Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles as dual serotonin 5-HT2C and 5-HT6 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2010.07.105

Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular C-H insertion of a carbene. The compounds act as dual serotonin 5-HT_2C- and 5-HT₆-ligands.

Full text of DOI:10.1016/j.bmcl.2010.07.105

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5431–5433
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles
as dual serotonin 5-HT2C and 5-HT6 receptor ligands
N. Krogsgaard-Larsen a, A. A. Jensen a, J. Kehler b,
*
a Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100, Denmark
b H. Lundbeck A/S, Department of Medicinal Chemistry, 9 Ottiliavej, DK-2500 Valby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-
step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology
for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular C–
H insertion of a carbene. The compounds act as dual serotonin 5-HT2C- and 5-HT6-ligands.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 June 2010
Revised 22 July 2010
Accepted 25 July 2010
Available online 3 August 2010
Keywords:
Carbene
C–H Insertion
Serotonin
5-HT2C
5-HT6
1,2,3,4,10,10a-Hexahydro-pyrazino[1,2-
a]indole
The serotonin 5-HT2C and 5-HT6 receptors are two of the 14 dis-
tinct serotonin receptor subtypes.1 The 5-HT receptors have been
classified into seven distinct subfamilies based on sequence simi-
larity, signal transduction, coupling and pharmacological charac-
teristics. All but one of these receptors are G-protein-coupled, the
exception being the 5-HT3 subtype, which is a ligand-gated ion
channel. Unlike the majority of 5-HT receptors, the 5-HT2C and 5-
HT6 receptors are exclusively localized in the CNS, especially in
many areas of the cortex, basal ganglia, hippocampus and thala-
mus.2–4 The 5-HT2C and 5-HT6 receptors are also among the five
key receptors (D3, D2, 5-HT2A, 5-HT2C, 5-HT6), which has been iden-
tified in an analysis of the receptor interaction profiles of various
marketed antipsychotics.5,6 Selective ligands for the 5-HT2C recep-
tor are being pursued clinically for the treatment of obesity and
schizophrenia,7 and selective ligands for the 5-HT6 receptor have
been shown to improve cognitive performances in a wide variety
of learning and memory paradigms.8 Dual acting compounds
might therefore act as CNS agents with an interesting pharmaco-
logical profile, and in this Letter we describe our initial hit-finding
approach towards ligands with affinity for both receptors.
due to its molecular weight (209), c Log D (0.9), and TPSA (15 Å2),
which are key molecular properties used to define the desirable
CNS drug space.10 The 5-HT2C SAR for a series of analogs of com-
pound 1, identified the 7-position as a position where a lipophilic
substituent resulted in the highest potency at the 5-HT2C-recep-
tor.9a Recently it was reported that it was possible to improve
the selectivity of compound 1 towards the 5-HT2A- and 5-HT2B
-
receptors by making 6,7-disubstited analogs of compound 1, which
is important since 5-HT2A-agonist have psychotomimetic proper-
ties and 5-HT2B-agonism is linked to cardiac toxicity.9b Numerous
5-HT6 ligands have been reported during the last decade,6,11 and
a 5-HT6 antagonist pharmacophoric model 2 has been suggested,
Hybrid with dual 5-HT2C
and 5HT6 receptor activity:
5-HT6 antagonistic
pharmacophore model:
5-HT2 agonist:
H
N
H
N
N
D
N
N
C
B
R
The 7-chloro-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole 1
(Fig. 1) is a potent 5-HT2C agonist,9 and we found it to be an attrac-
tive starting point for our ligand design, since it makes up a rigified
template, which is ideally placed within the CNS druggability space
A
Lipo
S
Cl
S
1
3a-k
2
Figure 1. Design strategy for the novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-
pyrazino[1,2-a]indoles, seen as a hybrid structure of the 5-HT2C ligand 1 and the
general 5-HT6 pharmacophore 2.
* Corresponding author.
E-mail address: jke@lundbeck.com (J. Kehler).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.105

