ligand for
σ
1
activity was 61 with a value of 76 nM and a σ
2
value of
4
.4 nM. This relatively poor activity for σ was still significantly
1
better than most other derivatives and also still possessed
better σ activity. Therefore, the σ activity for this series, along
with the consistently good selectivity values can be seen as sig-
2
2
Discussion
All synthesised ligands were tested for their σ1 and σ2 acti- nificant and consistent and validates pursuing this extended
vities, their σ selectivities determined and their C log P calcu- SAR study.
lated (Tables 1–3). The first series of compounds synthesised Fig. 2 shows a summary of the structure–activity results that
2
investigated the use of a conformationally restricted linker by have emerged from this study. Of the great variety of terminal
incorporating a six membered ring into the central chain – it aromatic moieties investigated, the benzofuran was the most
also varied the terminal aromatic moiety, including the use of potent, particularly with the presence of a C5-iodo substituent.
both aromatic carbocycles and heterocycles. Changing from The central linker is best if flexible and is optimal at six
the aromatic amide as in 22 to the benzofuran amide substi- methylenes. Although the dimethoxy substituted tetrahydro-
tution of 33 gave a more selective and active compound (σ
2
=
isoquinoline exhibits good in vitro activity with just
4
4 nM, σ /σ = 7.30) when compared to 22. Compounds 23 and one methoxy substituent, it does at the expense of selectivity
1
2
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Scheme 1 Reagents: (a) di-tert-butyldicarbonate, CH
2
Cl
2
, (b) PPh
3
, I
2
, imidazole, (c) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride,
2 3 2 2
TBAI, K CO , DMF, (d) CH Cl –TFA (2 : 1), (e) EDC, HOBt, DMF, R-COOH, (f) EDC, HOBt, DMF, 5-substituted-benzofuran-2-carboxylic acids.
2 n 2 3 4
Scheme 2 Reagents: (a) Br(CH ) CN, TBAI, K CO , DMF, (b) LiAlH , THF, (c) EDC, HOBt, DMF.
and appears to be optimal with 2 methoxy substituents and selective for the σ2 receptor, with the piperidine based
present.
core favoured in most cases. The halogenated benzofuran
derivatives 34 (K /σ = 292) and 35 (K /σ = 62.0) display-
i
σ
1
2
i
σ
1
2
ing good affinity and selectivity and increasing the confor-
mational freedom produced more σ2 active derivatives.
Conclusion
However, this also decreased σ
/σ = 886). Removal of the methoxy groups
. We from the isoquinoline ring did not produce a more selective or
have shown that this class of derivatives can be highly potent high affinity ligand than that seen for compound 59, and these
2
selectivity in all cases except
A series of tetrahydroisoquinolyl benzamides were synthesised for that of 59 (K
and tested for their binding affinities to both σ and σ
σ
i
1
2
1
2
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Table 1
1 2 i
σ and σ binding affinities (K ) for benzamides
n
C log P
σ
2
K
i
(nM)
σ
1
K
i
(nM)
1 2
σ /σ
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
3
2
3
3.16
3.29
3.38
3.05
2.38
2.77
3.08
2.76
4.20
3.51
3.63
3.22
3.96
4.25
3.99
4.02
3.83
4.36
367 ± 1.0
88 ± 5
97 ± 2
137 ± 7
283 ± 2
845 ± 15
115 ± 9
752 ± 23
40 ± 12
2180 ± 54
372 ± 11
95 ± 1
818 ± 6
82 ± 7.5
164 ± 5
475 ± 34
130 ± 12
3863 ± 153
77 ± 11
395 ± 39
322 ± 56
2545 ± 103
682 ± 181
360 ± 41
209 ± 21
184 ± 2
5.90
4.20
0.98
5.97
0.29
0.19
4.13
0.17
97
1.80
2.20 Fig. 2 Structure and activity relationships for the tetrahydroisoquino-
7.30 lines with pendent aromatics as σ selective ligands.
292
62.0
73.0
39.0
17.0
7.9
44 ± 5
160 ± 15
44 ± 7.0
8.7 ± 0.6
11.0 ± 1.2
4.9 ± 1.2
5.3 ± 0.2
10.6 ± 1.1
12.4 ± 0.9
2
results corroborate the need to have a flexible linker with a 6,7-
dimethoxy isoquinyl ring substitution for optimum σ binding
affinity. In addition, structural features were identified that
2
97.9 ± 8.0
result in extremely poor affinity and selectivity for both the σ1
and σ receptor subtypes. Therefore, the new information from
2
our study offers a useful guide for designing σ specific com-
2
Table 2
σ
1
and σ
2
binding affinities (K
i
) for benzamides
pounds and promising new lead compounds 34 and 59 were
2
produced, that show highly active σ activity with significant
selectivity, and have the potential to be utilised in future
SPECT radiochemistry studies.
Experimental
Chemistry – general considerations
R
1
n
C log P
σ
2
K
i
(nM)
σ
1
K
i
(nM)
σ
1
/σ
2
All reagents purchased were used without further purification.
Air sensitive reactions were performed under a positive
5
5
5
5
5
5
4
5
6
7
8
9
Br
Br
Br
I
I
I
1
2
3
1
2
3
3.63
3.81
3.94
3.82
3.91
4.47
15.0 ± 1.4
6.2 ± 0.4
8.0 ± 0.1
6.2 ± 1.2
8.9 ± 2.1
0.88 ± 0.5
3718 ± 650
410 ± 18.5
157 ± 2
752 ± 148
204 ± 10
248
66.1 pressure of nitrogen gas. THF and Et
O were distilled from
2
19.6
121
22.9
886
sodium under nitrogen gas. Petroleum ether (PE) of boiling
point range 40–60 °C was used. Melting points were recorded
on a Gallenkamp (Griffin) melting point apparatus with temp-
eratures reported in degrees Celsius (°C) and are uncorrected.
NMR spectra were performed on a Bruker Advance DPX 400
780 ± 127
1
operating at 400 MHz for H NMR spectra and 100 MHz for
1
3
Table 3
σ
1
2 i
and σ binding affinities (K ) for benzamides
C NMR spectra. Electron impact and electrospray mass
spectra were obtained using a Shimadzu QP-5000 GC-MS
spectrometer by direct insertion technique with a 70 eV elec-
tron beam and high resolution on a VG Autospec spectro-
meter. Ion mass to charge (m/z) values are stated and their
3
relative abundances as a percentage in parentheses. [ H]
3
Pentazocine and [ H] DTG were purchased from Perkin-Elmer
Life Sciences (Boston, MA, USA).
R
1
R
2
n
C log P
σ
2
K
i
(nM)
σ
1
K
i
(nM)
σ
1
/σ
2
The lipophilicity was assessed using RP-HPLC by determin-
3
1
ing the log P value using literature procedures. Samples, dis-
solved in methanol, were analyzed using a Waters, Xterra C18
column (5 μm, 4.6 mm × 150 mm) with a mobile phase con-
sisting of methanol/phosphate buffer (0.1 M, pH 7.5) and a
6
6
6
6
0
1
2
3
OMe
OMe
H
H
H
OMe
OMe
1
2
1
2
4.08
4.31
4.33
4.43
133 ± 3
4.4 ± 1.3
35 ± 5.3
31 ± 1.3
1277 ± 52
76 ± 16
616 ± 12
241 ± 33
9.6
17.3
17.6
7.8
H
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flow rate of 1 mL min− . The log P of a studied compound was (m, 4H), 2.75–2.81 (m, 2H), 3.06–3.09 (m, 2H), 3.51 (s, 2H),
1
1
3
estimated by a comparison of its retention time to that of com- 3.83 (s, 6H), 6.51 (s, 1H), 6.58 (s, 1H). C NMR δ 28.8, 32.4,
pounds of known log P value.
34.3, 46.7, 51.5, 56.1, 56.5, 65.2, 109.7, 111.6, 126.5, 127.1,
+
+
147.3, 147.6. MS-ES m/z 291 (MH , 40), 208 (100%); HRMS-EI
Preparation of compounds 16–18
calculated for C H N O : 290.1994, found 290.1996.
1
7
26 2 2
To a solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(2-(piperidin-4-yl)ethyl)-
1
2 3
hydrochloride (1.0 eq.), K CO (4 eq.) and TBAI (0.1 eq.) in isoquinoline [20]. Cream solid, mp 102–103 °C, yield 83%; H
DMF (20 mL) was added the appropriate piperidine 13, 14, or NMR (CDCl ) δ 1.16–1.54 (m, 5H), 1.69–1.78 (m, 2H), 2.50–2.69
3
1
5 (1.0 eq.). The solution was allowed to stir at rt for 3 days. (m, 6H), 2.80 (bs, 2H), 3.06 (bd, 2H, J = 9.8 Hz), 3.53 (s, 2H),
1
3
The solution was diluted with EtOAc (100 mL) and extracted 3.82 (s, 6H), 6.52 (s, 1H), 6.58 (s, 1H). C NMR δ 29.0, 33.7,
with H O (3 × 20 mL), sat. NaHCO (25 mL), brine (25 mL) and 34.8, 34.9, 46.8, 51.4, 56.0, 56.20, 56.22, 109.8, 111.7, 126.5,
2
3
+
+
H
(
2
O (20 mL). The organic layers were combined, dried 127.0, 147.5, 147.8. MS-ES m/z 305 (MH , 100%); HRMS-EI
Na SO ) and the organic solvent removed. The residue was calculated for C18 : 304.2151, found 304.1391.
1,2,3,4-Tetrahydro-6,7-dimethoxy-2-(3-(piperidin-4-yl)propyl)-
2
4
28 2 2
H N O
subjected to column chromatography (EtOAc–MeOH, 9 : 1) to
yield compounds 16–18.
