Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake

Article abstract of DOI:10.1016/j.bmcl.2004.08.005

A series of benzothienyloxy phenylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.

Full text of DOI:10.1016/j.bmcl.2004.08.005

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5395–5399
Benzothienyloxy phenylpropanamines, novel dual inhibitors of
serotonin and norepinephrine reuptake
J. R. Boot,a G. Brace,a C. L. Delatour,b N. Dezutter,b J. Fairhurst,a J. Findlay,a
b
b
a
a
P. T. Gallagher,a, I. Hoes, S. Mahadevan, S. N. Mitchell, R. E. Rathmell,
*
S. J. Richards,a R. G. Simmonds,a L. Wallacea and M. A. Whattona
aEli Lilly and Company, Ltd, Lilly Research Centre, Windlesham, Surrey, GU20 UK 6PH
´
Lilly Development Centre, Parc Scientifique de Louvain-la-Neuve, Rue Granbonpre 11, 1348 Mont-Saint-Guibert, Belgium
b
Received 5 May 2004; revised 3 August 2004; accepted 5 August 2004
Available online 9 September 2004
Abstract—A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin
and norepinephrine reuptake.
Ó 2004 Published by Elsevier Ltd.
Major depressive disorder is currently the fourth leading
cause of disease or disability world wide and is projected
to rise to second by 2020.1 Furthermore it has been sug-
gested that dual serotonin (5-HT) and norepinephrine
(NE) reuptake inhibitors offer the potential for superior
O
NHMe
S
anti-depressant activity.2 That enhancing both seroton-
ergic and noradrenergic neurotransmission results in
anti-depressant efficacy is now supported by clinical
Duloxetine (1)
CF3
experience with duloxetine (CymbaltaTM) (1), a dual 5-
HT and NE uptake inhibitor.3,4
O
O
NHMe
NHMe
Fluoxetine (2)
Prior to the development of duloxetine, exploration of
the aryloxypropanamine SAR had resulted in the identi-
Me
fication of fluoxetine (ProzacTM) (2) and atomoxetine
(StraterraTM) (3) (Fig. 1).
O
NHMe
Herein we report on the activity of a series of heterocy-
clic phenylpropylamines that extend the exploration of
the duloxetine SAR. As part of continuing investigation
Atomoxetine (3)
Figure 1.
into the diverse pharmacology mediated by the mono-
aminergic transporters, we wished to identify additional
agents that could be used to address emerging clinical
In parallel with the search for new dual reuptake inhib-
targets with dual NE and 5-HT reuptake inhibitors.
itors it was decided to address the stability in acid med-
ium of the new analogues. Early clinical development
showed that it was advisable to formulate duloxetine
in enteric coated tablets, due to its stability characteris-
tics in acid solutions.5
Keywords: Benzothiophene; Phenylpropanamine; Serotonin; Norepi-
nephrine; Reuptake; Dual.
*
Thus three molecules (4–6) (Fig. 2) were targeted in
order to gauge, which fragments were responsible for
Corresponding author. Tel.: +44 (0)1276 483536; fax: +44 (0)1276
483525; e-mail: gallagher_p@lilly.com
0960-894X/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2004.08.005

