SAR studies of capsazepinoid bronchodilators. Part 2: Chlorination and catechol replacement in the A-ring

Article abstract of DOI:10.1016/j.bmc.2007.11.061

Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlorin

Full text of DOI:10.1016/j.bmc.2007.11.061

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 2513–2528
SAR studies of capsazepinoid bronchodilators. Part 2:
Chlorination and catechol replacement in the A-ring
a
a,b
Magnus Berglund, Marıa F. Dalence-Guzman, Staffan Skogvallc and Olov Sternera,
*
´
´
aDivision of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden
bCentro de Tecnologia Agroindustrial, Facultad de Ciencias y Tecnologia, Universidad Mayor de San Simo´n, Cochabamba, Bolivia
cRespiratorius AB, Magistratsva¨gen 10, 226 43 Lund, Sweden
Received 8 December 2006; revised 14 November 2007; accepted 21 November 2007
Available online 28 November 2007
Abstract—Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From
a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This paper concerns the chlo-
rination of the A-ring as well as the replacement of the catechol with bioisosteric groups. It is revealed that chlorination of the A-
ring has a profound effect on activity. Moreover, di-chlorination of the 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline structure
results in a 10-fold increase in potency compared to capsazepine.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
b2-agonists such as formoterol (72) and salbutamol
(73) (Fig. 1). The results show that 4 not only has a high-
er efficacy but also that it acts through a different and
possibly novel mechanism,9 making it interesting as a
lead structure for the development of new drugs to treat
asthma and COPD.
b2-Agonists, among other bronchodilators, constitute
the mainstay of the symptomatic treatment of asthma
and chronic obstructive pulmonary disease (COPD).1–3
They act as functional antagonists, reversing and pre-
venting bronchoconstriction from the various broncho-
constrictor mechanisms that operate in these diseases.4
We have recently reported that capsazepine (2), a tran-
sient receptor potential vanilloid channel subfamily
member 1 (TRPV1) antagonist,5–7 induces in vitro bron-
chodilation of human small bronchi constricted with
various agents such as leukotriene D4 (LTD4), hista-
mine, prostaglandin D2 and acetylcholine.8
Compounds containing phenol and catechol moieties
can be attractive candidates for drug development due
to their ability to take part in electrostatic interactions,
such as hydrogen bonds. A characteristic of these types
of compounds is their rapid metabolism by conjugation
Cl
Cl
S
Cl
Cl
S
HO
HO
A systematic SAR study of the bronchorelaxing activity
of capsazepinoids, partly reported in this paper, eventu-
ally led to the synthesis of 4, which has superior potency
compared to 2.9 Additionally, its duration of action is
longer than the one of 2.9 The ability of 4 to inhibit
the induction of constriction in human small airway
smooth muscle has been compared to that of known
HO
HO
N
H
N
H
N
N
H
2
4
OH
H
N
H
N
O
O
HO
72
OH
H
N
OH
Keywords: Capsazepine; SAR; A-ring catechol; B-ring; Isoindoline;
1,2,3,4-Tetrahydroisoquinoline; 2,3,4,5-Tetrahydro-1H-2-azepine; 2,
3,4,5-Tetrahydro-1H-3-benzazepine; Bronchodilator; Small human
airways; Asthma; COPD.
H
N
HO
HO
HO
OH
74
73
*
Corresponding author. Tel.: +46 462228213; fax: +46 462228209;
e-mail: Olov.Sterner@organic.lu.se
Figure 1.
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.11.061

2514
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
Coupling
R1
R2
Cl
R1
S
Cl
HO
HO
HO
S
b
N
N
H
NH
HO
HO
N
N
H
HO
A
B
R2
C
77 R1=Cl R2=H
78 R1=Cl R2=Cl
16 R1=H R2=H
a
75 R1=Cl R2=H
Figure 2.
76 R1=Cl R2=Cl
Scheme 1. Reagents and conditions: (a) 1—di-tert-butyl dicarbonate,
Et3N, DMF rt, 2 h; 2—trifluoroacetic acid, CH2Cl2, anisol, rt, 1 h; 3—
SO2Cl2, AcOH, rt, 2.5 h; (b) Et3N, 2-(4-chlorophenyl)ethyl isothiocy-
anate, DMF, rt, 4 h.
with glucuronic acid and, in the case of catechols, meth-
ylation catalyzed by catechol-O-methyltransferase
(COMT). This is a major drawback when the drug is in-
tended for oral use,10 but it may be seen as an advantage
for inhaled drugs as the risk of side effects is diminished.
For example, phenol-containing bronchodilator agents
such as the b2-agonists 73 and 74 (Fig. 1) are distributed
directly to the target organ, that is, the airways, by
inhalation.
Cl
R1
R1
MeO
MeO
MeO
MeO
NH
R2
NH
R2
a
b
Cl
27 R1=Me R2=H
28 R1=H R2=Me
29 R1=Bn R2=H
79 R1=Me R2=H
80 R1=H R2=Me
81 R1=Bn R2=H
However, since the progressive deterioration of the air-
ways in diseases, such as chronic obstructive pulmonary
disease (COPD), greatly reduces the respiratory capac-
ity, inhalation is less suitable as administration route
when such diseases are to be treated.11 Consequently,
drugs directed against diseases such as COPD should
preferably not comprise hydroxyl groups, and attempts
have therefore been made to replace the hydroxyls in
the A-ring (Fig. 2).
Cl
Cl
R1
Cl
Cl
R1
S
HO
HO
HO
HO
NH
R2
N
N
H
c
R2
Cl
85 R1=Me R2=H
86 R1=H R2=Me
87 R1=Bn R2=H
82 R1=Me R2=H
83 R1=H R2=Me
84 R1=Bn R2=H
Scheme 2. Reagents and conditions: (a) SO2Cl2, AcOH, rt, 2.5 h; (b)
HBr (48% in H2O), reflux, 5 h; (c) Et3N, 2-(4-chlorophenyl)ethyl
isothiocyanate, DMF, rt, 4 h.
The structure of capsazepine has been divided into four
regions, which are shown in Figure 2, in order to system-
atically study the effect on the activity of structural vari-
ations of each region. In this paper, we investigate the
effect of chlorination of the A-ring in phenolic and cate-
cholic derivatives having different B-rings, and in B-
rings substituted with methyl/benzyl groups in various
positions. In addition, the effect of alternative A-ring
substituents is studied in 1,2,3,4-tetrahydroisoquinoline
derivatives. In the preceding paper,12 the importance
of a catechol moiety in the A-ring and how structural
differences in the B-ring affect the bronchodilating abil-
ity of the capsazepinoids is discussed, while the follow-
ing paper discusses the coupling region as well as the
C-region.13 To facilitate the comparison of the results
from the complete study, a continuous numbering of
the compounds has been used. Compounds discussed
in more than one paper consequently have the same
number everywhere. The preparation of compounds
having numbers below 72 is described in the preceding
paper.12
line, a methylsulfonyl amide, a phthalic acid, a phthalic
acid methylester or a phthalonitrile was investigated
(Schemes 5–7 and Table 2).
The synthesis of chlorinated isoindoline analogues is
outlined in Scheme 1. Attempts to chlorinate the
hydrobromic salt of 1614 with sulfuryl chloride in acetic
acid15 failed, a complex mixture of chlorinated and
brominated products was formed. This problem was
overcome by changing the counterion by N-Boc protec-
tion and deprotection with trifluoroacetic acid, yielding
the trifluoroacetic salt of 16 which was chlorinated
without problems to the intermediates 75 and 76. In
general, monochlorinations were achieved with 1.2
equivalents of sulfuryl chloride while dichlorinations
were accomplished with 2.2 equivalents of sulfuryl
chloride. Coupling with 2-(4-chlorophenyl)ethyl isothi-
ocyanate afforded the mono- and dichlorinated
products 77 and 78.
2. Chemistry
1,2,3,4-Tetrahydroisoquinoline analogues having
a
substituted B-ring, 85–87, were synthesized as illustrated
in Scheme 2. Dichlorination of the commercially avail-
able 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines 27-
29 was carried out with sulfuryl chloride in acetic acid,
to yield 79-81, which were demethylated in HBr (48%
in H2O) to give 82–84. Coupling of these intermediates
with 2-(4-chlorophenyl)ethyl isothiocyanate afforded
85–87.
Synthetic routes to mono- and dichlorinated capsazepi-
noids with a conformationally constrained B-ring as in
isoindolines (5-membered B-ring), tetrahydroisoquino-
lines (6-membered B-ring), and tetrahydro-1H-2-ben-
zazepines as well as tetrahydro-1H-3-benzazepines (7-
membered B-ring) were developed as this modification
was found to have a particularly strong effect on the
activity (Schemes 1–4 and Table 1). In addition, the ef-
fect of replacing the catechol or phenol moiety of the
1,2,3,4-tetrahydroisoquinoline ring system with an ani-
The chlorinated 1,2,3,4-tetrahydroisoquinoline deriva-
tives 94, 95, 4, 102–104 and 111–113 were prepared as

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2515
Cl
R1
R2
R1
R1
S
MeO
MeO
HO
HO
HO
HO
NR3
NH
N
N
H
c
d
R2
R2
26 R1=H R2=H R3=H
94 R1=Cl R2=H
95 R1=H R2=Cl
4 R1=Cl R2=Cl
91 R1=Cl R2=H
92 R1=H R2=Cl
93 R1=Cl R2=Cl
a
88 R1=Cl R2=H R3=Boc
89 R1=H R2=Cl R3=Boc
90 R1=Cl R2=Cl R3=H
b
Cl
S
R1
R1
R1
HO
N
N
H
NBoc
NH
c
d
HO
MeO
R2
R2
R2
44 R1=H R2=H
102 R1=Cl R2=H
103 R1=H R2=Cl
104 R1=Cl R2=Cl
99 R1=Cl R2=H
100 R1=H R2=Cl
101 R1=Cl R2=Cl
a
96 R1=Cl R2=H
97 R1=H R2=Cl
e
98 R1=Cl R2=Cl
Cl
R1
R1
R1
S
MeO
HO
HO
R2
NR3
NH
N
N
H
c
d
R2
R2
50 R1=H R2=H R3=Boc
111 R1=Cl R2=H
112 R1=H R2=Cl
113 R1=Cl R2=Cl
108 R1=Cl R2=H
109 R1=H R2=Cl
110 R1=Cl R2=Cl
a
105 R1=Cl R2=H R3=Boc
106 R1=H R2=Cl R3=Boc
107 R1=Cl R2=C R3=H
b
Scheme 3. Reagents and conditions: (a) 1—SO2Cl2 (1.1 equiv), AcOH, rt, 2.5 h; 2—di-tert-butyl dicarbonate, Et3N, DMF, rt, 2 h; (b) SO2Cl2 (2.1
equiv), AcOH, rt, 2.5 h; (c) HBr (48% in H2O), reflux, 5 h; (d) Et3N, 2-(4-chlorophenyl)ethyl isothiocyanate, DMF, rt, 4 h; (e) 1—SO2Cl2 (2.1 equiv),
AcOH, rt, 2.5 h; 2—di-tert-butyl dicarbonate, Et3N, DMF, rt, 2 h.
Cl
S
R1
R1
R1
R2
MeO
MeO
HO
HO
HO
HO
NR3
NH
N
N
H
c
d
R2
R2
57 R1=H R2=H R3=H
117 R1=Cl R2=H
118 R1=H R2=Cl
119 R1=Cl R2=Cl
120 R1=Cl R2=H
121 R1=H R2=Cl
122 R1=Cl R2=Cl
a
114 R1=Cl R2=H R3=Boc
115 R1=H R2=Cl R3=Boc
116 R1=Cl R2=Cl R3=Boc
b
Cl
S
R1
R1
R1
NR3
NH
N
N
H
c
d
MeO
HO
HO
R2
R2
R2
58 R1=H R2=H R3=H
126 R1=Cl R2=H
127 R1=H R2=Cl
128 R1=Cl R2=Cl
129 R1=Cl R2=H
130 R1=H R2=Cl
131 R1=Cl R2=Cl
a
123 R1=Cl R2=H R3=Boc
124 R1=H R2=Cl R3=Boc
125 R1=Cl R2=Cl R3=H
e
Cl
S
R1
R1
R1
MeO
HO
R2
HO
R2
NR3
NH
N
N
H
c
d
R2
64 R1=H R2=H R3=H
134 R1=Cl R2=H
135 R1=H R2=Cl
136 R1=Cl R2=H
137 R1=H R2=Cl
a
132 R1=Cl R2=H R3=Boc
133 R1=H R2=Cl R3=Boc
Cl
Cl
Cl
R1
S
HO
HO
HO
HO
MeO
c
NH
d
N
N
H
NH
MeO
Cl
Cl
R2
139
140
69 R1=H R2=H
e
138 R1=Cl R2=Cl
Scheme 4. Reagents and conditions: (a) 1—SO2Cl2 (1.1 equiv), AcOH, rt, 2.5 h; 2—di-tert-butyl dicarbonate, Et3N, DMF, rt, 2 h; (b) (1) SO2Cl2 (2.1
equiv), AcOH, rt, 2.5 h; 2—di-tert-butyl dicarbonate, Et3N, DMF, rt, 2 h; (c) HBr (48% in H2O), reflux, 5 h; (d) Et3N, 2-(4-chlorophenyl)ethyl
isothiocyanate, DMF, rt, 4 h; (e) 1—SO2Cl2 (2.1 equiv), AcOH, rt, 2.5 h.