1
3
isoquinoline [21]. Clear oil, yield 94%; H NMR (CDCl ) δ
tert-Butyl-4-((3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)- 1.12–1.30 (m, 5H), 1.56–1.71 (m, 4H), 2.45 (t, 2H, J = 7.7 Hz),
1
methyl)piperidine-1-carboxylate [16]. Clear oil, yield 78%; H 2.58–2.62 (m, 2H), 2.67 (t, 2H, J = 6.1 Hz), 2.80 (t, 2H, J = 5.8
3
NMR (CDCl ) δ 1.10–1.14 (m, 2H), 1.45 (s, 9H), 1.76–1.80 (m, Hz), 3.08 (bd, 2H, J = 12.0 Hz), 3.51 (s, 2H), 3.810 (s, 3H), 3.813
1
3
3
4
2
1
3
H), 2.33 (m, 2H), 2.67–2.80 (m, 6H), 3.52 (s, 2H), 3.83 (s, 6H), (s, 3H), 6.49 (s, 1H), 6.57 (s, 1H). C NMR (CDCl ) δ 24.3, 28.7,
1
3
.08–4.10 (bs, 2H), 6.52 (s, 1H), 6.59 (s, 1H). C NMR δ 28.6, 32.8, 34.8, 35.9, 46.2, 51.1, 55.88, 55.92, 58.6, 109.6, 111.4,
8.8, 34.1, 35.2, 37.2, 44.2, 51.5, 56.06, 56.08, 56.4, 64.4, 79.4, 126.3, 126.7, 147.2, 147.5. MS-EI m/z 318 (M , 26), 206
09.7, 111.6, 126.4, 126.8, 147.4, 147.7, 155.1. MS-ES m/z 391 (100%); HRMS-EI calculated for C19
+
+
H
30
N
2
O
2
: 318.2307, found
+
+
(MH , 100%); HRMS-ES calculated for C H N O : 391.2586, 318.2305.
22 34 2 4
found 391.2597.
tert-Butyl-4-(2-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-
Preparation of compounds 22–38
1
yl)ethyl)piperidine-1-carboxylate [17]. Clear oil, yield 62%; H To a stirred solution of the appropriate benzoic acid (1.0 eq.)
NMR (CDCl ) δ 1.12–1.24 (m, 2H), 1.45 (s, 9H), 1.49–1.70 (m, in anhydrous DMF (10 mL) was added, EDC (1.3 eq.), HOBt
H), 2.52 (t, 2H, J = 8.0 Hz), 2.66–2.71 (m, 2H), 2.81 (t, 2H, J = (1.1 eq.), and DIPEA (3.0 eq.) and the reaction mixture was
.8 Hz), 3.53 (s, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.06–4.15 (m, stirred at room temperature. After 5 min, a solution of the
3
5
5
2
3
1
1
3
H), 6.51 (s, 1H), 6.59 (s, 1H). C NMR δ 28.6, 28.7, 32.4, 34.0, amine 19, 20 or 21 (1.0 eq.) was added to this reaction
4.5, 44.2, 51.2, 55.8, 56.0, 56.1, 64.3, 79.4, 109.7, 111.6, 126.3, mixture, and then was stirred at room temperature for 2 days
26.9, 147.4, 147.5, 156.0. MS-EI m/z 404 (M , 8), 206 (100%); under N . The reaction mixture was diluted with EtOAc
+
2
HRMS-EI calculated for
04.2672.
tert-Butyl-4-(3-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)- (Na SO ) and solvent removed. The residue was subjected to
C
23
H
36
N
2
O
4
:
2 2 3
404.2675, found (80 mL), washed with H O (3 × 25 mL), sat. Na CO (15 mL),
4
H
2
O (20 mL) and brine (15 mL). The organic layer was dried
2
4
yl)propyl)piperidine-1-carboxylate [18]. Clear oil that solidified column chromatography (EtOAc–MeOH, 95 : 5) to yield com-
1
upon standing (mp 86–89 °C), yield 59%; H NMR (CDCl
3
)
pounds 22–38.
δ 1.06–1.09 (m, 2H), 1.25–1.29 (m, 2H), 1.30–1.44 (m, 1H), 1.42
(5-Bromo-2,3-dimethoxyphenyl)(4-((3,4-dihydro-6,7-dimethoxy-
(
(
(
(
s, 9H), 1.58–1.67 (m, 4H), 2.46 (t, 2H, J = 7.9 Hz), 2.65–2.69 isoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone
[22].
m, 4H), 2.80 (t, 2H, J = 8.0 Hz), 3.52 (s, 2H), 3.81 (s, 3H), 3.82 Prepared as white solid (250 mg, 41%) from 5-bromo-3,4-
1
3
27
1
s, 3H), 4.06–4.11 (m, 2H), 6.50 (s, 1H), 6.57 (s, 1H). C NMR dimethoxycarboxylic acid, mp 51–52 °C; H NMR (DMSO) δ
CDCl ) δ 24.5, 28.6, 28.7, 32.3, 34.5, 44.1, 51.2, 55.9, 56.01, 1.09–1.19 (m, 2H), 1.68–1.71 (bd, 2H, J = 12.4 Hz), 1.90–1.96
6.04, 58.6, 79.3, 109.6, 111.5, 126.3, 126.7, 147.3, 147.7, 155.0. (m, 1H), 2.35 (d, 2H, J = 8.0 Hz), 2.64 (t, 2H, J = 5.4 Hz), 2.74 (t,
3
5
+
+
+
MS-ES m/z 419 (MH , 35), 265 (100%); HRMS-ES calculated J = 5.6 Hz), 3.05 (bs, 2H), 3.49 (s, 2H), 3.737 (s, 3H), 3.742 (s,
for C24 : 419.2910, found 419.2919. 3H), 3.75 (s, 3H), 3.89 (s, 3H), 4.51 (bs, 2H), 6.65 (s, 1H), 6.68
39 2 4
H N O
1
3
(
2
s, 1H), 6.94–6.98 (m, 1H), 7.27 (s, 1H). C NMR (DMSO) δ
9.0, 30.8, 34.0, 47.3, 51.8, 56.43, 56.45, 56.47, 57.1, 64.2,
2
–TFA (10 mL, 2 : 1) was 111.2, 113.0, 116.5, 117.2, 121.4, 121.7, 126.9, 127.7, 147.9,
Preparation of compounds 19–21
A solution of 16, 17 or 18 in CHCl
stirred for 30 min at rt. The product was basified with aq. 148.1, 154.1, 165.1. MS-ES m/z 534 (MH , 100%); HRMS-EI
K CO (1 M, 200 mL) followed by aq. KOH (0.1 M, 50 mL) and calculated for C H
+
+
7
9
BrN O : 533.1651, found 533.1683.
2 5
2
3
26 33
extracted with CH
combined, dried (Na
0 or 21 which were used without further purification.
,2,3,4-Tetrahydro-6,7-dimethoxy-2-((piperidine-4-yl)methyl)- 2H), 1.80–1.84 (bs, 2H), 1.93 (m, 1H), 2.31 (d, 2H, J = 8 Hz),
2
Cl
2
(3 × 100 mL). The organic layers were
(4-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)methyl-
2
SO ) and the solvent removed to yield 19, piperidin-1-yl)(1H-inden-2-yl)methanone [33]. White solid,
4
1
2
mp 128–129 °C, yield 30%; H NMR (DMSO) δ 1.10–1.20 (m,
1
1
isoquinoline [19]. Yellow oil, yield 78%; H NMR (CDCl
3
) δ 2.60 (t, 2H, J = 6 Hz), 2.69 (t, J = 5.5 Hz), 3.03 (bs, 2H), 3.44 (s,
1
.11–1.15 (m, 2H), 1.72–1.80 (m, 3H), 2.32 (m, 2H), 2.58–2.68 2H), 3.680 (s, 3H), 3.684 (s, 3H), 4.28 (bs, 2H), 6.60 (s, 1H),
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+
+
6
8
3
1
1
31 3 3
.63 (s, 1H), 7.27–7.32 (m, 2H), 7.40 (m, 1H), 7.61 (d, 1H, J = m/z 446 (MH , 100%); HRMS-ES calculated for C27H N O :
1
3
.3 Hz), 7.70 (d, 1H, J = 7.8 Hz). C NMR (CDCl ) δ 29.0, 31.4, 446.2444, found 446.2454.
(4-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)methyl)-
13.0, 123.0, 124.3, 126.8, 126.9, 127.5, 127.6, 147.9, 148.1, piperidin-1-yl)(1H-indol-6-yl)methanone [27]. Light brown
49.6, 154.6, 159.6. MS: LRMS m/z (ES ) 435 [MH] (100%); solid, mp 210–213 °C, yield 42%; H NMR (DMSO) δ 1.13–1.23
: 435.2284, found 435.2291. (m, 2H), 1.80–1.83 (m, 2H), 1.92–1.97 (m, 1H), 2.38 (d, 2H, J =
-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)methyl)- 7.2 Hz), 2.66 (t, 2H, J = 6.2 Hz), 2.75 (t, 2H, J = 5.6 Hz),
piperidin-1-yl)(1H-indol-2-yl)methanone [23]. White solid, mp 2.94–3.00 (m, 2H), 3.51 (s, 2H), 3.74 (s, 3H), 3.75 (s, 3H),
08–210 °C, yield 48%; H NMR (DMSO) δ 1.16–1.26 (m, 2H), 4.15–4.24 (m, 2H), 6.51 (d, 1H, J = 2.9 Hz), 6.66 (s, 1H), 6.69 (s,
.88 (bd, 2H, J = 12.3 Hz), 1.96–2.03 (m, 1H), 2.38 (d, 2H, J = 1H), 7.05 (dd, 1H, J = 8.1 Hz, 1.3 Hz), 7.47 (m, 2H), 7.61 (s,
.2 Hz), 2.67 (t, 2H, J = 5.9 Hz), 2.76 (t, 2H, J = 5.3 Hz), 3.09 (bs, 1H). C NMR (DMSO) δ 30.0, 32.4, 35.0, 44.6, 52.7, 57.1, 57.3,
H), 3.52 (s, 2H), 3.74 (s, 3H), 3.75 (s, 3H), 4.47 (bs, 2H), 6.67 57.6, 65.4, 102.8, 111.7, 112.2, 113.4, 119.6, 121.3, 127.6, 128.4,
s, 1H), 6.70 (s, 1H), 6.77 (s, 1H), 7.07 (t, 1H, J = 7.2 Hz), 7.20 128.7, 130.0, 130.6, 136.7, 148.5, 148.8, 171.9. MS-ES m/z 434
t, 1H, J = 7.2 Hz), 7.45 (d, 1H, J = 8.2 Hz), 7.62 (d, 1H, J = 8.0 (MH , 100%); HRMS-ES calculated for C H N O : 434.2444,
3
4.0, 44.1, 51.7, 55.9, 56.0, 56.4, 64.1, 110.6, 111.2, 112.4,
+
+
1
30 2 4
HRMS: calculated for C26H N O
4
1
2
1
7
2
(
(
1
3
+
+
+
2
6
31 3 3
1
3
Hz). C NMR (DMSO) δ 29.0, 31.5, 34.1, 44.1, 51.8, 56.41, found 434.2450.