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J. R. Boot et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5395–5399
Table 2. Binding affinities at the serotonin, norepinephrine and
dopamine transporters for duloxetine (1) and compounds 4–6
S
S
Compd
5-HTa
NEa
DA
O
O
O
1 (duloxetine)
0.8 0.04
1.0 0.1
1.5 0.1
8.2 1.3
7.5 0.3
6.1 0.25
1.4 0.3
2.2 0.1
240 23
NHMe
NHMe
NHMe
4
5
6
190
120 10
220
3
S
4
5
6
5
Figure 2.
a Ki, nM. Binding affinities and displacement measurements were done
in triplicate.4
EtO
S
OEt
a
b,c
and demethylated with boron tribromide in DCM to
give 9 (Scheme 1).
S
SH
OH
OMe
OMe
9
7
8
The synthesis of 6 was achieved by taking the commer-
cially available (1R)-3-chloro-1-phenyl-1-propanol (10)
and converting with 4,4-(dimethyl-1,1-dioxido-1,2,5-thia-
diazolidin-2-yl)-triphenyl phosphonium (11) and phenol
9 (under Mitsunobu conditions) to give the intermediate
chloro-ether, which was subsequently converted to 6
with aqueous methylamine (Scheme 2).7,8
Scheme 1. Reagents and conditions: (a) BrCH2CH(OEt)2, K2CO3,
DMF, 98%, (b) PPA, 145°C, 45%, (c) BBr3, DCM, 38%.
S
Ph
OH
P+
N
O
N
O
a, b
O
Ph
S
Cl
Compound 5 was synthesised in an analogous manner
to 6 but using (1R)-3-chloro-1-(2-thienyl)-1-propanol
while 4 was synthesised analogously to 6 but with the
replacement of 1-naphthol for 9.9
Ph
NHMe
10
11
6
Scheme 2. Reagents: (a) 9, 11, THF, 37%, (b) MeNH2, H2O, EtOH,
66%.
The acid stability of compounds 4–6 was compared with
duloxetine (1) in 0.1M HCl solution at 37°C for 2h and
the percentage of parent remaining was determined
(Table 1).
Table 1. Acid stability of compounds 4–6 in acid medium
Compd
Acid stability (% parent remaining @
2h and 37°C)
The acid stability was reduced when the electron rich
thiophene susbtituent was present, so the SAR focused
on maintaining the phenyl ring of 4 and 6 and in finding
alternatives to 1-naphthalene and 7-benzothiophene.
1 (duloxetine)
18
99
40
99
4
5
6
Products of acid mediated decomposition were not identi-
fied. Compounds 4–6 were also assessed for their
ability to inhibit the binding to transporter receptors
(Table 2).
the observed acid instability. The synthesis of 4 required
the commercially available 1-naphthol, while that of 5
and 6 required 7-hydroxybenzothiophene (9).6 Thus
thiophenol 7 was alkylated with bromoacetaldehyde
diethyl acetal to give 8, which was cyclised with PPA
The activity of compounds 4–6 was comparable to 1 but
as 4 and 6 demonstrated greater acid stability and 6
Table 3. Binding affinities at the serotonin, norepinephrine and dopamine transporters for 6, 12–18
4
5
S
O
7
NHMe
Compd
Subs.
Stereo.
5-HTa
NEa
DA
6
7
7
4
4
5
5
6
6
S
R
R
S
R
S
R
S
8.2 1.3
1.9 0.15
5.4 1.5
0.5 0.1
1.2 0.05
1.7 0.1
1.9 0.1
0.5 0.3
2.2 0.1
1.8 0.3
220 5a
270 20a
930 15a
440 10a
260 16a
480 10a
À68 0.5%b
260 8a
12
13
14
15
16
17
18
10
4.4 0.25
47
1
3
300 16
24 0.3
62
2
a Ki, nM.
b % Inhibition @ 1lM. Binding affinities and displacement measurements were done in triplicate.