5432
N. Krogsgaard-Larsen et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5431–5433
O
O
O
O
O
O
N
N
F
N
N
N
N
b
a
c
O
O
O
S
Br
NH
O
N
N2
4
Br
Br
Br
6
5
7
d
O
O
O
O
H
N
N
N
f
e
N
N
N
R
R
S
S
Br
3a-k
9a-k
8
Scheme 1. Reagents and conditions: (a) Boc-piperazine, K2CO3, DMSO, 95 °C, four days; (b) tosylhydrazide, toluene, microwave irradiation, 12 min; (c) NaH (60%), toluene,
microwave irradiation, 135 °C; (d) microwave irradiation, 135 °C, 12 min; (e) Pd2(dba)3, (oxydi-2,1-phenylene)bis(diphenylphosphine), KO-t-Bu, substituted thiophenol,
toluene, 100 °C, 18 h; (f) 2 M HCl in Et2O, Et2O, MeOH, rt (18 h).
which contains four interactions points: A basic nitrogen, two lipo-
philic moieties, one represented by aromatic ring A and the other
lipophilic group (Lipo) bound via sulphur or sulphone (Fig. 1).11,12
Based on the 5-HT6 antagonist pharmacophoric model and the
5-HT2C SAR from 1, we proposed a 1,2,3,4,10,10a-hexahydro-pyr-
azino[1,2-a]indole with a arylthioether in the 7-position to be a
candidate for a compound with a dual activity at these receptors.
In this paper we describe the synthesis of a series of 7-phenylsulfa-
nyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles and their
in vitro binding pharmacology at human 5-HT2C and 5-HT6
receptors.
The compounds were synthesized using the six-step protocol
outlined in Scheme 1. Notably, the synthetic route make use of a
new and improved ring-closing methodology for the assembly of
the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on
intramolecular C–H insertion of a carbene (Scheme 1, step d).
The synthesis starts by a nucleophilic aromatic substitution reac-
tion (SNAr) from the commercially available 2-fluoro-benzalde-
hyde 4 using Boc-protected piperazine to give the Boc-protected
4-bromo-2-piperazino benzaldehyde 5 using reaction conditions
analogous to those previously described.13 The Boc-protected 4-
bromo-2-piperazino benzaldehyde 5 was then converted in high
yield into the tosylhydrazone intermediate 6 by sonication in tolu-
ene of a mixture of aldehyde 5 and tosylhydrazide.14 After drying
(MgSO4) and filtration, the tosylhydrazone 6 was converted into
the diazo intermediate 7 in situ by deprotonation using sodium hy-
dride followed by thermal elimination of sulfinate using micro-
wave irradiation to 135 °C.15
Interestingly, the ring-closing step performed by the intramo-
lecular C-H insertion as described in Scheme 1, appear to be a more
general methodology for the assembly of the hexahydro-pyrazi-
no[1,2-a]indole scaffold, where both many different aromatic sub-
stituents are tolerated and the piperazine can be replaced with for
example, morpholine or homopiperazine. Especially the homopip-
erazine raised the interesting aspect of regioselectivity of the C–H
insertion, however, we observed a complete lack of regioselectivity
in the C–H insertion in homopiperazine, probably due to the high
reactivity of the thermally generated carbene. We are currently
investigating and expanding the scope of this methodology.19
The binding affinities of the compounds at the human 5-HT2C
receptor was determined in a [3H]mesulergine binding assay using
tsA201 cells expressing the human 5-HT2C receptor and the bind-
ing affinities of the compounds at the human 5-HT6 receptor was
determined in a [3H]5-LSD ([N-methyl-3H]Lysergic acid, diethyl-
amide) binding assay using HeLa cells stably transfected with the
human 5-HT6 receptor. The IC50 values were determined by non-
linear curve fitting using XlFit (IDBS), and Ki values were calculated
from the Cheng–Prusoff equation and are shown in Table 2.
The binding affinities displayed by the compounds at the two
serotonin receptors appear to be affected similarly by the different
substitutions. Both receptors appeared relatively insensitive to the
size of the substitutions in the thiophenol moiety. The trifluoro-
methyl group is not detrimental to activity on 5-HT2C and 5-HT6
Table 1
Yields of cross-coupling products 9a–k and subsequent deprotection to give final
compounds 3a–k
Further heating at 135 °C led to the in situ generation of the
highly reactive carbene by thermal decomposition of the diazo
compound. The carbene reacted selectively with C–H insertion into
the piperazine fragment to give the protected hexahydro-pyrazi-
no[1,2-a]indole 8.16 Purification of the intermediary hydrazone
by recrystallisation did not improve overall yields, hence isolation
and purification of this intermediate can be omitted. The introduc-
tion of the lipophilic thioaryl ether moiety was performed by a pal-
ladium catalyzed coupling of substituted thiophenols with the Boc-
protected 7-bromo hexahydro-pyrazino[1,2-a]indole 817 and the
final compounds 3a–k were conveniently obtained after removal
of the Boc-protection group. The yields of the coupling reaction
and the removal of the Boc-group were generally high (Table 1).
Compd
R
% Yield of 9
% Yield of 3
a
b
c
d
e
f
g
h
i
2-Me
3-Me
4-Me
2-OMe
3-OMe
4-OMe
2-F
88
82
91
94
88
83
76
87
74
77
81
74
77
60
65
78
66
79
81
91
88
70
4-F
2-CF3
3-CF3
4-CF3
j
k