5
1
6.44, 64.3, 104.1, 111.2, 112.7, 113.0, 120.3, 121.9, 123.7,
(4-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)methyl)-
piperidin-1-yl)(naphthalen-1-yl)methanone [28]. White solid,
mp 58–60 °C, yield 35%; H NMR (DMSO) δ 1.10–1.30 (m, 2H),
+
26.9, 127.6, 127.7, 131.2, 136.6, 147.8, 148.1, 162.7. MS-ES
+
1
m/z 434 (MH , 100%); HRMS-EI calculated for C26
H
31
N
3
O
3
:
4
33.2365, found 433.2356.
1.60–1.70 (m, 1H), 1.90–1.97 (m, 2H), 2.36 (m, 2H), 2.64 (t, 2H,
(
Benzo[b]thiophen-2-yl)(4-((3,4-dihydro-6,7-dimethoxyiso- J = 5.7 Hz), 2.73 (t, J = 5.6 Hz), 2.93–3.10 (m, 2H), 3.48 (s, 2H),
quinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone [24]. Off- 3.732 (s, 3H), 3.736 (s, 3H), 4.69 (bs, 2H), 6.64 (s, 1H), 6.68 (s,
1
white solid, mp 80–82 °C, yield 41%; H NMR (DMSO) δ 1H), 7.40–7.50 (m, 1H), 7.56–7.63 (m, 3H), 7.76–7.83 (m, 1H),
1
3
1
1
5
4
(
(
.17–1.27 (m, 2H), 1.87 (bd, 2H, J = 12.2 Hz), 1.97–2.02 (m, 7.97–8.03 (m, 2H). C NMR (DMSO) δ 29.0, 31.1, 34.1, 47.6,
H), 2.37 (d, 2H, J = 7.2 Hz), 2.66 (t, 2H, J = 6.1 Hz), 2.75 (t, J = 51.8, 56.46, 56.49, 56.5, 64.2, 111.2, 113.0, 124.1, 125.4, 126.1,
.5 Hz), 3.09 (bs, 2H), 3.51 (s, 2H), 3.74 (s, 3H), 3.75 (s, 3H), 126.9, 127.1, 127.6, 127.7, 129.1, 129.3, 133.8, 135.7, 147.9,
+
+
+
.32 (bs, 2H), 6.66 (s, 1H), 6.69 (s, 1H), 7.45–7.46 (m, 2H), 7.70 148.2, 168.6. MS-ES m/z 445 (MH , 100%); HRMS-ES calcu-
1
3
s, 1H), 7.94–7.97 (m, 1H), 8.02–8.04 (m, 1H). C NMR lated for C28
DMSO) δ 29.0, 31.4, 34.0, 45.6, 51.8, 56.4, 56.5, 64.2, 111.2, (3a,7a-Dihydro-1H-indol-3-yl)(4-((3,4-dihydro-6,7-dimethoxy-
13.0, 123.2, 125.5, 125.52, 125.53, 126.4, 126.9, 127.7, 138.1, isoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone [29].
39.4, 140.0, 147.9, 148.1, 163.1. MS-ES m/z 451 (MH , 100%); Off-white solid, mp 206–207 °C, yield 39%; H NMR (DMSO) δ
32 2 3
H N O : 445.2491, found 445.2488.
1
1
+
+
1
HRMS-EI calculated for
50.1974.
C
26
H
30
N
2
O
3
S: 450.1977, found 1.13–1.23 (m, 2H), 1.81–1.84 (m, 2H), 1.95–2.03 (m, 1H), 2.37
(d, 2H, J = 6.2 Hz), 2.66 (t, 2H, J = 5.9 Hz), 2.74 (t, 2H, J =
4
(
E)-1-(4-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)- 5.5 Hz), 2.98–3.04 (m, 2H), 3.51 (s, 2H), 3.74 (s, 6H), 4.29–4.33
methyl)piperidin-1-yl)-3-phenylprop-2-en-1-one [25]. White (m, 2H), 6.66 (s, 1H), 6.69 (s, 1H), 7.13 (t, 1H, J = 7.1 Hz), 7.19
solid, mp 149–150 °C, yield 46%; H NMR (DMSO) δ 1.00–1.11 (t, 1H, J = 7.1 Hz), 7.47 (d, 1H, J = 8.1 Hz), 7.64 (d, 1H, J =
1
1
3
(
2
(
6
m, 2H), 1.83 (bd, 2H, J = 12.3 Hz), 1.90–1.95 (m, 1H), 2.35 (d, 2.4 Hz), 7.69 (d, 1H, J = 7.8 Hz). C NMR (DMSO) δ 28.1, 30.7,
H, J = 7.1 Hz), 2.65 (t, 2H, J = 6.0 Hz), 2.75 (t, J = 5.4 Hz), 3.11 33.3, 44.4, 50.9, 55.52, 55.54, 56.9, 63.5, 110.3, 110.4, 111.7,
bs, 2H), 3.50 (s, 2H), 3.74 (s, 3H), 3.75 (s, 3H), 4.38 (bs, 2H), 112.1, 119.8, 119.9, 121.5, 125.8, 126.0, 126.8, 127.1, 135.5,
+
+
+
.66 (s, 1H), 6.69 (s, 1H), 7.24 (d, 1H, J = 15.5 Hz), 7.37–7.46 147.0, 147.2, 165.3. MS-ES m/z 434 (MH , 100%); HRMS-ES
1
3
(m, 3H), 7.49 (d, 1H, J = 15.5 Hz), 7.70–7.73 (m, 2H). C NMR calculated for C26
31 3 3
H N O : 434.2454, found 434.2444.
(DMSO) δ 29.0, 31.4, 34.1, 44.1, 51.8, 56.4, 64.3, 111.2, 113.0, (5-Bromobenzofuran-2-yl)(4-((3,4-dihydro-6,7-dimethoxy-
1
1
19.6, 126.9, 127.7, 128.6, 129.4, 130.0, 136.1, 141.7, 147.9, isoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone
[34].
+
+
+
48.1, 165.1. MS-ES m/z 421 (MH , 31), 443 (MHNa)
Prepared as white solid using 5-bromobenzo[b]furan-2-
3
2
1
(100%); HRMS-EI calculated for C H N O : 420.2413, found carboxylic acid, mp 75–78 °C, yield 40%; H NMR (DMSO) δ
26 32 2 3
4
20.2401.
1.15–1.23 (m, 2H), 1.84–1.88 (m, 2H), 1.97–2.01 (m, 1H), 2.35
(4-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)methyl)- (d, 2H, J = 7.1 Hz), 2.64 (t, 2H, J = 6.2 Hz), 2.73 (t, J = 5.6 Hz),
piperidin-1-yl)(quinolin-3-yl)methanone [26]. Orange solid, 3.06 (m, 2H), 3.49 (s, 2H), 3.717 (s, 3H), 3.723 (s, 3H), 4.29 (m,
1
mp 70–72 °C, yield 48%; H NMR (DMSO) δ 1.19–1.29 (m, 2H), 2H), 6.63 (s, 1H), 6.67 (s, 1H), 7.31 (s, 1H), 7.56–7.59 (m, 1H),
1
3
1
7
2
6
8
.85 (bd, 2H, J = 12.3 Hz), 1.96–2.00 (m, 1H), 2.38 (d, 2H, J = 7.65 (d, 1H, J = 1.9 Hz), 7.95 (d, 1H, J = 7.9 Hz). C NMR
.1 Hz), 2.66 (t, 2H, J = 5.9 Hz), 2.75 (t, 2H, J = 5.4 Hz), 3.07 (bs, (DMSO) δ 29.0, 31.6, 34.0, 48.2, 51.8, 56.44, 56.46, 56.47, 64.1,
H), 3.50 (s, 2H), 3.739 (s, 3H), 3.742 (s, 3H), 4.51 (bs, 2H), 110.0, 111.2, 113.0, 114.5, 116.6, 125.4, 126.9, 127.7, 129.6,
+
.66 (s, 1H), 6.69 (s, 1H), 7.69–7.73 (m, 1H), 7.85–7.89 (m, 1H), 129.8, 147.9, 148.1, 150.8, 153.5, 159.2. MS-EI m/z 512 (M , 7),
7
9
.10 (m, 2H), 8.44 (d, 1H, J = 2.1 Hz), 8.92 (d, 1H, J = 2.1 Hz). 206 (100%); HRMS-EI calculated for C H
BrN O :
2 4
2
6
29
1
3
C NMR (DMSO) δ 29.0, 31.2, 34.0, 47.5, 51.8, 56.43, 56.46, 512.1311, found 512.1309.
6
1
4.2, 111.2, 113.0, 126.9, 127.4, 127.6, 128.0, 129.3, 129.5,
30.2, 131.2, 134.8, 147.9, 148.1, 148.3, 149.2, 167.4. MS-ES
(5-Bromo-1H-indol-2-yl)(4-((3,4-dihydro-6,7-dimethoxyiso-
quinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone [30]. White
+
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solid, mp 212–214 °C, yield 27%; H NMR (DMSO) δ 1.15–1.26 3.70 (s, 3H), 4.25 (bs, 2H), 6.62 (s, 1H), 6.64 (s, 1H), 7.28 (s,
(
m, 2H), 1.89 (bd, 2H, J = 12.3 Hz), 1.98–2.03 (m, 1H), 2.38 (d, 1H), 7.48 (d, 1H, J = 8.8 Hz), 7.60 (dd, 2H, J = 8.8, 2.0 Hz), 7.94
1
3
2
3
2
1
H, J = 7.1 Hz), 2.67 (t, 2H, J = 6.3 Hz), 2.76 (t, 2H, J = 5.6 Hz), (d, 1H, J = 2.0 Hz). C NMR (DMSO) δ 28.2, 31.9, 32.8, 33.4,
.09 (bs, 2H), 3.51 (s, 2H), 3.74 (s, 3H), 3.75 (s, 3H), 4.42 (bs, 50.6, 54.6, 54.9, 55.1, 55.51, 55.54, 109.1, 110.2, 112.0,
H), 6.66 (s, 1H), 6.70 (s, 1H), 6.76 (s, 1H), 7.31 (dd, 1H, J = 8.7, 113.7, 115.7, 124.6, 126.0, 126.8, 128.7, 128.9, 146.9,
1
3
+
+
.9 Hz), 7.42 (d, 1H, J = 8.6 Hz), 7.82 (d, 1H, J = 1.9 Hz).