2516
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
Table 1. Remaining contraction after pretreatment with different capszepinoids (10 lM)
Cl
S
N
H
A
R1
R1 R5
R1
R4
R1
R4
R2
R3
R2
R3
R2
R3
R2
R3
N
N
N
N
A:
R6
R4
R4
I
II
III
IV
Compound
A
R1
R2
R3
R4
R5
R6
Remaining contractiona
17b
77
I
I
I
H
OH
OH
OH
OH
OH
OH
H
H
Cl
56 10.0 (5)
65 13.1 (4)
31 7.7 (4)
Cl
Cl
—
—
—
—
78
35b
85
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
H
Cl
H
Cl
H
Cl
H
Cl
H
Cl
H
H
H
H
H
Cl
H
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
Cl
H
Cl
H
Cl
H
H
Cl
Cl
H
H
Cl
Cl
H
H
H
H
Me
Me
H
H
H
58 11.7 (5)
48 8.4 (4)
70 10.1 (4)
31 7.6 (4)
79 5.4 (4)
84 5.8 (4)
36 6.5 (5)
49 1.2 (5)
40 10.5 (4)
14 2.7 (16)
52 6.8 (4)
73 3.2 (4)
69 4.8 (4)
55 4.3 (4)
75 7.0 (4)
47 9.2 (4)
69 6.5 (4)
57 11.4 (3)
36b
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
86
H
37b
87
Bn
Bn
H
34b
94
95
4c
H
H
H
48b
102
103
104
52b
111
112
113
H
Cl
H
H
Cl
H
H
OH
OH
OH
OH
H
H
Cl
H
H
Cl
H
2b
III
III
III
III
III
III
III
III
III
III
III
H
Cl
H
Cl
H
H
H
H
H
Cl
H
OH
OH
OH
OH
H
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
Cl
Cl
H
H
Cl
Cl
H
H
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
55 3.0 (24)
63 14.8 (3)
64 7.0 (2)
38 10.0 (4)
53 4.7 (3)
49 5.7 (4)
67 10.3 (3)
30 2.4 (3)
40 9.9 (4)
46 6.6 (4)
56 11.9 (3)
120
121
122
61b
129
130
131
66b
136
137
Cl
H
Cl
OH
OH
OH
H
Cl
71b
140
IV
IV
H
Cl
OH
OH
OH
OH
H
Cl
—
—
—
—
54 5.5 (4)
29 3.0 (2)
a Arithmetic mean the standard error of the mean of the percent remaining contraction in small human airways contracted with LTD4 in the
presence of 10 lM test substance compared to a full contraction evoked by LTD4 in the absence of test compound. Number of times tested in
parentheses.
b Compounds reported previously.12
c A detailed study of the pharmacological effects of 4 has been reported.9
Cl
tection of the mixtures to facilitate purification yielded
88, 89, 96–98 and 105–107. Intermediate 90 was ob-
tained as the only product and Boc-protection was not
required. Deprotection and coupling with 2-(4-chloro-
phenyl)ethyl isothiocyanate was carried out as described
above.
S
N
N
H
NH
a
141
142
Scheme 5. Reagents and condition: (a) Et3N, 2-(4-chlorophenyl)ethyl
isothiocyanate, DMF, rt, 4 h.
The general synthesis of the capsazepine derivatives
120–122, 129–131, 136–137 and 140 is outlined in
Scheme 4. The preparation of the dichlorinated deriva-
described in Scheme 3. Chlorination of intermediates 26,
44 and 5014 with sulfuryl chloride followed by Boc-pro-

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2517
Table 2. Remaining contraction after pretreatment with different
capszepinoids (10 lM) with various substitution of the A-ring
O
R1
R2
R1
R2
NH
N
NH
a
c
Cl
S
R1
143 R1=H R2=NO2
144 R1=NO2 R2=H
147 R1=H R2=NH2
148 R1=NH2 R2=H
141
N
N
H
b
R2
145 R1=H R2=NH2
146 R1=NH2 R2=H
d
Compound R1
R2
Remaining contractiona
Cl
S
48b
153
155
H
H
H
OH
NH2
52 6.8 (4)
62 6.0 (4)
R1
R2
R1
R2
e
NBoc
g
N
N
H
NHSO2Me 75 6.7 (4)
149 R1=H
R2=NH2
153 R1=H R2=NH2
154 R1=NH2 R2=H
155 R1=H R2=NHMs
156 R1=NHMs R2=H
52b
154
156
OH
NH2
H
H
H
75 7.0 (4)
79 4.6 (4)
72 7.5 (4)
150 R1=NH2 R2=H
f
151 R1=H R2=NHMs
152 R1=NHMs R2=H
NHSO2Me
Scheme 6. Reagents and conditions: (a) 1—Ac2O, 0 ꢁC, 3 h; 2—
HNO3/H2SO4, 0 ꢁC, 4 h; (b) H2 (1 atm), Pd/C, HCl, MeOH, rt, 1 h; (c)
HBr (aq), reflux, 4 h; (d) Et3N, 2-(4-chlorophenyl)ethyl isothiocyanate,
DMF, rt, 4 h; (e) Boc2O, THF, H2O, rt, 3 h; (f) MsCl, Et3N, CH2Cl2,
0 ꢁC–rt, 2 h; (g) 1—trifluoroacetic acid, CH2Cl2, anisol, rt, 1 h; 2—
Et3N, 2-(4-chlorophenyl)ethyl isothiocyanate, DMF, rt, 4 h.
142
34b
162
163
164
H
OH
H
OH
83 2.2 (4)
36 6.5 (5)
84 10.6 (4)
87 1.8 (4)
99 4.3 (4)
CN
CO2Me
CO2H
CN
CO2Me
CO2H
a Arithmetic mean the standard error of the mean of the percent
remaining contraction in small human airways contracted with
LTD4 in the presence of 10 lM test substance compared to a full
contraction evoked by LTD4 in the absence of test compound.
Number of times tested in parentheses.
HO
HO
TfO
TfO
NC
NC
NR
NBoc
NBoc
Cl
b
c
b Compounds synthesized previously.12
30 R1=H
159
158
a
d
157 R1=Boc
S
R1
afforded 147 and 148, which after coupling with 2-(4-
chlorophenyl)ethyl isothiocyanate gave 153 and 154.
Selective N-Boc protection of the secondary amine of
147 and 148 afforded 149 and 150, which could be mesy-
lated to afford 151 and 152. Deprotection of 151 and 152
with trifluoroacetic acid and coupling with 2-(4-chloro-
phenyl)ethyl isothiocyanate afforded 155 and 156.
R1
R1
NH
d
f
N
N
H
R1
162 R1=CN
163 R1=CO2Me
164 R1=CO2H
160 R1=CO2Me
e
161 R1=CO2H
Scheme 7. Reagents and conditions: (a) Boc2O, Et3N, THF, H2O, rt,
17 h, 68%; (b) Tf2O, Et3N, CH2Cl2, 0 ꢁC–rt, 3 h, 95%; (c) Zn(CN)2,
Pd2(dba)3, dppf, DMF 80 ꢁC, 2 h, 42%; (d) 1—trifluoroacetic acid,
CH2Cl2, anisol, rt, 1 h; 2—Et3N, 2-(4-chlorophenyl)ethyl isothiocya-
nate, DMF, rt, 4 h; (e) 1–NaOH, H2O, reflux, 48 h; 2—H2SO4, MeOH,
reflux, 17 h, 35%; (e) LiOHÆH2O, THF, H2O, rt, 48 h; (f) Et3N, 2-(4-
chlorophenyl)ethyl isothiocyanate, DMF, rt, 4 h.
The preparation of additional analogues with cyano, car-
boxylic acid and methyl carboxylate groups in the A-ring
is described in Scheme 7. The N-Boc protection of 30
yielded 157, which was converted to 158 with triflic anhy-
dride. Aromatic triflates have been reported to be con-
verted nitriles in a palladium (0) catalyzed reaction,14
but this method did not yield 159 from 158. However,
changing the ligand from triphenylphoshine to the
strongly chelating ligand 1,10-bis(diphenylphosphino)fer-
rocene and the palladium source from palladium tetraki-
tive of 64 failed, even with up to 5 equivalents of sulfuryl
chloride. Only the monochlorinated products were
obtained.
striphenylphoshine
to
tris(dibenzylideneacetone)
The effect of substituting the hydroxyl groups in the A-
ring with other functional groups that also can participate
in hydrogen bonds was investigated. As indicated in the
preceding paper,12 the 1,2,3,4-tetrahydroisoqouinolines
are considered to be the most interesting of the capsazepi-
noids and consequently this part of the study was limited
to 1,2,3,4-tetrahydroisoquinolines. For reference, the
non-substituted 1,2,3,4-tetrahydroisoquinoline 142 was
prepared, according to Scheme 5, by coupling of 141 with
2-(4-chlorophenyl)ethyl isothiocyanate.
dipalladium, and adding the Zn(CN)2 in portions as pre-
viously suggested for catechols,15 enabled us to prepare
159, which was deprotected and coupled with 2-(4-chloro-
phenyl)ethyl isothiocyanate to yield 162. Basic hydrolysis
of the phthalonitrile 159 and in situ Fischer esterification
produced the phthalic acid methylester 160. The esterifi-
cation was necessary to facilitate isolation of 160, and ba-
sic hydrolysis of 160 afforded the phthalic acid 161.
Coupling of 160 and 161 with 2-(4-chlorophenyl)ethyl
isothiocyanate afforded 163 and 164.
In Scheme 6, the syntheses of the derivatives in which the
hydroxyl groups in the A-ring are replaced by an amino
group or a methylsulfonyl amide moiety are shown.
Acylation of 141 and subsequent nitration afforded a
mixture of 143 and 144, which were isolated by chroma-
tography. Hydrogenation and hydrolysis of 143 and 144
3. Results and discussion
The bronchorelaxing effect of the derivatives synthesized
was evaluated in vitro, as previously described,8,16 in