J. R. Boot et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5395–5399
5397
more diverse SAR possibilities 6 formed the basis of fur-
ther SAR.
yield of the intermediate chloro-ethers from the Mitsun-
obu reaction ranged from 37% to 89%, the chloro-ethers
were then converted to compounds 12–18 (Table 3) in
yields ranging from 52% to 98%. From Table 3 it can
be seen that the 5- and 6-substitution patterns have
markedly reduced NE uptake activity but still retain 5-
HT uptake activity.
After demonstrating dual 5-HT and NE uptake activity
with 6 it was decided to explore if the dual uptake activ-
ity could be extended to either the 4-, 5- or 6-substitu-
tion of benzothiophene. The three phenols needed to
initiate this exercise were reported in the literature.10–12
The Mitsunobu route using (1R)-3-chloro-1-phenyl-1-
propanol was used to provide the three (S)-enantiomers
while, (1R)-3-chloro-1-phenyl-1-propanol was used to
provide the four (R)-enantiomers (Table 3). Thus the
Having prioritised the 4- and 7-linked benzothiophenes
for further investigation we next sought to understand
the contribution to activity that phenyl ring substitution
could make. To do this a rapid parallel Mannich reac-
tion was developed (Scheme 3) to provide racemic ami-
noethers that were subsequently separated by chiral
chromatography.
O
From the substituents (Table 4) examined the influence
on 5-HT and NE uptake inhibition is negligible. The
notable exception being compound 29 the 3-trifluoro-
methyl substituent phenyl analogue (isomer 1),
which had reduced affinity for both 5-HT and NE
transporter.
a
b
d
R
N
Me
NHMe
Cl
S
OH
O
R
R
c
N
N
As substitution in the phenyl ring offered no significant
enhancement in activity it was decided to progress the
(R)-enantiomer of the 7-benzothienyl propanamine
bearing no substituent on the phenyl ring (12). On fur-
ther development the metabolic profile of 12 was exam-
ined. Thus human liver microsomes were incubated with
12 and the resultant oxidative products identified (Fig.
3). Of the metabolites identified the dihydrodiol (31),
and the phenolic metabolites 32 and 33 were the most
prevalent. Of particular concern is the presence of the
dihydrodiol metabolites that occur through the hydra-
tion of intermediate epoxides. As epoxides are known
to form adducts that could lead to toxicity in vivo, the
development of 12 was halted.13 Metabolic profiling of
the 4-linked benzothiophene indicated no dihydrodiol
Me
Me
S
S
S
g
e,f
+
O
O
O
R
R
R
NHMe
NHMe
NHMe
= Macroporous polystyrene (ArgoPoreTM
)
Scheme 3. Reagents and conditions: (a) MeNH2, THF, (b) ArCOCH3,
HCHO, HCl, THF, H2O, (c) NaBH4, EtOH, tri(ethyleneglycol)
dimethyl ether, (d) 9, PPh3, t-BuO2CN@NCO2t-Bu, (e)
ClCO2CHClCH3, HunigÕs base, THF, (f) MeOH, reflux, (g) Chiral
chromatography on 5M Chiracel-OD, 20% heptane/20% ethanol/0.2%
dimethylethylamine, 0.5mL/min.
Table 4. Binding affinities at the serotonin, norepinephrine and dopamine transporters for compounds 19–30
S
O
NHMe
R
Compd
R
Isomer
5-HTa
NEa
DA
114 4a
19
20
21
22
23
24
25
26
27
28
29
30
3-Me
3-Me
2-F
1
2
1
2
1
2
1
2
1
2
1
2
2.2 0.4
2.4 0.1
0.4 0.05
1.5 0.1
1.4 0.1
1.1 0.1
1.1 0.05
0.5 0.1
2.2 0.3
2.4 0.3
2.2 0.5
0.6 0.1
147 2a
À61.4 1%b
À55.0 1%b
100 3a
1
0.1
2-F
3-F
1.1 0.1
0.7 0.1
0.4 0.05
3-F
4-F
134 2a
2
0.1
164 7a
4-F
0.6 0.1
4.6 0.2
0.9 0.1
176 9a
3-MeO
3-MeO
3-CF3
3-CF3
196 4a
177 11a
À54.2 0.1%b
208 3a
13
3.2 0.1
1
23
0.5 0.05
2
a Ki, nM.
b % Inhibition @ 1lM. Binding affinities and displacement measurements were done in triplicate.