C
147.2, 149.9, 152.6, 158.3. MS-ES m/z 528 (MH , 100%);
+
79
32 2 4
NMR (DMSO) δ 29.0, 31.4, 34.1, 46.0, 51.8, 56.45, 56.46, 64.2, HRMS-ES calculated for C27H N O Br: 528.6352, found
1
1
03.5, 111.2, 112.8, 113.0, 114.7, 124.1, 126.3, 126.9, 127.7, 528.6360.
+
29.5, 132.7, 135.3, 147.9, 148.1, 162.2. MS-ES m/z 511.8
(5-Bromobenzofuran-2-yl)(4-(3-(3,4-dihydro-6,7-dimethoxy-
calculated for isoquinolin-2(1H)-yl)propyl)piperidin-1-yl)methanone [37].
White foam, mp 62–64 °C, yield 36%; H NMR (CDCl ) δ
+
+
(MH , 75), 230 (100%); HRMS-ES
7
9
1
C H
BrN O : 512.1549, found 512.1532.
3 3
2
6
30
3
(
4-Bromo-3-methylphenyl)(4-((3,4-dihydro-6,7-dimethoxy- 1.23–1.29 (m, 4H), 1.62–1.66 (m, 3H), 1.82 (bd, 2H, J =
isoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone [31]. 11.7 Hz), 2.47–2.51 (m, 2H), 2.70 (t, 2H, J = 6.1 Hz), 2.82 (t, 2H,
White solid, mp 50–51 °C, yield 55%; H NMR (DMSO) δ J = 5.8 Hz), 3.20 (bs, 2H), 3.55 (s, 2H), 3.825 (s, 3H), 3.832 (s,
.09–1.19 (m, 2H), 1.77–1.84 (m, 2H), 1.92–1.98 (m, 1H), 2.35 3H), 4.52 (bd, 2H), 6.51 (s, 1H), 6.58 (s, 1H), 7.15 (s, 1H), 7.31
d, 2H, J = 7.1 Hz), 2.41 (s, 3H), 2.65 (t, 2H, J = 6.0 Hz), 2.74 (t, (d, 1H, J = 8.7 Hz), 7.46 (dd, 2H, J = 8.8, 2.0 Hz), 7.76 (d, 1H, J =
1
1
(
1
3
J = 5.6 Hz), 2.93–3.04 (m, 2H), 3.50 (s, 2H), 3.73 (s, 3H), 3.74 (s, 1.9 Hz). C NMR (CDCl ) δ 21.6, 24.0, 32.2, 33.4, 35.8, 43.4,
3
3
8
H), 4.05 (bs, 2H), 6.65 (s, 1H), 6.69 (s, 1H), 7.15 (dd, 1H, J = 49.1, 52.1, 54.8, 56.1, 56.2, 109.4, 110.6, 111.4, 113.5, 116.7,
1
3
.2, 2.1 Hz), 7.38 (s, 1H), 7.66 (d, 1H, J = 8.1 Hz). C NMR 118.2, 122.6, 124.8, 129.1, 129.4, 148.8, 149.4, 150.5, 153.3,
+
+
(DMSO) δ 22.9, 29.0, 31.2, 34.0, 47.5, 51.7, 56.36, 56.38, 64.2, 159.4. MS-ES m/z 542 (MH , 100%); HRMS-EI calculated for
7
9
1
1
11.1, 113.0, 125.6, 126.6, 126.9, 127.7, 130.0, 132.8, 136.8,
C
26
H
33
N
2
O
4
Br: 541.1689, found 541.1693.
(4-(2-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)ethyl)-
BrN O : 487.1596, found piperidin-1-yl)(5-iodobenzofuran-2-yl)methanone [38]. Brown
+
+
38.3, 147.8, 148.1, 168.6. MS-ES m/z 488 (MH , 100%);
7
9
HRMS-EI calculated for C H
4
2
5
31
2 3
1
87.1581.
3
wax, yield 50%; H NMR (CDCl ) δ 1.22–1.29 (m, 2H),
(
5-Bromo-1H-indol-3-yl)(4-((3,4-dihydro-6,7-dimethoxyiso- 1.57–1.59 (m, 2H), 1.79 (m, 1H), 1.82 (bd, 2H, J = 11.7 Hz), 2.55
quinolin-2(1H)-yl)methyl)piperidin-1-yl)methanone [32]. Off- (t, 2H, J = 8.0 Hz), 2.69 (t, 2H, J = 6.4 Hz), 2.81 (t, 2H, J =
1
white solid, mp 215–217 °C, yield 38%; H NMR (DMSO) δ 5.6 Hz), 3.13 (bs, 2H), 3.54 (s, 2H), 3.820 (s, 3H), 3.824 (s, 3H),
1
1
.07–1.18 (m, 2H), 1.78 (bd, 2H, J = 10.9 Hz), 1.89–1.94 (m, 4.58 (bd, 2H), 6.51 (s, 1H), 6.58 (s, 1H), 7.13 (s, 1H), 7.27 (d,
H), 2.32 (d, 2H, J = 7.1 Hz), 2.61 (t, 2H, J = 6.1 Hz), 2.71 (t, 2H, 1H, J = 8.9 Hz), 7.63 (dd, 1H, J = 8.8, 2.0 Hz), 7.96 (d, 1H, J =
1
3
J = 5.3 Hz), 2.98 (bt, 2H, J = 11.4 Hz), 3.46 (s, 2H), 3.700 (s, 3H), 1.2 Hz). C NMR (CDCl
3
) δ 14.8, 28.9, 32.9, 33.7, 34.5, 44.6,
.703 (s, 3H), 4.26 (bd, 2H, J = 11.1 Hz), 6.61 (s, 1H), 6.65 (s, 47.3, 51.2, 55.6, 55.9, 56.0, 87.1, 109.6, 110.3, 111.5, 113.9,
H), 7.26 (dd, 1H, J = 8.6, 1.9 Hz), 7.40 (d, 1H, J = 8.6 Hz), 7.68 126.2, 126.6, 129.8, 131.0, 134.9, 147.3, 147.7, 150.2, 153.9,
3
1
1
3
+
(s, 1H), 7.82 (d, 1H, J = 1.9 Hz). C NMR (DMSO) δ 28.1, 30.6, 159.3. MS-EI m/z 574 (M , 39), 206 (100%); HRMS-EI calculated
3
1
1
3.3, 44.4, 50.9, 55.5, 55.6, 56.7, 63.4, 109.7, 110.2, 112.0, for C27
12.6, 113.7, 122.3, 124.2, 126.0, 126.7, 128.0, 128.5, 134.3, (4-(3-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)propyl)-
46.9, 147.2, 164.5. MS-EI m/z 512 (M , 100%); HRMS-EI calcu- piperidin-1-yl)(5-iodobenzofuran-2-yl)methanone [39]. White
31 2 4
H N O I: 574.4526, found 574.4530.
+
79
1
lated for C26
H
31
N
3
O
3
Br: 512.1549, found 512.1542.
3
solid, yield 43%, mp 162–163 °C; H NMR (CDCl ) δ 1.23–1.29
(4-((3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)methyl)- (m, 4H), 1.62–1.66 (m, 1H), 1.82 (m, 4H), 2.87–3.20 (m, 8H),
piperidin-1-yl)(5-iodobenzofuran-2-yl)methanone [35]. Pre- 3.83 (s, 3H), 3.85 (s, 3H), 4.06 (s, 2H), 4.50 (bd, 2H), 6.52 (s,
3
3
pared from 5-iodobenzo[b]furan-2-carboxylic acid as a clear 1H), 6.61 (s, 1H), 7.14 (s, 1H), 7.28 (d, 1H, J = 1.7 Hz), 7.63 (dd,
1
13
film, yield 42%; H NMR (CDCl ) δ 1.23–1.30 (m, 2H), 1H, J = 8.7, 1.8 Hz), 7.96 (d, 1H, J = 1.7 Hz). C NMR (CDCl ) δ
3
3
1
.93–2.03 (m, 3H), 2.39 (d, 2H, J = 6.4 Hz), 2.51 (m, 2H), 2.70 25.5, 29.8, 32.9, 33.6, 35.6, 43.6, 49.6, 53.4, 56.09, 56.14, 60.5,
(
3
t, 2H, J = 6.0 Hz), 2.82–2.95 (m, 2H), 3.54 (s, 2H), 3.83 (s, 3H), 87.1, 109.5, 110.2, 111.4, 114.0, 124.3, 129.8, 129.9, 131.1,
.84 (s, 3H), 4.36–4.66 (m, 2H), 6.52 (s, 1H), 6.60 (s, 1H), 7.14 135.0, 147.9, 148.3, 150.2, 154.0, 159.4. MS-EI m/z 588 (M , 42),
+
(
s, 1H) 7.27 (d, 1H, J = 8.4 Hz), 7.63 (dd, 1H, J = 8.8, 2.0 Hz), 341 (100%); HRMS-EI calculated for C28 I: 588.1301,
.97 (d, 1H, J = 2.0 Hz). C NMR (CDCl ) δ 28.8, 30.8, 34.3, found 588.1289.
3
33 2 4
H N O
1
3
7
4
1
1
3.5, 47.3, 51.6, 56.07, 56.09, 56.5, 64.2, 87.1, 109.6, 110.1,
11.6, 114.0, 126.4, 126.8, 129.9, 131.1, 135.0, 147.4, 147.7,
50.3, 154.0, 159.5. MS-ES m/z 561.2 (MH , 100%); HRMS-ES
Preparation of compounds 40–46
+
+
+
To a solution of the appropriate nitrile derivative (1 eq.) in
DMF (20 mL) was added either 6,7-dimethoxy-1,2,3,4-tetra-
calculated for C H N O I: 561.4236, found 561.4240.
2
6
30 2 4
5
-Bromobenzofuran-2-yl)(4-(2-(3,4-dihydro-6,7-dimethoxyiso- hydroisoquinoline hydrochloride (1 eq.), or 6-methoxy-1,2,3,4-
3
4
quinolin-2(1H)-yl)ethyl)piperidin-1-yl)methanone [36]. White tetrahydroisoquinoline hydrochloride (1 eq.), or 7-methoxy-
solid, mp 92–95 °C, yield 51%; H NMR (DMSO) δ 1.16–1.24 1,2,3,4-tetrahydroisoquinoline hydrochloride (1 eq.), followed
1
(
2
2
m, 2H), 1.49 (q, 2H, J = 7.2 Hz), 1.67–1.70 (m, 1H), 1.79 (bd, by K
2
CO
H, J = 12.5 Hz), 2.45–2.51 (m, 2H), 2.60 (t, 2H, J = 6.0 Hz), tion stirred for 16 h. The reaction mixture was then diluted
.70 (t, 2H, J = 5.5 Hz), 3.00 (bs, 2H), 3.45 (s, 2H), 3.69 (s, 3H), with EtOAc (100 mL) and extracted with H O (3 × 20 mL), sat.