N. Krogsgaard-Larsen et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5431–5433
5433
Table 2
In conclusion, a series of novel 7-phenylsulfanyl-1,2,3,4,10,10a-
hexahydro-pyrazino[1,2-a]indoles have been synthesized. Notably,
the synthesis route make use of a new and improved ring-closing
methodology for the assembly of the hexahydro-pyrazino[1,2-a]in-
dole scaffold, which is based on intramolecular C–H insertion of a
carbene. The compounds act as dual serotonin 5-HT2C- and 5-HT6-
ligands.
The pharmacological data from testing 10, 11a, 11b and 3a–3k in 5-HT2C and 5-HT6
binding assays and the corresponding data for representative antipsychotics
H
H
N
N
NH2
N
N
R
R
S
S
S
Supplementary data
10
11
3a-k
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.07.105.
b
Compd
R
5-
HT2C
5-HT6
Molecular Polar
weight
c Log D
(7.4)
a
Ki
surface
Ki (nM) (nM)
area (Å2)
Aripiprazole18
Clozapine18
Olanzapine18
Risperidone18
Sertindole18
Ziprasidone18
1012
—
—
—
—
—
—
H
H
4-
OMe
2-
Me
3-
Me
4-
Me
2-F
4-F
2-
OMe
3-
OMe
4-
OMe
2-
22
15
14
33
1
13
150
91
74
574
17
6
224
5
61
nt
nt
448
327
312
410
441
413
226
270
300
45
31
31
62
41
48
25
15
25
4.4
3.5
2.8
1.8
4.1
4.0
1.4
2.3
2.3
References and notes
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et al Brain Res. 1997, 746, 207.
11a
11b
nt
5. Graul, A. I. Drugs Future 2003, 28, 1103.
6. Meltzer, H. Y. Neuropsychopharmacology 1999, 21, 106S.
7. (a) Wacker, D. A.; Miller, K. J. Curr. Opin. Drug Disc. Dev. 2008, 11, 438; (b)
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2008, 117, 207.
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A. J. Med. Chem. 2006, 49, 5217.
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15. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds. From Cyclopropanes to Ylides; John Wiley &
Sons Inc., 1998.
3a
3b
3c
49
77
68
81
296
296
296
15
15
15
2.8
2.8
2.8
50
110
3d
3e
3f
41
120
57
23
110
78
312
312
312
25
25
25
1.9
2.3
2.3
3g
3h
3i
49
61
150
160
330
300
760
300
300
350
350
350
15
15
15
15
15
2.5
2.5
3.3
3.3
3.3
83
CF3
3-
CF3
4-
3j
180
280
3k
CF3
16. Synthesis of compound 8: compound 5 (902 mg, 2.44 mmol) was dissolved in
10 mL toluene and tosylhydrazide (485 mg, 2.60 mmol) was added. The
mixture was exposed to sonification at room temperature for 4 h. The
mixture was semi concentrated in vacuo (azeotrope water-removal), toluene
and MgSO4 were added and after 10 min of standing the mixture was filtered
into a 20 mL microwave vial. Toluene was added until a total volume of 20 mL,
NaH (105 mg, 2.63 mmol) was added and the mixture purged with argon for
15 min. The vial was sealed and heated using microwave irradiation at 135 °C
for 10 min. The mixture was added EtOAc and washed with saturated NaHCO3,
brine, dried over MgSO4, filtered, concentrated in vacuo and purified using
flash chromatography to yield 8 387 mg (45%) of yellowish oil.
17. General method for syntheses of compounds 9a–k: toluene was purged with argon
Calculated molecular properties relevant for judging CNS druggability are also
presented.
nt = not tested.
a
Ki-values reported are means of at least four experiments, and a typical stan-
dard deviation was 30%.
b
Ki-values reported are means of at least four experiments, and a typical stan-
dard deviation was 30%.
(3i–3k) but it seems to weaken the affinity for both receptors. The
CF3-group is electron withdrawing, lipophilic and very large (same
volume as an isopropyl), but due to the limited number of com-
pounds in the present study it is not possible to determine which
of the three factors actually drives the drop in potency seen espe-
cially on 5-HT6. The 2-fluorine derivative 3d displays an affinity of
23 nM for the 5-HT6, which is approximately 15 times more potent
than the 2-trifluoromethyl derivative 3i. Generally, substituents in
the 3-position seemed marginally favoured compared to substitu-
ents in the 2-position. Substitutions in the 4-position were disfa-
voured with the methyl substituted derivative (3c) being the
exception. The most potent compound in this series is the 2-fluo-
rine derivative 3d which displays an affinity of 23 nM for the 5-
HT6 receptor and 41 nM for the 5-HT2C receptor.
for 20 min
8 (300 mg, 0.85 mmol), tris(dibenzylideneacetone)-dipalladium
(15.6 mg, 0.02 equiv), (oxydi-2,1-phenylene)bis(di-phenylphosphine) (36.6
mg, 0.08 equiv) and potassium tert-butoxide (114 mg, 1.2 equiv) were
suspended in toluene (2.5 mL) in a 5 mL vial. The mixture was purged with
argon, the thiol (1.1 equiv) was added and the vial was immediately sealed
afterwards. The mixture was stirred for 18 h at 100 °C. The mixture was
transferred to a test tube containing Et2O and 2 M NaOH. After thorough mixing,
the organic phase was isolated and the aqueous phase was reextracted with
Et2O. The combined organic phases were washed with brine, and after extraction
of the brine with Et2O, the combined organic phases were dried over MgSO4,
filtered through a plug of Celite, concentrated in vacuo and purified by flash
chromatography using a Flash Master (20 g column).
18. Richtand, N. M.; Welge, J. A.; Logue1, A. D.; Keck, P. E., Jr.; Strakowski, S. M.;
McNamara, R. K. Neuropsychopharmacology 2007, 32, 1715.
19. Krogsgaard-Larsen, N.; Kehler, J. Synthesis, manuscript in preparation.