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Novel Mast Cell-Stabilising Amine Derivatives of 3,4 Novel Mast Cell-Stabilising Amine Derivatives of 3,4
Dihydronaphthalen-1(2H)-One and 6,7,8,9-Tetrahydro-5H-Dihydronaphthalen-1(2H)-One and 6,7,8,9-Tetrahydro-5H-
benzo[7]annulen-5-one benzo[7]annulen-5-one
James W. Barlow
University of Dublin, Trinity College
Tao Zhang
Technological University Dublin
, tao.zhang@tudublin.ie
Orla Woods
University of Dublin, Trinity College
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Recommended Citation Recommended Citation
Barlow, J.W., Zhang, T., Woods, O., Byrne, A.J. and Walsh, J.J. (2011). Novel mast cell-stabilising amine
derivatives of 3,4 dihydronaphthalen-1(2H)-one and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.
Medicinal Chemistry
, 7, 213-223. doi:10.2174/157340611795564222
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Medicinal Chemistry, 2011, 7, 213-223 213
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Novel Mast Cell-Stabilising Amine Derivatives of 3,4-Dihydronaphthalen-
1(2H)-one and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-one
James W. Barlow, Tao Zhang, Orla Woods, Adam J. Byrne and John J. Walsh*
School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity College, Dublin 2, Ireland
Abstract: In an investigation of 4-amino-3,4-dihydronaphthalen-1(2H)-ones as novel modulators of allergic and
inflammatory phenomena, we have investigated a series of cyclic analogues. Tertiary amines of structural types 9, 10, 20
and 21 were synthesised and evaluated for mast cell stabilising activity. In vitro and in vivo studies showed that of these
compounds, the cyclohexenylamino derivatives of tetralone and benzosuberone of series 20 and 21 exhibited interesting
activity both in vitro and in vivo.
O
N
R
O
N
R
O
N
R
O
N
R
9a-b R=Ar/Alkyl
10 R=CH
3
20a-f R=Ar/Alkyl 21a-n R=Ar/Alkyl
Keywords: Anti-allergic, benzosuberone, mast cell, tetralone.
INTRODUCTION
Mast cells are densely granulated cells, historically
associated with the pathogenesis of allergic reactions and
protective responses to parasites; however, their further roles
are increasingly being recognised. For example, mast cells
are involved in cell-mediated immune reactions, are a
component of the host reaction to infection, and have
functions in angiogenesis and tissue repair after injury. Much
interest focuses on their possible involvement in promoting
persistent inflammation and remodeling in chronic airway
disease [1]. Apart from lung disease, mast cells have been
implicated in cardiovascular disease and cancer. Several
studies point at their role in the pathogenesis
of
atherosclerosis and acute coronary syndromes [2]. Due to the
association between inflammation and carcinogenesis, a
possible contribution of these cells to tumour development
has emerged, and it has been suggested that mast cells may
even serve as a novel therapeutic target for cancer treatment
[3]. Drugs in clinical use that modify the degranulation of
both mast cells and their circulating counterparts the
basophils include the prototypic agent sodium cromoglycate
and its analogue nedocromil [4]. Additional agents including
the cycloheptathiophene ketotifen, the phthalazin-1-one
azelastine and the propylidene benzoxepin olopatadine
*Address correspondence to this author at the School of Pharmacy and
Pharmaceutical Sciences, University of Dublin, Trinity College, Dublin 2,
Ireland; Tel: +353 1 8962806; Fax: +353 1 896 2804;
E-mail: jjwalsh@tcd.ie (J. J. Walsh)
exhibit both mast cell stabilising and antihistaminic
properties, the latter effect mainly attributable to an
additional diarylalkylamine pharmacophore [5]. It is now
accepted that although mast cell stabilisation is a clinically
relevant mechanism of cromoglycate-like drugs, it only
partially explains the effects of these drugs in vivo and that
other targets are important: one such is reflected by the
recent demonstration that they suppress eicosanoid
generation by promoting the release of the powerful anti-
inflammatory protein annexin-A1 [6]. In addition to
clinically established drugs, many diverse molecular entities
have demonstrated both anti-allergic and anti-inflammatory
activities, including natural products such as flavonoids and
pterosins. Within the latter class of secondary metabolites,
indane derivatives based on the indanone pterosin Z have
been investigated as smooth muscle relaxants [7]; with both
indanes and aminoindanes showing interesting activity [8].