2518
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
human small airways (0.5–1.5 mm in diameter). The
constriction evoked by 10 nM LTD4 on untreated prep-
arations and on the same preparations exposed to
10 lM of the test compound for 1.5 h was compared.
The results, summarized in Tables 1 and 2, are shown
as the percentage of the remaining contraction after
1.5 h exposure to the test substance compared to the full
contraction. All compounds were assayed in the same
way, in the same concentration and for the same time
of exposure, in order to get comparable values. The ef-
fects can vary between 100% remaining contraction for
an inactive compound and 0% remaining contraction
for a compound with a maximal effect. This is a func-
tional assay that is carried out with human tissue ob-
tained from lung cancer patients. Until the target has
been characterized and its function understood it is
not possible to assess how the lipophilicity and other
physicochemical properties of the compounds may affect
their ability to reach and interact with the target. Two
compounds reported to be equally active in this investi-
gation may therefore differ if the concentration or time
of exposure is changed. The SARs discussed here are
consequently limited to the activities recorded in the as-
say used in this investigation.
(17 vs 77, 34 vs 94 and 95, 2 vs 120 and 121). On the
other hand, dichlorination of the same derivatives re-
sulted in considerably more potent compounds (78, 4
and 122). The effect of chlorination on the bronchore-
laxing properties of the capsazepinoids can be expected
to be due to a combination of steric hindrance and
changes in the electronic properties of the molecules. It
is interesting to note that dichlorination of the 6,7-
dihydroxylated isoquinolines 35 and 37, that are substi-
tuted in position 1 with a methyl group (35) or a benzyl
group (37), does not result in potent derivatives. As al-
ready suggested,12 substituents in the B-ring appear to
be unfavourable for steric reasons, and dichlorination
will not affect the potency of compounds having a big
group (e.g., benzyl) in position 1. However, position 3
appears to be less critical as the dichlorination of 36,
having a methyl group in position 3, results in 86 that
is rather potent. The disparity of the results suggests that
depending on the relative position of the hydroxyl group
and chlorine with respect to each other, either steric or
electronic factors will determine the strength of the
interactions, presumably hydrogen bonds, of the hydro-
xyl group and hence the activity of the specific com-
pound. In addition, the lipophilicity will increase upon
addition of chlorines, which in general would be ex-
pected to facilitate the approach of the compound to
the target, especially if it is intracellular. However, as
mentioned above, no solid information about the target
is available.
The importance of hydroxyl groups in various positions
in the different structure types has been discussed in the
preceding paper,12 where it was suggested that the
hydroxyls participate in intermolecular bonds with the
target protein. In an effort to investigate how the inter-
actions of the hydroxyl groups may be modulated by
other substituents in the A-ring, a number of chlori-
nated derivatives were prepared and assayed (results
shown in Table 1). In an effort to investigate the neces-
sity of the hydroxyl groups for the activity of the iso-
quinolines, a number of derivatives having other
substituents in positions 6 and 7 were prepared and as-
sayed (results are shown in Table 2). Both tables also
contain the activity of a few derivatives reported in the
preceding paper,12 in order to facilitate comparison.
In an effort to investigate the necessity of the hydroxyl
groups for the activity of the isoquinolines, a number
of derivatives having other substituents in positions 6
and 7 were prepared (Schemes 5–7) and assayed (Table
2).
Compared to the corresponding phenol 48, the aniline
153 displayed a somewhat lower potency, which may
be explained by the lower hydrogen bond donating abil-
ity of the amino group compared to the hydroxyl
group.17 An amino group at C-7 (154) instead of a hy-
droxyl group (52) did not increase the potency, even
compared to the non-substituted 142. These findings
support our suggestion that the hydroxyl group of 48
acts as a hydrogen bond donor.12 Like phenols, anilines
are known to be glucuronidated, although less rapidly,
and altogether they are not attractive as a bioisostere
to phenols in capsazepinoids. 2 was originally reported
as a capsaicin and TRPV1 antagonist.7 Replacement
of the hydroxyl group with the biosteric methylsulfony-
lamido group and removal of the methoxy group con-
verts vanilloids displaying TRPV1-agonism into
antagonists, especially if the methoxy group is replaced
with fluorine.18 Inspired by this, the methylsulfonyl
amides 155 and 156 were prepared. However, mesyla-
tion of the aniline 154 did not enhance its low potency,
instead mesylation of the aniline 153 resulted in a drop
in potency. Although metabolically more stable, the
methylsulfonylamido group does seem less interesting
as a bioisostere to the hydroxyl group in capsazepinoids.
Previous findings have indicated that the binding site
has limited volume around C-6, which may explain the
drop in potency from the aniline 153 to the methylsulfo-
The monochlorination of the phenolic derivatives does
not result in a clear effect. For the isoquinolines, 102
and 103 are both less potent compared to their non-
chlorinated analogue 48, while 111 is more potent and
112 equally potent compared to 52. For the 1H-2-ben-
zazepines, 129 is equally potent while 130 less potent
compared to 61, and 136 is equally potent while 137 is
less potent compared to 66. Dichlorination of the phe-
nols has a clearer effect. 113 and 131 are both signifi-
cantly more potent compared to 52 and 61, while 104
is equally potent as 48. The dichlorinated phenolic tetra-
hydro-1H-2-benzazepine 131 is also considerably better
than the corresponding monochlorinated phenols 129
and 130, and this could be seen as an electronic effect
facilitating the interaction of the hydroxyl group of
131 with the target. However, as the catechols in general
are more potent than the phenols,12 adding chlorine to
one or both remaining positions in the catechols may
be more interesting. For the three B-ring systems isoind-
oline, 1,2,3,4-tetrahydroisoquinoline and 2,3,4,5-tetra-
hydro-1H-2-benzazepine, the general trend for
monochlorination of a catechol is decreased activity

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2519
nyl amide 155.12 The catechol 34 is more potent than
either of the phenols 48 or 52. We have argued that this
might be caused by both hydroxyl groups of the catechol
moiety taking part in specific interactions, for example,
hydrogen bonds.12 The phthalic acid derivative 164 and
derivatives thereof, 162 and 163, are all possible hydro-
gen bond donors/acceptors. Unfortunately neither of
them is potent, which might be because of the limited
volume in the binding site where the A-ring binds. The
phthalic acid derivative 164 is devoid of activity, possi-
bly because it is charged at physiological pH and cannot
pass cell membranes. The localization of the binding site
of capsazepinoids acting as inhibitors of bronchocon-
striction, as discussed above, is unknown, but if intracel-
lularly located, as the capsaicin binding site of TRPV1,
the complete lack of activity of 164 is explainable.19,20
(in CDCl3 or CD3OD) were recorded with a Bruker
ARX 300 spectrometer at 300 MHz (1H) and at
75 MHz (13C) and with a Bruker DRX 400 spectrometer
at 400 MHz (1H) and at 100 MHz (13C). Chemical shifts
are given in ppm relative to TMS using the residual
CHCl3 peak in CDCl3 or the residual CD2HOD peak
in CD3OD solution as internal standard (7.26 or 3.32
and 77.2 or 49.0 ppm, respectively, relative to TMS).
˚
All flash chromatography was performed on 60 A 35–
70 lm Matrex silica gel (Grace Amicon). TLC analyses
were made on Silica Gel 60 F254 (Merck) plates and visu-
alized with ninhydrin/acetic acid and heating. The purity
1
of the assayed compounds was verified with H NMR
and HPLC, and only used if more than 98% pure.
5.2. Synthesis
5.2.1. General procedure for demethylation. The corre-
sponding amine was dissolved in HBr (48% in H2O).
The mixture was heated to 105 ꢁC for 5 h and then con-
centrated. The residue was suspended in EtOAc and
concentrated again.
4. Conclusions
Capsazepinoids, a novel class of bronchodilators, have
been shown to be potent in vitro inhibitors of broncho-
constriction in human small airways. If similar effects
are at hand also in vivo, they constitute a promising novel
pharmaceutical principle to prevent and revoke airway
obstruction caused by asthma or COPD. SAR studies
of the capsazepinoids have revealed the importance of a
phenol, or even better, a catechol moiety in the A-ring
for the activity, and the effect of chlorination of the A-
ring was studied. In addition, in an attempt to counteract
the metabolic instability of phenols and catechols,
alternatives to the hydroxyl groups in the A-ring were
evaluated. The following conclusions could be drawn:
5.2.2. Procedure A for chlorinations. The corresponding
amine (1.0 equiv) was suspended in glacial acetic acid,
SO2Cl2 (2.2 equiv for dichlorinations) was added drop-
wise. After stirring for 2.5 h the mixture was
concentrated.
5.2.3. Procedure B for chlorinations. The corresponding
amine (1.0 equiv) was suspended in glacial acetic acid,
SO2Cl2 (1.2 equiv for monochlorinations and 2.2 equiv
for dichlorinations) was added dropwise. After stirring
for 2.5 h the mixture was concentrated. The crude mix-
ture was dissolved in anhydrous DMF, triethylamine
(3.0 equiv) and di-tert-butyl dicarbonate (1.5 equiv)
were added. The reaction mixture was stirred for 2 h
at room temperature, then it was concentrated under
vacuum, H2O was added to the residue and several
extractions were made with EtOAc. The combined or-
ganic phases were dried (MgSO4) and concentrated.
1. Monochlorination of the phenol derivatives does not
provide any clear SARs, while dichlorination of the
phenols in general enhances the activity.
2. Monochlorination of the catechol derivatives gives
less potent compounds, while dichlorination of the
catechols gives more potent compounds.
3. All the compounds with amino, (methylsulfo-
nyl)amido, carboxy, methoxycarbonyl and cyano
substituents instead of hydroxyl groups in the A-ring
were less active compared to the corresponding phe-
nols and catechols.
4. The two evaluated anilines (153 and 154) displayed a
similar activity pattern as the corresponding phenols
(48 and 52), supporting the suggestion that these
groups interact with the target protein by donating
a hydrogen bond.
5.2.4. General procedure for coupling of amines with 2-(4-
chlorophenyl)ethyl isothiocyanate. The corresponding
amine (usually as a salt) (1.0 equiv) was dissolved in
anhydrous DMF and triethylamine (3.0 equiv) was
added. This mixture was stirred for 15 min and then 2-
(4-chlorophenyl)ethyl isothiocyanate (1.2 equiv) was
added. This mixture was stirred for additional 4 h and
then concentrated. The residue was dissolved in EtOAc
and washed with water. The organic phase was dried
(MgSO4) and concentrated.
5. Experimental
5.1. Materials
5.2.4.1. 4,7-Dichloroisoindoline-5,6-diol hydrochloride
(76). Compound 16 (1.0 equiv) was dissolved in anhy-
drous DMF, di-tert-butyldicarbonate (1.2 equiv) and
triethylamine (2.0 equiv) were added. The mixture was
stirred for 1 h and then concentrated. The residue was
dissolved in EtOAc and washed with water. The organic
phase was dried (MgSO4) and concentrated. The residue
was dissolved in a mixture of 80% trifluoroacetic acid,
19% dichloromethane and 1% anisol and stirred for
1 h. After evaporation a grey solid of 5,6-dihydroxyiso-
Materials were obtained from commercial suppliers and
were used without further purification unless otherwise
noted. DMF was distilled under reduced pressure. All
moisture- and air-sensitive reactions were carried out
under an atmosphere of dry nitrogen using oven-dried
glassware. HRMS (ESI) spectra were recorded with a
Micromass Q-TOF Micro spectrometer. NMR spectra