3
(4 eq.), TBAI (0.1 eq.) and KI (0.01 eq.) and the solu-
2
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NaHCO
3
(25 mL), brine (25 mL) and H
2
O (20 mL). The organic
5-(3,4-Dihydro-7-methoxyisoquinolin-2(1H)-yl)pentanenitrile
1
layers were combined, dried (Na SO ) and the organic solvent [46]. White solid, yield 59%; H NMR (CDCl ) δ 1.74–1.78 (m,
2
4
3
removed. The residue was purified column chromatography 4H), 2.40–2.43 (m, 2H), 2.52–2.56 (m, 2H), 2.60 (t, 2H, J = 6.0
EtOAc–MeOH, 9 : 1). Hz), 2.83 (t, 2H, J = 5.8 Hz), 3.59 (s, 2H), 3.78 (s, 3H), 6.56 (d,
-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butane- 1H, J = 2.6 Hz), 6.71 (dd, 1H, J = 8.4, 2.7 Hz,), 7.01 (d, 1H, J =
(
4
2
7
1
13
nitrile. [40]. White solid, mp 106–108 °C, yield 85%;
H
3
8.4 Hz). C NMR (CDCl ) δ 17.2, 23.5, 26.1, 28.3, 51.2, 55.4,
NMR (CDCl ) δ 2.47 (t, 2H, J = 7.1 Hz), 2.62 (t, 2H, J = 6.7 Hz), 56.4, 57.1, 111.4, 112.7, 119.8, 126.5, 129.7, 135.7, 157.7. MS-EI
3
+
2
3
2
.70 (t, 2H, J = 6.1 Hz), 2.81 (t, 2H, J = 5.8 Hz), 3.54 (s, 2H), m/z 244 (M , 23), 176 (100%); HRMS-EI calculated for
.83 (s, 3H), 3.84 (s, 3H), 6.51 (s, 1H), 6.59 (s, 1H,). MS-EI m/z
60 (M , 42), 164 (100%).
15 20 2
C H N O: 244.1576, found 244.1564.
+
5
-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)pentane-
1
Preparation of compounds 47–53
m, 4H), 2.39 (t, 2H, J = 6.6 Hz), 2.53 (t, 2H, J = 6.6 Hz), 2.69 (t, To a suspension of LiAlH (3 eq.) in dry THF (50 mL) was
H, J = 6.0 Hz), 2.81 (t, 2H, J = 5.8 Hz), 3.54 (s, 2H), 3.83 (s, added the appropriate nitrile (1 eq.) in dry THF (25 mL) drop-
3
nitrile [41]. Clear oil, yield 83%; H NMR (CDCl ) δ 1.73–1.77
(
4
2
3
1
1
1
3
H), 3.84 (s, 3H), 6.52 (s, 1H), 6.59 (s, 1H). C NMR (CDCl
3
) δ wise under a stream of N
2
. The resulting mixture was heated at
. To the cooled solution at 0 °C was
19.8, 126.2, 126.4, 147.4, 147.6. MS-EI m/z 274 (M , 33), 206 added iced H O (5 mL) and 10% NaOH (15 mL). The solution
7.2, 23.5, 26.0, 28.6, 51.0, 55.8, 55.99, 56.02 57.0, 109.6, 111.5, reflux for 18 h under N
2
+
2
(
2
100%); HRMS-EI calculated for C16
74.3210.
H
22
N
2
O
2
: 274.3206, found was warmed to rt and allowed to stir for 15 min. The resulting
suspension was filtered through celite and the filter cake
6
-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)hexane- washed with EtOAc (50 mL). The organic layer was dried
1
nitrile [42]. Red oil, yield 86%; H NMR (CDCl
3
) δ 1.73–1.77 (Na
2 4
SO ) and solvent removed to give 46–52 which were used
(m, 4H), 2.40–2.42 (m, 2H), 2.52–2.55 (m, 2H), 2.69 (t, 2H, J = without further purification.
6
.0 Hz), 2.81 (t, 2H, J = 5.8 Hz), 3.54 (s, 2H), 3.83 (s, 3H), 3.84
4-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butan-
1
3
1
(s, 3H), 6.52 (s, 1H), 6.59 (s, 1H). C NMR (CDCl
3
) δ 17.2, 23.5, 1-amine [47]. Yellow oil, yield 65%; H NMR (CDCl
3
) δ 1.49
2
1
5.9, 26.0, 28.6, 51.0, 52.3, 55.7, 56.0, 57.0, 109.6, 111.5, 119.8, (m, 2H), 1.62 (m, 2H), 2.49 (t, 2H, J = 8.0 Hz), 2.71 (m, 4H),
+
26.2, 126.4, 147.4, 147.7. MS-EI m/z 288 (M , 2), 206 (100%); 2.80 (t, 2H, J = 5.6 Hz), 3.53 (s, 2H), 3.81 (s, 3H), 3.83 (s, 3H),
1
3
HRMS-EI calculated for
C
17
H
24
N
2
O
2
:
288.6578, found 6.50 (s, 1H), 6.57 (s, 1H). C NMR (CDCl
3
) δ 25.0, 27.2, 30.6,
2
88.6583.
-(3,4-Dihydro-6-methoxyisoquinolin-2(1H)-yl)butanenitrile 147.2, 148.8. MS-ES m/z 265.1 (MH , 100%); HRMS calculated
43]. White solid. yield 76%, from 6-methoxy-1,2,3,4-tetra- for C15 : 264.1838, found 264.1832.
5-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)pentan-
41.0, 53.1, 54.9, 56.0, 56.1, 58.9, 110.9, 112.5, 126.1, 129.1,
+
+
4
[
24 2 2
H N O
3
4 1
hydroisoquinoline hydrochloride;
3
H NMR (CDCl ) δ 1.92
1
(
pentet, 2H, J = 6.9 Hz), 2.47 (t, 2H, J = 7.1 Hz), 2.62 (t, 2H, J = 1-amine [48]. Yellow oil, yield 62%; H NMR (CDCl ) δ
3
6
2
2
2
1
.7 Hz), 2.71 (t, 2H, J = 6.1 Hz), 2.87 (t, 2H, J = 5.8 Hz), 3.55 (s, 1.23–1.62 (m, 6H), 2.45–2.49 (m, 2H), 2.67–2.71 (m, 4H), 2.80
H), 3.77 (s, 3H), 6.63 (d, 1H, J = 2.6 Hz), 6.70 (dd, 1H, J = 8.4, (t, 2H, J = 5.9 Hz), 3.52 (s, 2H), 3.805 (s, 3H), 3.81 (s, 3H), 6.50
1
3
13
.6 Hz), 6.92 (d, 1H, J = 8.4 Hz). C NMR (CDCl ) δ 15.0, 23.3, (s, 1H), 6.56 (s, 1H). C NMR (CDCl ) δ 25.0, 27.2, 28.7, 33.6,
3
3
9.5, 51.0, 55.4, 55.6, 56.2, 112.3, 113.4, 120.0, 126.8, 127.6, 42.0, 51.2, 55.9, 56.0, 56.02, 58.4, 109.6, 111.5, 126.3, 126.8,
+
+
+
35.5, 158.2. MS-EI m/z 230 (M , 28), 176 (100%); HRMS-EI 147.3, 147.6. MS-ES m/z 279 (MH , 41), 181 (100%); HRMS-EI
calculated for C H N O : 278.1994, found 278.1977.
calculated for C H N O: 230.1340, found 230.1334.
1
4
18
2
16 26 2 2
5
-(3,4-Dihydro-6-methoxyisoquinolin-2(1H)-yl)pentanenitrile
6-(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)hexan-
1
1
[
4
6
(
8
5
44]. White solid, yield 61%; H NMR (CDCl
3
) δ 1.73–1.76 (m, 1-amine [49]. Yellow oil, yield 68%; H NMR (CDCl
H), 2.39–2.42 (m, 2H), 2.51–2.55 (m, 2H), 2.69 (t, 2H, J = 1.22–1.46 (m, 8H), 1.58 (bs, 2H), 2.48 (t, 2H, J = 7.8 Hz),
.0 Hz), 2.87 (t, 2H, J = 5.8 Hz), 3.54 (s, 2H), 3.77 (s, 3H), 6.63 2.60–2.66 (m, 4H), 2.76 (t, 2H, J = 5.6 Hz), 3.48 (s, 2H), 3.77 (s,
3
) δ
1
3
d, 1H, J = 2.6 Hz), 6.71 (dd, 1H, J = 8.4, 2.7 Hz), 7.01 (d, 1H, J = 3H), 3.78 (s, 3H), 6.51 (s, 1H), 6.57 (s, 1H). C NMR (CDCl
.4 Hz). C NMR (CDCl ) δ 17.2, 23.5, 26.1, 29.5, 51.0, 55.3, 26.9, 27.2, 27.5, 28.7, 33.5, 42.0, 51.1, 55.8, 55.9, 56.0, 58.4,
5.8, 57.2, 112.2, 113.3, 119.8, 127.0, 127.6, 135.5, 158.1. MS-EI 110.6, 111.9, 126.8, 127.1, 147.6, 147.9. MS-ES m/z 293 (MH ,
3
) δ
1
3
3
+
+
+
m/z 244 (M , 23), 176 (100%); HRMS-EI calculated for 50), 188 (100%); HRMS-EI calculated for
C H N O: 244.1497, found 244.1497. 292.2151, found 292.2144.