Separately, it is of interest that the dual M2 / H1 receptor
antagonist dimethindene maleate, possessing a 2-(1H-inden-
2-yl)-ethylamine fragment in its structure, has also been
shown to modulate mast cell histamine secretion and to
produce a comparable, dose-dependent inhibition of anti-
IgE-induced histamine release from the same cell type [9].
Our earlier work [10] showed that, among a series of 4-
amino-3,4-dihydronaphthalen-1(2H)-ones, the tertiary
benzylated compound 1 exhibited the most potent activity in
anti-allergic assays (Fig. 1). In addition, incorporation of the
second N-benzyl within a second carbocyclic or heterocyclic
architecture afforded dimeric compounds such as those
214 Medicinal Chemistry, 2011, Vol. 7, No. 3 Barlow et al.
represented by the general structure 2, and these also
displayed interesting activities in preliminary screens [11]. In
the present study, we developed a series of analogous cyclic
compounds, varying the ring size of both hydroaromatic and
alicyclic ring components of 1, to investigate whether this
would result in augmentation or annihilation of the requisite
activity. There is no literature precedent for these molecules;
although benzamido derivatives of 6,7,8,9-tetrahydro-(5H)-
benzocycloheptene-5-one have been synthesized by Ritter
reaction of 6,7-dihydro-(5H)-benzocycloheptene-5-ones with
benzonitrile [12], and a non-pharmacophoric structural
aminotetrahydro benzocycloheptenone motif occurs in
compounds exhibiting effects as diverse as fungicidal [13]
and 5HT-binding [14] activities.
CHEMISTRY
Using analogous methodology to the synthesis of the
cyclopentyl derivatives [10], we obtained amines 9a-b as
outlined in Scheme 1. Wohl-Ziegler bromination [15] of
1,2,3,4-tetrahydro-naphthalen-1-yl acetate gave bromo
acetate 3. Incorporation of the cyclohexylamino ring was
achieved by substitution of 3 with cyclohexylamine in basic
media. Acyl hydrolysis using K
2
CO
3
in methanol followed
by oxidation with Cr (VI) (Jones reagent) [16] yielded
ketone 5. Alkylation to 9a-b was accomplished using
standard N-alkylation conditions [17]. These compounds
were isolated as diastereomeric mixtures of two enantiomeric
pairs and were tested as such in the initial assays employed.
Expansion of the hydroaromatic tetralone ring to that of a
benzosuberyl moiety was the next synthetic target.
Compared to 4-bromotetralone, the benzylic monobromide 6
of benzosuberone [18] is a more stable molecule, so much so
that nucleophilic substitution with cyclopentylamine
proceeded slowly and was not a clean transformation,
producing considerable quantities of imine 7. Acidic
hydrolysis of the imine followed by methylation afforded 10,
as shown in Scheme 1.
Introduction of unsaturation into the cyclohexyl ring of 5
to yield 18 was accomplished readily by reaction of 3-
bromocyclohexene with 4-amino-3,4-dihydro-2H-
naphthalen-1-one [19] 16 as shown in Scheme 2. Alkylation
as before gave tertiary amines 20a-f. To complement the
synthesis and testing of the cyclopentyl-substituted
tetrahydro-benzocyclohepten-5-one 10, it was decided to
produce cyclohexenyl-substituted analogues. The synthetic
rationale for the preparation of these compounds was similar
to that used to generate 18, namely the reaction of 3-
bromocyclohexene with 9-amino-6,7,8,9-tetrahydro-
benzocyclohepten-5-one 17, which in turn was produced
from 6, as shown in Scheme 2. As with the compounds of
series 20, compounds 21a-n were isolated and tested as
mixtures of stereoisomers.
PHARMACOLOGY
Mast Cell Stabilising Activity
Test compounds were evaluated for inhibition of
compound 48/80-induced degranulation of rat peritoneal
mast cells (RPMC), isolated as previously reported [20, 21].
Unpurified cell populations as used for initial screening
(Table 1) were of >90% viability and mast cells comprised
1.4% of the total cell count, whereas Percoll-purified cells
(used to determine IC
50
values, Table 2) comprised 81.6% of
O
N
12
X = C, O
n = 1,2
O
N
( )
n
Fig. (1). Lead structural types 1 and 2.
O
Br
(a) K
2
CO
3
, MeOH, (b) Jones reagent, CH
3
COCH
3
, (c) RX, K
2
CO
3
, CH
3
COCH
3
, (d) 2M HCl/MeOH (1:1)
O
O
HN
O
Br
O
HN
N
Et
3
N, DCM
NH
2
NH
2
Et
3
N, DCM
34
6
7
O
HN
( )
n
( )
n'
O
RN
( )
n
( )
n'
5: n=1, n'=2
8: n=2, n'=1
9a-b: n=1, n'=2, R= a) CH
3
; b) CH
2
Ph
10: n=2, n'=1, R= CH
3
a, b
d
c
Scheme 1. Synthetic methods for the preparation of 9a-b and 10.