2520
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
indoline trifluoroacetic acid salt remained. The salt was
suspended in glacial acetic acid and SO2Cl2 (3.0 equiv)
was added dropwise. After stirring for 2.5 h the mixture
was concentrated. Toluene was added and the mixture
concentrated again, to afford 76 (quantitative). 1H
NMR (CD3OD 300 MHz) d 4.62 (s, 4H).
5.2.4.5. 5,8-Dichloro-6,7-dimethoxy-3-methyl-1,2,3,4-
tetrahydroisoquinoline hydrochloride (80). Compound
80 was synthesized from 28, using the procedure A for
chlorinations (quantitative). 1H NMR (CD3OD
300 MHz) d 1.54 (d, J = 6.4 Hz, 3H), 2.76 (m, 1H),
3.26 (m, 1H), 3.61 (m, 1H), 3.92 (s, 6H), 4.30 (d,
J = 16.4 Hz, 1H), 4.40 (d, J = 16.4 Hz, 1H).
5.2.4.2. 4-Chloro-N-[2-(4-chlorophenyl)ethyl]-5,6-dihy-
droxy-1,3-dihydro-2H-isoindole-2-carbothioamide (77).
Compound 16 (1.0 equiv) was dissolved in anhydrous
DMF, di-tert-butyldicarbonate (1.2 equiv) and triethyl-
amine (2.0 equiv) were added. The mixture was stirred
for 1 h and then concentrated. The residue was dissolved
in EtOAc and washed with water. The organic phase
was dried (MgSO4) and concentrated. The residue was
dissolved in a mixture of 80% trifluoroacetic acid, 19%
dichloromethane and 1% anisol and stirred for 1 h.
After evaporation a grey solid of 5,6-dihydroxyisoindo-
line trifluoroacetic acid salt remained. This salt was sus-
pended in glacial acetic acid and SO2Cl2 (2.0 equiv) was
added dropwise. After stirring for 2.5 h, the mixture was
concentrated. H2O was added and extractions were
made with EtOAc. The organic phases were dried
(MgSO4) and concentrated affording 75 which was used
for the next step without further purification. 75 was dis-
solved in anhydrous DMF and triethylamine (3.0 equiv)
was added. This mixture was stirred for 15 min and then
2-(4-chlorophenyl)ethyl isothiocyanate (1.2 equiv) was
added. This mixture was stirred for additional 3 h and
then concentrated. The residue was dissolved in EtOAc
and washed with water. The organic phase was dried
(MgSO4) and concentrated. 77 was purified by flash col-
umn chromatography (silica, pet. ether/EtOAc 7:3)
(27%). 1H NMR (CD3OD 400 MHz) d 2.92 (t,
J = 7.6 Hz, 2H), 3.78 (t, J = 7.6 Hz, 2H), 4.68 (br s,
4H), 6.64 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.26 (d,
J = 8.5 Hz, 2H). 13C NMR (CD3OD 100 MHz) d 35.9,
47.7, 53.5, 58.8, 108.5, 116.1, 126.5, 128.2, 129.4,
129.4, 131.5, 131.5, 133.0, 139.5, 142.8, 147.9, 179.8.
HRMS (ESI) calculated for C17H17Cl2N2O2S (M+H)
383.0388, found 383.0371.
5.2.4.6. 1-Benzyl-5,8-dichloro-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline hydrochloride (81). Compound
81 was synthesized from 29, using the procedure A for
chlorinations (quantitative). 1H NMR (CDCl3
300 MHz) d 3.21 (m, 5H), 3.86 (m, 1H), 3.89 (s, 3H),
3.93 (s, 3H), 5.06 (s, 1H), 7.25 (m, 5H).
5.2.4.7. 5,8-Dichloro-1-methyl-1,2,3,4-tetrahydroiso-
quinoline-6,7-diol hydrobromide (82). Compound 82
was prepared from 79 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.65 (d, J = 6.8 Hz, 3H), 3.00 (m, 1H),
3.12 (m, 1H), 3.58 (m, 2H), 4.80 (q, J = 6.8 Hz, 1H).
5.2.4.8. 5,8-Dichloro-3-methyl-1,2,3,4-tetrahydroiso-
quinoline-6,7-diol hydrobromide (83). Compound 83
was prepared from 80 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.53 (d, J = 6.5 Hz, 3H), 2.68 (dd,
J = 17.6 Hz, J = 11.0 Hz, 1H), 3.17 (dd, J = 17.6 Hz,
J = 4.5 Hz, 1H), 3.63 (m, 1H), 4.22 (d, J = 16.4 Hz,
1H), 4.41 (d, J = 16.4 Hz, 1H).
5.2.4.9. 1-Benzyl-5,8-dichloro-1,2,3,4-tetrahydroiso-
quinoline-6,7-diol hydrobromide (84). Compound 84
was prepared from 81 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 3.08 (m, 3H), 3.47 (m, 2H), 3.71 (m, 1H),
5.01 (m, 1H), 7.41 (m, 5H).
5.2.4.10. 5,8-Dichloro-N-[2-(4-chlorophenyl)ethyl]-6,7-
dihydroxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-car-
bothioamide (85). Compound 85 was prepared from 82
as described in the general procedure for coupling and
purified by flash column chromatography (silica, pet.
5.2.4.3. 4,7-Dichloro-N-[2-(4-chlorophenyl)ethyl]-5,6-
dihydroxy-1,3-dihydro-2H-isoindole-2-carbothioamide
(78). Compound 78 was prepared from 76 as described
in the general procedure for coupling and purified by
flash column chromatography (silica, pet. ether/EtOAc
6:4) (78%). 1H NMR (CD3OD 400 MHz) d 2.93 (t,
J = 7.6 Hz, 2H), 3.78 (t, J = 7.6 Hz, 2H), 4.76 (br s,
4H), 7.22 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H).
13C NMR (CD3OD 100 MHz) d 35.8, 47.8, 54.0, 58.5,
115.0, 115.0, 126.8, 126.8, 129.5, 129.5, 131.5, 131.5,
133.0, 139.5, 144.2, 144.2, 180.0. HRMS (ESI) calcu-
lated for C17H16Cl3N2O2S (M+H) 416.9998, found
416.9994.
1
ether/EtOAc 3:2+1%AcOH) (58%). H NMR (CD3OD
300 MHz) d 1.48 (d, J = 6.6 Hz, 3H), 2.85 (m, 2H),
2.94 (t, J = 6.9 Hz, 2H), 3.56 (m, 1H), 3.83 (m, 2H),
4.23 (br s, 1H), 6.29 (br s, 1H), 7.19 (d, J = 8.6 Hz,
2H), 7.23 (t, J = 8.6 Hz, 2H). 13C NMR (CD3OD
75 MHz) d 19.4, 26.6, 35.6, 41.5, 47.9, 53.8, 118.4,
120.2, 122.3, 125.1, 129.4, 129.4, 131.5, 131.5, 133.0,
139.6, 142.8, 143.1, 181.7. HRMS (ESI) calculated for
C19H20Cl3N2O2S (M+H) 445.0311, found 445.0302.
5.2.4.11. 5,8-Dichloro-N-[2-(4-chlorophenyl)ethyl]-6,7-
dihydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-car-
bothioamide (86). Compound 86 was prepared from 83
as described in the general procedure for coupling and
purified by flash column chromatography (silica, pet.
5.2.4.4. 5,8-Dichloro-6,7-dimethoxy-1-methyl-1,2,3,4-
tetrahydroisoquinoline hydrochloride (79). Compound
79 was synthesized from 27, using the procedure A for
chlorinations (quantitative). 1H NMR (CD3OD
300 MHz) d 1.67 (d, J = 6.8 Hz, 3H), 3.00 (m, 1H),
3.18 (m, 1H), 3.60 (m, 2H), 3.91 (s, 3H), 3.92 (s, 6H),
4.89 (m, 1H).
1
ether/EtOAc 3:2+1%AcOH) (52%). H NMR (CD3OD
300 MHz)
d 1.05 (d, J = 6.7 Hz, 3H), 2.85 (d,
J = 3.3 Hz, 2H), 2.96 (dt, J = 1.8 Hz, J = 7.5 Hz, 2H),
3.86 (m, 2H), 4.29 (d, J = 17.1 Hz, 1H), 5.04 (d,
J = 17.1 Hz, 1H), 5.46 (br s, 1H), 7.22 (d, J = 8.8 Hz,

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2521
2H), 7.26 (t, J = 8.8 Hz, 2H). 13C NMR (CD3OD
75 MHz) d 17.0, 32.7, 35.6, 45.2, 47.9, 49.8, 119.6,
120.8, 122.6, 123.6, 129.4, 129.4, 131.5, 131.5, 133.0,
139.6, 143.0, 143.2, 182. HRMS (ESI) calculated for
C19H20Cl3N2O2S (M+H) 445.0311, found 445.0296.
ation (quantitative). 1H NMR (CD3OD 300 MHz) d
3.02 (t, J = 6.3 Hz, 2H), 3.51 (t, J = 6.3 Hz, 2H), 4.28
(s, 2H).
5.2.4.18. 8-Chloro-N-[2-(4-chlorophenyl)ethyl]-6,7-dihy-
droxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide (94).
This compound was prepared from 91 as described in
the general procedure for coupling and purified by flash
column chromatography (silica, pet. ether/EtOAc/
5.2.4.12. 1-Benzyl-5,8-dichloro-N-[2-(4-chlorophenyl)
ethyl]-6,7-dihydroxy-3,4-dihydroisoquinoline-2(1H)-car-
bothioamide (87). Compound 87 was prepared from 84
as described in the general procedure for coupling and
purified by flash column chromatography (silica, pet.
1
AcOH 50:50:1) (53%). H NMR (CD3OD 300 MHz) d
2.72 (t, J = 5.5 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 3.83
(t, J = 7.2 Hz, 2H), 3.93 (t, J = 5.5 Hz, 2H), 4.79 (s,
2H), 6.57 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.24 (t,
J = 8.6 Hz, 2H). 13C NMR (CD3OD 75 MHz) d 29.1,
35.6, 46.6, 47.9, 48.9, 114.3, 119.5, 122.9, 128.1, 129.4,
129.4, 131.5, 131.5, 133.0, 139.6, 141.7, 146.2, 182.3.
HRMS (ESI) calculated for C18H19Cl2N2O2S (M+H)
397.0544, found 397.0531.
1
ether/EtOAc 4:1+1%AcOH) (75%). H NMR (CD3OD
400 MHz) d 2.60 (m, 1H), 2.81 (m, 3H), 3.08 (m, 1H),
3.32 (m, 1H), 3.67 (m, 3H), 4.17 (br s, 1H), 6.48 (br s,
1H), 7.20 (m, 9H). 13C NMR (CD3OD 100 MHz) d
26.0, 35.4, 40.4, 42.3, 47.8, 59.1, 119.0, 125.8, 127.6,
129.3, 129.3, 129.5, 129.5, 130.7, 130.7, 131.5, 131.5,
133.0, 139.3, 139.6, 142.7, 143.3, 152.5, 153.8, 182.9.
HRMS (ESI) calculated for C25H24Cl3N2O2S (M+H)
521.0624, found 521.0619.
5.2.4.19. 5-Chloro-N-[2-(4-chlorophenyl)ethyl]-6,7-dihy-
droxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide (95).
This compound was prepared from 92 as described in
the general procedure for coupling and purified by flash
column chromatography (silica, pet. ether/EtOAc/
5.2.4.13. tert-Butyl 8-chloro-6,7-dimethoxy-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (88) and tert-butyl 5-
chloro-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-car-
boxylate (89). These compounds were synthesized from
compound 26, using procedure B for chlorinations (1.1
equiv of SO2Cl2) affording 88 and 89 in 1:1.7 ratio. Puri-
fication was done by flash column chromatography (sil-
ica, gradient elution, 15–20% EtOAc in pet. ether)
(51%).
1
AcOH 50:50:1) (24%). H NMR (CD3OD 400 MHz) d
2.81 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 3.82
(t, J = 7.4 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 4.77 (s,
2H), 6.55 (s, 1H), 7.23 (m, 4H). 13C NMR (CD3OD
100 MHz) d 26.9, 35.6, 46.5, 47.9, 50.3, 112.2, 121.2,
125.0, 126.4, 129.4, 129.4, 131.5, 131.5, 133.0, 139.6,
142.1, 146.0, 182.0. HRMS (ESI) calculated for
C18H19Cl2N2O2S (M+H) 397.0544, found 397.0585.
1
Compound 88: H NMR (CDCl3 300 MHz) d 1.49 (s,
9H), 2.76 (t, J = 5.6 Hz, 2H), 3.61 (t, J = 5.6 Hz, 2H),
3.84 (s, 3H), 3.85 (s, 3H), 4.49 (s, 2H), 6.60 (s, 1H).
5.2.4.20. 5,8-Dichloro-N-[2-(4-chlorophenyl)ethyl]-6,7-
dihydroxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(4). This compound was prepared from 93 as de-
scribed in the general procedure for coupling and
purified by flash column chromatography (silica, pet.
ether/EtOAc 60:40+1%AcOH) (51%). 1H NMR
(CD3OD 400 MHz) d 2.77 (t, J = 5.8 Hz, 2H), 2.93
(t, J = 7.4 Hz, 2H), 3.82 (t, J = 7.4 Hz, 2H), 3.95 (t,
J = 5.8 Hz, 2H), 4.85 (s, 2H), 7.20 (m, 4H). 13C
NMR (CD3OD 100 MHz) d 27.1, 35.5, 45.8, 47.9,
49.3, 118.4, 120.2, 124.2, 125.8, 129.4, 129.4, 131.5,
131.5, 133.0, 139.5, 142.6, 142.9, 182.5. HRMS (ESI)
calculated for C18H18Cl3N2OS (M+H) 431.0154,
found 431.0210.
1
Compound 89: H NMR (CDCl3 300 MHz) d 1.48 (s,
9H), 2.77 (t, J = 6.0 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H),
3.83 (s, 3H), 3.84 (s, 3H), 4.50 (s, 2H), 6.56 (s, 1H).
5.2.4.14. 5,8-Dichloro-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline hydrochloride (90). Compound 90 was
synthesized from compound 26, using procedure A for
chlorinations (quantitative). 1HNMR (CDCl3 300
MHz) d 3.10 (t, J = 6.3 Hz, 2H), 3.53 (t, J = 6.3 Hz,
2H), 3.91 (s, 3H), 3.92 (s, 3H), 4.36 (s, 2H)
5.2.4.15. 8-Chloro-1,2,3,4-tetrahydroisoquinoline-6,7-
diol hydrobromide (91). This compound was prepared
from 88 using the general procedure for demethylation
(quantitative). 1H (CD3OD 300 MHz) d 2.98 (t, J =
6.2 Hz, 2H), 3.44 (t, J = 6.2 Hz, 2H), 4.24 (s, 2H), 6.64
(s, 1H).
5.2.4.21. tert-Butyl 7-chloro-6-methoxy-3,4-dihydro-
isoquinoline-2(1H)-carboxylate (96) and tert-butyl 5-
chloro-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carbox-
ylate (97). These compounds were synthesized from 44,
using procedure B for chlorinations (1.1 equiv of
SO2Cl2) affording tert-butyl 7-chloro-6-methoxy-3,4-
dihydroisoquinoline-2(1H)-carboxylate and tert-butyl
5-chloro-6-methoxy-3,4-dihydroisoquinoline-2(1H)-car-
boxylate in a 2:11 ratio. Purification was done by flash
column chromatography (silica, gradient elution 10–
90% EtOAc in pet. ether) (35%).
5.2.4.16. 5-Chloro-1,2,3,4-tetrahydroisoquinoline-6,7-
diol hydrobromide (92). This compound was prepared
from 89 using the general procedure for demethylation
1
(quantitative). H NMR (CD3OD 300 MHz) d 3.00 (t,
J = 6.5 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 4.21 (s, 2H),
6.60 (s, 1H).
1
5.2.4.17. 5,8-Dichloro-1,2,3,4-tetrahydroisoquinoline-
6,7-diol hydrobromide (93). This compound was pre-
pared from 90 using the general procedure for demethyl-
Compound 96: H NMR (CDCl3 300 MHz) d 1.48 (s,
9H), 2.78 (t, J = 5.7 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H),
3.87 (s, 3H), 4.47 (s, 2H), 6.67 (s, 1H), 7.10 (s, 1H).

