Novel 3-aminochromans as potential pharmacological tools for the serotonin 5-HT7 receptor

Article abstract of DOI:10.1016/j.bmcl.2004.11.013

The synthesis of novel C6-aryl substituted derivatives of 3-(dimethylamino)chroman is described. The novel derivatives display 5-HT ₇ receptor affinities that varies from nM to μM, indicating that this small set of derivatives constitute a nove

Full text of DOI:10.1016/j.bmcl.2004.11.013

Bioorganic & Medicinal Chemistry Letters 15 (2005) 747–750
Novel 3-aminochromans as potential pharmacological tools for
the serotonin 5-HT7 receptor
Pa¨r Holmberg,a Lars Tedenborg,a Susanne Rosqvistb and Anette M. Johanssona,c,
*
aOrganic Pharmaceutical Chemistry, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
bDepartment of Lead Generation, AstraZeneca R&D So¨derta¨lje, SE 151-85 So¨derta¨lje, Sweden
cDiscovery Chemistry Research & Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 1 September 2004; revised 3 November 2004; accepted 4 November 2004
Available online 26 November 2004
Abstract—The synthesis of novel C6–aryl substituted derivatives of 3-(dimethylamino)chroman is described. The novel derivatives
display 5-HT7 receptor affinities that varies from nM to lM, indicating that this small set of derivatives constitute a novel and inter-
esting starting point for further structure-serotonin 5-HT7 activity relationship (SAR) studies.
Ó 2004 Elsevier Ltd. All rights reserved.
The most recent member of the serotonin (5-HT) recep-
tor family is the 5-HT7 receptor subtype. It has been
identified in rat,1–4 mouse,5 human,6 and guinea pig7
independently by several groups. The human 5-HT7
receptor consists of 445 amino acids and is positively
linked to adenylyl cyclase. Two additional isoforms of
the human 5-HT7 receptor, 5-HT7b, and 5-HT7d, which
have different C-terminal tails due to alternative splic-
ing, have also been identified.8–10 The discrete expres-
sion of 5-HT7 receptor mRNA in the central and
peripheral nervous systems (CNS and PNS) suggests
that it is involved in psychosis,11 in the regulation of
the circadian rhythm2,12–14 and that it mediates relaxa-
tion of blood vessels.15–17 Therefore, the 5-HT7 receptor
is a new interesting target for drug discovery.
H
N
O
O
N
N
S
N
H
N
Cl
O
O
Ph
1 (SB-656104)
2
O
N
HN
N
OMe O
N
N
N
H
Me
3
4
Figure 1. Serotonin 5-HT7 receptor antagonists and agonists.
agonist.23 The interaction of 5 and 6 with 5-HT7 recep-
tors was shown to be stereoselective, the (R)-isomer
being the most potent isomer (Fig. 2).
Although several well-known compounds have high
affinity for the 5-HT7 receptor11,18 it was only recently
that the first selective 5-HT7 receptor antagonists, 1
and 2, were published.19,20 Some nonselective 5-HT7
agonists (3-4) have also recently been reported21,22
(Fig. 1).
In order to further study SAR of 5-HT7 ligands we here
present the synthesis of a new series of 6-arylated (S)-3-
(dimethylamino)chromans. The new derivatives are
OMe
O
MeO
OMe
O1
MeO
8
In our search for compounds with selectivity for the 5-
HT7 receptor we recently identified 5 as a potent 5-
HT7 receptor agonist and 6 as a partial 5-HT7 receptor
O
2
7
6
3
NMe2 Ar
NMe2
NPr2
4
5
5
6
(S)-6-aryl-3-aminochroman
Figure 2. Based on the activities of 8-arylated 5 and 6 for the 5-HT7
receptors (S)-6-aryl-3-aminochromans were suggested as structures
with potential of generating high affinity ligands for the 5-HT7
receptor.
Keywords: 3-Aminochromans; Serotonin 5-HT7 receptor ligands;
Pharmacological tools.
*
Corresponding author. Fax: +1 317 279 5431; e-mail:
johansson_anette@lilly.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.11.013