4-(3,4-Dihydro-6-methoxyisoquinolin-2(1H)-yl)butan-1-amine
17 28 2 2
C H N O :
1
5
20 2
4
-(3,4-Dihydro-7-methoxyisoquinolin-2(1H)-yl)butanenitrile
1
1
[
45]. White solid, yield 77%; H NMR (CDCl
3
) δ 1.91 (pentet, [50]. Yellow oil, yield 94%; H NMR (CDCl
3
) δ 1.54–1.56 (m,
2
2
3
H, J = 6.9 Hz), 2.45 (t, 2H, J = 7.1 Hz), 2.63 (t, 2H, J = 6.7 Hz), 2H), 1.67 (m, 2H), 2.52 (t, 2H, J = 7.6 Hz), 2.64–2.77 (m, 4H),
.71 (t, 2H, J = 6.1 Hz), 2.82 (t, 2H, J = 5.8 Hz), 3.59 (s, 2H), 2.86–2.89 (m, 2H), 3.61 (s, 2H), 3.78 (s, 3H), 6.61 (d, 1H, J =
.77 (s, 3H), 6.56 (d, 1H, J = 2.7 Hz), 6.72 (dd, 1H, J = 8.4, 2.7 2.6 Hz), 6.68 (dd, 1H, J = 8.4, 2.6 Hz), 6.90 (dd, 1H, J = 8.3,
1
3
13
Hz), 7.01 (d, 1H, J = 8.4 Hz). C NMR (CDCl ) δ 15.0, 23.2, 2.8 Hz). C NMR (CDCl ) δ 24.6, 29.4, 31.7, 42.0, 50.9, 55.2,
3
3
2
1
8.3, 51.1, 55.4, 56.0, 56.3, 111.3, 112.7, 119.9, 126.4, 129.7, 55.7, 58.3, 112.1, 113.2, 127.1, 127.5, 135.5, 157.9. MS-EI m/z
+
+
35.6, 157.7. MS-EI m/z 230 (M , 74), 176 (100%); HRMS-EI 234 (M , 1), 162 (100%); HRMS-EI calculated for C14
234.1654, found 234.1653.
22 2
H N O:
calculated for C H N O: 230.1419, found 230.1422.
1
4
18 2
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5
-(3,4-Dihydro-6-methoxyisoquinolin-2(1H)-yl)pentan-1-amine 2.48–2.54 (m, 2H), 2.70 (t, 2H, J = 6.1 Hz), 2.81 (t, 2H, J =
1
[
51]. Yellow oil, yield 95%; H NMR (CDCl ) δ 1.34–1.62 (m, 5.8 Hz), 3.47 (m, 2H), 3.54 (s, 2H), 3.82 (s, 3H), 3.83 (s, 3H),
3
8
5
H), 2.48 (t, 2H, J = 7.8 Hz), 2.67–2.70 (m, 4H), 2.86 (t, 2H, J = 6.50 (s, 1H), 6.58 (s, 1H), 6.62 (t, 1H, J = 5.3 Hz), 7.38 (m, 2H),
1
3
.8 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 6.61 (d, 1H, J = 2.4 Hz), 6.66 7.49 (dd, 1H, J = 8.8, 2.0 Hz), 7.80 (d, 1H, J = 1.9 Hz). C NMR
13
(
(
dd, 1H, J = 8.4, 2.5 Hz), 6.91 (d, 1H, J = 8.4 Hz). C NMR (CDCl ) δ 26.6, 27.1, 26.8, 27.8, 29.6, 39.5, 50.7, 55.2, 56.01,
3
CDCl ) δ 24.9, 27.1, 29.4, 33.6, 42.0, 51.0, 55.3, 55.7, 58.5, 56.04, 57.6, 109.5, 109.6, 111.4, 113.4, 116.9, 125.2, 125.4,
3
+
1
4
12.1, 113.2, 127.2, 127.5, 135.5, 158.0. MS-EI m/z 248 (M , 18), 129.6, 129.9, 131.2, 147.5, 147.9, 150.1, 153.5, 158.5.
2 (100%); HRMS-EI calculated for C H N O: 248.3602, MS-ES− m/z 513 (M − 1, 100%); HRMS-ES calculated for
−
1
5
24 2
7
9
found 248.3612.
C
26
H
30
N
2
O
4
Br: 513.1389, found 513.1375.
5-Iodo-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)-
52]. Yellow oil, yield 89%; H NMR (CDCl ) δ 1.48–1.84 (m, butyl)-1-benzofuran-2-carboxamide [57]. White wax, yield
4
-(3,4-Dihydro-7-methoxyisoquinolin-2(1H)-yl)butan-1-amine
1
[
3
1
6
H), 2.50 (t, 2H, J = 7.7 Hz), 2.71 (m, 4H), 2.82 (t, 2H, J = 5.8 47%; H NMR (CDCl
3
) δ 1.73–1.74 (m, 4H), 2.55 (m, 2H), 2.71
Hz), 3.59 (s, 2H), 3.76 (s, 3H), 6.55 (d, 1H, J = 2.5 Hz), 6.69 (dd, (t, 2H, J = 6.0 Hz), 2.82 (t, 2H, J = 5.6 Hz), 3.50 (m, 2H), 3.55 (s,
1
3
1
2
1
H, J = 8.4, 2.6 Hz), 6.99 (d, 1H, J = 8.4 Hz) C NMR (CDCl ) δ 2H), 3.79 (s, 3H), 3.82 (s, 3H), 6.47 (s, 1H), 6.56 (s, 1H), 7.05 (d,
3
4.7, 28.3, 31.7, 42.1, 51.3, 55.3, 56.4, 62.4, 111.4, 112.6, 126.5, 1H, J = 8.7 Hz), 7.23 (s, 1H), 7.38 (m, 1H), 7.59 (d, 1H, J = 8.7
29.6, 135.9, 157.7. MS-EI m/z 234 (M , 15), 162 (100%); Hz,), 7.90 (s, 1H). C NMR (CDCl ) δ 24.9, 27.4, 28.6, 39.5,
3
+
13
HRMS-EI calculated for C H N O: 234.1732, found 234.1737. 50.7, 55.99, 56.02, 57.5, 87.2, 108.9, 109.6, 111.5, 113.8, 126.2,
1
4
22 2
5
-(3,4-Dihydro-7-methoxyisoquinolin-2(1H)-yl)pentan-1-amine 126.5, 130.2, 131.4, 135.2, 147.4, 147.7, 149.8, 154.0, 158.5.
1
+
+
[
53]. Yellow oil, yield 77%; H NMR (CDCl
3
) δ 1.35–1.63 (m, MS-ES m/z 535 (MH , 100%); HRMS-EI calculated for
6
2
H), 1.79 (bs, 2H), 2.48 (t, 2H, J = 7.6 Hz), 2.67–2.70 (m, 4H), C H N O I: 534.1016, found 534.1011.
2
4
27 2 4
.81 (m, 2H, J = 5.6 Hz), 3.57 (s, 2H), 3.75 (s, 3H), 6.54 (dd, 1H,
5-Iodo-N-(5-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)-
J = 2.4 Hz), 6.68 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 6.98 (d, 1H, J = 8.4 pentyl)-1-benzofuran-2-carboxamide [58]. Brown wax, yield
1
3
1
Hz). C NMR (CDCl ) δ 24.9, 27.2, 28.3, 33.7, 42.2, 51.3, 55.3, 30%; H NMR (CDCl ) δ 1.46–1.50 (m, 2H), 1.62–1.70 (m, 4H),
3
3
5
2
2
6.5, 58.4, 111.4, 112.6, 126.6, 129.6, 136.0, 157.7. MS-EI m/z 2.51 (m, 2H), 2.69 (t, 2H, J = 6.2 Hz), 2.80 (t, 2H, J = 5.7 Hz),
+
48 (M , 15), 32 (100%); HRMS-EI calculated for C14
48.3604, found 248.3609.
H
22
N
2
O: 3.48 (t, 2H, J = 7.0 Hz), 3.53 (s, 2H), 3.82 (s, 3H), 3.82 (s, 3H),
6.50 (s, 1H), 6.56 (s, 1H), 6.71 (m, 1H), 7.22 (d, 1H, J = 8.7 Hz),
7
1
.34 (s, 1H), 7.64 (dd, 1H, J = 8.7, 1.8 Hz), 7.98 (d, 1H, J =
.7 Hz). C NMR (CDCl ) δ 23.7, 24.9, 26.9, 28.7, 39.4, 51.1,
3
Preparation of compounds 54–63
13
Compounds 54–63 were prepared using the same method for 55.9, 56.97, 57.00, 58.1, 87.2, 109.1, 109.6, 111.5, 113.7, 126.3,
compounds 22–39. 126.7, 128.0, 131.5, 135.4, 147.3, 147.6, 149.7, 154.0, 158.4.
-Bromo-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)- MS-ES m/z 549 (MH , 100%); HRMS-ES calculated for
yl)butyl)-1-benzofuran-2-carboxamide [54]. Clear film, yield C H N O I: 549.1250, found 549.1262.
+
+
+
5
2
5
30 2 4
1
2
2
5
3%; H NMR (CDCl
3
) δ 1.74 (m, 4H), 2.57 (t, 2H, J = 6.7 Hz),
5-Iodo-N-(6-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)-
.74 (t, 2H, J = 6.2 Hz), 2.83 (t, 2H, J = 5.6 Hz), 3.50 (dt, 2H, J = hexyl)-1-benzofuran-2-carboxamide [59]. Brown wax, yield
1
.8 Hz), 3.56 (s, 2H), 3.79 (s, 3H), 3.82 (s, 3H), 7.16 (s, 1H), 7.18 41%; H NMR (CDCl ) δ 1.41 (m, 4H), 1.62 (m, 4H), 2.48 (m,
3
(
s, 1H), 7.25 (m, 2H), 7.38 (m, 1H), 7.43 (dd, 1H, J = 8.8, 2.0 2H), 2.68 (t, 2H, J = 6.1 Hz), 2.80 (t, 2H, J = 5.7 Hz), 3.45 (t, 2H,
1
3
Hz), 7.71 (d, 1H, J = 2.0 Hz). C NMR δ 24.8, 27.3, 28.5, 39.4, J = 7.0 Hz), 3.53 (s, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 6.50 (s, 1H),
5
1
1
0.7, 55.9, 55.99, 56.00, 57.4, 109.2, 109.6, 111.5, 113.3, 116.7, 6.57 (s, 1H), 6.66 (m, 1H), 7.24 (d, 1H, J = 8.7 Hz), 7.35 (s, 1H),
25.2, 126.1, 126.2, 129.5, 129.6, 147.5, 147.8, 150.2, 153.4, 7.65 (dd, 1H, J = 8.7, 1.8 Hz), 7.98 (d, 1H, J = 1.7 Hz). C NMR
1
3
+
+
+
58.6. MS-ES m/z 488 (MH , 100%); HRMS-ES calculated for δ 27.0, 27.2, 27.3, 28.7, 29.7, 39.5, 51.1, 55.9, 56.00, 56.02, 58.4,
7
9
C H N O Br: 488.3659, found 488.3652.