2522
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
1
Compound 97: H NMR (CDCl3 300 MHz) d 1.48 (s,
9H), 2.87 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H),
3.88 (s, 3H), 4.51 (s, 2H), 6.81 (d, J = 8.4 Hz, 1H),
6.99 (d, J = 8.4 Hz, 1H).
35.6, 46.2, 47.9, 50.2, 115.5, 121.7, 126.3, 127.1, 129.4,
129.4, 131.6, 131.6, 133.0, 135.2, 139.6, 153.2, 182.2.
HRMS (ESI) calculated for C18H19Cl2N2OS (M+H)
381.0595, found 381.0609.
5.2.4.22. tert-Butyl 5,7-dichloro-6-methoxy-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (98). This compound
was synthesized from 44, using procedure B for chlori-
nations (2.2 equiv of SO2Cl2). Purification was done
by flash column chromatography (silica, pet. ether/
EtOAc 8:1) to afford tert-butyl 5,7-dichloro-6-meth-
oxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (29%).
1H NMR (CDCl3 400 MHz) d 1.47 (s, 9H), 2.81 (t,
J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H),
4.49 (s, 2H), 7.06 (s, 1H).
5.2.4.28. 5,7-Dichloro-N-[2-(4-chlorophenyl)ethyl]-6-
hydroxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(104). This compound was prepared from 101 as de-
scribed in the general procedure for coupling and puri-
fied by flash column chromatography (silica, LC, pet.
1
ether/EtOAc/AcOH 40:10:1) (58%). H NMR (CD3OD
2.84 (t, J = 6.0 Hz, 2H), 2.92 (t,
300 MHz)
d
J = 7.4 Hz, 2H), 3.81 (t, J = 7.4 Hz, 2H), 3.98 (t,
J = 6.0 Hz, 2H), 4.79 (s, 2H), 7.05 (s, 1H), 7.17 (d,
J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H). 13C NMR
(CD3OD 75 MHz) d 27.5, 35.6, 46.0, 47.9, 49.8, 121.1,
122.8, 126.6, 127.7, 129.4, 129.4, 131.5, 131.5, 133.0,
133.9, 139.5, 149.2, 182.2. HRMS (ESI) calculated for
C18H18Cl3N2OS (M+H) 415.0205, found 415.0195.
5.2.4.23. 7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-ol
hydrobromide (99). This compound was prepared from
96 using the general procedure for demethylation (quan-
titative). 1H NMR (CD3OD 300 MHz) d 3.05 (t,
J = 6.4 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 4.27 (s, 2H),
6.80 (s, 1H), 7.20 (s, 1H).
5.2.4.29. tert-Butyl 8-chloro-7-methoxy-3,4-dihydro-
isoquinoline-2(1H)-carboxylate (105) and tert-butyl 6-
chloro-7-methoxy-3,4-dihydroisoquinoline-2(1H)-carbox-
ylate (106). These compounds were synthesized from 50,
using procedure B for chlorinations (1.1 equiv of
SO2Cl2) to yield a mixture containing both compounds.
Purification was not possible, so the mixture was used
for further synthesis.
5.2.4.24. 5-Chloro-1,2,3,4-tetrahydroisoquinolin-6-ol
hydrobromide (100). This compound was prepared from
97 using the general procedure for demethylation (quan-
titative). 1H NMR (CD3OD 300 MHz) d 3.11 (t,
J = 6.6 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 4.29 (s, 2H),
6.90 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H).
5.2.4.30. tert-Butyl 6,8-dichloro-7-methoxy-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (107). This compound
was synthesized from 50, using procedure B for chlori-
nations (2.2 equiv of SO2Cl2). Purification was done
by flash column chromatography (silica, pet. ether/
EtOAc 5:1) to afford 107 along with the 105 in a 1:2.2
ratio (57%). 1H NMR (CDCl3 300 MHz) d 1.50 (s,
9H), 2.77 (br s, 2H), 3.65 (br s, 2H), 3.87 (s, 3H), 4.53
(s, 2H), 7.10 (s, 1H).
5.2.4.25. 5,7-Dichloro-1,2,3,4-tetrahydroisoquinolin-6-
ol hydrobromide (101). This compound was prepared
from 98 using the general procedure for demethylation
(quantitative). H NMR (CD3OD 300 MHz) d 3.08 (t,
J = 6.5 Hz, 2H), 3.56 (t, J = 6.5 Hz, 2H), 4.31 (s, 2H),
7.24 (s, 1H).
1
5.2.4.26. 7-Chloro-N-[2-(4-chlorophenyl)ethyl]-6-hydro-
xy-3,4-dihydroisoquinoline-2(1H)-carbothioamide (102).
This compound was prepared from 99 as described in
the general procedure for coupling and purified by flash
column chromatography (silica, pet. ether/EtOAc/
5.2.4.31. 8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-ol
hydrobromide (108) and 6-chloro-1,2,3,4-tetrahydroiso-
quinolin-7-ol hydrobromide (109). The mixture contain-
ing 105 and 106 was treated as described in the
general method for demethylation affording a mixture
containing 105 and 106 which was used for further syn-
thesis without purification.
1
AcOH 50:50:1) (53%). H NMR (CDCl3:CD3OD, 5:1,
300 MHz)
d
2.68 (t, J = 5.8 Hz, 2H), 2.82 (t,
J = 7.3 Hz, 2H), 3.75 (m, 4H), 3.89 (br s, 1H), 4.60 (s,
2H), 6.63 (s, 1H), 6.86 (s, 1H), 7.05 (d, J = 8.3 Hz,
2H), 7.13 (d, J = 8.3 Hz, 2H). 13C NMR
(CDCl3:CD3OD, 5:1, 75 MHz) d 28.3, 34.6, 45.3, 46.7,
48.2, 115.5, 118.5, 125.1, 127.3, 128.5, 128.5, 130.1,
130.1, 132.0, 135.0, 137.6, 151.3, 180.6. HRMS (ESI)
calculated for C18H19Cl2N2OS (M+H) 381.0595, found
381.0588.
5.2.4.32. 6,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-
ol hydrobromide (110). This compound was prepared
from 107, using the general procedure for demethylation
1
(quantitative). H NMR (CD3OD 300 MHz) d 2.77 (t,
J = 5.8 Hz, 2H), 3.49 (t, J = 5.8 Hz, 2H), 4.35 (s, 2H),
7.28 (s, 1H).
5.2.4.27. 5-Chloro-N-[2-(4-chlorophenyl)ethyl]-6-hydro-
xy-3,4-dihydroisoquinoline-2(1H)-carbothioamide (103).
This compound was prepared from 100 as described in
the general procedure for coupling and purified by flash
column chromatography (silica, pet. ether/EtOAc/
5.2.4.33. 8-Chloro-N-[2-(4-chlorophenyl)ethyl]-7-hydro-
xy-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(111)
and 6-chloro-N-[2-(4-chlorophenyl)ethyl]-7-hydroxy-3,4-
dihydroisoquinoline-2(1H)-carbothioamide (112). These
compounds were prepared from the mixture containing
108 and 109 as described in the general procedure for
coupling. Purification was done first by flash column
chromatography (silica, pet. ether/EtOAc/ AcOH
50:50:1) and then with normal phase HPLC (Microsorb,
1
AcOH 50:50:1) (80%). H NMR (CD3OD 300 MHz) d
2.92 (t, J = 5.9 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 3.83
(t, J = 7.6 Hz, 2H), 3.99 (t, J = 5.9 Hz, 2H), 4.81 (s,
2H), 6.82 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H),
7.23 (m, 4H). 13C NMR (CD3OD 75 MHz) d 27.6,