Novel Mast Cell-Stabilising Amine Derivatives Medicinal Chemistry, 2011, Vol. 7, No. 3 215
the total cell count. The results were compared with the
reference compound disodium cromoglycate (DSCG). The
IC
50
values of selected compounds (21d-f, 21i, 21l and 21n)
were determined using both compound 48/80 and the
calcium ionophore A23187.
Passive Cutaneous Anaphylaxis (PCA)
Passive cutaneous anaphylaxis is an immediate type of
hypersensitivity reaction caused by the interaction of
antibodies with mast cells of the skin. This technique was
developed in 1958 by Ovary [22]. In our study, an antiserum
was raised by means of intraperitoneal inoculation of Wistar
rats with 1 mL of heat-killed Bordetella pertussis suspension
(10
10
organisms per mL) and 0.5 mL of chicken egg albumin
solution (1 mg per animal) in 0.5M NaCl. After 14 days, the
animals were exsanguinated and the serum was isolated. The
prepared serum was intradermally injected, and after 48
hours, the rats were intravenously challenged via the tail vein
with 2.5 mg albumin in 0.25 mL 2% Evans Blue, with
O
Br
n=1, 11
n=2, 6
O
N
3
n=1, 12
n=2, 13
( )
n
( )
n
a
O
HN
( )
n
O
NH
2
( )
n
O
HN
( )
n
O
N
( )
n
R
b
c
d
e
n=1, 14
n=2, 15
n=1, 16
n=2, 17
n=1, 18
n=2, 19
n=1, 20a-f
n=2, 21a-n
Series 20: R= a) CH
3
; b) CH
2
CH=CH
2
; c) Bz; d) 4-CH
3
Bz; e) 3,4,5-(CH
3
O)
3
Bz; f) 2'naphthylmethyl
Series 21: R= a) CH
3
; b) CH
2
CH=CH
2
: c) Bz; d) 2,3,4-(CH
3
O)
3
Bz; e) 3,4,5-(CH
3
O)
3
Bz; f) 4-(OCF
3
)Bz; g) 3-(OCF
3
)Bz;
h) 2,4,6-(F
3
)Bz: i) 4-(COOMe)Bz; j) 4-(CH
2
COOMe)Bz; k) 2-PhBz; l) CH(Ph)
2
; m) 4-NO
2
Bz; n) 4-CNBz
(a) NaN
3
, DMF, <50
o
C, (b) H
2
, Pd/C, EtOH/EtOAc (2:1), Di-tert-butyl dicarbonate, R.T., (c) CF
3
COOH, DCM, 0
O
C-R.T., (d) 3-bromocyclohexene,
Et
3
N, DCM, R.T., (e) For 20a-f: RX, K
2
CO
3
, CH
3
COCH
3
, ; For 21a-n: RX, N,N-diisopropylethylamine, CH
3
CN, N
2
,
C
O
O
Scheme 2. Synthetic Methods for the Preparation of 20a-f and 21a-n.
Table 1. Mast Cell Stabilising Activity of Novel Compounds
a,b
Compounds % Inhibitor SEM
9a NI
9b 99 (NI)
c
1
10 NI
20a 13 8
20b 68 14
20c 100
20d 77 10
20e 88 (64)
c
6 (3)
21f 5 6
21a NI
21b 42 7
21c 99 1
21d 58 6
12e 101 10
21f 24 8
21h 90 5
21i 89 7
21j 95 11
21k 87 5
21l 11 4
21m 91 13
21n 90 14
DSCG 10 3
a
Values are mean of at least n=5, test compounds and DSCG at 2 x 10
-5
M, challenge
with compound 48/80 at 0.2g mL
-1
, 5 min exposure;
b
NI, no inhibition at
concentration tested;
c
Value in brackets reflect anti-IgE as clicitor.
Table 2. Protective Activity of Selected Compounds Against
Degranulation of Percoll-purified RPMC Induced by
Various Elicitors
a,b
Compounds Compound 48/80
Ca
2+
ionophore
A23187
IC50 (M)
21d 1.5 8.2
21e 7.6 8.4
21f 1.2 20.7
21i 2.1 5.6
21l - 2.6
21n - 1.8
a
value are obtained from a mean of four experiments
b
Calcium iono
p
hore used at 1
g
mL
-1