87.3, 109.2, 109.6, 111.5, 113.8, 126.3, 126.8, 130.4, 131.6,
2
4
38 2 4
+
+
5
-Bromo-N-(5-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)- 135.5, 147.3, 147.6, 149.7, 154.1, 158.4. MS-ES m/z 563 (MH ,
+
yl)pentyl)-1-benzofuran-2-carboxamide [55]. Clear film, yield 100%); HRMS-ES calculated for C26
H
32
N
2
O
4
I: 563.1407, found
1
2
2
5
3
7
2
5
1
1
3%; H NMR (CDCl ) δ 1.45–1.49 (m, 2H), 1.62–1.69 (m, 4H), 563.1413.
3
.48 (t, 2H, J = 7.5 Hz), 2.67 (t, 2H, J = 6.1 Hz), 2.78 (t, 2H, J =
.6 Hz), 3.44–3.49 (m, 2H), 3.52 (s, 2H), 3.80 (s, 3H), 3.81 (s, 1-benzofuran-2-carboxamide [60]. White solid, mp 72–74 °C,
H), 6.49 (s, 1H), 6.55 (s, 1H), 6.74 (bt, 1H, J = 3.9 Hz), yield 51%; H NMR (CDCl ) δ 1.74 (m, 4H), 2.56 (t, 2H, J =
.26–7.35 (m, 2H), 7.46 (dd, 1H, J = 8.8, 2.0 Hz), 7.75 (d, 1H, J = 6.6 Hz), 2.72 (t, 2H, J = 6.0 Hz), 2.88 (t, 2H, J = 5.7 Hz), 3.50 (m,
5-Iodo-N-(4-(3,4-dihydro-6-methoxyisoquinolin-2(1H)-yl)butyl)-
1
3
1
3
3
.0 Hz). C NMR (CDCl ) δ 24.8, 26.9, 28.7, 29.6, 39.4, 51.1, 2H), 3.58 (s, 2H), 3.76 (s, 3H), 6.61 (d, 1H, J = 2.5 Hz), 6.69 (dd,
5.87, 55.92, 55.95, 58.1, 109.4, 109.5, 111.4, 113.2, 116.7, 1H, J = 8.4, 2.6 Hz), 6.91 (d, 1H, J = 8.4 Hz), 7.06 (d, 1H, J =
25.3, 126.2, 126.6, 129.6, 129.8, 147.2, 147.5, 150.0, 153.4, 8.7 Hz), 7.22 (s, 1H), 7.40 (m, 1H), 7.60 (dd, 1H, J = 8.7,
+
+
+
13
58.4. MS-ES m/z 502 (MH , 100%); HRMS-ES calculated for 1.7 Hz), 7.90 (d, 1H, J = 1.6 Hz). C NMR (CDCl
3
) δ 24.9, 27.4,
29.4, 39.5, 50.6, 55.4, 55.9, 57.6, 87.2, 108.9, 112.3, 113.4,
-Bromo-N-(6-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)- 113.8, 126.9, 127.6, 130.3, 131.5, 135.3, 135.5, 149.8, 154.1,
7
9
C H N O Br: 502.5639 found 502.5643.
2
5
28 2 4
5
+
+
+
yl)hexyl)-1-benzofuran-2-carboxamide [56]. Clear film, yield 158.1, 158.5 (CO). MS-ES m/z 505 (MH , 100%); HRMS-ES
3
1
5%; H NMR (CDCl ) δ 1.39–1.46 (m, 4H), 1.61–1.68 (m, 4H), calculated for C H N O I: 505.0988, found 505.0982.
3 23 26 2 3
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-Iodo-N-(5-(3,4-dihydro-6-methoxyisoquinolin-2(1H)-yl)pentyl)-
Notes and references
1
1
-benzofuran-2-carboxamide [61]. Brown wax, yield 34%,
H
NMR (CDCl ) δ 1.47 (m, 2H), 1.66 (m, 4H), 2.50 (t, 2H, J =
3
1 (a) J. M. Walker, W. D. Bowen, F. O. Walker,
R. R. Matsumoto, B. De Costa and K. C. Rice, Pharmacol.
Rev., 1990, 42, 355; (b) M. Hanner, F. F. Moebius,
A. Flandorfer, H. Knaus, J. Striessnig, E. Kempner and
H. Glossman, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 8072.
2 T. P. Su, Eur. J. Biochem., 1991, 200, 633.
3 (a) R. Quirion, W. D. Bowen, Y. Itzhak, J. L. Junien,
J. M. Musacchio, R. B. Rothman, T. P. Su, S. W. Tam and
D. P. Taylor, Trends Pharmacol. Sci., 1992, 13, 85;
(b) S. B. Hellewell, A. Bruce, G. Feinstein, J. Orringer,
W. Williams and W. D. Bowen, Eur. J. Pharmacol., 1994,
268, 9.
4 (a) T. Hayashi and T. P. Su, Cell, 2007, 131, 596;
(b) T. Maurice and T. P. Su, Pharmacol. Ther., 2009, 124,
195; (c) M. P. Morin-Surun, T. Collin, M. Denavit-Saubie,
E. E. Baulieu and F. P. Monnet, Proc. Natl. Acad.
Sci. U. S. A., 1999, 96, 8196.
6
2
3
1
2
1
1
.7 Hz), 2.69 (t, 2H, J = 5.6 Hz), 2.86 (t, 2H, J = 5.3 Hz), 3.47 (dt,
H, J = 6.3 Hz), 3.54 (s, 2H), 3.76 (s, 3H), 6.61 (s, 1H), 6.67 (m,
H), 6.91 (d, 1H, J = 8.4 Hz), 7.23 (d, 1H, J = 8.7 Hz), 7.35 (s,
1
3
3
H), 7.65 (d, 1H, J = 8.7 Hz), 7.99 (s, 1H). C NMR (CDCl ) δ
4.9, 26.9, 29.5, 29.6, 39.5, 51.0, 55.3, 55.8, 58.3, 87.2, 109.2,
12.1, 113.3, 113.8, 127.2, 127.6, 130.3, 131.6, 135.4, 135.6,
+
+
49.7, 154.1, 158.0, 158.4. MS-ES m/z 519 (MH , 100%);
+
HRMS-ES calculated for C H N O I: 519.1145, found
2
4
28 2 3
5
19.1155.
-Iodo-N-(4-(3,4-dihydro-7-methoxyisoquinolin-2(1H)-yl)butyl)-
5
1
1
-benzofuran-2-carboxamide [62]. Brown wax, yield 30%;
) δ 1.75–1.77 (m, 4H), 2.55–2.58 (m, 2H), 2.74 (t,
H, J = 6.0 Hz), 2.84 (t, 2H, J = 5.7 Hz), 3.51–3.53 (m, 2H), 3.62
s, 2H), 3.76 (s, 3H), 6.53 (d, 1H, J = 2.6 Hz), 6.72 (dd, 1H, J =
H
NMR (CDCl
3
2
(
8
7
.4, 2.7 Hz), 7.00–7.07 (m, 2H), 7.23 (s, 1H), 7.42–7.44 (m, 1H),
.61 (dd, 1H, J = 8.7, 1.8 Hz), 7.91 (d, 1H, J = 1.7 Hz). C NMR
13
(
CDCl ) δ 24.9, 27.4, 28.2, 39.4, 50.8, 55.4, 56.6, 57.4, 87.2,
5 W. D. Bowen, Pharm. Acta Helv., 2000, 74, 211.
3
1
1
08.9, 111.4, 112.7, 113.8, 126.5, 129.7, 130.3, 131.5, 135.3,
6 (a) H. Ishiguro, T. Ohtsuke, M. Toru, M. Itokawa, J. Aoki,
H. Shibuya, A. Kurumaji, Y. Okubo, A. Iwawaki, K. Ota,
H. Shimizu, H. Hamaguchi and T. Arinami, Neurosci. Lett.,
1998, 257, 45; (b) T. Hayashi and T. P. Su, CNS Drugs, 2004,
18, 269; (c) T. Hayshi and T. P. Su, Expert Opin. Ther.
Targets, 2008, 12, 45; (d) J. L. Diaz, D. Zamanillo,
J. Corbera, J. M. Baeyens, R. Maldonado, M. A. Pericàs,
J. M. Vela and A. Torrens, Cent. Nerv. Syst. Agents Med.
Chem., 2009, 9, 172.
7 (a) B. J. Vilner, C. S. John and W. D. Bowen, Cancer Res.,
1995, 55, 408; (b) A. van Waarde, A. A. Rybczynska,
N. K. Ramakrishnan, K. Ishiwata, P. H. Elsinga and
R. Dierckx, Curr. Pharm. Des., 2010, 16, 3519;
(c) K. T. Wheeler, L. M. Wang, C. A. Wallen, S. R. Childers,
J. M. Cline, P. C. Keng and R. H. Mach, Br. J. Cancer, 2000,
82, 1223.
+
+
35.7, 149.8, 154.1, 157.8, 158.6. MS-ES m/z 505 (MH , 100%);
+
HRMS-ES calculated for C H N O I: 505.0988, found
2
3
26 2 3
5
05.0980.
-Iodo-N-(5-(3,4-dihydro-7-methoxyisoquinolin-2(1H)-yl)pentyl)-
5
1
1
-benzofuran-2-carboxamide [63]. Brown wax, yield 36%;
H
NMR (CDCl
3
) δ 1.43–1.47 (m, 2H), 1.62–1.69 (m, 4H), 2.50 (t,
2
3
6
8
8
2
1
1
H, J = 7.5 Hz), 2.69 (t, 2H, J = 6.0 Hz), 2.80 (t, 2H, J = 5.7 Hz),
.46 (m, 2H), 3.57 (s, 2H), 3.74 (s, 3H), 6.52 (d, 1H, J = 2.5 Hz),
.67 (dd, 1H, J = 8.4, 2.6 Hz), 6.75 (m, 1H), 6.96 (d, 1H, J =
.4 Hz), 7.21 (d, 1H, J = 8.7 Hz), 7.33 (s, 1H), 7.63 (dd, 1H, J =
.7, 1.7 Hz), 7.96 (d, 1H, J = 1.7 Hz). C NMR (CDCl ) δ
4.9, 26.8, 28.2, 29.6, 39.4, 51.2, 55.3, 56.4, 58.0, 87.2, 109.1,
11.4, 112.6, 113.8, 126.5, 129.6, 130.3, 131.5, 135.4, 135.8,
1
3
3
+
+
49.7, 154.0, 157.7, 158.4. MS-ES m/z 519 (MH , 100%);
+
HRMS-ES calculated for
19.1133.
24 28 2 3
C H N O I: 519.1145, found
5
8 G. E. Thomas, M. Szucs, J. Y. Mamone, W. T. Bem,
M. D. Rush, F. E. Johnson and C. J. Coscia, Life Sci., 1990,
46, 1279.