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2523
silica 5 lm, 250 · 10 mm, 4.0 ml/min of 28 % EtOAc in
petroleum ether, detection at 280 nm) (55%).
(m, 2H), 3.69 (m, 2H), 3.90 (s, 3H), 3.91 (s, 3H),
4.73 (s, 2H).
1
Compound 111: H NMR (CDCl3 300 MHz) d 2.74 (t,
5.2.4.37. 9-Chloro-2,3,4,5-tetrahydro-1H-2-benzaze-
pine-7,8-diol hydrobromide (117). This compound was
prepared from 114 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.95 (m, 2H), 2.95 (m, 2H), 3.46 (m, 2H),
4.54 (s, 2H), 6.68 (s, 1H).
J = 5.7 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H), 3.11, (br s,
2H), 3.85 (t, J = 7.1 Hz, 2H), 3.93 (t, J = 5.7 Hz, 2H),
4.66 (s, 2H), 6.76 (d, J = 8.3 Hz, 1H), 6.86 (d,
J = 8.3 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.20 (d,
J = 8.4 Hz, 2H). 13C NMR (CDCl3 75 MHz) d 27.9,
34.5, 45.7, 46.7, 47.4, 114.1, 117.9, 127.2, 127.5, 128.6,
128.6, 130.1, 130.1, 130.6, 132.2, 137.5, 150.8, 181.2.
HRMS (ESI) calculated for C18H19Cl2N2OS (M+H)
381.0595, found 381.0612.
5.2.4.38. 6-Chloro-2,3,4,5-tetrahydro-1H-2-benzaze-
pine-7,8-diol hydrobromide (118). This compound was
prepared from 115 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.93 (m, 2H), 3.21 (m, 2H), 3.44 (m, 2H),
4.27 (s, 2H), 6.79 (s, 1H).
1
Compound 112: H NMR (CDCl3 300 MHz) d 2.77 (t,
J = 5.9 Hz, 2H), 2.84 (br s, 2H), 2.92 (t, J = 7.2 Hz,
2H), 3.77 (t, J = 7.2 Hz, 2H), 3.87 (t, J = 5.9 Hz, 2H),
4.76 (s, 2H), 6.71 (s, 1H), 7.08 (s, 1H), 7.14 (d,
J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H). 13C NMR
(CDCl3 75 MHz) d 27.6, 34.6, 45.3, 46.7, 49.0, 114.0,
118.9, 127.3, 128.5, 128.6, 128.6, 130.1, 130.1, 132.2,
132.8, 137.5, 150.8, 180.9. HRMS (ESI) calculated for
C18H19Cl2N2OS (M+H) 381.0595, found 381.0591.
5.2.4.39. 6,9-Dichloro-2,3,4,5-tetrahydro-1H-2-ben-
zazepine-7,8-diol hydrobromide (119). This compound
was prepared from 116 using the general procedure for
1
demethylation, to afford 119 (quantitative). H NMR
(CD3OD 300 MHz) d 1.96 (m, 2H), 3.31 (m, 2H), 3.46
(m, 2H), 4.61 (s, 2H).
5.2.4.34. 6,8-Dichloro-N-[2-(4-chlorophenyl)ethyl]-7-
hydroxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(113). This compound was prepared from 110 as de-
scribed in the general procedure for coupling and puri-
fied by flash chromatography (silica, heptane/EtOAc/
5.2.4.40.
9-Chloro-N-[2-(4-chlorophenyl)ethyl]-7,8-
dihydroxy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbo-
thioamide (120). This compound was prepared from 117
as described in the general procedure for coupling and
purified by flash column chromatography (silica,
1
1
AcOH 66:33:1) (56%). H NMR (CD3OD 400 MHz) d
CH2Cl2) (48%). H NMR (CD3OD 400 MHz) d 1.80
2.78 (t, J = 5.7 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 3.84
(t, J = 7.4 Hz, 2H), 3.93 (t, J = 5.7 Hz, 2H), 4.89 (s,
2H), 7.12 (s, 1H), 7.22 (m, 4H). 13C NMR (CD3OD
100 MHz) d 28.6, 35.6, 46.1, 48.0, 49.5, 121.1, 121.5,
128.7, 129.3, 129.4, 131.5, 131.5, 132.0, 133.0, 139.5,
139.6, 148.9, 182.8. HRMS (ESI) calculated for
C18H18Cl3N2O2S (M+H) 415.0205, found 415.0214.
(m, 2H), 2.80 (m, 2H), 2.87 (t, J = 7.0 Hz, 2H), 3.82 (t,
J = 7.0 Hz, 2H), 4.21 (br s, 2H), 4.80 (s, 2H), 6.60 (s,
1H), 7.13 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H).
13C NMR (CD3OD 100 MHz) d 28.7, 35.5, 35.5, 47.9,
50.7, 55.4, 116.8, 121.1, 125.4, 129.5, 129.5, 131.5,
131.5, 133.1, 135.2, 139.4, 141.0, 146.6, 181.3. HRMS
(ESI) calculated for C19H21Cl2N2O2S (M+H)
411.0701, found 411.0690.
5.2.4.35. tert-Butyl 9-chloro-7,8-dimethoxy-1,3,4,5-
tetrahydro-2H-2-benzazepine-2-carboxylate (114) and
tert-butyl 6-chloro-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-
2-benzazepine-2-carboxylate (115). These compounds
were synthesized from compound57, using procedure
B for chlorinations (1.1 equiv of SO2Cl2), affording a
mixture of 114 and 115 in 1:1 ratio. Purification was
done by flash column chromatography (silica, pet.
ether/EtOAc 6:1) (45%).
5.2.4.41.
6-Chloro-N-[2-(4-chlorophenyl)ethyl]-7,8-
dihydroxy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbo-
thioamide (121). This compound was prepared from 118
as described in the general procedure for coupling and
purified by flash column chromatography (silica,
1
CH2Cl2) (31%). H NMR (CD3OD 500 MHz) d 1.75
(m, 2H), 2.87 (t, J = 7.3 Hz, 2H), 3.03 (m, 2H), 3.75 (t,
J = 7.3 Hz, 2H), 4.93 (br s, 2H), 4.77 (s, 2H), 6.82 (s,
1H), 7.01 (d, J = 8.4 Hz, 2H), 7.21 ( d, J = 8.4 Hz,
2H). 13C NMR (CD3OD 125 MHz) d 27.6, 29.6, 35.6,
47.8, 52.8, 55.5, 116.8, 122.1, 129.4, 129.4, 129.6,
130.7, 131.6, 131.6, 133.0, 139.6, 142.3, 144.7, 181.4.
HRMS (ESI) calculated for C19H19Cl2N2O2S (MꢀH)
409.0545, found 409.0557.
1
Compound 114: H NMR (CDCl3 300 MHz) d 1.43 (s,
9H), 1.85 (m, 2H), 2.90 (m, 2H), 3.69 (m, 2H), 3.84 (s,
3H), 3.87 (s, 3H), 4.66 (s, 2H), 6.64 (s, 1H).
1
Compound 115: H NMR (CDCl3 300 MHz) d 1.43 (s,
9H), 1.75 (m, 2H), 3.12 (m, 2H), 3.65 (m, 2H), 3.85 (s,
3H), 3.88 (s, 3H), 4.35 (s, 2H), 6.72 (s, 1H).
5.2.4.42. 6,9-Dichloro-N-[2-(4-chlorophenyl)ethyl]-7,8-
dihydroxy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbo-
thioamide (122). This compound was prepared from 119
as described in the general procedure for coupling and
purified by flash column chromatography (silica,
5.2.4.36. tert-Butyl 6,9-dichloro-7,8-dimethoxy-1,3,4,5-
tetrahydro-2H-2-benzazepine-2-carboxylate (116). This
compound was synthesized from 57, using procedure
B for chlorinations (2.2 equiv of SO2Cl2). Purification
was done by flash column chromatography (silica,
1
CH2Cl2) (44%). H NMR (CD3OD 400 MHz) d 1.82
(m, 2H), 2.88 (t, J = 7.2 Hz, 2H), 3.06 (m, 2H), 3.82 (t,
J = 7.2 Hz, 2H), 4.07 (br s, 2H), 4.92 (s, 2H), 7.14 (d,
J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H). 13C NMR
1
pet. ether/EtOAc 6:1) to afford 116 (45%). H NMR
(CDCl3 300 MHz) d 1.43 (s, 9H), 1.85 (m, 2H), 3.15

2524
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
(CD3OD 100 MHz) d 27.2, 29.9, 35.5, 47.9, 51.1, 53.1,
120.2, 121.3, 126.3, 129.5, 129.5, 131.5, 131.5, 131.8,
133.1, 139.4, 142.1, 143.7, 181.7. HRMS (ESI) calcu-
lated for C19H20Cl3N2O2S (M+H) 445.0311, found
445.0313.
1.75 (m, 2H), 2.84 (m, 4H), 3.75 (t, J = 7.2 Hz, 2H),
4.02 (br s, 2H), 4.73 (s, 2H), 6.73 (s, 1H), 7.08 (d,
J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H). 7.29 (s, 1H).
13C NMR (CD3OD, 100 MHz) d 28.5, 35.3, 35.6, 47.8,
49.7, 54.5, 118.1, 119.0, 129.4, 129.4, 130.1, 131.5,
131.5, 132.0, 132.9, 139.4, 142.0, 153.4, 181.3. HRMS
(ESI) calculated for C19H21Cl2N2OS (M+H) 395.0752,
found 395.0761.
5.2.4.43. tert-Butyl 8-chloro-7-methoxy-1,3,4,5-tetra-
hydro-2H-2-benzazepine-2-carboxylate (123) and tert-
butyl 6-chloro-7-methoxy-1,3,4,5-tetrahydro-2H-2-ben-
zazepine-2-carboxylate (124). These compounds were
synthesized from 58 using procedure B for chlorinations
(1.1 equiv of SO2Cl2), affording 123 and 124 along with
the 6,8-dichloro derivative 125 in a 4.2:1:2.2 ratio. Puri-
fication was done by flash column chromatography (sil-
ica, gradient elution 10–20% EtOAc in pet. ether), (70%).
5.2.4.49. 6-Chloro-N-[2-(4-chlorophenyl)ethyl]-7-hydro-
xy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbothioamide
(130). This compound was prepared from 127 as de-
scribed in the general procedure for coupling and puri-
fied by flash column chromatography (silica, CH2Cl2/
MeOH 99:1) (36%). 1H NMR (CD3OD 300 MHz) d
1.78 (br s, 2H), 2.86 (t, J = 7.3 Hz, 2H), 3.12 (br s,
2H), 3.75 (t, J = 7.3 Hz, 2H), 3.97 (br s, 2H), 4.77 (s,
2H), 6.66 (d, J = 8.2 Hz, 1H), 7.08 (m, 3H), 7.21 (d,
J = 7.4 Hz, 2H). 13C NMR (CD3OD 75 MHz) d 27.2,
30.2, 35.5, 47.7, 53.0, 55.0, 114.0, 121.9, 129.4, 129.4,
129.6, 129.9, 131.5, 131.5, 133.0, 139.5, 140.9, 154.0,
181.3. HRMS (ESI) calculated for C19H21Cl2N2OS
(M+H) 395.0752, found 395.0749.
Compound 123: 1H NMR (CDCl3 300 MHz) d 1.39
(s, 9H), 1.76 (m, 2H), 2.90 (m, 2H), 3.66 (m, 2H), 3.87
(s, 3H), 4,26 (s, 2H), 6.72 (s, 1H), 7.16 (s, 1H).
1
Compound 124: H NMR (CDCl3 300 MHz) d 1.40 (s,
9H), 1.76 (m, 2H), 3.20 (m, 2H), 3.67 (m, 2H), 3.89
(s, 3H), 4,35 (s, 2H), 6.71 (d, J = 8.2 Hz, 1H), 7.05
(d, J = 8.2 Hz, 1H).
5.2.4.50. 6,8-Dichloro-N-[2-(4-chlorophenyl)ethyl]-7-
hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbo-
thioamide (131). This compound was prepared from 128
as described in the general procedure for coupling and
purified by flash column chromatography (silica,
5.2.4.44. tert-Butyl 6,8-dichloro-7-methoxy-1,3,4,5-
tetrahydro-2H-2-benzazepine-2-carboxylate (125). This
compound was synthesized from 58 using procedure B
for chlorinations (2.2 equiv SO2Cl2). Purification was
done by flash column chromatography (silica, gradient
elution 12.5–20 EtOAc in pet. ether) affording 125
(58%). 1H NMR (CDCl3 300 MHz) d 1.40 (s, 9H),
1.75 (m, 2H), 3.14 (m, 2H), 3.68 (m, 2H), 3.86 (s, 3H),
4.31 (s, 2H), 7.12 (s, 1H).
1
CH2Cl2) (71%). H NMR (CD3OD 400 MHz) d 1.78
(m, 2H), 2.85 (t, J = 7.3 Hz, 2H) 3.13 (m, 2H), 3.75 (t,
J = 7.3 Hz, 2H), 3.97 (br s, 2H), 4.83 (s, 2H), 7.09 (d,
J = 8.5 Hz, 2H), 7.21 ( d, J = 8.5 Hz, 2H), 7.33 (s, 1H).
13C NMR (CD3OD 100 MHz) d 27.2, 30.6, 35.5, 47.8,
53.23, 54.68, 119.5, 123.5, 129.4, 129.4, 130.3, 131.0,
131.5, 131.5, 133.0, 139.5, 139.9, 150.0, 181.7. HRMS
(ESI) calculated for C19H19Cl3N2OSNa (M+Na)
451.0182, found 451.0182.
5.2.4.45. 8-Chloro-2,3,4,5-tetrahydro-1H-2-benzaze-
pin-7-ol hydrobromide (126). This compound was pre-
pared from 123 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.97 (m, 2H), 2.96 (m, 2H), 3.44 (m, 2H),
4.28 (s, 2H), 6.85 (s, 1H), 7.34 (s, 1H).
5.2.4.51. tert-Butyl 9-chloro-8-methoxy-1,3,4,5-tetra-
hydro-2H-2-benzazepine-2-carboxylate (132) and tert-
butyl 7-chloro-8-methoxy-1,3,4,5-tetrahydro-2H-2-ben-
zazepine-2-carboxylate (133). These compounds were
synthesized from 64, using procedure B for chlorinations
(1.1 equiv of SO2Cl2) to yield a mixture containing both
compounds. Purification was not possible, so the mix-
ture was used for further synthesis.
5.2.4.46. 6-Chloro-2,3,4,5-tetrahydro-1H-2-benzaze-
pin-7-ol hydrobromide (127). This compound was pre-
pared from 124 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.97 (m, 2H), 3.31 (m, 2H), 3.45 (m, 2H),
4.35 (s, 2H), 6.81 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2
Hz, 1H).
5.2.4.52. 9-Chloro-2,3,4,5-tetrahydro-1H-2-benzaze-
pin-8-ol hydrobromide (134) and 7-chloro-2,3,4,5-tetra-
hydro-1H-2-benzazepin-8-ol hydrobromide (135). The
mixture containing 132 and 133 was treated as described
in the general method for demethylation affording a
mixture containing 134 and 135. The mixture was used
for further synthesis without purification.
5.2.4.47. 6,8-Dichloro-2,3,4,5-tetrahydro-1H-2-ben-
zazepin-7-ol hydrobromide (128). This compound was
prepared from 125, using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 1.97 (m, 2H), 3.31 (m, 2H), 3.46 (m, 2H),
4.36 (s, 2H), 7.38 (s, 1H).
5.2.4.53. 9-Chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydro-
xy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbothioamide
(136) and 7-chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydroxy-
1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbothioamide
(137). These compounds were prepared from the mix-
ture containing 134 and 135, as described in the
general procedure for coupling. Purification was done
5.2.4.48. 8-Chloro-N-[2-(4-chlorophenyl)ethyl]-7-hydro-
xy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbothioamide
(129). This compound was prepared from 126 as de-
scribed in the general procedure for coupling and puri-
fied by flash column chromatography (silica, CH2Cl2/
MeOH 99:1) (38%). 1H NMR (CD3OD 400 MHz) d