5398
J. R. Boot et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5395–5399
subsequent demethylation with boron tribromide gave
HO
S
OH
2-fluoro-4-hydroxybenzothiophene (36) in 26% yield
for the two steps. For 5-fluoro-4-hydroxybenzothio-
phene (41) a ring closure of a mercaptocinammic acid
was used to give the benzothiophene.15 Thus commer-
cially available 3-fluorosalicylaldehyde (37) was methyl-
ated with dimethylsulfate and condensed with rhodanine
to give the thiazolidinone (38) in 78% for the two steps.
The thiazolidinone (38) was hydrolysed under basic con-
ditions to give 2-mercapto-3-phenylpropenoic acid (39)
that in turn was cyclised with iodine in the microwave
at 120°C to give 5-fluoro-4-hydroxybenzothiophene-
carboxylic acid (40) in 63% yield from the thiazolidi-
none. Decarboxylation of 40 was achieved with DBU
and microwave heating. Subsequent demethylation of
40 to give 41 was effected with boron tribromide in a
low yield of 5% for the two steps.
S
OH
S
12
OH
+
O
O
O
NHMe
NHMe
NHMe
31
32
33
Figure 3.
formation and this series was then exemplified further
by selected substitution on the benzothiophene ring.
For the synthesis of the 4-linked analogues substituted
4-hydroxybenzothiophenes were needed and the synthe-
ses are exemplified in Scheme 4.
Thus taking 4-methoxy benzothiophene14 (34) and
fluorinating with perchloryl fluoride gave ether 35 and
The synthesis of the 7-fluoro-4-hydroxybenzothiophene
(46) necessitated the synthesis of a tetra-substituted
benzaldehyde intermediate (43). This was achieved by
the formylation of commercially available 2,4-difluoro-
anisole (42) in 95% yield with LDA and dimethyl-
formamide. Compound 43 was then converted to the
benzothiophene ester 44 by nucleophilic displacement
of the activated fluorine with thioglycollic acid and tri-
ethylamine and subsequent cyclisation in 87% yield.16
The benzothiophene ester (44) was then hydrolysed with
aqueous sodium hydroxide (97%) and decarboxylated
with copper and quinoline to give (45) in 84%. Finally
demethylation was effected with boron tribromide to
give 46 in 79% yield.
2-Fluoro-4-hydroxybenzothiophene
OH
OMe
OMe
a
b
F
F
S
S
S
35
34
36
5-Fluoro-4-hydroxybenzothiophene
OMe
OH
OMe
O
F
CO2H
F
CHO
F
c, d
e
NH
SH
39
S
S
38
37
2-Cyano-4-hydroxybenzothiophene (49) was synthesised
from 4-methoxybenzothiophene-2-carboxylic acid17 (47)
via the primary carboxamide with methanesulfonyl chlo-
ride and ammonia to give the carbonitrile (48) in 74%
yield. Demethylation of 48 to give cyanobenzothiophene
49 was effected with boron tribromide in 95% yield.
OMe
OMe
OH
f
g, b
F
F
CO2H
SH
F
CO2H
S
S
40
39
41
7-Fluoro-4-hydroxybenzothiophene
OMe
OMe
OMe
Following the method used for the synthesis of 6 (utilis-
ing phenols 36, 41, 46 and 49) the analogues in Table 5
were produced. Thus the yield of the intermediate
chloro-ethers from the Mitsunobu reaction ranged from
47% to 95%, the chloro-ethers were then converted to
compounds 50–55 (Table 5) in yields ranging from
40% to 89%. As amination of the interemediate
chloro-nitriles proved low yielding, due to side product
formation, a Finkelstein (NaI, acetone, 56°C) reaction
was used to convert the chloro-ethers to iodo-ethers
(2-R iodide 90%, 2-S iodide 80%) prior to amination
to provide 56 and 57.
CHO
h
i
CO2Me
S
F
F
F
F
F
43
44
42
OH
OMe
OMe
j, k
b
CO2Me
S
S
S
F
46
F
45
F
44
2-Cyano-4-hydroxybenzothiophene
OMe
OMe
OH
l
b
The impact of fluorination on 5-HT transporter affinity
is minimal (Table 5), but inhibition of NE uptake is
more variable, in particular 2-fluorination is detrimental
to NE uptake. Introducing the polar (and larger than
hydrogen or fluorine) electron withdrawing nitrile func-
tionality markedly reduces NE transporter inhibition. In
conclusion and considering the increased synthetic com-
plexity of 40, used in the synthesis of the potent dual
inhibitors 52 and 53, it was decided to advance 14
into in vivo studies. Thus in in vivo microdialysis
CO2H
CN
CN
S
S
S
47
49
48
Scheme 4. Reagents and conditions: (a) lithium tetramethylpiperidide,
THF, perchloryl fluoride, 48%, (b) BBr3, CH2Cl2, 21–95%, (c) K2CO3,
acetone Me2SO4, 100%, (d) rhodanine, H4NOAc, toluene, 78%, (e)
NaOH, H2O, 94%, (f) I2, DME, 120°C, microwave, 67%, (g) DBU,
DMA, 200°C, microwave, 23%, (h) LDA, THF, DMF, 95%, (i)
HSCH2CO2Me, Et3N, DMF, 87%, (j) NaOH, MeOH, H2O, 97%, (k)
Cu, quinoline, 190°C, 84%, (l) MeSO2Cl, NH3, 74%.

J. R. Boot et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5395–5399
5399
Table 5. Binding affinities at the serotonin, norepinephrine and dopamine transporters for compounds 13, 14, 50–57
S
R
O
NHMe
Compd
R
Stereo.
5-HTa
NE
10 1a
DA
930 15a
13
14
50
51
52
53
54
55
56
57
H
R
S
R
S
R
S
R
S
R
S
5.4 1.5
0.5 0.1
1.95 0.5
4.1 1.1
0.4 0.1
0.4 0.1
0.7 0.05
0.9 0.1
H
4.4 0.25a
32 4a
440 10a
À57 2%b
À47 2%b
À57 1%b
2-F
2-F
5-F
5-F
7-F
7-F
2-CN
2-CN
18 1.3a
1.4 0.1a
0.6 0.05a
11 2a
À57 1 %b
540 20%a
1400 100%a
À58 1%b
À22 1%b
12 1a
13
0.25 0.05
2
À41 1 %b
À47 1.5%b
a Ki, nM.
b % Inhibition @ 1lM. Binding affinities and displacement measurements were done in triplicate.
7. Castro, J. L.; Matassa, V. G.; Ball, R. G. J. Org. Chem.
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