9
W. T. Bem, G. E. Thomas, J. Y. Mamone, S. M. Homan,
B. K. Levy, F. E. Johnson and C. J. Coscia, Cancer Res., 1991,
51, 6558.
Measurement of biological activity
Competition binding assays for ligands at σ
were performed using [ H](+)-PTZ (σ
1
2
and σ receptors
3
3
1
), [ H]DTG/500 nM 10 (a) J. Simony-Lafontaine, M. Esslimani, E. Bribes,
(
+)-PTZ (σ ) and membranes from fresh-frozen, male Sprague
S. Gourgou, N. Lequeux, R. Lavail, J. Grenier, A. Kramar
and P. Casellas, Br. J. Cancer, 2000, 82, 1958; (b) B. Wang,
R. Rouzier, C. T. Albarracin, A. Sahin, P. Wagner, Y. Yang,
T. L. Smith, F. Meric Bernstam, A. C. Marcelo,
G. N. Hortobagyi and L. Pusztai, Breast Cancer Res. Treat.,
2004, 87, 205.
2
3
5
Dawley rat brains as previously described. The animal experi-
ments were performed according to the Australian Code of Prac-
tice for the Care and Use of Animals for Scientific Purposes and
were approved by the Animal Care and Ethics Committee of
Australian Nuclear Science and Technology Organisation. The
animals were obtained from the Animal Resource Centre Pty 11 H. Kashiwagi, J. E. McDunn, P. O. Simon,
Ltd (Perth, Australia). Receptor binding assays were performed
in triplicate and repeated three independent experiments. IC50
values were calculated using Prism software and converted to
P. S. Goedegebuure, J. Xu, L. Jones, K. Chang, F. Johnston,
K. Trinkaus, R. S. Hotchkiss, R. H. Mach and
W. G. Hawkins, Mol. Cancer, 2007, 6, 48.
3
6
their corresponding K
i
values using Cheng-Prusoff equation,
12 R. H. Mach, C. R. Smith, I. al-Nabulsi, B. R. Whirrett,
S. R. Childers and K. T. Wheeler, Cancer Res., 1997, 57,
156.
3
based on a K of 2.5 nM for [ H](+)-PTZ and a K of 77 nM for
d
d
3
35
[
H]DTG.
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View Article Online
Paper
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1
3 B. J. Vilner, B. R. de Costa and W. D. Bowen, J. Neurosci.,
995, 117.
J. D. Mikkelsen, E. Meier and C. Thomsen, Neuropharma-
cology, 2002, 43, 95.
1
1
4 (a) Z. Wei, D. D. Mousseau, Y. Dai, X. Cao and X. M. Li, 24 (a) W. D. Bowen, B. J. Vilner, W. Williams, C. M. Bertha,
Pharmacogenomics J., 2006, 6, 279; (b) A. A. Rybczynska,
R. A. Dierckx, K. Ishiwata, P. H. Elsinga and A. van Waarde,
J. Nucl. Med., 2008, 49, 2049.
M. E. Kuehne and A. E. Jacobson, Eur. J. Pharmacol., 1995,
279, R1–R3; (b) R. H. Mach, C. R. Smith and S. R. Childers,
Life Sci., 1995, 57, PL57.
1
5 K. T. Wheeler, L. M. Wang, C. A. Wallen, S. R. Childers, 25 (a) R. H. Mach, L. Wu, T. West, B. R. Whirrett and
J. M. Cline, P. C. Keng and R. H. Mach, Br. J. Cancer, 2000,
, 1223.
6 K. W. Crawford, A. Coop and W. D. Bowen,
Eur. J. Pharmacol., 2002, 443, 207.
S. R. Childers, Life Sci., 1999, 64, PL131; (b) C. Ghelardini,
N. Galeotti and A. Bartolini, Pharmacol. Biochem. Behav.,
2000, 67, 659.
8
1
1
26 R. H. Mach, C. Zeng and W. G. Hawkins, J. Med. Chem.,
2013, 56, 7137.
7 (a) B. A. Spruce, L. A. Campbell, N. McTavish,
M. A. Cooper, M. V. Appleyard, M. O’Neill, J. Howie, 27 (a) R. Mach, Y. Huang, R. A. Freeman, L. Wu,
J. Samson, S. Watt, K. Murray, D. McLean, N. R. Leslie,
S. T. Safrany, M. J. Ferguson, J. A. Peters, A. R. Prescott,
G. Box, A. Hayes, B. Nutley, F. Raynaud, C. P. Downes,
J. J. Lambert, A. M. Thompson and S. Eccles, Cancer Res.,
S. Vangveravong and R. Luedtke, Bioorg. Med. Chem. Lett.,
2004, 14, 195; (b) S. Vangveravong, J. B. Xu, C. B. Zeng and
R. H. Mach, Bioorg. Med. Chem., 2006, 14, 6988;
(c) S. Arttamangkul, V. Alvarez-Maubecin, G. Thomas,
J. T. Williams and D. K. Grandy, Mol. Pharmacol., 2000, 58,
1570; (d) R. Xu, J. R. Lever and S. Z. Lever, Bioorg. Med.
Chem. Lett., 2007, 17, 2594; (e) K.-H. Fan, J. R. Lever and
S. Z. Lever, Bioorg. Med. Chem., 2011, 19, 1852;
(f) A. R. Hajipour, L.-W. Guo, A. Pal, T. Mavlyutov and
A. E. Ruoho, Bioorg. Med. Chem., 2011, 19, 7435.
2
004, 64, 4875; (b) S. Hazelwood and W. D. Bowen, Proc.
Am. Assoc. Cancer Res., 2006, 47; (c) K. W. Crawford and
W. D. Bowen, Cancer Res., 2002, 62, 313; (d) A. Azzariti,
N. A. Colabufo, F. Berardi, L. Porcelli, M. Niso,
G. M. Simone, R. Perrone and A. Paradiso, Mol. Cancer
Ther., 2006, 5, 1807.
1
8 (a) H. Kashiwagi, J. E. McDunn, P. O. Simon Jr., 28 (a) C. Zeng, S. Vangveravong, J. Xu, K. C. Chang,
P. S. Goedegebuure, J. Xu, L. Jones, K. Chang, F. Johnston,
K. Trinkaus, R. S. Hotchkiss, R. H. Mach and
W. G. Hawkins, Mol. Cancer, 2007, 6, 48; (b) C. Abate,
S. Ferorelli, M. Contino, R. Marottoli, N. A. Colabufo,
R. Perrone and F. Berardi, Eur. J. Med. Chem., 2011, 46,
R. S. Hotchkiss, K. T. Wheeler, D. Shen, Z. P. Zhuang,
H. F. Kung and R. H. Mach, Cancer Res., 2007, 67, 6708;
(b) C. Zeng, S. Vangveravong, L. A. Jones, K. Hyrc,
K. C. Chang, J. B. Xu, J. M. Rothfuss, M. P. Goldberg,
R. S. Hotchkiss and R. H. Mach, Mol. Imaging, 2011, 10,
420.
4
733; (c) N. A. Colabufo, C. Abate, M. Contino, C. Inglese,
M. Niso, F. Berardi and R. Perrone, Bioorg. Med. Chem. 29 (a) J. B. Xu, Z. D. Tu, L. A. Jones, S. Vangveravong,
Lett., 2008, 18, 1990; (d) Z. Tu, J. Xu, L. A. Jones, S. Li,
D. Zeng, M.-P. Kung, H. F. Kung and R. H. Mach, Appl.
Radiat. Isot., 2010, 68, 2268; (e) D. J. Rowland, Z. Tu, J. Xu,
D. Ponde, R. H. Mach and M. J. Welch, J. Nucl. Med., 2006,
K. T. Wheeler and R. H. Mach, Eur. J. Pharmacol., 2005,
525, 8; (b) Z. Tu, C. S. Dence, D. E. Ponde, L. Jones,
K. T. Wheeler, M. J. Welch and R. H. Mach, Nucl. Med.
Biol., 2005, 32, 423; (c) Z. Tu, J. B. Xu, L. A. Jones, S. H. Li,
C. Dumstorff, S. Vangveravong, D. L. Chen, K. T. Wheeler,
M. J. Welch and R. H. Mach, J. Med. Chem., 2007, 50, 3194.
4
7, 1041.
1
9 J. Xu, C. Zeng, W. Chu, F. Pan, J. M. Rothfuss, F. Zhang,
Z. Tu, D. Zhou, D. Zeng, S. Vangeravong, F. Johnston, 30 R. N. Waterhouse, T. Lee-Collier and J. C. O’Brien,
D. Spitzer, K. C. Chang, R. S. Hotchkiss, W. G. Hawkins,
J. Labelled Compd. Radiopharm., 1996, 38, 595.
K. T. Wheeler and R. H. Mach, Nat. Commun., 2011, 2, 380.
31 R. N. Waterhouse, Mol. Imaging Biol., 2003, 5, 376.
2
2
0 I. S. Ahmed, H. J. Rohe, K. E. Twist and M. N. Matingly, 32 T. R. Kelly, A. Szabados and Y. J. Lee, J. Org. Chem., 1997,
J. Pharmacol. Exp. Ther., 2010, 333, 564. 62, 428.
1 (a) G. Ronsisvalle, A. Marrazzo, O. Prezavento, A. Cagnotto, 33 A. H. Newman, P. Grundt, G. Cyriac, J. R. Deschamps,
T. Mennini, C. Parenti and G. Scoto, Pure Appl. Chem.,
001, 73, 1499; (b) E. J. Cobos, J. M. Entrena, F. R. Nieto,
M. Taylor, R. Kumar, D. Ho and P. R. Luedtke, J. Med.
Chem., 2009, 52, 2559.
2
C. M. Cendán and E. Del Pozo, Curr. Neuropharmacol., 34 H. M. Zhong, F. J. Villani and R. Marzouq, Org. Process Res.
008, 6, 344. Dev., 2007, 11, 463.
2 W. D. Bowen, C. M. Bertha, B. J. Vilner and K. C. Rice, 35 V. H. Nguyen, M. Kassiou, G. A. R. Johnston and
Eur. J. Pharmacol., 1995, 278, 257. M. J. Christie, Eur. J. Pharmacol., 1996, 311, 233.
3 (a) J. Perregaard, E. K. Moltzen, E. Meier and C. Sanchez, 36 Y. C. Cheng and W. H. Prusoff, Biochem. Pharmacol., 1973,
J. Med. Chem., 1995, 38, 1998; (b) K. K. Soby, 22, 3099.
2
2
2
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014