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2525
by flash column chromatography (silica, CH2Cl2/MeOH
99:1) affording 136 and 137 (23%, 1:1).
5.2.4.58. 1-(3,4-Dihydro-6-nitroisoquinolin-2(1H)-yl)
ethanone (143) and 1-(3,4-dihydro-7-nitroisoquinolin-
2(1H)-yl)ethanone (144). 1,2,3,4-Tetrahydroisoquino-
line, 141 (2.0 g, 15 mmol), was cooled on ice and acetic
anhydride (2.3 g, 22 mmol) was added dropwise. The
mixture was stirred for 2 h and then diluted with EtOAc.
The organic phase was washed with NaHCO3 (satd),
dried (MgSO4) and concentrated to give 1-(3,4-dihydro-
isoquinolin-2(1H)-yl)ethanone (2.1 g, 81%). Without
further purification 1-(3,4-dihydroisoquinolin-2(1H)-
yl)ethanone (1.5 g, 8.7 mmol) was cooled on ice and a
20 ml of mixture of concentrated nitric and concentrated
sulfuric acid (1:1) was added dropwise. The mixture was
stirred on ice for 4 h and then poured into a mixture of
ice and water. The water phase was extracted with
EtOAc. The combined organic phases were washed with
NaHCO3 (satd), dried (MgSO4) and concentrated to
give 1-(3,4-dihydro-mononitroisoquinolin-2(1H)-yl)eth-
anone as a crude mixture of regioisomers. Pure isomers
were obtained by HPLC (Microsorb, silica 5 lm,
250 · 21.4 mm, 20 ml/min of 100% EtOAc, detection at
300 nm), 143 (409 mg, 21%) and 144 (210 mg, 11%).
1
Compound 136: H NMR (CD3OD 400 MHz) d 2.82
(m, 2H), 2.86 (m, 4H), 3.81 (t, J = 7.1 Hz, 2H), 4.19
(br s, 2H), 4.94 (s, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.94
(d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.21 (d,
J = 8.4 Hz, 2H). 13C NMR (CD3OD 100 MHz) d 28.5,
35.0, 35.4, 47.9, 51.4, 54.9, 116.1, 120.8, 129.5, 129.5,
130.3, 131.5, 131.5, 133.1, 135.1, 135.6, 139.3, 152.8,
181.6. HRMS (ESI) calculated for C19H21Cl2N2OS
(M+H) 395.0751, found 395.0757.
1
Compound 137: H NMR (CD3OD 400 MHz) d 1.74
(m, 2H), 2.82 (m, 2H), 2.86 (t, J = 7.4 Hz, 2H), 3.74 (t,
J = 7.4 Hz, 2H), 3.95 (br s, 2H), 4.83 (s, 2H), 6.98 (s,
1H), 7.08 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.20 (d,
J = 8.4 Hz, 2H). 13C NMR (CD3OD 100 MHz) d 28.6,
34.5, 35.5, 47.8, 53.9, 55.6, 119.7, 119.9, 129.4, 129.4,
131.5, 131.6, 131.6, 132.9, 134.9, 137.9, 139.5, 151.9,
181.6. HRMS (ESI) calculated for C19H21Cl2N2OS
(M+H) 395.0765, found 395.0765.
1
5.2.4.54. 6,9-Dichloro-7,8-dimethoxy-2,3,4,5-tetrahy-
dro-1H-3-benzazepine hydrochloride (138). This com-
pound was synthesized from 69 using procedure A for
chlorinations (quantitative). 1H NMR (CD3OD
300 MHz) d 3.33 (m, 4H), 3.46 (m, 4H), 3.89 (s, 6H).
Compound 143: H NMR (CDCl3) d (rotameric mix-
ture) 2.19 (ma) (s, 3H), 2.21 (mi) (s, 3H), 2.94 (mi) (t,
J = 5.9 Hz, 2H), 3.01 (ma) (t, J = 5.9 Hz, 2H), 3,73
(ma) (t, J = 5.9 Hz, 2H), 3.86 (mi) (t, J = 5.9 Hz, 2H),
4.72 (mi) (s, 2H), 4.82 (ma) (s, 2H), 7.32 (m, 1H), 8.02
(m, 2H).
5.2.4.55. 6,9-Dichloro-2,3,4,5-tetrahydro-1H-3-ben-
zazepine-7,8-diol hydrobromide (139). This compound
was prepared from 138 using the general procedure for
demethylation (quantitative). 1H NMR (CD3OD
300 MHz) d 3.14 (br s, 4H), 3.24 (br s, 4H).
1
Compound 144: H NMR (CDCl3) d (rotameric mix-
ture) 2.20 (s, 3H), 2.95 (mi) (t, J = 5.9 Hz, 2H), 3.02
(ma) (t, J = 5.9 Hz, 2H), 3,74 (ma) (t, J = 5.9 Hz, 2H),
3.87 (mi) (t, J = 5.9 Hz, 2H), 4.72 (mi) (s, 2H), 4.83
(ma) (s, 2H), 7.32 (m, 1H), 8.04 (m, 2H).
5.2.4.56. 6,9-Dichloro-N-[2-(4-chlorophenyl)ethyl]-7,8-
dihydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carbo-
thioamide (140). This compound was prepared from 139
as described in the general procedure for coupling and
purified by flash column chromatography (silica,
CH2Cl2/MeOH 99:1) (24%). 1H NMR (CD3OD
5.2.4.59. 1-(6-Amino-3,4-dihydroisoquinolin-2(1H)-yl)
ethanone hydrochloride (145). To a solution of 143
(253 mg, 1.15 mmol) in MeOH and some HCl (10% in
water), palladium oncarbon (5%) wasadded. Themixture
was stirred under hydrogen atmosphere for 1 h, filtered
through Celite and concentrated to give 145 (265 mg,
400 MHz)
d
2.85 (t, J = 7.4 Hz, 2H), 3.21 (t,
1
J = 5.8 Hz, 4H), 3.74 (t, J = 7.4 Hz, 2H), 3.95 (t,
J = 5.8 Hz, 4H), 7.14 (d, J = 8.4 Hz, 2H), 7.24 (d,
J = 8.4 Hz, 2H). 13C NMR (CD3OD 100 MHz) d 31.5,
31.5, 35.6, 48.0, 49.0, 49.0, 121.0, 121.0, 129.5, 129.5,
129.7, 129.7, 131.5, 131.5, 133.0, 139.7, 142.4, 142.4,
182.6. HRMS (ESI) calculated for C19H20Cl3N2O2S
(M+H) 445.0311, found 445.0294.
quant.). H NMR (CD3OD) d (rotameric mixture) 2.24
(ma) (s, 3H), 2.25 (mi) (s, 3H), 2.94 (mi) (t, J = 5.6 Hz,
2H), 3.03 (ma) (t, J = 5.9 Hz, 2H), 3.81 (m, 2H), 4.76
(ma) (s, 2H), 4.79 (mi) (s, 2H), 7.27 (m, 2H), 7.38 (m, 1H).
5.2.4.60. 1-(7-Amino-3,4-dihydroisoquinolin-2(1H)-yl)
ethanone hydrochloride (146). Compound 146 was syn-
thesized as described for145 from 144 (89%). H NMR
1
5.2.4.57. N-[2-(4-Chlorophenyl)ethyl]-3,4-dihydroiso-
quinoline-2(1H)-carbothioamide (142). This compound
was prepared from 141 as described in the general
procedure for coupling and purified by flash chroma-
tography (silica, pet. ether/etoac 4:1) affording 142
(96%) spectroscopic data. 1H NMR (CDCl3
300 MHz) d 2.95 (m, 4H), 3.86 (t, J = 6.0 Hz, 2H),
3.97 (m, 2H), 4.85 (s, 2H), 5.34 (br s, 1H), 7.22 (m,
8H). 13C NMR (CDCl3 75 MHz) d 29.0, 34.8, 45.5,
46.8, 49.4, 126.6, 126.9, 127.4, 127.9, 128.9, 128.9,
130.3. 130.3, 132.5, 133.0, 135.3, 137.5, 181.5. HRMS
(ESI) calculated for C18H20ClN2O (M+H) 331.1036,
found 331.1022.
(CD3OD) d (rotameric mixture) 2.27 (ma) (s, 3H), 2.30
(mi) (s, 3H), 2.94 (mi) (br s, 2H), 3.02 (ma) (br s, 2H),
3.84 (m, 2H), 4.79 (ma) (s, 2H), 4.84 (mi) (s, 2H), 7.25
(m, 2H), 7.38 (m, 1H).
5.2.4.61. 1,2,3,4-Tetrahydroisoquinolin-6-amine dihyd-
robromide (147). Compound 145 (265 mg, 1.2 mmol)
was dissolved in concentrated HBr (48% in H2O) and
heated to reflux for 4 hours. The mixture was then con-
centrated to give 147 (289 mg, 80%). 1H NMR
(CD3OD)
d
3.21 (t, J = 6.4 Hz, 2H), 3.56 (t,
J = 6.4 Hz, 2H), 3.84 (s, 2H), 6.44 (d, J = 2.1 Hz, 1H),
6.56 (dd, J = 2.1, 8.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H).