748
P. Holmberg et al. / Bioorg. Med. Chem. Lett. 15 (2005) 747–750
regioisomers of 5 and 6 and were synthesized in order to
study structural factors of importance for the generation
of high affinity ligands at serotonin 5-HT7 receptors.
The affinity of the compounds for cloned rat 5-HT7
receptors was evaluated in vitro. The novel derivatives
display 5-HT7 receptor affinities varying from nM to
lM, indicating that this small set of derivatives consti-
tutes an interesting starting point for further structure-
5-HT7 receptor activity relationship (SAR) studies.
The enantiomeric purity of 8 was indirectly determined
on the corresponding diastereomeric (S)-Mosher amides
of 8 to be >99% ee as analyzed by HPLC. Reductive
alkylation of 8 by formaldehyde and NaBH3CN gave
9. Demethylation of 9 gave the phenol, which was trea-
ted with triflic anhydride to give triflate 10. The hydro-
gen analogue 1125 was obtained by a palladium
catalyzed reduction of 10. Bromination of 11 afforded
the key intermediate 12.
The synthesis of the novel compounds 12–17 is outlined
in Schemes 1 and 2. The starting material 724 contained
about 10% of the (R)-isomer and was further resolved by
recrystallization of the D-(ꢀ)-tartrate in H2O to give 8.
The novel derivatives 13–16 were synthesized from 12
using palladium mediated Suzuki-coupling reactions26
with various arylboronic acids facilitated by microwave
irradiation.27 The dimethyl ether 13 was converted to
the resorcinol derivative 17 by treatment with HBr.
O
O
O
a
b
2,6-Dimethylphenyl-, 2,6-dimethoxyphenyl- and 1-meth-
oxy-2-naphthylboronic acids were prepared from 2-
bromo-1,3-dimethylbenzene, 2,6-dimethoxy-benzene and
1-methoxy-naphthalene, respectively. The arenes were
lithiated with BuLi and then treated with trimethyl-
borate followed by acid hydrolysis to yield the corres-
ponding boronic acids.
NH2
NMe2
NH2
8
7
OMe
OMe 9
OMe
c
O
O
O
e
d
NMe2
Br
NMe2
NMe2
12
11
10
H
OTf
The ability of the novel compounds to bind to serotonin
5-HT7 receptors was studied. The affinities of the com-
pounds for cloned rat 5-HT7 receptors expressed in
Sf9-cells and labeled by [3H]5-HT as well as for cloned
5-HT1A receptors expressed in CHO-cells and labeled
by [3H]8-OH-DPAT were determined in vitro. Efficacy
of 14 at the 5-HT7 receptor was determined by measur-
ing its effect on cAMP production in CHO cells in rela-
tion to the effect elicited by 5-HT.28 The results are
presented in Table 1 and compounds 1, 5, and 6 are in-
cluded for comparative purposes.
Scheme 1. Reagents: (a) D-tartaric acid, H2O (63%); (b) HCHO,
NaBH3CN, MeOH (93%); (c) (i) 48% aq HBr; (ii) Tf2O, Et3N, CH2Cl2
(81%); (d) HCOOH, Et3N, (PPh3)2PdCl2, dppf, DMF, (60%); (e) Br2,
HOAc (76%).
O
O
a
N(Me)2
N(Me)2
Br
Ar
12
13: Ar= 2,6-(MeO)2Ph
14: Ar= 2,6-(Me)2Ph
b
15: Ar= Ph
16: Ar= 1-MeO-2-naphthyl
17: Ar= 2,6-(HO)2Ph
Whereas the C6–phenyl derivative 15 does not bind to 5-
HT7 receptors, the corresponding 2,6-dimethyl-phenyl
derivative 14 has high affinity for the 5-HT7 receptor
and is a highly efficacious 5-HT7 receptor partial agon-
Scheme 2. Reagents: (a) ArB(OH)2, (PPh3)4Pd, DME/EtOH/H2O,
Na2CO3, 45W; (b) 48% aq HBr.
Table 1. Physical and biological data of the novel derivatives 13–17
O
Ar
NMe2
23
½aꢁD
a
Compound Ar
Yield Mp
(%)
Anal.b
Ki (nM)c
Ratio
5-HT1A
5-HT7
Efficacy
(%)
(°C)
/
[3H]8-OH-DPAT [3H]5-HT
(5-HT1A
)
(5-HT7)
13
14
15
16
17
1d
5e
2,6-DiMeOPh
2,6-DiMePh
Ph
76
57
71
220–222 ꢀ72
220–223 ꢀ66
C
C
19H23NO3ÆHClÆ1/4H2O
19H23NOÆHClÆ1/4H2O 75.1
367 11
13.4 15
>1000
6
76 11
232
192
ꢀ110 C17H19NOÆHCl
1-MeO-2-Naphthyl 73
2,6-DiOHPh 69
ꢀ94
C
C
22H23NO2ÆHClÆ1/4H2O 594
17H19NO3ÆHClÆ1/4H2O
562
75.9 15
>1000
1.99
8
310–306 ꢀ88
282
Antagonist
154 11
174 15
>1000
6.44 1.39 27
5.29 0.09 >189
6e
28
3
a (c 1.0, MeOH).
b The compounds were analyzed for C, H, and N and the results were within 0.4% of the theoretical value.
c For experimental conditions see Ref. 28.
d See Ref. 19.
e See Ref. 23.

P. Holmberg et al. / Bioorg. Med. Chem. Lett. 15 (2005) 747–750
749
ist. Introduction of diortho substituents into a phenyl
ring has previously been shown to affect both the affinity
and selectivity for 5-HT7 receptors.23,28 Changing the
ortho substituents from dimethyl to dimethoxy as in
compound 13, decreases the affinity 27 times for the 5-
HT7 receptor. This is in contrast to the 8-aryl-3-amino-
chroman series where the dimethoxy derivatives were
identified as having high affinity for the receptor.23
The corresponding resorcinol derivative 17 is devoid of
or has low affinity to the 5-HT7 receptor. The 1-meth-
oxy-2-naphthyl derivative 16 showed both some affinity
and selectivity for 5-HT7 receptors.
dated in the binding site of the serotonin 5-HT7
receptor.
Acknowledgements
Financial support was obtained from AstraZeneca R&D
So¨derta¨lje, Sweden. We are grateful to Personal Chem-
istry for providing the Smith Microwave Synthesizers
and to Dr. A. Karlen for the computational chemistry.
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