2526
M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
5.2.4.62. 1,2,3,4-Tetrahydroisoquinolin-7-amine dihyd-
robromide (148). Compound 148 was synthesized as de-
5.2.4.68.
7-Amino-N-[2-(4-chlorophenyl)ethyl]-3,4-
dihydroisoquinoline-2(1H)-carbothioamide (154). This
compound was prepared from 148 as described in
the general procedure for coupling. The crude prod-
uct was recrystallized from EtOAc to give 154
(80%). 1H NMR ((CD3)2SO) d 2.67 (t, J = 5.7 Hz,
2H), 2.86 (t, J = 7.4 Hz, 2H), 3.69 (m, 2H), 3.85 (t,
J = 5.7 Hz, 2H), 4.73 (s, 2H), 4.93 (s, 2H), 6.34 (d,
J = 2.0 Hz, 1H), 6.42 (dd, J = 8.0, 2.0 Hz, 1H), 6.83
(d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.34
(d, J = 8.3 Hz, 2H), 7.72 (t, J = 5.0 Hz, 1H). 13C
NMR ((CD3)2SO) d 27.2, 34.2, 45.7, 46.5, 49.3,
111.0, 112.9, 121.2, 128.3, 128.3, 128.5, 130.5, 130.5,
130.7, 133.9, 138.6, 146.9, 180.6. HRMS (ESI) calcu-
lated for C18H21ClN3S (M+H) 346.1145, found
346.1135.
1
scribed for 147 from 146 (91%). H NMR (CD3OD)
d2.69 (t, J = 5.9 Hz, 2H), 3.02 (t, J = 5.9 Hz, 2H), 4.45
(s, 2H), 7.34 (m, 2H), 7.45 (d, J = 9.0 Hz, 1H).
5.2.4.63. tert-Butyl 6-amino-3,4-dihydro-isoquinoline-
2(1H)-carboxylate (149). To a suspension of the free
amine of 147 (83 mg, 0.56 mmol) in THF, water and
di-tert-butyldicarbonate (116 mg, 0.53 mmol) were
added. The solution was stirred at room temperature
for 3 h. The reaction mixture was concentrated, dis-
solved in H2O and extracted with EtOAc. The organic
phase was dried (MgSO4), filtered and concentrated.
The residue was chromatographed on silica gel (pet.
ether/EtOAc 1:1) to afford 149 (101 mg, 73%). 1H
NMR (CDCl3) d 1.48 (s, 9H), 2.71 (t, J = 5.7 Hz, 2H),
3.59 (br s, 4H), 4.47 (s, 2H), 6.44 (d, J = 2.3 Hz, 1H),
6.52 (dd, J = 2.3, 8.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H).
5.2.4.69. N-[2-(4-Chlorophenyl)ethyl]-6-[(methylsulfo-
nyl)amino]-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(155). Compound 151 was stirred for 40 min in trifluoro-
acetic acid/CH2Cl2/anisol (80:19:1) and then concen-
trated. The residue was coupled with 2-(4-
chlorophenyl)ethyl isothiocyanate as described in the
general procedure for coupling. The crude product was
chromatographed on silica (pet. ether/EtOAc+AcOH
5.2.4.64. tert-Butyl 7-amino-3,4-dihydro-isoquinoline-
2(1H)-carboxylate (150). Compound 150 was synthe-
sized as described for 149 from 148 (47%). H NMR
1
(CDCl3) d 1.48 (s, 9H), 2.71 (t, J = 5.8 Hz, 2H), 3.59
(br s, 2H), 3.66 (br s, 2H), 4.45 (s, 2H), 6.45 (d,
J = 2.0 Hz, 1H), 6.52 (dd, J = 2.0, 8.1 Hz, 1H), 6.87 (d,
J = 8.1 Hz, 1H).
2:3+1%) (65%). 1H NMR (CDCl3)
d
2.89 (t,
J = 5.9 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 3.00 (s, 3H),
3.82 (t, J = 5.9 Hz, 2H), 3.95 (dt, J = 6.9, J = 5.5 Hz,
2H), 4.85 (s, 2H), 5.54 (br s, 1H), 6.89 (s, 1H), 7.09
(m, 3H), 7.16 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.3 Hz,
1H). 13C NMR (CDCl3) d 29.0, 34.8, 39.6, 45.1, 46.9,
49.1, 119.5, 120.3, 127.9, 128.9, 128.9, 130.3, 130.3,
130.5, 132.6, 135.9, 137.0, 137.5, 181.5. HRMS (ESI)
calculated for C19H23N3O2S2Cl (M+H) 424.0920, found
424.0929.
5.2.4.65. tert-Butyl 6-[(methylsulfonyl)-amino]-3,4-
dihydroisoquinoline-2(1H)-carboxylate (151). To a solu-
tion of 149 (101 mg, 0.41 mmol) in CH2Cl2 cooled on
ice, methanesulfonyl chloride (49 mg, 0.43 mmol) and
triethylamine (47 mg, 0.47 mmol) were added. The solu-
tion was stirred for 2 h, then diluted with H2O and ex-
tracted with CH2Cl2. The organic phase was dried
(MgSO4) and concentrated. The residue was chromato-
graphed on silica gel (pet. ether/EtOAc 3:2) to afford 151
5.2.4.70. N-[2-(4-Chlorophenyl)ethyl]-7-[(methylsulfo-
nyl)amino]-3,4-dihydroisoquinoline-2(1H)-carbothioamide
(156). Compound 156 was synthesized as described for
155 from 152. The crude product was chromatographed
1
(96 mg, 72%). H NMR (CDCl3) d 1.48 (s, 9H), 2.80 (t,
J = 5.8 Hz, 2H), 2.99 (s, 3H), 3.62 (t, J = 5.8 Hz, 2H),
4.53 (s, 2H), 7.02 (m, 4H).
1
on silica (pet. ether/EtOAc+AcOH 2:3+1%) (56%). H
5.2.4.66. tert-Butyl 7-[(methylsulfonyl)-amino]-3,4-
dihydroisoquinoline-2(1H)-carboxylate (152). Compound
152 was synthesized as described for 151 from 150
(46%). 1H NMR (CDCl3) d 1.48 (s, 9H), 2.79 (t,
J = 5.7 Hz, 2H), 2.99 (s, 3H), 3.63 (t, J = 5.7 Hz, 2H),
4.54 (s, 2H), 7.07 (m, 4H).
NMR (CDCl3) d 2.86 (t, J = 5.7 Hz, 2H), 2.94 (t,
J = 7.1 Hz, 2H), 2.97 (s, 3H), 3.87 (t, J = 5.7 Hz, 2H),
3.94 (m, 2H), 4.85 (s, 2H), 5.81 (t, J = 5.2 Hz, 1H),
7.09 (m, 3H), 7.18 (d, J = 8.3 Hz, 1H), 7.27 (d,
J = 8.3 Hz, 1H), 7.38 (br s, 1H). 13C NMR (CDCl3) d
28.3, 34.8, 39.4, 45.4, 47.0, 49.3, 119.2, 120.2, 128.8,
128.8, 129.2, 130.3, 130.3, 132.3, 132.5, 134.5, 135.4,
137.5, 181.2. HRMS (ESI) calculated for C19H23N3O2S2
Cl (M+H) 424.0920, found 424.0918.
5.2.4.67. 6-Amino-N-[2-(4-chlorophenyl)ethyl]-3,4-dihy-
droisoquinoline-2(1H)-carbothioamide (153). This com-
pound was prepared from 147 as described in the
general procedure for coupling and purified by flash col-
umn chromatography (pet. ether/EtOAc 1:2) to give 153
5.2.4.71. tert-Butyl 6,7-dihydroxy-3,4-dihydroisoquin-
oline-2(1H)-carboxylate (157). To a suspension of 30
(3.77 g, 15.3 mmol) in H2O (15 ml), di-tert-butyldicar-
bonate (3.51 g, 16.1 mmol) and triethylamine (3.26 g,
32.2 mmol) in 40 ml THF were added dropwise. The
mixture was stirred overnight. The mixture was concen-
trated, dissolved in EtOAc and washed with water. The
organic phase was dried (MgSO4), concentrated and
chromatographed on silica gel (pet. ether/EtOAc 3:2)
1
(72%). H NMR (CD3OD) d 2.77 (t, J = 6.0 Hz, 2H),
2.93 (t, J = 7.5 Hz, 2H), 3.82 (t, J = 7.5 Hz, 2H), 3.89
(t, J = 6.0 Hz, 2H), 4.71 (s, 2H), 6.57 (d, J = 2.3 Hz,
1H), 6.60 (dd, J = 8.0, 2.3 Hz, 1H), 6.87 (d, J = 8.0 Hz,
1H), 7.20 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H).
13C NMR (CD3OD) d 29.9, 35.8, 47.1, 47.9, 50.1,
115.2, 115.7, 124.1, 128.0, 129.4, 129.4, 131.5, 131.5,
133.0, 137.4, 139.7, 147.6, 181.8. HRMS (ESI) calcu-
lated for C18H21ClN3S (M+H) 346.1145, found
346.1140.
1
to give 157 (2.8 g, 68%). H NMR (CDCl3) d 1.49 (s,
9H), 2.70 (t, J = 5.9 Hz, 2H), 3.60 (t, J = 5.9 Hz, 2H),
4.44 (s, 3H), 6.65 (s, 2H).

M. Berglund et al. / Bioorg. Med. Chem. 16 (2008) 2513–2528
2527
5.2.4.72. tert-Butyl 6,7-bis{[(trifluoromethyl)sulfo-
nyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate (158).
Trifluoromethanesulfonic anhydride (2.6 g, 9.1 mmol)
was added slowly to an ice-cold solution of 157
(1.17 g, 4.4 mmol) and triethylamine (1.1 g, 11.1 mmol)
in dry CH2Cl2 (25 ml). The mixture was allowed to
reach room temperature. After 2 h the mixture was
poured into NaHCO3 (satd). The water phase was ex-
tracted with CH2Cl2. The organic phase was dried
(MgSO4) and concentrated to give 158 (2.2 g, 95%).
1H NMR (CDCl3) d 1.49 (s, 9H), 2.88 (t, J = 5.7 Hz,
2H), 3.68 (t, J = 5.7 Hz, 2H), 4.61 (s, 3H), 7.21 (s,
1H), 7.24 (s, 1H).
(t, J = 5.9 Hz, 2H), 3.93 (m, 2H), 5.07 (s, 2H), 5.68 (br
s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz,
2H), 7.61 (s, 1H), 7.64 (s, 1H). 13C NMR (CD3OD) d
28.9, 34.5, 44.0, 47.0, 49.3, 114.0, 114.3, 115.3, 115.3,
129.0, 129.0, 130.3, 130.3, 131.8, 132.6, 133.4, 137.3,
140.0, 141.7, 182.1. HRMS (ESI) calculated for
C20H18ClN4S (M+H) 381.0941, found 381.0943.
5.2.4.77. Dimethyl 2-({[2-(4-chlorophenyl)ethyl]amino-
carbono-thioyl)-1,2,3,4-tetrahydroisoquinoline-6,7-dicar-
boxylate (163). Compound 163 was synthesized as
described in the general procedure for coupling from
160. The crude product was chromatographed on silica
(pet. ether/EtOAc 2:1) (56%). 1H NMR (CDCl3) d
2.95 (m, 4H), 3.88 (m, 2H), 3.89 (s, 3H), 3.90 (s, 3H),
3.94 (m, 2H), 4.91 (s, 2H), 5.59 (br s, 1H), 7.15 (d,
J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.52 (s, 1H),
7.53 (s, 1H). 13C NMR (CD3OD) d 28.8, 34.7, 44.9,
46.9, 49.1, 53.8, 53.8, 127.4, 128.8, 129.0, 129.0, 130.3,
130.3, 131.1, 131.1, 132.6, 136.4, 137.4, 138.8, 167.6,
5.2.4.73. tert-Butyl 6,7-dicyano-3,4-dihydroisoquino-
line-2(1H)-carboxylate (159). To a mixture of 158
(2.2 g, 4.3 mmol), tris(dibenzylideneacetone)dipalladium
(156 mg, 0.17 mmol) and 1,10-bis(diphenylphos-
phino)ferrocene (371 mg, 0.67 mmol) in DMF heated
to 80 ꢁC, Zn(CN)2 (30 mg, 0.25 mmol) was added every
6th minute over 2 h (600 mg. 5.0 mmol in total). The
mixture was poured into aqueous Na2CO3 (satd), and
the water phase was extracted with CH2Cl2. The com-
bined organic phases were washed with water, dried
(MgSO4) and concentrated. The residue was chromato-
graphed on silica gel (pet. ether/EtOAc 14:1 to 1:1) to
167.9,
181.9.
HRMS
(ESI)
calculated
for
C22H23ClN2NaO4S (M+Na) 469.0965, found 469.0974.
5.2.4.78. 2-({[2-(4-Chlorophenyl)ethyl]amino}carbon-
othioyl)-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylic
acid (164). Compound 164 was synthesized as described
in the general procedure for coupling from 161. The
crude mixture was washed with diethyl ether to give
164 (28% over two steps). 1H NMR (CD3OD
300 MHz) d 2.96 (m, 4H), 3.84 (t, J = 7.4 Hz, 2H),
4.03 (t, J = 5.7 Hz, 2H), 4.96 (s, 2H), 7.21 (d,
J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H),
7.62 (s, 1H). 13C NMR (CD3OD 75 MHz) d 29.4,
35.6, 46.3, 48.0, 50.3, 128.5, 129.5, 129.5, 130.3, 131.5,
131.5, 132.1, 132.9, 133.0, 137.8, 139.6, 140.0, 170.0,
1
give 159 (500 mg, 42%). H NMR (CDCl3) d 1.49 (s,
9H), 2.93 (t, J = 5.7 Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H),
4.66 (s, 3H), 7.56 (s, 1H), 7.59 (s, 1H).
5.2.4.74. Dimethyl 1,2,3,4-tetrahydroisoquinoline-6,7-
dicarboxylate (160). A suspension of compound 159
(112 mg) in 50% aqueous NaOH was heated to reflux
for 15 h. The mixture was concentrated and the residue
extracted with MeOH. H2SO4 was added to the organic
phase, which then was refluxed for 15 h. The mixture
was concentrated and the residue suspended in aqueous
NaHCO3. The water phase was extracted with EtOAc.
The combined organic phases were dried (MgSO4) and
concentrated to give 160 (44 mg, 35% over two steps).
1H NMR (CDCl3) d 2.87 (br s, 2H), 3.20 (br s, 2H),
3.88 (s, 6H), 4.10 (br s, 2H), 7.40 (s, 1H), 7.46 (s, 1H)
MS (ESI) calculated for C13H16NO4 (M+H) 250.1,
found 250.1.
171.3,
C20H20ClN2O4S (M+H) 419.0832, found 419.0819.
182.6.
HRMS
(ESI)
calculated
for
Acknowledgments
Financial support from the Swedish Board for Scientific
Research (VR) and SIDA/Sarec is gratefully
acknowledged.
5.2.4.75. 1,2,3,4-Tetrahydroisoquinoline-6,7-dicarbox-
ylic acid hydrochloride (161). To a solution of the di-ester
160 (39 mg) in 10 ml THF/H2O, LiOHÆH2O (33 mg, 5
equiv) was added. The mixture was stirred at room tem-
perature for 3 days and then HCl (10% in H2O) was
added. The resulting acidic mixture was concentrated
to give 161 (used in the synthesis of 164 without further
References and notes
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1
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